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the control of blood glucose&#44; blood pressure&#44; dyslipidemia&#44; and the use of inhibitors of the renin-angiotensin system &#40;iSRA&#41; have been the only strategies available to reduce cardiovascular and renal risk in this population&#46; Although strict glycemic control has beneficial effects on microvascular complications &#40;retinopathy&#44; nephropathy or neuropathy&#41;&#44; it does not seem to reduce the risk of cardiovascular disease&#44; and it is associated with an increased risk of hypoglycemia in patients with DM2&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;6</span></a> Until recently&#44; the antihyperglycemic drugs available have improved glycemic control&#44; but without much benefits on cardiovascular and&#47;or renal risk&#46; Furthermore&#44; some were these drugs were associated with potential undesirable effects&#44; such as the risk of heart failure or fractures &#40;complications that are especially prevalent in patients with CKD&#41;&#44; this is the case of thiazolidinediones&#44; and the use of sulfonylureas and insulin are associated with weight gain or the risk of hypoglycemia&#46; In addition&#44; the antihyperglycemic effect of sodium-glucose cotransporter type 2 &#40;iSGLT2&#41; inhibitors is reduced as glomerular filtration rate &#40;GFR&#41; decreases&#44; especially if GFR&#8239;&#60;&#8239;45&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">CKD affects 20&#8211;40&#37; of the patients with diabetes<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#59; in Spain&#44; its current prevalence ranges between 28&#8211;33&#37;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> and it is a recognized as a cardiovascular risk factor and increases the mortality in this population&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;15</span></a> Furthermore&#44; in patients with DM2 and advanced CKD there are limitations in the prescription of certain antihyperglycemic drugs &#40;e&#46;g&#46;&#44; metformin or sulfonylureas&#41; and there is an increased risk of hypoglycemia with antihyperglycemic treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> a complication that is associated with increased cardiovascular risk<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and hinders the achievement of glycemic control targets&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The intensive treatment of the multiple risk factors reduces the development&#47;progression of renal disease<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> which is why guidelines insist on comprehensive management of the patient with diabetes &#40;glycemic control and control of cardiovascular risk factors&#44; use of renin-angiotensin system inhibitors&#44; as well as lifestyle changes&#44; including smoking cessation or weight loss in overweight&#47;obese individuals&#44; among others&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However&#44; the residual renal risk remains very high in optimally treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> More recently&#44; iSGLT2 has been shown to reduce the risk of cardiovascular and renal events&#44; but still&#44; the residual risk of renal disease progression remains high&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> Nevertheless&#44; although the rate of diabetes-related complications &#40;such as myocardial infarction&#44; stroke&#44; lower limb amputations or mortality&#41; have decreased significantly in recent decades&#44; this is not the same for CKD patients requiring renal replacement therapy attributed to diabetic kidney disease &#40;DKD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Therefore new treatments are needed that improve glycemic control independently of GFR&#44; with a low risk of hypoglycemia and able to reduce cardiovascular and renal risk in this population&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Glucagon-like peptide-1 &#40;GLP-1&#41; receptor agonists are a family of antihyperglycemic drugs that have demonstrated potent HbA1c reduction&#44; low risk of hypoglycemia&#44; with associated weight reduction&#44; and proven cardiovascular and renal benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In this review we describe this type of drugs&#44; their cardiovascular and renal benefits&#44; as well as their clinical potential in patients with DKD&#44; especially with the new oral semaglutide formulation&#44; now available on the market&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Glucagon-like peptide type 1 receptor agonists</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Incretin effect and systemic effects of glucagon-like peptide type 1 and its agonists</span><p id="par0025" class="elsevierStylePara elsevierViewall">The incretin effect describes the phenomenon whereby oral glucose elicits higher &#40;2&#8211;3 times&#41; insulin secretory responses than does intravenous glucose&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> This is due to incretin hormones&#44; such as GLP-1 or glucose-dependent insulinotropic polypeptide&#44; which stimulate insulin secretion in response to food intake&#46; GLP-1 is a peptide secreted by L-type enteroendocrine cells in the ileum and colon in response to different nutrients&#44; mainly glucose and lipids&#44; whereas glucose-dependent insulinotropic polypeptide is produced by K cells present in the duodenum and the first portion of the jejunum&#46; GLP-1&#44; acting on its receptor&#44; has physiological actions on multiple target organs&#58; it increases glucose-stimulated insulin secretion in pancreatic beta cells&#44; reduces glucagon secretion by &#945; cells&#44; improves insulin sensitivity and reduces food intake&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In cellular and murine models GLP-1 promotes &#946; cell neogenesis and inhibits their apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Insulin secretion induced by GLP-1 is dependent of the glycemia and therefore does not induce hypoglycemia &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In patients with DM2 the incretin response is diminished&#44; but the insulinotropic effect of GLP-1 is conserved&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Under normal conditions GLP-1 has a short half-life &#40;approximately 2&#8239;min&#41;&#44; as it is rapidly degraded by dipeptidylpeptidase 4&#44; so GLP-1 analogues resistant to this enzyme have been developed for the treatment of DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The GLP-1 receptor &#40;rGLP-1&#41; belongs to the B family of G protein-coupled receptors and is expressed in the pancreas&#44; gastrointestinal tract&#44; central nervous system &#40;CNS&#41;&#44; kidneys&#44; lungs and heart&#46; They are also expressed in other tissues&#44; such as blood vessels or adipose tissue<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> although their localization in different tissues and organs yields discrepant results&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">GLP-1 or its agonists slow gastric emptying&#46; They also act on the CNS promoting satiety&#44; reducing food intake and favoring weight loss&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;29</span></a> Agonists of rGLP-1 &#40;arGLP-1&#41; have also demonstrated neuroprotective and antiapoptotic effects&#44; a reduction of oxidative stress and inflammation&#44; and improve cognitive and memory function &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">With respect to the vascular system&#44; rGLP-1 activation induces modest decreases in blood pressure&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a> it has a vasodilator effect&#44; improves arterial stiffness&#44; and prevents atherosclerotic plaque formation-and has plaque stabilizing effects-through its anti-inflammatory and antiapoptotic effects as demonstrated in animal models&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;35&#8211;38</span></a> Despite controversies about rGLP-1 expression in vascular smooth muscle and endothelial cells&#44; studies have shown that arGLP-1 has antiproliferative effects on these cells&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> reduces oxidative stress&#44; improves endothelial function&#44; and increases nitric oxide production in experimental models&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#8211;40</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the heart they produce a discrete increase in heart rate &#40;2&#8211;4 beats&#47;min&#41;&#44; although this does not seem to be associated with an increase in arrhythmias or cardiovascular events&#46; They increase glucose uptake and utilization and improve cardiac metabolism&#44; as well as left ventricular function<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;41</span></a>&#59; increase the release of atrial natriuretic peptide&#59; have anti-inflammatory&#44; anti-ischemic and anti-fibrotic effects and inhibit myocardiocyte apoptosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;42</span></a> More recently&#44; it has been reported that they also reduce epicardial fat&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> They also inhibit platelet aggregation and thrombosis&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the lungs&#44; rGLP-1 activation conferred protection against lipopolysaccharide-induced acute lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In adipose tissue they favor adipocyte differentiation&#44; decreases lipid deposition in white fat and facilitate its conversion to brown fat&#44; as well as thermogenesis and energy consumption<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;46&#8211;48</span></a>&#59; the effect on the intestine results in a reduction of postprandial lipidemia and chylomicron secretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a> In the muscles&#44; they improve insulin sensitivity and increase glucose uptake&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Renal expression of rGLP-1 has not been fully characterized due to insufficient specificity and sensitivity of the antibodies used&#44; although it have been non-uniformly detected in endothelial cells&#44; macrophages&#44; juxtaglomerular cells and proximal tubule in several animal models and human tissue&#46; GLP-1 infusion increases natriuresis by reducing tubular sodium reabsorption and reduces hyperfiltration in obese subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Chronic treatment with arGLP-1 in patients with DM2 has shown no effect on measured GFR and effective renal plasma flow in the fasting or postprandial state&#44; however it maintains its natriuretic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> GLP-1 and its agonists induce natriuresis by inhibition of the Na&#43;&#47;H&#8239;&#43;&#8239;exchanger type 3 in the proximal tubule&#44; although interactions with the renin&#44; insulin&#44; or glucagon system cannot be excluded<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#8211;54</span></a> because they reduce circulating levels of RAS components<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;53&#8211;55</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Metabolic effects of glucagon-like peptide-1 receptor agonists</span><p id="par0065" class="elsevierStylePara elsevierViewall">The arGLP-1&#8239;s show a potent antihyperglycemic effect with decreases between 0&#46;5&#37; and 1&#46;3&#37; of HbA1c&#44; which is greater in those with a long half-life<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> with low risk of hypoglycemia&#44; as has been shown in cardiovascular safety studies&#44; where there were no differences in hypoglycemia rates versus placebo&#44; except if associated with sulfonylureas or insulin&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#8211;64</span></a> The low risk of hypoglycemia has been observed even in patients with DKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">65&#8211;67</span></a> who are more susceptible to this complication&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">It is also important to highlight the loss of weight and waist circumference with arGLP-1&#44; mainly as a consequence of a reduction in body fat and not in lean mass&#44; which is maintained during long-term follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> This weight loss is attributed to the slowing of gastric emptying which increases satiety&#44; to the increase in resting energy consumption and its direct effects on appetite and satiety control centers in the CNS&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Obesity and overweight&#44; which are common in patients with DM2&#44; are a factors that favor the development&#47;progression of CKD through both direct and indirect effects&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Although the precise mechanisms the association between obesity and CKD are not totally defined it has been proposed that hypertension&#44; glomerular hyperfiltration&#44; hyperglycemia&#44; lipid toxicity&#44; inflammation or the role of adipose tissue and its adipokines are involved&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> Weight reduction by bariatric surgery&#44; pharmacological treatment or dietary measures are associated with a nephroprotective effect&#44;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">71&#8211;73</span></a> so that weight reduction is a fundamental objective in the nephroprotection of patients with DKD&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Hepatic steatosis is closely related to insulin resistance&#44; diabetes mellitus or metabolic syndrome&#44; and is associated with increased risk of cardiovascular and renal disease&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> Hepatic steatosis has been associated with the prevalence and incidence of renal disease&#46; The decreased in GFR or albuminuria has been associated with the presence of nonalcoholic steatohepatitis or the severity of fibrosis&#44; whereas improvement in liver histology is associated with improvement in CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> arGLP1 improves insulin levels&#44; regulates autophagy&#44; inhibits hepatic neoglycogenesis&#44; reduces hepatic fat content&#44; plasma liver enzyme levels and hepatic histological improvements have been described with liraglutide and semaglutide&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;76</span></a> Likewise&#44; epicardial and perirenal fat are associated with increased cardiorenal risk&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> so that the reduction in ectopic fat<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> as demonstrated with the use of arGLP-1 has could be beneficial in CKD&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Finally&#44; arGLP-1 has been shown to improve the pre- and postprandial lipid profile&#44; with a reduction in the levels of free fatty acids&#44; triglycerides and LDL cholesterol&#44; as well as the fraction of small and dense LDL and a reduction of the increase levels of triglycerides and apo-B48 postprandial&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#8211;82</span></a> Likewise&#44; it has been reported a reduction in markers of inflammation&#44; plasminogen activator inhibitor type 1 and leptin whereas adiponectin levels increase&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;48</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Regarding the adverse effects of this family&#44; the most important are gastrointestinal&#44; especially nausea and vomiting of mild-moderate intensity&#44; which are reduced with time&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">All this translates into an improvement in glycemic