ReviewExploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials
Graphical abstract
Introduction
Diabetes mellitus (DM) is a multifactorial disease [1] associated with serious comorbidities. This condition has recently reached epidemic proportions, as its occurrence has exponentially increased in the general population. Over 400 million people worldwide were estimated to have DM and total mortality increased by 32.1% from 2005 to 2015. Diabetes caused 5 million deaths in 2015, representing the seventh leading cause of death in the United States [[2], [3]]. Moreover, the risk of both microvascular and macrovascular complications has significantly increased, including diabetic kidney disease (DKD), an independent risk factor for coronary artery and peripheral vascular disease. Hyperglycemia triggers many mechanisms resulting in alteration of kidney architecture, oxidative and inflammatory stress, and eventually progressive loss of renal function [[4], [5]].
Strict glucose control through lifestyle changes (i.e., diet, physical exercise, and weight loss) is crucial for slowing DKD progression. However, most type 2 diabetic patients need also medications such as oral hypoglycemic agents and insulin to achieve sustained control of hyperglycemia [6]. Other pharmacological treatments have a positive effect on renal function, retarding the evolution to end-stage renal disease (ESRD) [7]. For instance, renin–angiotensin system (RAS) inhibitors [8] as well as the use of antioxidant agents [9] have demonstrated significant renoprotection, particularly related to their anti-proteinuric activity. Interestingly, the anti-inflammatory and hemorrheologic drug pentoxifylline may also afford renoprotective effects, even though there is still no conclusive evidence supporting its widespread use for improving renal outcomes in subjects with chronic kidney disease (CKD) of various etiology [10]. Some drugs specifically used to treat diabetes, like incretin-based therapies, represent a relatively new tool against the global epidemic of DM. Incretin-based drugs include glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) and inhibitors of dipeptidyl-peptidase-4 (DPP-4). They basically promote a significant decrease in serum glucose that is accompanied by low risk of hypoglycemia and weight loss (with GLP-1RAs) or weight neutrality (with DPP-4 inhibitors) when compared to conventional therapies (metformin monotherapy or combination therapy) [[11], [12]]. However, conflicting results have been obtained with these drugs: some clinical studies, in fact, have shown positive pleiotropic effects in retarding DKD [[13], [14], [15], [16]], whereas others pointed out the possible accumulation of these agents in patients with impaired renal function, thereby exposing them to adverse events [[17], [18], [19], [20], [21], [22]].
In the first part of this review, we describe the incretin system, explaining its main physiological and pathophysiological characteristics and discussing the pleiotropic effects of DPP-4 inhibitor therapy, particularly with regard to renal protection. We then report on pre-clinical results in animal models, followed by evidence on the progression or regression of renal damage following DPP-4 inhibitor therapy obtained by an analysis of clinical studies.
Section snippets
Main pharmacologic features of DPP-4 inhibitors: an overview
Drugs that inhibit DPP-4 activity, commonly referred to as gliptins, represent a relatively new class of non-insulin glucose-lowering agents endowed with great ability to improve glycemic control, with a favorable tolerability and safety profile [[23], [24]]. DPP-4 belongs to a family of proteolytic enzymes that are ubiquitously expressed in several tissues where they exert different functions. In particular, the DPP-4 enzyme exists in two forms, a soluble form circulating in the blood and a
Pleiotropic effects of DPP-4 inhibitors beyond glycemic control
Beyond the pancreas, GLP-1R and DPP-4 are expressed in a wide variety of organs and tissues, such as the central and peripheral nervous system, heart, lung, gastrointestinal tract, eye and kidney, thereby explaining the pleiotropic effects of the incretin system [[43], [44], [45]]. Some of these extra-pancreatic effects might be exploited to prevent or treat diabetes-related complications, independently of the achievement of glycemic control. Accordingly, GLP-1 has been shown to prevent
Effects of DPP-4 inhibitors on kidney function: physiological settings
GLP-1 signaling mediates important renal functions [101], as suggested by the expression of both DPP-4 and GLP-1R in the kidney of several species, including humans [102]. However, controversial data exists on the specific expression pattern of these proteins, based on the specificity and sensitivity of detection methods [[88], [103]]. Few studies suggest their presence in the renal blood vessels, glomerular cells and tubular cells [102]. Studies on rodents show that DPP-4 is extensively
Potential benefits of DPP-4 inhibition in diabetic kidney disease (DKD)
The above preclinical and clinical evidence of gliptin-related renoprotective actions beyond glycemic control might account for the potential ability of DPP-4 inhibition to improve the pathophysiological processes leading to DKD. Although hyperglycemia, increased intra-glomerular pressure, and hyperfiltration are key players in the pathogenesis of DN [101], accruing evidence indicates that alternative mechanisms, including the enhanced production of inflammatory cytokines and ROS, advanced
Clinical evidence of renal benefits or detriments of DPP-4 inhibitors from randomized controlled clinical trials
The clinical impact of DPP-4is on renal outcomes represents a timely and controversial issue, as findings from various clinical studies are somewhat conflicting. In order to catch the most relevant evidence on this topic, we approached the existing literature by using predefined search criteria (see below) in order to find the most relevant randomized controlled trials (RCTs) and meta-analyses dealing with the effects of these agents on renal outcomes in individuals with evidence of renal
Conclusions
DPP-4is are among the most used and effective oral antidiabetic agents. They have many advantages, including high glucose-lowering potency, low risk of hypoglycemia, no association with weight gain, and tolerability by chronic renal failure patients. However, their efficacy for preventing diabetic complications, especially DN, is not well established.
In summary, diabetes management is complex, multi-dimensional and potentially expensive in patients with T2DM and renal insufficiency. Our
Conflict of interest
The Authors declare no conflict of interest related to the present work
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These two Authors equally contributed to the present work