control and dyslipidemia&#44; a reduction in blood pressure&#44; weight&#44; and ectopic visceral fat deposits&#44; as well as inflammation and coagulation&#44; which could translate into greater cardiovasculorenal protection with the use of these drugs&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Key differential aspects of the group of glucagon-like peptide-1 receptor agonist drugs</span><p id="par0100" class="elsevierStylePara elsevierViewall">There are several arGLP-1&#8239;s approved or under study for the use in DM2&#58; exenatide &#40;exenatide and exenatide LAR or weekly&#41;&#44; liraglutide&#44; lixisenatide&#44; dulaglutide&#44; semaglutide&#44; albiglutide &#40;withdrawn from the market&#41;&#44; and efpeglenatide &#40;in clinical development&#41;&#46; Almost all are administered subcutaneously&#44; although oral semaglutide is currently available in Spain &#40;see below&#41;&#46; These drugs are divided into&#58; incretinmimetics&#44; derived from exendin-4 &#40;a peptide obtained from the saliva of the Gila monster &#91;Heloderma suspectum&#93;&#41;&#59; or analogs of human GLP-1&#44; with changes in the amino acid sequence that make them resistant to dipeptidylpeptidase 4&#46; The arGLP-1&#8239;s present other differences in clinically relevant biological properties &#40;half-life&#44; dosing interval and molecular weight&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Short half-life agents &#40;exenatide twice daily or lixisenatide&#41; produce spikes with transient increases in plasma arGLP-1 levels&#44; resulting in intermittent activation of the receptor and have a potent effect on gastric emptying and postprandial glycemia by reducing the rate of glucose entry into the duodenum&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Those with a long half-life &#40;weekly exenatide&#44; efpeglenatide&#44; liraglutide&#44; semaglutide&#44; albiglutide and dulaglutide&#41; produce a sustained activation of rGLP1&#44; resulting in a greater reduction in HbA1c&#44; basal glycemia and body weight and would have fewer gastrointestinal side effects&#59; they do not have a significant effect on gastric emptying due to a tachyphylaxis phenomenon&#44; and have a modest effect on postprandial glycemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;78</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Those of small molecular weight &#40;exenatide&#44; lixisenatide&#44; liraglutide and semaglutide&#41; can penetrate the blood-brain barrier more easily than those of high molecular weight &#40;dulaglutide&#44; albiglutide and epfeglenatide&#41; and could generate differential effects on central appetite signaling pathways and weight loss&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;33&#44;83</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Exendin-4 analogues are eliminated by the the kidneys&#44; so their use is not recommended in patients with advanced CKD &#40;GFR&#8239;&#60;&#8239;30&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#44; while GLP-1 analogues have other elimination routes and can be prescribed in patients up to CKD stage 4 &#40;GFR15&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">All this means that there are differences between these compounds in terms of their potency in reducing HbA1c&#44; baseline glycemia or weight reduction&#44; among other factors&#44; which should be considered when choosing drugs from this family&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#44;83&#44;84</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Cardiovascular protection of glucagon-like peptide type 1 receptor agonists</span><p id="par0130" class="elsevierStylePara elsevierViewall">Several randomized clinical trials have analyzed the cardiovascular safety of arGLP1 versus standard therapy&#46; All trials analyzed the composite of 3 major adverse cardiovascular events &#40;MACE&#41;&#44; which included cardiovascular death&#44; non-fatal myocardial infarction&#44; or non-fatal stroke&#44; except the lixisenatide study that considered 4-point MACE&#44; which also included hospitalization for heart failure &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#8211;64</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Although all the studies with arGLP-1 have demonstrated cardiovascular safety &#40;noninferiority vs&#46; placebo&#41;&#44; most of them &#40;liraglutide&#44; semaglutide SC&#44; dulaglutide&#44; albiglutide&#44; and efpeglenatide&#41; have also demonstrated a reduction in MACE with respect to placebo&#44; while weekly exenatide or oral semaglutide showed a tendency to reduce MACE&#46; In the LEADER study with liraglutide&#44; in patients with CKD stage &#8805;3&#44; this cardiovascular benefit proved to be greater&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Although the cardiovascular safety studies were not powered to detect differences in individual components of MACE&#44; some differences between studies were seen in these individual components&#59; thus liraglutide and oral semaglutide significantly reduced cardiovascular death&#44; subcutaneous semaglutide and dulaglutide significantly reduced nonfatal stroke&#44; albiglutide reduced the risk of nonfatal myocardial infarction&#44; and epfeglenatide reduced the incidence of heart failure&#44; while weekly exenatide or lixisenatide showed no significant benefit on any component of MACE&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">However&#44; it is difficult to discern whether these differences between studies are due to real differences between the molecules in terms of their cardiovascular effects&#46; Potential explanations include differences in the type of patients included&#44; adherence to study treatment&#44; sample size&#44; duration of drug exposure&#44; and GLP1 receptor activation with greater HbA1c reduction with longer-acting human GLP1-based analogs than with some short-acting exendin-4 analogs&#46; Recent results from the AMPLITUDE-O trial with efpeglenatide<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> suggest that the cardiovascular benefits of this family are not exclusive of the human GLP-1 analogs&#46; Likewise&#44; the cardiovascular benefit of efpeglenatide was independent of GFR or the concomitant use of iSGLT-2&#44; suggesting its additive and independent effect from the latter&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> as was also observed in the EXSCEL study&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">A recent meta-analysis of the 8 published cardiovascular safety clinical trials&#44; and which included a total of 60&#46; 080 patients&#44; concluded that&#44; overall&#44; arGLP-1 reduces MACE by 14&#37; &#40;HR 0&#46;86&#44; 95&#37; CI&#58; 0&#46;80&#8722;0&#46;93&#44; p&#8239;&#60;&#8239;0&#46;0001&#41;&#44; with no significant differences regarding structural homology with human GLP-1&#44; risk of cardiovascular events &#40;based on the risk of MACE in the placebo group as low&#44; medium or high&#41;&#44; presence or not of cardiovascular disease&#44; baseline HbA1c&#44; body mass index&#44; duration of follow-up&#44; administration interval &#40;daily or weekly&#41; or renal function&#46; Analyzing the individual components of MACE&#44; the use of arGLP-1 reduced the risk of cardiovascular death &#40;HR 0&#46;87&#44; 95&#37; CI&#58; 0&#46;80&#8722;0&#46;94&#59; p&#8239;&#61;&#8239;0&#46;001&#41;&#44; fatal and non-fatal myocardial infarction &#40;HR 0&#46;90&#44; 95&#37; CI&#58; 0&#46;83&#8722;0&#46;98&#59; p&#8239;&#61;&#8239;0&#46;020&#41; and fatal or non-fatal stroke &#40;HR 0&#46;83&#44; 95&#37; CI&#58; 0&#46;76&#8722;0&#46;92&#59; p&#8239;&#61;&#8239;0&#46;0002&#41;&#46; ArGLP-1 also reduced total mortality &#40;HR 0&#46;88&#44; 95&#37; CI 0&#46;82&#8722;0&#46;94&#44; p&#8239;&#61;&#8239;0&#46;0001&#41; and hospital admission due to heart failure &#40;HR 0&#46;89&#44; 95&#37; CI 0&#46;82&#8722;0&#46;98&#44; p&#8239;&#61;&#8239;0&#46;013&#41;&#44; all without increasing the risk of severe hypoglycemia&#44; pancreatic problems or retinopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> A recent post hoc analysis of CVOT with semaglutide has shown a gain in time free of cardiovascular disease of 1&#46;7 years in those patients with CKD vs&#46; 0&#46;2 years in diabetic patients with cardiovascular risk factors only&#44; suggesting an additional benefit of semaglutide in this population with high cardiovascular risk&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The mechanisms involved in the cardiovascular benefits of this family are various&#46; A meta-regression study suggested a linear relationship between HbA1c reduction and MACE risk in patient with arGLP-1&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> Publication on mediation analyses also suggest that cardiovascular benefit could be mediated in part by effects on HbA1c&#44; on blood pressure or reduction in urine albumin-creatinine ratio<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">90&#44;91</span></a> &#40;see below&#41;&#44; as well as by their effect on lipid profile&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> However&#44; in subgroup analyses of cardiovascular safety studies&#44; baseline HbA1c&#44; weight&#44; previous cardiovascular disease&#44; or renal function did not predict the beneficial effects of these drugs on MACE&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> so other mechanisms&#44; such as the previously mentioned anti-inflammatory&#44; antifibrotic&#44; antiatherogenic&#44; vasodilator&#44; or endothelial function-enhancing effects&#44; have been suggested to influence the cardiovascular benefit of these drugs<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;78</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Renal protection with glucagon-like peptide type 1 receptor agonists</span><p id="par0155" class="elsevierStylePara elsevierViewall">In CVOTs of arGLP1 renal outcomes were prespecified as key secondary outcomes in 4 studies done with liraglutide&#44; subcutaneous semaglutide&#44; dulaglutide&#44; and efpeglenatide&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59&#44;63&#44;64</span></a> or were collected as safety parameters in other studies&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Overall&#44; the prevalence of CKD stage &#8805;3 in these studies was low &#40;20&#8211;30&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">In those studies that prospectively evaluated renal targets as key secondary endpoints&#44; included a composite renal episode that consist of the development of macroalbuminuria&#44; the development of end-stage CKD or the need for renal replacement therapy or a significant reduction in renal function from baseline&#44; which included a GFR&#60;45&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> and a doubling of serum creatinine<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a> or a decrease in GFR&#8239;&#8805;&#8239;30&#37;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> or &#8805;40&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> The combined renal target was reduced by approximately 15&#37;&#8211;35&#37; with liraglutide&#44; semaglutide SC&#44; dulaglutide&#44; or efpeglenatide compared with placebo&#44; basically at the expense of reducing the risk of developing macroalbuminuria&#44; without reaching statistical significance for the other components &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; However&#44; in a sensitivity analysis of the REWIND study with dulaglutide&#44; the relative risk reduction for a 40&#37; or 50&#37; decrease in eGFR was 30&#37; and 44&#37;&#44; both significant&#44; in the dulaglutide group compared to placebo&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> This lower risk of developing macroalbuminuria was also confirmed in an exploratory analysis of the ELIXA &#40;lixisenatide&#41; study&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> In the EXSCEL study &#40;exenatide LAR&#41;&#44; renal episodes were analyzed as additional microvascular episodes&#44; and no differences were observed in the risk of episodes related to decreased eGFR&#44; but differences were observed in the composite episode&#44; which included decreased eGFR and macroalbuminuria&#44; although only after adjustment<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">The effects on the evolution of eGFR during follow-up are variable among the different trials&#44; with minimal differences between the active group and placebo&#44;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;63&#44;64</span></a> although an exploratory analysis of the EXSCEL study demonstrated a smaller fall in eGFR in patients with albuminuria greater than 100&#8239;mg&#47;g and 200&#8239;mg&#47;g of urine albumin&#47;creatinine&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> Likewise&#44; in a post-hoc analysis of the LEADER and SUSTAIN studies&#44; a smaller fall in eGFR was observed in those with eGFR&#60;60&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a> Reduced albuminuria &#40;or less increase&#41; is the most consistent finding in these studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59&#44;64&#44;93</span></a> as well as in a post hoc analysis of the SUSTAIN 1&#8211;7 trials with semaglutide SC<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> and those with dulaglutide&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">In the aforementioned Sattar meta-analysis the composite renal endpoint of renal function deterioration&#44; need for renal replacement therapy&#44; renal death and development of macroalbuminuria was reduced by 21&#37; &#40;HR 0&#46;79&#44; 95&#37; CI&#58; 0&#46;73&#8722;0&#46;87&#44; p&#8239;&#60;&#8239;0&#46;0001&#41;&#44; but was not significant for episodes of renal function deterioration &#40;HR 0&#46;86&#44; 95&#37; CI&#58; 0&#46;72&#8211;1&#46;02&#44; p&#8239;&#61;&#8239;0&#46;089&#41;&#44; although they were also reduced significantly after excluding the ELIXA87 study&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The renal effects of arGLP1 in patients with CKD have been evaluated in other studies&#46; The study &#34;Liraglutide versus placebo as an adjunct to glucose-lowering therapy in patients with type 2 diabetes and moderate renal failure&#34; &#40;LIRA-RENAL&#41; did not demonstrate a benefit of liraglutide in lowering eGFR&#44; although the duration of the study &#40;26 weeks&#41; may have been insufficient to show an effect&#46; This study also showed a non-significant 17&#37; reduction in albuminuria&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> The AWARD-7 study analyzed the efficacy of dulaglutide in patients with DM2 and moderate-severe CKD &#40;mean eGFR 38&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46; The decrease in mean GFR at 52 weeks was smaller in the high &#40;1&#46;5&#8239;mg&#41; and low dose dulaglutide &#40;0&#46;75&#8239;mg&#41; treatment groups &#40;both &#8722;0&#46;7&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41; vs&#46; the insulin glargine group &#40;&#8722;3&#46;3&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46; This benefit was greater in patients with macroalbuminuria<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Thus&#44; arGLP-1 reduces albuminuria in patients with ESRD&#44; but its effects on the progression of renal disease are not conclusive&#46; However&#44; albuminuria is a potent predictor of eGFR decline&#44; so these drugs could delay progression in DKD by reducing albuminuria&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> In a subgroup analysis of the LEADER trial the effect of liraglutide vs&#46; placebo in the fall of eGFR was better among patients with macroalbuminuria or in those with eGFR between 30&#8722;60&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a> and in the AWARD-7 trial the effect of dulaglutide on renal clinical outcomes and eGFR decline was more pronounced in participants with macroalbuminuria at baseline&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> Likewise&#44; in a post hoc analysis of the LEADER study those patients who experienced a 30&#37; reduction in albuminuria during follow-up had fewer cardiovascular and renal events&#44;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> which confirms that a reduction in albuminuria is associated with a reduction in cardiovascular and renal events&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">99&#44;102</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Finally&#44; the renal benefits of arGLP-1 appear to be additive to those of iSGLT2&#44; which is of particular interest in patients with DKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86&#44;103</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Cardiovascular and renal benefits of these drugs have been also demonstrated in real-life studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">104&#8211;105</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">The causes of renal protection by some arGLP-1&#8239;s are unclear&#46; Post hoc adjustment for HbA1C and other traditional renal risk factors did not have a major influence on renal benefit by liraglutide&#44; semaglutide&#44; or dulaglutide in CVOTs&#44; nor were there differences in glycemic control in the AWARD-7<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> study&#46; In fact&#44; mediation analyses performed suggested that only approximately 25&#37; of the benefit on renal outcomes may be mediated by improved glycemic control and 9&#8211;22&#37; by changes on blood pressure&#44;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">92&#44;106</span></a> suggesting the role of direct mechanisms&#58; reduction of hyperfiltration&#44; oxidative stress and inflammation&#44; antifibrotic effects&#44; improvement of endothelial dysfunction and&#47;or possible reduction of angiotensin II levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#44;54&#44;107&#8211;109</span></a> In experimental studies of DKD&#44; treatment with arGLP-1 has been associated with histological improvements &#40;reduction of glomerular hypertrophy&#44; mesangial expansion&#44; thickening of the glomerular basement membrane and tubulointerstitial damage&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">110&#44;111</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">In fact&#44; the KDIGO guidelines for the management of patients with diabetes and CKD rank arGLP-1 as a second line of treatment and suggest its use in patients with DM2 and CKD who have not reached individualized glycemic targets despite the use of metformin and iSGLT2&#44; or in those who cannot use these drugs since liraglutide&#44; semaglutide and dulaglutide &#40;results with epfeglenatide have not been published&#41; have demonstrated cardiovascular benefits&#44; especially among patients with established cardiovascular disease&#44; associated with favorable renal benefits with a substantial reduction in albuminuria and probable preservation of eGFR&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a> as well as other guidelines in patients with DM2 and high&#47;very high cardiovascular risk&#44; such as patients with DKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;113</span></a> Furthermore&#44; arGLP-1&#8239;s are more potent antihyperglycemic agents than iSGLT2s in patients with DKD&#44; and some such as semaglutide also confer greater potential for weight loss&#46; Finally&#44; some clinical case studies and short series suggest their benefits also in patients with CKD stage 5D&#44; although it should be recalled that this indication is not included in the labeling of arGLP-1&#8239;s&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">114&#44;115</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">The Effect of semaglutide versus placebo on the progression of renal impairment in subjects with type 2 diabetes and chronic kidney disease &#40;FLOW&#41;&#44; a phase 3 clinical trial involving more than 3&#44;000 patients with type 2 DM and moderate-severe CKD &#40;eGFR 25&#8722;75&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> and Urine Alb&#47;Cr ratio of 300&#8722;5&#44;000&#8239;mg&#47;g&#41; is currently underway &#40;NCT03819153&#41;&#46; The primary endpoint is a renal composite episode defined by a decrease in GFR&#8239;&#8805;&#8239;50&#37;&#44; end-stage renal failure&#44; and death from a renal-cause or cardiovascular-caused death&#44; and it is scheduled for completion in 2024&#46; This trial is the first to include renal disease outcomes as a primary target with the use of this family of drugs&#46; This study will define the clinical efficacy and renal safety of an arGLP-1 and thereby will inform about future evidence-based recommendations for treatment of DKD&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Oral semaglutide</span><p id="par0210" class="elsevierStylePara elsevierViewall">Semaglutide oral is the first oral arGLP-1&#46; Semaglutide oral is co-formulated with sodium N-&#40;8-&#91;8-&#91;2-hydroxybenzoyl&#93;amino&#41; caprylate &#40;sodium salcaprozate or SNAC&#41; which allows absorption of semaglutide across the gastric mucosa&#46; Oral semaglutide has been approved and recently marketed in Spain following evidence from the <span class="elsevierStyleItalic">Phase 3 clinical trial program Peptide InnOvatioN for Early diabEtes tReatment &#40;PIONEER&#41;</span>&#46; This program evaluated the efficacy and safety of oral semaglutide in patients with DM2 from monotherapy to insulin addition&#44; including HbA1c and body weight reduction outcomes&#44; in addition to other relevant efficacy and safety endpoints&#44; as compared to both placebo and other common antihyperglycemic drugs&#46; Oral semaglutide at doses of 7 and 14&#8239;mg&#47;day reduced HbA1c and body weight across the entire spectrum of DM2&#44; as well as other endpoints&#44; such as fasting blood glucose&#46; Oral semaglutide was superior to placebo and other antihyperglycemic drugs&#44; such as iDPP4 &#40;sitagliptin&#41;&#44; iSGLT2 &#40;empagliflozin&#41; or other arGLP-1 &#40;liraglutide&#41; in reducing HbA1c or weight&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">116</span></a> Oral semaglutide was well tolerated&#44; with a safety profile similar to that of other arGLP-1&#8239;s&#46; The most frequently reported side effects were gastrointestinal side effects of mild-moderate intensity and were transient over time&#46; Its cardiovascular safety in patients with cardiovascular disease or high cardiovascular risk was demonstrated in the aforementioned PIONEER-6 study&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> In the PIONEER 5 study&#44; in patients with CKD stage 3&#44; it was evaluated the efficacy and safety of a 14&#8239;mg dose&#44; resulting superior to placebo in terms of reduction of HbA1c &#40;-0&#46;8&#37; vs&#46; placebo&#41; and body weight &#40;&#8722;2&#46;5&#8239;kg vs&#46; placebo&#41;&#44; with a higher percentage of patients achieving HbA1c&#60;7&#46;0&#37; levels &#40;57&#46;8&#37; vs 22&#46;6&#37; in placebo&#41; and weight loss &#8805;5&#37; &#40;35&#46;7&#37; vs&#46; 9&#46;7&#37; in placebo&#41;&#46; The most frequent adverse effects consisted of mild-moderate nausea that decreased over time &#40;19&#37; vs&#46; 8&#37; on placebo&#41; and with low risk of symptomatic or confirmed hypoglycemia &#40;5&#46;5&#37; vs&#46; 1&#46;9&#37; on placebo&#41;&#46; There were no differences in eGFR between the two groups&#44; but there was a reduction in albuminuria with oral semaglutide vs&#46; an increase in the placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Results from the PIONEER program demonstrate that oral semaglutide is effective&#44; safe&#44; and well tolerated for glycemic control in patients with DM2&#44; including those with DKD&#44; with the specific benefits of this family of drugs&#46; The availability of oral semaglutide may help to broaden treatment options and facilitate the adoption of earlier treatment with arGLP-1 in the management of DM2&#46; A heart disease study of semaglutide in patients with type 2 diabetes &#40;SOUL&#44; NCT03914326&#41; evaluating the cardiovascular benefit of oral semaglutide is currently underway&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0220" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall">The prevalence of CKD is high in DM2 and DKD is associated with increased cardiovascular risk&#44; mortality and progression to end-stage CKD&#44; requiring early and intensive treatment to minimize these complications&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0230" class="elsevierStylePara elsevierViewall">The arGLP-1&#8239;s have demonstrated a CV benefit in patients with DM2 that appears to extend to patients with reduced renal function&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0235" class="elsevierStylePara elsevierViewall">Some arGLP-1&#8239;s reduce progression to overt albuminuria&#44; decrease albuminuria during follow-up&#44; and may delay progression of renal dysfunction in DKD&#44; especially in the subgroup with established CKD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0240" class="elsevierStylePara elsevierViewall">Oral semaglutide is effective&#44; safe and well tolerated in patients with DM2&#44; even in those with DKD&#44; with the benefits inherent to this family of drugs&#44; which may facilitate the earlier introduction of an arGLP-1 in the management of DM2&#46;</p></li></ul></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">Aleix Cases declares having received a grant&#44; consulting and speaking fees from Vifor Pharma&#44; speaking and consulting fees from Astellas&#44; Astra Zeneca&#44; Bayer and Novo Nordisk&#59; consulting fees from Boehringer Ingelheim&#44; GSK and Otsuka and speaking fees from Amgen and Sanofi &#40;Mexico&#41;&#44; but has not received funding in relation to the writing of this article&#46;</p></span></span>"
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          "titulo" => "Glucagon-like peptide type 1 receptor agonists"
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              "titulo" => "Incretin effect and systemic effects of glucagon-like peptide type 1 and its agonists"
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              "titulo" => "Metabolic effects of glucagon-like peptide-1 receptor agonists"
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              "titulo" => "Key differential aspects of the group of glucagon-like peptide-1 receptor agonist drugs"
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          "titulo" => "Cardiovascular protection of glucagon-like peptide type 1 receptor agonists"
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          "titulo" => "Renal protection with glucagon-like peptide type 1 receptor agonists"
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          "titulo" => "Oral semaglutide"
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            0 => "Type 2 diabetes mellitus"
            1 => "Diabetic kidney disease"
            2 => "Cardioprotection"
            3 => "Nephroprotection"
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            1 => "Enfermedad renal diab&#233;tica"
            2 => "Cardioprotecci&#243;n"
            3 => "Nefroprotecci&#243;n"
            4 => "Agonistas del receptor del p&#233;ptidosimilar al glucag&#243;n tipo 1 GLP-1"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Diabetic kidney disease&#44; a common complication in patients with type 2 diabetes mellitus&#44; is associated with a markedly increased morbidity and mortality&#44; especially of cardiovascular origin&#44; and faster progression to end-stage renal disease&#46; To date&#44; reducing cardiovascular and renal risk in this population was based on strict control of cardiovascular risk factors and the renin-angiotensin system blockade&#46; More recently&#44; sodium-glucose cotransporter type 2 inhibitors have demonstrated to offer cardiovascular and renal protection&#44; but the residual risk remains high and their antihyperglycemic efficacy is limited in moderate-severe CKD&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Therefore&#44; drugs with a potent antihyperglycemic effect&#44; independent of the glomerular filtration rate&#44; with a low risk of hypoglycemia&#44; that reduce weight in overweight&#47;obese patients and that provide cardiovascular and renal protection&#44; such as GLP-1 receptor agonists&#44; are needed&#46; However&#44; these drugs require subcutaneous administration&#44; which may limit their early use&#46; The recent availability of oral semaglutide may facilitate the early introduction of this family with proven cardiovascular and renal benefits and excellent safety profile&#46; In this review the family is analyzed as well as their cardiovascular and renal effects</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La enfermedad renal diab&#233;tica&#44; frecuente en pacientes con diabetes mellitus tipo 2&#44; se asocia con un marcado incremento de la morbimortalidad&#44; especialmente cardiovascular&#44; y de progresi&#243;n a enfermedad renal cr&#243;nica terminal&#46; Hasta la fecha&#44; la reducci&#243;n del riesgo cardiovascular y renal en esta poblaci&#243;n se ha basado en el control estricto de los factores de riesgo cardiovascular y el uso de inhibidores del sistema renina-angiotensina&#46; Mas recientemente&#44; los inhibidores del cotransportador sodio-glucosa tipo 2 han demostrado ofrecer protecci&#243;n cardiovascular y renal&#44; pero el riesgo residual sigue siendo alto y su eficacia antihiperglucemiante es limitada en ERC moderada-severa&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Por ello se precisan f&#225;rmacos con un potente efecto antihiperglucemiante&#44; independiente del filtrado glomerular&#44; con bajo riesgo de hipoglicemia&#44; que reduzcan el peso en pacientes con sobrepeso&#47;obesidad y que proporcionen una protecci&#243;n cardiovascular y renal&#44; como los agonistas del receptor de GLP-1&#46; Sin embargo&#44; estos f&#225;rmacos precisan de su administraci&#243;n subcut&#225;nea&#44; lo que puede limitar su uso temprano&#46; La reciente disponibilidad de semaglutida oral puede ayudar a la introducci&#243;n precoz de esta familia con beneficios cardiovasculares y renales probados y excelente perfil de seguridad&#46; En esta revisi&#243;n se revisa la familia y sus efectos cardiovasculares y renales&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">arGLP-1&#58; glucagon-like peptide 1 receptor agonist&#59; VSMF&#58; vascular smooth muscle fiber&#59; ANP&#58; atrial natriuretic peptide&#59; RAAS&#58; renin-angiotensin-aldosterone system&#46; Modified from M&#252;ller et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0010"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">CV&#44; cardiovascular&#59; CKD&#44; Chronic kidney disease stage &#8805;3 &#40;FGe&#60;60&#8239;ml&#47;min&#47;1&#44;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#59; AHF&#44; Hospital admission due to heart failure&#59; MI&#44; myocardial infarction&#59; MACE 3P&#44; 3-point cardiovascular composite episode&#59; MACE 4P&#44; 4-point cardiovascular composite episode&#44; including hospitalization due to non-stable angina&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug&#47;study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sample size&#47;follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Compared with&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Episodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HR &#40;CI 95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liraglutida&#47;LEADER<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;340&#47;3&#44;8 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#44;4&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;87 &#40;0&#44;78&#8722;0&#44;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 24&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85 &#40;0&#44;74&#8722;0&#44;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;78 &#40;0&#44;66&#8722;0&#44;93&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;73&#8722;1&#44;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;71&#8722;1&#44;06&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;87 &#40;0&#44;73&#8722;1&#44;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Semaglutida SC&#47;SUSTAIN 6<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;297&#47;2&#44;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#44;2&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;58&#8722;0&#44;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 24&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;05 &#40;0&#44;74&#8722;1&#44;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;98 &#40;0&#44;65&#8722;1&#44;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI &#40;non fatal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;51&#8722;1&#44;08&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stroke &#40;non fatal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;61 &#40;0&#44;38&#8722;0&#44;99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;11 &#40;0&#44;77&#8722;1&#44;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lixisenatida&#47;ELIXA<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;068&#47;2&#44;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recent acute coronary syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 4P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;02 &#40;0&#44;89&#8722;1&#44;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD &#8805; 3&#44; 23&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;94 &#40;0&#44;78&#8722;1&#44;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;98 &#40;0&#44;78&#8722;1&#44;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;03 &#40;0&#44;87&#8722;1&#44;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;12 &#40;0&#44;79&#8722;1&#44;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;96 &#40;0&#44;75&#8722;1&#44;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exenatida SR &#47; EXSCEL<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;752&#47;3&#44;2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73&#44;1&#37; with CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;91 &#40;0&#44;83&#8722;1&#44;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 21&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;77&#8722;0&#44;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;88 &#40;0&#44;76&#8722;1&#44;02&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;97 &#40;0&#44;85&#8722;1&#44;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85 &#40;0&#44;70&#8722;1&#44;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;94 &#40;0&#44;78&#8722;1&#44;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albiglutida &#47; HARMONY outcomes<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9463&#47;1&#44;6 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;78 &#40;0&#44;68&#8722;0&#44;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;95 &#40;0&#44;79&#8722;1&#44;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 23&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;93 &#40;0&#44;73&#8722;1&#44;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;75 &#40;0&#44;61&#8722;0&#44;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;66&#8722;1&#44;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF and CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85 &#40;0&#44;70&#8722;1&#44;04&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Semaglutida oral &#47; PIONEER 6<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3183&#47;15&#46;9 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#44;7&#37; with CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;79 &#40;0&#44;57&#8722;1&#44;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 26&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;51 &#40;0&#44;31&#8722;0&#44;84&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;49 &#40;0&#44;27&#8722;0&#44;92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI no fatal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;18 &#40;0&#44;73&#8722;1&#44;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stroke no fatal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;35&#8722;1&#44;57&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;48&#8722;1&#44;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dulaglutida &#47; REWIND<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;901&#47;5&#44;4 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#44;5&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;88 &#40;0&#44;79&#8722;0&#44;99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 22&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;90 &#40;0&#44;80&#8722;1&#44;01&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;91 &#40;0&#44;78&#8722;1&#44;06&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;96 &#40;0&#44;79&#8722;1&#44;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;76 &#40;0&#44;62&#8722;0&#44;94&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;93 &#40;0&#44;77&#8722;1&#44;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Efpeglenatida &#47; AMPLITUDE-O<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;076&#47;1&#44;81 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&#44;6&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;73 &#40;0&#44;58&#8211;0&#44;92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 31&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;78 &#40;0&#44;58&#8722;1&#44;06&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;72 &#40;0&#44;50&#8722;1&#44;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;75 &#40;0&#44;54&#8722;1&#44;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;47&#8722;1&#44;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;61 &#40;0&#44;38&#8722;0&#44;98&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Alb&#47;Cr&#44; ratio alb&#250;min&#47; creatinine in urine&#59; eGFR&#44; estimated glomerular filtration rate&#44; ARF&#44; acute renal failure&#59; LSM&#44; least squares mean&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Renal episodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liraglutida<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;100</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LEADER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcome&#58; reduction in the combined renal event of persistent new-onset macroalbuminuria&#44; persistent doubling of serum creatinine&#44; end-stage renal failure&#44; or renal death in the liraglutide group &#40;HR 0&#46;78&#59; 95&#37; CI 0&#46;67&#8722;0&#46;92&#59; p&#8239;&#61;&#8239;0&#46;003&#41;Decrease in eGFR at 36 months was 2&#37; lower with liraglutide vs&#46; placebo &#40;1&#46;02&#59; 95&#37; CI&#58; 1&#46;00&#8722;1&#46;03&#59; p&#8239;&#61;&#8239;0&#46;01&#41;Alb&#47;Cr at 36 months 17&#37; lower with liraglutide vs&#46; placebo &#40;0&#46;83&#59; 95&#37; CI&#58; 0&#46;79&#8722;0&#46;88&#59; p&#8239;&#60;&#8239;0&#46;001&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Semaglutida SC<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SUSTAIN-6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcome&#58; reduction in the combined renal event of persistent new-onset macroalbuminuria&#44; persistent doubling of serum creatinine&#44; end-stage renal failure or renal death in the semaglutide group vs&#46; placebo &#40;HR 0&#46;64&#59; 95&#37; CI 0&#46;46&#8722;0&#46;88&#59; p&#8239;&#61;&#8239;0&#46;005&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dulaglutida<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;92</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">REWIND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcome&#58; new-onset macroalbuminuria&#44; sustained decrease in GFRe&#8805;30&#37; from baseline or chronic renal replacement therapy in the dulaglutide group vs&#46; placebo &#40;HR 0&#46;85&#44; 95&#37; CI&#58; 0&#46;77&#8722;0&#46;93&#44; p&#8239;&#61;&#8239;0&#46;0004&#41;New macroalbuminuria &#40;HR 0&#46;77&#44; 95&#37; CI&#58; 0&#46;68&#8722;0&#46;87&#44; p&#8239;&#60;&#8239;0&#46;0001&#41;Sustained decrease in GFR&#8239;&#8805;&#8239;30&#37; &#40;HR 0&#46;89&#44; 95&#37; CI 0&#46;78&#8722;1&#46;01&#59; p&#8239;&#61;&#8239;0&#46;066&#41;&#46;Sensitivity analysis&#58; sustained decrease in FGe&#8805;40&#37; &#40;HR 0&#46;70&#44; 95&#37; CI&#58; 0&#46;57&#8722;0&#46;85&#41; and &#8805;50&#37; &#40;HR 0&#46;56&#44; 95&#37; CI&#58; 0&#46;41&#8722;0&#46;76&#41;&#46;Change in Alb&#47;Cr &#40;MMC 0&#46;82&#44; 95&#37; CI 0&#46;78&#8722;0&#46;86&#59; p&#8239;&#60;&#8239;0&#46;0001&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exenatida LAR<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;94&#44;95</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EXSCEL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prespecified secondary renal outcomes&#58;New macroalbuminuria&#58; 2&#46;2&#37; vs&#46; 2&#46;5&#37; in the exenatide and placebo groups&#44; respectively &#40;HR 0&#46;87&#59; 95&#37; CI 0&#46;70&#8722;1&#46;07&#41;&#46; Change in Alb&#47;Cr vs&#46; placebo &#8722;25&#37;&#46;No difference for composite renal event 1 &#40;40&#37; decrease in eGFR&#44; renal replacement therapy or renal death&#41; &#40;HR 0&#46;88&#44; 95&#37; CI 0&#46;74&#8722;1&#46;05&#41;&#46;No difference for renal composite 2 &#40;40&#37; decrease in eGFR&#44; renal replacement therapy&#44; renal death or macroalbuminuria&#41; &#40;HR 0&#46;88&#44; 95&#37; CI 0&#46;76&#8722;1&#46;01&#41;&#44; although significant after adjustment &#40;HR 0&#46;85&#44; 95&#37; CI 0&#46;74&#8722;0&#46;98&#41;&#46;In patients with baseline Alb&#47;Cr&#62;100&#8239;mg&#47;g differences in fall in eGFR vs&#46; placebo &#40;0&#46;79&#8239;ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#47;yr&#44; 95&#37; CI&#58; 0&#46;24&#8722;1&#46;34&#41; and Alb&#47;Cr &#62;200&#8239;mg&#47;g &#40;1&#46;32&#8239;ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#47;yr&#44; 95&#37; CI&#58; 0&#46;57&#8722;2&#46;06&#41;&#44; but not in lower Alb&#47;Cr thresholds&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Efpeglenatida<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AMPLITUDE-O&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prespecified secondary renal composite outcome&#58; incident macroalbuminuria&#44; sustained decline in GFR&#8239;&#8805;&#8239;40&#37;&#44; end-stage renal disease or need for renal replacement therapy &#40;HR 0&#46;68&#44; 95&#37; CI&#58; 0&#46;57&#8722;0&#46;79&#44; p&#8239;&#60;&#8239;0&#46;001&#41;Renal function event &#40;sustained decline in GFR&#8239;&#8805;&#8239;40&#37;&#44; end-stage renal disease or need for renal replacement therapy or death&#41; &#40;HR 0&#46;77&#44; 95&#37; CI 0&#46;57&#8722;1&#46;02&#41;Alb&#47;Cr 21&#37; lower &#40;95&#37; CI&#58; 14&#8722;28&#41; and eGFR 0&#46;9&#8239;ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span> &#40;95&#37; CI&#58; 0&#46;3&#8722;1&#46;5&#41; higher with epfeglenatide vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lixisenatida<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;93</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ELIXA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Change in Alb&#47;Cr from baseline&#58; 24&#37; vs&#46; 34&#37;&#44; p&#8239;&#61;&#8239;0&#46;004 &#40;lixisenatide vs&#46; placebo&#41;&#46;Exploratory analysis&#58; percent change in urine Alb&#47;Cr vs&#46; placebo&#58; &#8722;1&#46;69&#37; &#40;95&#37; CI&#58; &#8722;11&#46;69&#8722;8&#46;30&#41; in normoalbuminurics &#8722;21&#46;10&#37; &#40;95&#37; CI&#58; &#8722;42&#46;25&#8722;0&#46;04&#44; p&#8239;&#61;&#8239;0&#46;0502&#41; in microalbuminurics and &#8722;39&#46;18&#37; &#40;95&#37; CI&#58; &#8722;68&#46;53 to &#8722;9&#46;84&#44; p&#8239;&#61;&#8239;0&#46;007&#41; in macroalbuminuricsReduced risk of new-onset macroalbuminuria vs&#46; placebo adjusted for baseline HbA1c &#40;HR 0&#46;808&#44; 95&#37; CI&#58; 0&#46;660&#8722;0&#46;991&#59; p&#8239;&#61;&#8239;0&#46;0404&#41; or adjusted for baseline and in the trial HbA1c &#40;HR 0&#46;815&#44; 95&#37; CI&#58; 0&#46;665&#8722;0&#46;999&#59; p&#8239;&#61;&#8239;0&#46;0491&#41;&#46; No differences in the decrease in eGFR&#44; nor in the percentage of patients who doubled creatinine during follow-up &#40;1&#37; in each group&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albiglutida<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HARMONY Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Difference eGFR &#8722;1&#46;11 &#40;95&#37; CI&#58; &#8722;1&#46;84 to &#8722;0&#46;39&#41; month 8 and &#8722;0&#46;43 &#40;95&#37; CI&#58; &#8722;1&#46;26 to 0&#46;41&#41; at month 16 vs&#46; placebo&#46;Renal involvement&#58; HR 0&#46;87 &#40;95&#37; CI&#58; 0&#46;75&#8722;1&#46;02&#41; &#40;ARF 70 vs&#46; 80 cases&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dulaglutida<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AWARD-7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcomes&#58; eGFR was higher at 52 weeks with dulaglutide 1&#46;5&#8239;mg &#40;MMC 34&#46;0&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41; &#40;p&#8239;&#61;&#8239;0&#46;005&#41;&#44; as well as with dulaglutide 0&#46;75&#8239;mg &#40;MMC 33&#46;8&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41; &#40;p&#8239;&#61;&#8239;0&#46;009&#41; vs&#46; insulin glargine &#40;LSM 31&#46;3&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46;Reduction of eGFR in patients with macroalbuminuria&#58; &#8722;5&#46;5&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> in the insulin glargine group vs&#46; &#8722;0&#46;7&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> and &#8722;0&#46;5&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> in the dulaglutide 0&#46;75&#8239;mg and 1&#46;5&#8239;mg groups&#44; respectivelyUrine Alb&#47;Cr reduction with dulaglutide was not statistically different from that with insulin glargine at 52 weeks&#44; but there was a dose-dependent reduction in patients with macroalbuminuria &#40;14&#37; insulin glargine&#44; 23&#37; dulaglutide 0&#46;75&#8239;mg and 43&#37; dulaglutide 1&#46;5&#8239;mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Liraglutida<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">LIRA-RENAL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Renal outcomes&#58; estimated proportional change for eGFR &#40;MDRD&#41; at week 26 ratio from baseline was 0&#46;99 &#40;-1&#37;&#41; for liraglutide and 1&#46;01 &#40;&#43;1&#37;&#41; in the placebo group &#40;NS&#41;&#46; The estimated ratio from week 26 to baseline for Alb&#47;Cr was 0&#46;87 with liraglutide and 1&#46;05 with placebo &#40;NS&#41;&#44; the estimated ratio of treatment was 0&#46;83 &#40;95&#37; CI 0&#46;62&#8722;1&#46;10&#44; p&#8239;&#61;&#8239;0&#46;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Review
Glucagon-like peptide 1(GLP-1) receptor agonists in the management of the patient with type 2diabetes mellitus and chronic kidney disease: an approach for the nephrologist
Agonistas del receptor de péptido similar al glucagon tipo 1 (GLP-1) en el manejo del paciente con diabetes mellitus tipo 2. Una aproximación para el nefrólogo
Aleix Cases
Corresponding author
acases@ub.edu

Corresponding author.
Departament de Medicina, Facultat de Medicina, Campus Clínic, Universitat de Barcelona, Barcelona, Spain
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the control of blood glucose&#44; blood pressure&#44; dyslipidemia&#44; and the use of inhibitors of the renin-angiotensin system &#40;iSRA&#41; have been the only strategies available to reduce cardiovascular and renal risk in this population&#46; Although strict glycemic control has beneficial effects on microvascular complications &#40;retinopathy&#44; nephropathy or neuropathy&#41;&#44; it does not seem to reduce the risk of cardiovascular disease&#44; and it is associated with an increased risk of hypoglycemia in patients with DM2&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;6</span></a> Until recently&#44; the antihyperglycemic drugs available have improved glycemic control&#44; but without much benefits on cardiovascular and&#47;or renal risk&#46; Furthermore&#44; some were these drugs were associated with potential undesirable effects&#44; such as the risk of heart failure or fractures &#40;complications that are especially prevalent in patients with CKD&#41;&#44; this is the case of thiazolidinediones&#44; and the use of sulfonylureas and insulin are associated with weight gain or the risk of hypoglycemia&#46; In addition&#44; the antihyperglycemic effect of sodium-glucose cotransporter type 2 &#40;iSGLT2&#41; inhibitors is reduced as glomerular filtration rate &#40;GFR&#41; decreases&#44; especially if GFR&#8239;&#60;&#8239;45&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">CKD affects 20&#8211;40&#37; of the patients with diabetes<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#59; in Spain&#44; its current prevalence ranges between 28&#8211;33&#37;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> and it is a recognized as a cardiovascular risk factor and increases the mortality in this population&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;15</span></a> Furthermore&#44; in patients with DM2 and advanced CKD there are limitations in the prescription of certain antihyperglycemic drugs &#40;e&#46;g&#46;&#44; metformin or sulfonylureas&#41; and there is an increased risk of hypoglycemia with antihyperglycemic treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> a complication that is associated with increased cardiovascular risk<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and hinders the achievement of glycemic control targets&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The intensive treatment of the multiple risk factors reduces the development&#47;progression of renal disease<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> which is why guidelines insist on comprehensive management of the patient with diabetes &#40;glycemic control and control of cardiovascular risk factors&#44; use of renin-angiotensin system inhibitors&#44; as well as lifestyle changes&#44; including smoking cessation or weight loss in overweight&#47;obese individuals&#44; among others&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However&#44; the residual renal risk remains very high in optimally treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> More recently&#44; iSGLT2 has been shown to reduce the risk of cardiovascular and renal events&#44; but still&#44; the residual risk of renal disease progression remains high&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> Nevertheless&#44; although the rate of diabetes-related complications &#40;such as myocardial infarction&#44; stroke&#44; lower limb amputations or mortality&#41; have decreased significantly in recent decades&#44; this is not the same for CKD patients requiring renal replacement therapy attributed to diabetic kidney disease &#40;DKD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Therefore new treatments are needed that improve glycemic control independently of GFR&#44; with a low risk of hypoglycemia and able to reduce cardiovascular and renal risk in this population&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Glucagon-like peptide-1 &#40;GLP-1&#41; receptor agonists are a family of antihyperglycemic drugs that have demonstrated potent HbA1c reduction&#44; low risk of hypoglycemia&#44; with associated weight reduction&#44; and proven cardiovascular and renal benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In this review we describe this type of drugs&#44; their cardiovascular and renal benefits&#44; as well as their clinical potential in patients with DKD&#44; especially with the new oral semaglutide formulation&#44; now available on the market&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Glucagon-like peptide type 1 receptor agonists</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Incretin effect and systemic effects of glucagon-like peptide type 1 and its agonists</span><p id="par0025" class="elsevierStylePara elsevierViewall">The incretin effect describes the phenomenon whereby oral glucose elicits higher &#40;2&#8211;3 times&#41; insulin secretory responses than does intravenous glucose&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> This is due to incretin hormones&#44; such as GLP-1 or glucose-dependent insulinotropic polypeptide&#44; which stimulate insulin secretion in response to food intake&#46; GLP-1 is a peptide secreted by L-type enteroendocrine cells in the ileum and colon in response to different nutrients&#44; mainly glucose and lipids&#44; whereas glucose-dependent insulinotropic polypeptide is produced by K cells present in the duodenum and the first portion of the jejunum&#46; GLP-1&#44; acting on its receptor&#44; has physiological actions on multiple target organs&#58; it increases glucose-stimulated insulin secretion in pancreatic beta cells&#44; reduces glucagon secretion by &#945; cells&#44; improves insulin sensitivity and reduces food intake&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In cellular and murine models GLP-1 promotes &#946; cell neogenesis and inhibits their apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Insulin secretion induced by GLP-1 is dependent of the glycemia and therefore does not induce hypoglycemia &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In patients with DM2 the incretin response is diminished&#44; but the insulinotropic effect of GLP-1 is conserved&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Under normal conditions GLP-1 has a short half-life &#40;approximately 2&#8239;min&#41;&#44; as it is rapidly degraded by dipeptidylpeptidase 4&#44; so GLP-1 analogues resistant to this enzyme have been developed for the treatment of DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The GLP-1 receptor &#40;rGLP-1&#41; belongs to the B family of G protein-coupled receptors and is expressed in the pancreas&#44; gastrointestinal tract&#44; central nervous system &#40;CNS&#41;&#44; kidneys&#44; lungs and heart&#46; They are also expressed in other tissues&#44; such as blood vessels or adipose tissue<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> although their localization in different tissues and organs yields discrepant results&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">GLP-1 or its agonists slow gastric emptying&#46; They also act on the CNS promoting satiety&#44; reducing food intake and favoring weight loss&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;29</span></a> Agonists of rGLP-1 &#40;arGLP-1&#41; have also demonstrated neuroprotective and antiapoptotic effects&#44; a reduction of oxidative stress and inflammation&#44; and improve cognitive and memory function &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">With respect to the vascular system&#44; rGLP-1 activation induces modest decreases in blood pressure&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a> it has a vasodilator effect&#44; improves arterial stiffness&#44; and prevents atherosclerotic plaque formation-and has plaque stabilizing effects-through its anti-inflammatory and antiapoptotic effects as demonstrated in animal models&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;35&#8211;38</span></a> Despite controversies about rGLP-1 expression in vascular smooth muscle and endothelial cells&#44; studies have shown that arGLP-1 has antiproliferative effects on these cells&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> reduces oxidative stress&#44; improves endothelial function&#44; and increases nitric oxide production in experimental models&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#8211;40</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the heart they produce a discrete increase in heart rate &#40;2&#8211;4 beats&#47;min&#41;&#44; although this does not seem to be associated with an increase in arrhythmias or cardiovascular events&#46; They increase glucose uptake and utilization and improve cardiac metabolism&#44; as well as left ventricular function<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;41</span></a>&#59; increase the release of atrial natriuretic peptide&#59; have anti-inflammatory&#44; anti-ischemic and anti-fibrotic effects and inhibit myocardiocyte apoptosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;42</span></a> More recently&#44; it has been reported that they also reduce epicardial fat&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> They also inhibit platelet aggregation and thrombosis&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the lungs&#44; rGLP-1 activation conferred protection against lipopolysaccharide-induced acute lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In adipose tissue they favor adipocyte differentiation&#44; decreases lipid deposition in white fat and facilitate its conversion to brown fat&#44; as well as thermogenesis and energy consumption<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;46&#8211;48</span></a>&#59; the effect on the intestine results in a reduction of postprandial lipidemia and chylomicron secretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a> In the muscles&#44; they improve insulin sensitivity and increase glucose uptake&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Renal expression of rGLP-1 has not been fully characterized due to insufficient specificity and sensitivity of the antibodies used&#44; although it have been non-uniformly detected in endothelial cells&#44; macrophages&#44; juxtaglomerular cells and proximal tubule in several animal models and human tissue&#46; GLP-1 infusion increases natriuresis by reducing tubular sodium reabsorption and reduces hyperfiltration in obese subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Chronic treatment with arGLP-1 in patients with DM2 has shown no effect on measured GFR and effective renal plasma flow in the fasting or postprandial state&#44; however it maintains its natriuretic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> GLP-1 and its agonists induce natriuresis by inhibition of the Na&#43;&#47;H&#8239;&#43;&#8239;exchanger type 3 in the proximal tubule&#44; although interactions with the renin&#44; insulin&#44; or glucagon system cannot be excluded<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#8211;54</span></a> because they reduce circulating levels of RAS components<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;53&#8211;55</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Metabolic effects of glucagon-like peptide-1 receptor agonists</span><p id="par0065" class="elsevierStylePara elsevierViewall">The arGLP-1&#8239;s show a potent antihyperglycemic effect with decreases between 0&#46;5&#37; and 1&#46;3&#37; of HbA1c&#44; which is greater in those with a long half-life<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> with low risk of hypoglycemia&#44; as has been shown in cardiovascular safety studies&#44; where there were no differences in hypoglycemia rates versus placebo&#44; except if associated with sulfonylureas or insulin&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#8211;64</span></a> The low risk of hypoglycemia has been observed even in patients with DKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">65&#8211;67</span></a> who are more susceptible to this complication&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">It is also important to highlight the loss of weight and waist circumference with arGLP-1&#44; mainly as a consequence of a reduction in body fat and not in lean mass&#44; which is maintained during long-term follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> This weight loss is attributed to the slowing of gastric emptying which increases satiety&#44; to the increase in resting energy consumption and its direct effects on appetite and satiety control centers in the CNS&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Obesity and overweight&#44; which are common in patients with DM2&#44; are a factors that favor the development&#47;progression of CKD through both direct and indirect effects&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Although the precise mechanisms the association between obesity and CKD are not totally defined it has been proposed that hypertension&#44; glomerular hyperfiltration&#44; hyperglycemia&#44; lipid toxicity&#44; inflammation or the role of adipose tissue and its adipokines are involved&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> Weight reduction by bariatric surgery&#44; pharmacological treatment or dietary measures are associated with a nephroprotective effect&#44;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">71&#8211;73</span></a> so that weight reduction is a fundamental objective in the nephroprotection of patients with DKD&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Hepatic steatosis is closely related to insulin resistance&#44; diabetes mellitus or metabolic syndrome&#44; and is associated with increased risk of cardiovascular and renal disease&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> Hepatic steatosis has been associated with the prevalence and incidence of renal disease&#46; The decreased in GFR or albuminuria has been associated with the presence of nonalcoholic steatohepatitis or the severity of fibrosis&#44; whereas improvement in liver histology is associated with improvement in CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> arGLP1 improves insulin levels&#44; regulates autophagy&#44; inhibits hepatic neoglycogenesis&#44; reduces hepatic fat content&#44; plasma liver enzyme levels and hepatic histological improvements have been described with liraglutide and semaglutide&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;76</span></a> Likewise&#44; epicardial and perirenal fat are associated with increased cardiorenal risk&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> so that the reduction in ectopic fat<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> as demonstrated with the use of arGLP-1 has could be beneficial in CKD&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Finally&#44; arGLP-1 has been shown to improve the pre- and postprandial lipid profile&#44; with a reduction in the levels of free fatty acids&#44; triglycerides and LDL cholesterol&#44; as well as the fraction of small and dense LDL and a reduction of the increase levels of triglycerides and apo-B48 postprandial&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#8211;82</span></a> Likewise&#44; it has been reported a reduction in markers of inflammation&#44; plasminogen activator inhibitor type 1 and leptin whereas adiponectin levels increase&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;48</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Regarding the adverse effects of this family&#44; the most important are gastrointestinal&#44; especially nausea and vomiting of mild-moderate intensity&#44; which are reduced with time&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">All this translates into an improvement in glycemic control and dyslipidemia&#44; a reduction in blood pressure&#44; weight&#44; and ectopic visceral fat deposits&#44; as well as inflammation and coagulation&#44; which could translate into greater cardiovasculorenal protection with the use of these drugs&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Key differential aspects of the group of glucagon-like peptide-1 receptor agonist drugs</span><p id="par0100" class="elsevierStylePara elsevierViewall">There are several arGLP-1&#8239;s approved or under study for the use in DM2&#58; exenatide &#40;exenatide and exenatide LAR or weekly&#41;&#44; liraglutide&#44; lixisenatide&#44; dulaglutide&#44; semaglutide&#44; albiglutide &#40;withdrawn from the market&#41;&#44; and efpeglenatide &#40;in clinical development&#41;&#46; Almost all are administered subcutaneously&#44; although oral semaglutide is currently available in Spain &#40;see below&#41;&#46; These drugs are divided into&#58; incretinmimetics&#44; derived from exendin-4 &#40;a peptide obtained from the saliva of the Gila monster &#91;Heloderma suspectum&#93;&#41;&#59; or analogs of human GLP-1&#44; with changes in the amino acid sequence that make them resistant to dipeptidylpeptidase 4&#46; The arGLP-1&#8239;s present other differences in clinically relevant biological properties &#40;half-life&#44; dosing interval and molecular weight&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Short half-life agents &#40;exenatide twice daily or lixisenatide&#41; produce spikes with transient increases in plasma arGLP-1 levels&#44; resulting in intermittent activation of the receptor and have a potent effect on gastric emptying and postprandial glycemia by reducing the rate of glucose entry into the duodenum&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Those with a long half-life &#40;weekly exenatide&#44; efpeglenatide&#44; liraglutide&#44; semaglutide&#44; albiglutide and dulaglutide&#41; produce a sustained activation of rGLP1&#44; resulting in a greater reduction in HbA1c&#44; basal glycemia and body weight and would have fewer gastrointestinal side effects&#59; they do not have a significant effect on gastric emptying due to a tachyphylaxis phenomenon&#44; and have a modest effect on postprandial glycemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;78</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Those of small molecular weight &#40;exenatide&#44; lixisenatide&#44; liraglutide and semaglutide&#41; can penetrate the blood-brain barrier more easily than those of high molecular weight &#40;dulaglutide&#44; albiglutide and epfeglenatide&#41; and could generate differential effects on central appetite signaling pathways and weight loss&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;33&#44;83</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Exendin-4 analogues are eliminated by the the kidneys&#44; so their use is not recommended in patients with advanced CKD &#40;GFR&#8239;&#60;&#8239;30&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#44; while GLP-1 analogues have other elimination routes and can be prescribed in patients up to CKD stage 4 &#40;GFR15&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">All this means that there are differences between these compounds in terms of their potency in reducing HbA1c&#44; baseline glycemia or weight reduction&#44; among other factors&#44; which should be considered when choosing drugs from this family&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#44;83&#44;84</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Cardiovascular protection of glucagon-like peptide type 1 receptor agonists</span><p id="par0130" class="elsevierStylePara elsevierViewall">Several randomized clinical trials have analyzed the cardiovascular safety of arGLP1 versus standard therapy&#46; All trials analyzed the composite of 3 major adverse cardiovascular events &#40;MACE&#41;&#44; which included cardiovascular death&#44; non-fatal myocardial infarction&#44; or non-fatal stroke&#44; except the lixisenatide study that considered 4-point MACE&#44; which also included hospitalization for heart failure &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#8211;64</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Although all the studies with arGLP-1 have demonstrated cardiovascular safety &#40;noninferiority vs&#46; placebo&#41;&#44; most of them &#40;liraglutide&#44; semaglutide SC&#44; dulaglutide&#44; albiglutide&#44; and efpeglenatide&#41; have also demonstrated a reduction in MACE with respect to placebo&#44; while weekly exenatide or oral semaglutide showed a tendency to reduce MACE&#46; In the LEADER study with liraglutide&#44; in patients with CKD stage &#8805;3&#44; this cardiovascular benefit proved to be greater&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Although the cardiovascular safety studies were not powered to detect differences in individual components of MACE&#44; some differences between studies were seen in these individual components&#59; thus liraglutide and oral semaglutide significantly reduced cardiovascular death&#44; subcutaneous semaglutide and dulaglutide significantly reduced nonfatal stroke&#44; albiglutide reduced the risk of nonfatal myocardial infarction&#44; and epfeglenatide reduced the incidence of heart failure&#44; while weekly exenatide or lixisenatide showed no significant benefit on any component of MACE&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">However&#44; it is difficult to discern whether these differences between studies are due to real differences between the molecules in terms of their cardiovascular effects&#46; Potential explanations include differences in the type of patients included&#44; adherence to study treatment&#44; sample size&#44; duration of drug exposure&#44; and GLP1 receptor activation with greater HbA1c reduction with longer-acting human GLP1-based analogs than with some short-acting exendin-4 analogs&#46; Recent results from the AMPLITUDE-O trial with efpeglenatide<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> suggest that the cardiovascular benefits of this family are not exclusive of the human GLP-1 analogs&#46; Likewise&#44; the cardiovascular benefit of efpeglenatide was independent of GFR or the concomitant use of iSGLT-2&#44; suggesting its additive and independent effect from the latter&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> as was also observed in the EXSCEL study&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">A recent meta-analysis of the 8 published cardiovascular safety clinical trials&#44; and which included a total of 60&#46; 080 patients&#44; concluded that&#44; overall&#44; arGLP-1 reduces MACE by 14&#37; &#40;HR 0&#46;86&#44; 95&#37; CI&#58; 0&#46;80&#8722;0&#46;93&#44; p&#8239;&#60;&#8239;0&#46;0001&#41;&#44; with no significant differences regarding structural homology with human GLP-1&#44; risk of cardiovascular events &#40;based on the risk of MACE in the placebo group as low&#44; medium or high&#41;&#44; presence or not of cardiovascular disease&#44; baseline HbA1c&#44; body mass index&#44; duration of follow-up&#44; administration interval &#40;daily or weekly&#41; or renal function&#46; Analyzing the individual components of MACE&#44; the use of arGLP-1 reduced the risk of cardiovascular death &#40;HR 0&#46;87&#44; 95&#37; CI&#58; 0&#46;80&#8722;0&#46;94&#59; p&#8239;&#61;&#8239;0&#46;001&#41;&#44; fatal and non-fatal myocardial infarction &#40;HR 0&#46;90&#44; 95&#37; CI&#58; 0&#46;83&#8722;0&#46;98&#59; p&#8239;&#61;&#8239;0&#46;020&#41; and fatal or non-fatal stroke &#40;HR 0&#46;83&#44; 95&#37; CI&#58; 0&#46;76&#8722;0&#46;92&#59; p&#8239;&#61;&#8239;0&#46;0002&#41;&#46; ArGLP-1 also reduced total mortality &#40;HR 0&#46;88&#44; 95&#37; CI 0&#46;82&#8722;0&#46;94&#44; p&#8239;&#61;&#8239;0&#46;0001&#41; and hospital admission due to heart failure &#40;HR 0&#46;89&#44; 95&#37; CI 0&#46;82&#8722;0&#46;98&#44; p&#8239;&#61;&#8239;0&#46;013&#41;&#44; all without increasing the risk of severe hypoglycemia&#44; pancreatic problems or retinopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> A recent post hoc analysis of CVOT with semaglutide has shown a gain in time free of cardiovascular disease of 1&#46;7 years in those patients with CKD vs&#46; 0&#46;2 years in diabetic patients with cardiovascular risk factors only&#44; suggesting an additional benefit of semaglutide in this population with high cardiovascular risk&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The mechanisms involved in the cardiovascular benefits of this family are various&#46; A meta-regression study suggested a linear relationship between HbA1c reduction and MACE risk in patient with arGLP-1&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> Publication on mediation analyses also suggest that cardiovascular benefit could be mediated in part by effects on HbA1c&#44; on blood pressure or reduction in urine albumin-creatinine ratio<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">90&#44;91</span></a> &#40;see below&#41;&#44; as well as by their effect on lipid profile&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> However&#44; in subgroup analyses of cardiovascular safety studies&#44; baseline HbA1c&#44; weight&#44; previous cardiovascular disease&#44; or renal function did not predict the beneficial effects of these drugs on MACE&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> so other mechanisms&#44; such as the previously mentioned anti-inflammatory&#44; antifibrotic&#44; antiatherogenic&#44; vasodilator&#44; or endothelial function-enhancing effects&#44; have been suggested to influence the cardiovascular benefit of these drugs<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;78</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Renal protection with glucagon-like peptide type 1 receptor agonists</span><p id="par0155" class="elsevierStylePara elsevierViewall">In CVOTs of arGLP1 renal outcomes were prespecified as key secondary outcomes in 4 studies done with liraglutide&#44; subcutaneous semaglutide&#44; dulaglutide&#44; and efpeglenatide&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59&#44;63&#44;64</span></a> or were collected as safety parameters in other studies&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Overall&#44; the prevalence of CKD stage &#8805;3 in these studies was low &#40;20&#8211;30&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">In those studies that prospectively evaluated renal targets as key secondary endpoints&#44; included a composite renal episode that consist of the development of macroalbuminuria&#44; the development of end-stage CKD or the need for renal replacement therapy or a significant reduction in renal function from baseline&#44; which included a GFR&#60;45&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> and a doubling of serum creatinine<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a> or a decrease in GFR&#8239;&#8805;&#8239;30&#37;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> or &#8805;40&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> The combined renal target was reduced by approximately 15&#37;&#8211;35&#37; with liraglutide&#44; semaglutide SC&#44; dulaglutide&#44; or efpeglenatide compared with placebo&#44; basically at the expense of reducing the risk of developing macroalbuminuria&#44; without reaching statistical significance for the other components &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; However&#44; in a sensitivity analysis of the REWIND study with dulaglutide&#44; the relative risk reduction for a 40&#37; or 50&#37; decrease in eGFR was 30&#37; and 44&#37;&#44; both significant&#44; in the dulaglutide group compared to placebo&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> This lower risk of developing macroalbuminuria was also confirmed in an exploratory analysis of the ELIXA &#40;lixisenatide&#41; study&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> In the EXSCEL study &#40;exenatide LAR&#41;&#44; renal episodes were analyzed as additional microvascular episodes&#44; and no differences were observed in the risk of episodes related to decreased eGFR&#44; but differences were observed in the composite episode&#44; which included decreased eGFR and macroalbuminuria&#44; although only after adjustment<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">The effects on the evolution of eGFR during follow-up are variable among the different trials&#44; with minimal differences between the active group and placebo&#44;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;63&#44;64</span></a> although an exploratory analysis of the EXSCEL study demonstrated a smaller fall in eGFR in patients with albuminuria greater than 100&#8239;mg&#47;g and 200&#8239;mg&#47;g of urine albumin&#47;creatinine&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> Likewise&#44; in a post-hoc analysis of the LEADER and SUSTAIN studies&#44; a smaller fall in eGFR was observed in those with eGFR&#60;60&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a> Reduced albuminuria &#40;or less increase&#41; is the most consistent finding in these studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59&#44;64&#44;93</span></a> as well as in a post hoc analysis of the SUSTAIN 1&#8211;7 trials with semaglutide SC<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> and those with dulaglutide&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">In the aforementioned Sattar meta-analysis the composite renal endpoint of renal function deterioration&#44; need for renal replacement therapy&#44; renal death and development of macroalbuminuria was reduced by 21&#37; &#40;HR 0&#46;79&#44; 95&#37; CI&#58; 0&#46;73&#8722;0&#46;87&#44; p&#8239;&#60;&#8239;0&#46;0001&#41;&#44; but was not significant for episodes of renal function deterioration &#40;HR 0&#46;86&#44; 95&#37; CI&#58; 0&#46;72&#8211;1&#46;02&#44; p&#8239;&#61;&#8239;0&#46;089&#41;&#44; although they were also reduced significantly after excluding the ELIXA87 study&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The renal effects of arGLP1 in patients with CKD have been evaluated in other studies&#46; The study &#34;Liraglutide versus placebo as an adjunct to glucose-lowering therapy in patients with type 2 diabetes and moderate renal failure&#34; &#40;LIRA-RENAL&#41; did not demonstrate a benefit of liraglutide in lowering eGFR&#44; although the duration of the study &#40;26 weeks&#41; may have been insufficient to show an effect&#46; This study also showed a non-significant 17&#37; reduction in albuminuria&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> The AWARD-7 study analyzed the efficacy of dulaglutide in patients with DM2 and moderate-severe CKD &#40;mean eGFR 38&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46; The decrease in mean GFR at 52 weeks was smaller in the high &#40;1&#46;5&#8239;mg&#41; and low dose dulaglutide &#40;0&#46;75&#8239;mg&#41; treatment groups &#40;both &#8722;0&#46;7&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41; vs&#46; the insulin glargine group &#40;&#8722;3&#46;3&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46; This benefit was greater in patients with macroalbuminuria<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Thus&#44; arGLP-1 reduces albuminuria in patients with ESRD&#44; but its effects on the progression of renal disease are not conclusive&#46; However&#44; albuminuria is a potent predictor of eGFR decline&#44; so these drugs could delay progression in DKD by reducing albuminuria&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> In a subgroup analysis of the LEADER trial the effect of liraglutide vs&#46; placebo in the fall of eGFR was better among patients with macroalbuminuria or in those with eGFR between 30&#8722;60&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a> and in the AWARD-7 trial the effect of dulaglutide on renal clinical outcomes and eGFR decline was more pronounced in participants with macroalbuminuria at baseline&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> Likewise&#44; in a post hoc analysis of the LEADER study those patients who experienced a 30&#37; reduction in albuminuria during follow-up had fewer cardiovascular and renal events&#44;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> which confirms that a reduction in albuminuria is associated with a reduction in cardiovascular and renal events&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">99&#44;102</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Finally&#44; the renal benefits of arGLP-1 appear to be additive to those of iSGLT2&#44; which is of particular interest in patients with DKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86&#44;103</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Cardiovascular and renal benefits of these drugs have been also demonstrated in real-life studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">104&#8211;105</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">The causes of renal protection by some arGLP-1&#8239;s are unclear&#46; Post hoc adjustment for HbA1C and other traditional renal risk factors did not have a major influence on renal benefit by liraglutide&#44; semaglutide&#44; or dulaglutide in CVOTs&#44; nor were there differences in glycemic control in the AWARD-7<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> study&#46; In fact&#44; mediation analyses performed suggested that only approximately 25&#37; of the benefit on renal outcomes may be mediated by improved glycemic control and 9&#8211;22&#37; by changes on blood pressure&#44;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">92&#44;106</span></a> suggesting the role of direct mechanisms&#58; reduction of hyperfiltration&#44; oxidative stress and inflammation&#44; antifibrotic effects&#44; improvement of endothelial dysfunction and&#47;or possible reduction of angiotensin II levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#44;54&#44;107&#8211;109</span></a> In experimental studies of DKD&#44; treatment with arGLP-1 has been associated with histological improvements &#40;reduction of glomerular hypertrophy&#44; mesangial expansion&#44; thickening of the glomerular basement membrane and tubulointerstitial damage&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">110&#44;111</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">In fact&#44; the KDIGO guidelines for the management of patients with diabetes and CKD rank arGLP-1 as a second line of treatment and suggest its use in patients with DM2 and CKD who have not reached individualized glycemic targets despite the use of metformin and iSGLT2&#44; or in those who cannot use these drugs since liraglutide&#44; semaglutide and dulaglutide &#40;results with epfeglenatide have not been published&#41; have demonstrated cardiovascular benefits&#44; especially among patients with established cardiovascular disease&#44; associated with favorable renal benefits with a substantial reduction in albuminuria and probable preservation of eGFR&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a> as well as other guidelines in patients with DM2 and high&#47;very high cardiovascular risk&#44; such as patients with DKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;113</span></a> Furthermore&#44; arGLP-1&#8239;s are more potent antihyperglycemic agents than iSGLT2s in patients with DKD&#44; and some such as semaglutide also confer greater potential for weight loss&#46; Finally&#44; some clinical case studies and short series suggest their benefits also in patients with CKD stage 5D&#44; although it should be recalled that this indication is not included in the labeling of arGLP-1&#8239;s&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">114&#44;115</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">The Effect of semaglutide versus placebo on the progression of renal impairment in subjects with type 2 diabetes and chronic kidney disease &#40;FLOW&#41;&#44; a phase 3 clinical trial involving more than 3&#44;000 patients with type 2 DM and moderate-severe CKD &#40;eGFR 25&#8722;75&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> and Urine Alb&#47;Cr ratio of 300&#8722;5&#44;000&#8239;mg&#47;g&#41; is currently underway &#40;NCT03819153&#41;&#46; The primary endpoint is a renal composite episode defined by a decrease in GFR&#8239;&#8805;&#8239;50&#37;&#44; end-stage renal failure&#44; and death from a renal-cause or cardiovascular-caused death&#44; and it is scheduled for completion in 2024&#46; This trial is the first to include renal disease outcomes as a primary target with the use of this family of drugs&#46; This study will define the clinical efficacy and renal safety of an arGLP-1 and thereby will inform about future evidence-based recommendations for treatment of DKD&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Oral semaglutide</span><p id="par0210" class="elsevierStylePara elsevierViewall">Semaglutide oral is the first oral arGLP-1&#46; Semaglutide oral is co-formulated with sodium N-&#40;8-&#91;8-&#91;2-hydroxybenzoyl&#93;amino&#41; caprylate &#40;sodium salcaprozate or SNAC&#41; which allows absorption of semaglutide across the gastric mucosa&#46; Oral semaglutide has been approved and recently marketed in Spain following evidence from the <span class="elsevierStyleItalic">Phase 3 clinical trial program Peptide InnOvatioN for Early diabEtes tReatment &#40;PIONEER&#41;</span>&#46; This program evaluated the efficacy and safety of oral semaglutide in patients with DM2 from monotherapy to insulin addition&#44; including HbA1c and body weight reduction outcomes&#44; in addition to other relevant efficacy and safety endpoints&#44; as compared to both placebo and other common antihyperglycemic drugs&#46; Oral semaglutide at doses of 7 and 14&#8239;mg&#47;day reduced HbA1c and body weight across the entire spectrum of DM2&#44; as well as other endpoints&#44; such as fasting blood glucose&#46; Oral semaglutide was superior to placebo and other antihyperglycemic drugs&#44; such as iDPP4 &#40;sitagliptin&#41;&#44; iSGLT2 &#40;empagliflozin&#41; or other arGLP-1 &#40;liraglutide&#41; in reducing HbA1c or weight&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">116</span></a> Oral semaglutide was well tolerated&#44; with a safety profile similar to that of other arGLP-1&#8239;s&#46; The most frequently reported side effects were gastrointestinal side effects of mild-moderate intensity and were transient over time&#46; Its cardiovascular safety in patients with cardiovascular disease or high cardiovascular risk was demonstrated in the aforementioned PIONEER-6 study&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> In the PIONEER 5 study&#44; in patients with CKD stage 3&#44; it was evaluated the efficacy and safety of a 14&#8239;mg dose&#44; resulting superior to placebo in terms of reduction of HbA1c &#40;-0&#46;8&#37; vs&#46; placebo&#41; and body weight &#40;&#8722;2&#46;5&#8239;kg vs&#46; placebo&#41;&#44; with a higher percentage of patients achieving HbA1c&#60;7&#46;0&#37; levels &#40;57&#46;8&#37; vs 22&#46;6&#37; in placebo&#41; and weight loss &#8805;5&#37; &#40;35&#46;7&#37; vs&#46; 9&#46;7&#37; in placebo&#41;&#46; The most frequent adverse effects consisted of mild-moderate nausea that decreased over time &#40;19&#37; vs&#46; 8&#37; on placebo&#41; and with low risk of symptomatic or confirmed hypoglycemia &#40;5&#46;5&#37; vs&#46; 1&#46;9&#37; on placebo&#41;&#46; There were no differences in eGFR between the two groups&#44; but there was a reduction in albuminuria with oral semaglutide vs&#46; an increase in the placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Results from the PIONEER program demonstrate that oral semaglutide is effective&#44; safe&#44; and well tolerated for glycemic control in patients with DM2&#44; including those with DKD&#44; with the specific benefits of this family of drugs&#46; The availability of oral semaglutide may help to broaden treatment options and facilitate the adoption of earlier treatment with arGLP-1 in the management of DM2&#46; A heart disease study of semaglutide in patients with type 2 diabetes &#40;SOUL&#44; NCT03914326&#41; evaluating the cardiovascular benefit of oral semaglutide is currently underway&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0220" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall">The prevalence of CKD is high in DM2 and DKD is associated with increased cardiovascular risk&#44; mortality and progression to end-stage CKD&#44; requiring early and intensive treatment to minimize these complications&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0230" class="elsevierStylePara elsevierViewall">The arGLP-1&#8239;s have demonstrated a CV benefit in patients with DM2 that appears to extend to patients with reduced renal function&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0235" class="elsevierStylePara elsevierViewall">Some arGLP-1&#8239;s reduce progression to overt albuminuria&#44; decrease albuminuria during follow-up&#44; and may delay progression of renal dysfunction in DKD&#44; especially in the subgroup with established CKD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0240" class="elsevierStylePara elsevierViewall">Oral semaglutide is effective&#44; safe and well tolerated in patients with DM2&#44; even in those with DKD&#44; with the benefits inherent to this family of drugs&#44; which may facilitate the earlier introduction of an arGLP-1 in the management of DM2&#46;</p></li></ul></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">Aleix Cases declares having received a grant&#44; consulting and speaking fees from Vifor Pharma&#44; speaking and consulting fees from Astellas&#44; Astra Zeneca&#44; Bayer and Novo Nordisk&#59; consulting fees from Boehringer Ingelheim&#44; GSK and Otsuka and speaking fees from Amgen and Sanofi &#40;Mexico&#41;&#44; but has not received funding in relation to the writing of this article&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Glucagon-like peptide type 1 receptor agonists"
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              "titulo" => "Incretin effect and systemic effects of glucagon-like peptide type 1 and its agonists"
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              "titulo" => "Metabolic effects of glucagon-like peptide-1 receptor agonists"
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              "titulo" => "Key differential aspects of the group of glucagon-like peptide-1 receptor agonist drugs"
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          "titulo" => "Cardiovascular protection of glucagon-like peptide type 1 receptor agonists"
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          "titulo" => "Renal protection with glucagon-like peptide type 1 receptor agonists"
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          "identificador" => "sec0040"
          "titulo" => "Oral semaglutide"
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          "titulo" => "Conclusions"
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    "fechaRecibido" => "2022-02-28"
    "fechaAceptado" => "2022-07-23"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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            0 => "Type 2 diabetes mellitus"
            1 => "Diabetic kidney disease"
            2 => "Cardioprotection"
            3 => "Nephroprotection"
            4 => "Glucagon-like peptide 1 GLP-1 receptor agonists"
            5 => "Oral semaglutide"
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          "palabras" => array:6 [
            0 => "Diabetes mellitus tipo 2"
            1 => "Enfermedad renal diab&#233;tica"
            2 => "Cardioprotecci&#243;n"
            3 => "Nefroprotecci&#243;n"
            4 => "Agonistas del receptor del p&#233;ptidosimilar al glucag&#243;n tipo 1 GLP-1"
            5 => "Semaglutida oral"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Diabetic kidney disease&#44; a common complication in patients with type 2 diabetes mellitus&#44; is associated with a markedly increased morbidity and mortality&#44; especially of cardiovascular origin&#44; and faster progression to end-stage renal disease&#46; To date&#44; reducing cardiovascular and renal risk in this population was based on strict control of cardiovascular risk factors and the renin-angiotensin system blockade&#46; More recently&#44; sodium-glucose cotransporter type 2 inhibitors have demonstrated to offer cardiovascular and renal protection&#44; but the residual risk remains high and their antihyperglycemic efficacy is limited in moderate-severe CKD&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Therefore&#44; drugs with a potent antihyperglycemic effect&#44; independent of the glomerular filtration rate&#44; with a low risk of hypoglycemia&#44; that reduce weight in overweight&#47;obese patients and that provide cardiovascular and renal protection&#44; such as GLP-1 receptor agonists&#44; are needed&#46; However&#44; these drugs require subcutaneous administration&#44; which may limit their early use&#46; The recent availability of oral semaglutide may facilitate the early introduction of this family with proven cardiovascular and renal benefits and excellent safety profile&#46; In this review the family is analyzed as well as their cardiovascular and renal effects</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La enfermedad renal diab&#233;tica&#44; frecuente en pacientes con diabetes mellitus tipo 2&#44; se asocia con un marcado incremento de la morbimortalidad&#44; especialmente cardiovascular&#44; y de progresi&#243;n a enfermedad renal cr&#243;nica terminal&#46; Hasta la fecha&#44; la reducci&#243;n del riesgo cardiovascular y renal en esta poblaci&#243;n se ha basado en el control estricto de los factores de riesgo cardiovascular y el uso de inhibidores del sistema renina-angiotensina&#46; Mas recientemente&#44; los inhibidores del cotransportador sodio-glucosa tipo 2 han demostrado ofrecer protecci&#243;n cardiovascular y renal&#44; pero el riesgo residual sigue siendo alto y su eficacia antihiperglucemiante es limitada en ERC moderada-severa&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Por ello se precisan f&#225;rmacos con un potente efecto antihiperglucemiante&#44; independiente del filtrado glomerular&#44; con bajo riesgo de hipoglicemia&#44; que reduzcan el peso en pacientes con sobrepeso&#47;obesidad y que proporcionen una protecci&#243;n cardiovascular y renal&#44; como los agonistas del receptor de GLP-1&#46; Sin embargo&#44; estos f&#225;rmacos precisan de su administraci&#243;n subcut&#225;nea&#44; lo que puede limitar su uso temprano&#46; La reciente disponibilidad de semaglutida oral puede ayudar a la introducci&#243;n precoz de esta familia con beneficios cardiovasculares y renales probados y excelente perfil de seguridad&#46; En esta revisi&#243;n se revisa la familia y sus efectos cardiovasculares y renales&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">arGLP-1&#58; glucagon-like peptide 1 receptor agonist&#59; VSMF&#58; vascular smooth muscle fiber&#59; ANP&#58; atrial natriuretic peptide&#59; RAAS&#58; renin-angiotensin-aldosterone system&#46; Modified from M&#252;ller et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">CV&#44; cardiovascular&#59; CKD&#44; Chronic kidney disease stage &#8805;3 &#40;FGe&#60;60&#8239;ml&#47;min&#47;1&#44;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#59; AHF&#44; Hospital admission due to heart failure&#59; MI&#44; myocardial infarction&#59; MACE 3P&#44; 3-point cardiovascular composite episode&#59; MACE 4P&#44; 4-point cardiovascular composite episode&#44; including hospitalization due to non-stable angina&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug&#47;study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sample size&#47;follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Compared with&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Episodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HR &#40;CI 95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liraglutida&#47;LEADER<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;340&#47;3&#44;8 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#44;4&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;87 &#40;0&#44;78&#8722;0&#44;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 24&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85 &#40;0&#44;74&#8722;0&#44;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;78 &#40;0&#44;66&#8722;0&#44;93&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;73&#8722;1&#44;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;71&#8722;1&#44;06&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;87 &#40;0&#44;73&#8722;1&#44;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Semaglutida SC&#47;SUSTAIN 6<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;297&#47;2&#44;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#44;2&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;58&#8722;0&#44;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 24&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;05 &#40;0&#44;74&#8722;1&#44;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;98 &#40;0&#44;65&#8722;1&#44;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI &#40;non fatal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;51&#8722;1&#44;08&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stroke &#40;non fatal&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;61 &#40;0&#44;38&#8722;0&#44;99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;11 &#40;0&#44;77&#8722;1&#44;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lixisenatida&#47;ELIXA<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;068&#47;2&#44;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recent acute coronary syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 4P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;02 &#40;0&#44;89&#8722;1&#44;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD &#8805; 3&#44; 23&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;94 &#40;0&#44;78&#8722;1&#44;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;98 &#40;0&#44;78&#8722;1&#44;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;03 &#40;0&#44;87&#8722;1&#44;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;12 &#40;0&#44;79&#8722;1&#44;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;96 &#40;0&#44;75&#8722;1&#44;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exenatida SR &#47; EXSCEL<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;752&#47;3&#44;2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73&#44;1&#37; with CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;91 &#40;0&#44;83&#8722;1&#44;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 21&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;77&#8722;0&#44;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;88 &#40;0&#44;76&#8722;1&#44;02&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;97 &#40;0&#44;85&#8722;1&#44;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85 &#40;0&#44;70&#8722;1&#44;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;94 &#40;0&#44;78&#8722;1&#44;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albiglutida &#47; HARMONY outcomes<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9463&#47;1&#44;6 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;78 &#40;0&#44;68&#8722;0&#44;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;95 &#40;0&#44;79&#8722;1&#44;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 23&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;93 &#40;0&#44;73&#8722;1&#44;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;75 &#40;0&#44;61&#8722;0&#44;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;66&#8722;1&#44;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF and CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85 &#40;0&#44;70&#8722;1&#44;04&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Semaglutida oral &#47; PIONEER 6<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3183&#47;15&#46;9 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#44;7&#37; with CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;79 &#40;0&#44;57&#8722;1&#44;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 26&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;51 &#40;0&#44;31&#8722;0&#44;84&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;49 &#40;0&#44;27&#8722;0&#44;92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI no fatal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;18 &#40;0&#44;73&#8722;1&#44;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stroke no fatal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;35&#8722;1&#44;57&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;48&#8722;1&#44;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dulaglutida &#47; REWIND<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;901&#47;5&#44;4 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#44;5&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;88 &#40;0&#44;79&#8722;0&#44;99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 22&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;90 &#40;0&#44;80&#8722;1&#44;01&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;91 &#40;0&#44;78&#8722;1&#44;06&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;96 &#40;0&#44;79&#8722;1&#44;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;76 &#40;0&#44;62&#8722;0&#44;94&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;93 &#40;0&#44;77&#8722;1&#44;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Efpeglenatida &#47; AMPLITUDE-O<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;076&#47;1&#44;81 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&#44;6&#37; with established CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MACE 3&#8239;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;73 &#40;0&#44;58&#8211;0&#44;92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD&#8239;&#8805;&#8239;3&#44; 31&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total Mortalidad&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;78 &#40;0&#44;58&#8722;1&#44;06&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;72 &#40;0&#44;50&#8722;1&#44;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;75 &#40;0&#44;54&#8722;1&#44;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;47&#8722;1&#44;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;61 &#40;0&#44;38&#8722;0&#44;98&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Alb&#47;Cr&#44; ratio alb&#250;min&#47; creatinine in urine&#59; eGFR&#44; estimated glomerular filtration rate&#44; ARF&#44; acute renal failure&#59; LSM&#44; least squares mean&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Renal episodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liraglutida<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;100</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LEADER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcome&#58; reduction in the combined renal event of persistent new-onset macroalbuminuria&#44; persistent doubling of serum creatinine&#44; end-stage renal failure&#44; or renal death in the liraglutide group &#40;HR 0&#46;78&#59; 95&#37; CI 0&#46;67&#8722;0&#46;92&#59; p&#8239;&#61;&#8239;0&#46;003&#41;Decrease in eGFR at 36 months was 2&#37; lower with liraglutide vs&#46; placebo &#40;1&#46;02&#59; 95&#37; CI&#58; 1&#46;00&#8722;1&#46;03&#59; p&#8239;&#61;&#8239;0&#46;01&#41;Alb&#47;Cr at 36 months 17&#37; lower with liraglutide vs&#46; placebo &#40;0&#46;83&#59; 95&#37; CI&#58; 0&#46;79&#8722;0&#46;88&#59; p&#8239;&#60;&#8239;0&#46;001&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Semaglutida SC<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SUSTAIN-6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcome&#58; reduction in the combined renal event of persistent new-onset macroalbuminuria&#44; persistent doubling of serum creatinine&#44; end-stage renal failure or renal death in the semaglutide group vs&#46; placebo &#40;HR 0&#46;64&#59; 95&#37; CI 0&#46;46&#8722;0&#46;88&#59; p&#8239;&#61;&#8239;0&#46;005&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dulaglutida<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;92</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">REWIND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcome&#58; new-onset macroalbuminuria&#44; sustained decrease in GFRe&#8805;30&#37; from baseline or chronic renal replacement therapy in the dulaglutide group vs&#46; placebo &#40;HR 0&#46;85&#44; 95&#37; CI&#58; 0&#46;77&#8722;0&#46;93&#44; p&#8239;&#61;&#8239;0&#46;0004&#41;New macroalbuminuria &#40;HR 0&#46;77&#44; 95&#37; CI&#58; 0&#46;68&#8722;0&#46;87&#44; p&#8239;&#60;&#8239;0&#46;0001&#41;Sustained decrease in GFR&#8239;&#8805;&#8239;30&#37; &#40;HR 0&#46;89&#44; 95&#37; CI 0&#46;78&#8722;1&#46;01&#59; p&#8239;&#61;&#8239;0&#46;066&#41;&#46;Sensitivity analysis&#58; sustained decrease in FGe&#8805;40&#37; &#40;HR 0&#46;70&#44; 95&#37; CI&#58; 0&#46;57&#8722;0&#46;85&#41; and &#8805;50&#37; &#40;HR 0&#46;56&#44; 95&#37; CI&#58; 0&#46;41&#8722;0&#46;76&#41;&#46;Change in Alb&#47;Cr &#40;MMC 0&#46;82&#44; 95&#37; CI 0&#46;78&#8722;0&#46;86&#59; p&#8239;&#60;&#8239;0&#46;0001&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exenatida LAR<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;94&#44;95</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EXSCEL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prespecified secondary renal outcomes&#58;New macroalbuminuria&#58; 2&#46;2&#37; vs&#46; 2&#46;5&#37; in the exenatide and placebo groups&#44; respectively &#40;HR 0&#46;87&#59; 95&#37; CI 0&#46;70&#8722;1&#46;07&#41;&#46; Change in Alb&#47;Cr vs&#46; placebo &#8722;25&#37;&#46;No difference for composite renal event 1 &#40;40&#37; decrease in eGFR&#44; renal replacement therapy or renal death&#41; &#40;HR 0&#46;88&#44; 95&#37; CI 0&#46;74&#8722;1&#46;05&#41;&#46;No difference for renal composite 2 &#40;40&#37; decrease in eGFR&#44; renal replacement therapy&#44; renal death or macroalbuminuria&#41; &#40;HR 0&#46;88&#44; 95&#37; CI 0&#46;76&#8722;1&#46;01&#41;&#44; although significant after adjustment &#40;HR 0&#46;85&#44; 95&#37; CI 0&#46;74&#8722;0&#46;98&#41;&#46;In patients with baseline Alb&#47;Cr&#62;100&#8239;mg&#47;g differences in fall in eGFR vs&#46; placebo &#40;0&#46;79&#8239;ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#47;yr&#44; 95&#37; CI&#58; 0&#46;24&#8722;1&#46;34&#41; and Alb&#47;Cr &#62;200&#8239;mg&#47;g &#40;1&#46;32&#8239;ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#47;yr&#44; 95&#37; CI&#58; 0&#46;57&#8722;2&#46;06&#41;&#44; but not in lower Alb&#47;Cr thresholds&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Efpeglenatida<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AMPLITUDE-O&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prespecified secondary renal composite outcome&#58; incident macroalbuminuria&#44; sustained decline in GFR&#8239;&#8805;&#8239;40&#37;&#44; end-stage renal disease or need for renal replacement therapy &#40;HR 0&#46;68&#44; 95&#37; CI&#58; 0&#46;57&#8722;0&#46;79&#44; p&#8239;&#60;&#8239;0&#46;001&#41;Renal function event &#40;sustained decline in GFR&#8239;&#8805;&#8239;40&#37;&#44; end-stage renal disease or need for renal replacement therapy or death&#41; &#40;HR 0&#46;77&#44; 95&#37; CI 0&#46;57&#8722;1&#46;02&#41;Alb&#47;Cr 21&#37; lower &#40;95&#37; CI&#58; 14&#8722;28&#41; and eGFR 0&#46;9&#8239;ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span> &#40;95&#37; CI&#58; 0&#46;3&#8722;1&#46;5&#41; higher with epfeglenatide vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lixisenatida<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;93</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ELIXA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Change in Alb&#47;Cr from baseline&#58; 24&#37; vs&#46; 34&#37;&#44; p&#8239;&#61;&#8239;0&#46;004 &#40;lixisenatide vs&#46; placebo&#41;&#46;Exploratory analysis&#58; percent change in urine Alb&#47;Cr vs&#46; placebo&#58; &#8722;1&#46;69&#37; &#40;95&#37; CI&#58; &#8722;11&#46;69&#8722;8&#46;30&#41; in normoalbuminurics &#8722;21&#46;10&#37; &#40;95&#37; CI&#58; &#8722;42&#46;25&#8722;0&#46;04&#44; p&#8239;&#61;&#8239;0&#46;0502&#41; in microalbuminurics and &#8722;39&#46;18&#37; &#40;95&#37; CI&#58; &#8722;68&#46;53 to &#8722;9&#46;84&#44; p&#8239;&#61;&#8239;0&#46;007&#41; in macroalbuminuricsReduced risk of new-onset macroalbuminuria vs&#46; placebo adjusted for baseline HbA1c &#40;HR 0&#46;808&#44; 95&#37; CI&#58; 0&#46;660&#8722;0&#46;991&#59; p&#8239;&#61;&#8239;0&#46;0404&#41; or adjusted for baseline and in the trial HbA1c &#40;HR 0&#46;815&#44; 95&#37; CI&#58; 0&#46;665&#8722;0&#46;999&#59; p&#8239;&#61;&#8239;0&#46;0491&#41;&#46; No differences in the decrease in eGFR&#44; nor in the percentage of patients who doubled creatinine during follow-up &#40;1&#37; in each group&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albiglutida<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HARMONY Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Difference eGFR &#8722;1&#46;11 &#40;95&#37; CI&#58; &#8722;1&#46;84 to &#8722;0&#46;39&#41; month 8 and &#8722;0&#46;43 &#40;95&#37; CI&#58; &#8722;1&#46;26 to 0&#46;41&#41; at month 16 vs&#46; placebo&#46;Renal involvement&#58; HR 0&#46;87 &#40;95&#37; CI&#58; 0&#46;75&#8722;1&#46;02&#41; &#40;ARF 70 vs&#46; 80 cases&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dulaglutida<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AWARD-7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secondary renal outcomes&#58; eGFR was higher at 52 weeks with dulaglutide 1&#46;5&#8239;mg &#40;MMC 34&#46;0&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41; &#40;p&#8239;&#61;&#8239;0&#46;005&#41;&#44; as well as with dulaglutide 0&#46;75&#8239;mg &#40;MMC 33&#46;8&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41; &#40;p&#8239;&#61;&#8239;0&#46;009&#41; vs&#46; insulin glargine &#40;LSM 31&#46;3&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span>&#41;&#46;Reduction of eGFR in patients with macroalbuminuria&#58; &#8722;5&#46;5&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> in the insulin glargine group vs&#46; &#8722;0&#46;7&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> and &#8722;0&#46;5&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> in the dulaglutide 0&#46;75&#8239;mg and 1&#46;5&#8239;mg groups&#44; respectivelyUrine Alb&#47;Cr reduction with dulaglutide was not statistically different from that with insulin glargine at 52 weeks&#44; but there was a dose-dependent reduction in patients with macroalbuminuria &#40;14&#37; insulin glargine&#44; 23&#37; dulaglutide 0&#46;75&#8239;mg and 43&#37; dulaglutide 1&#46;5&#8239;mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Liraglutida<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">LIRA-RENAL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Renal outcomes&#58; estimated proportional change for eGFR &#40;MDRD&#41; at week 26 ratio from baseline was 0&#46;99 &#40;-1&#37;&#41; for liraglutide and 1&#46;01 &#40;&#43;1&#37;&#41; in the placebo group &#40;NS&#41;&#46; The estimated ratio from week 26 to baseline for Alb&#47;Cr was 0&#46;87 with liraglutide and 1&#46;05 with placebo &#40;NS&#41;&#44; the estimated ratio of treatment was 0&#46;83 &#40;95&#37; CI 0&#46;62&#8722;1&#46;10&#44; p&#8239;&#61;&#8239;0&#46;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information
ISSN: 20132514
Original language: English
DOI:10.1016/j.nefroe.2023.09.003
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