Chronic kidney disease (CKD) is increasingly recognized as a global public health problem.1 Type 2 diabetes mellitus (DM) is one of the most common cause of CKD.2 Furthermore, DM contribute to the progression of CKD like other risk factors including, dyslipidemia, ischemia, infection, toxins, and autoimmune and inflammatory diseases.3 In this regard, DM holds therapeutic promise as a potential modifiable risk factor for CKD.

Dipeptidyl peptidase (DPP)-4 inhibitors exert beneficial effects on renal morphology and function in rodent diabetes models4–8 and some of these renal protection effects are independent from their glucose-lowering effects.9 There is a broad range of substrates for the DPP-4 enzyme including brain natriuretic peptide, substance P, peptide YY, neuropeptide Y, and stromal cell-derived factor-1 alpha, which are thought to contribute to beneficial renal effects10,11; however, the underlying mechanisms have not yet been fully elucidated. In diabetic mouse models, Takashima et al.’s study suggested that renal stromal cell-derived factor-1 upregulation by DPP-4 inhibition produces multiple protective actions on the diabetic kidney.12

Linagliptin is a selective DPP-4 inhibitor and preliminary clinical data demonstrated that linagliptin had glucose-lowering efficacy and hypothesized potential kidney benefits.13,14 Linagliptin can lower albuminuria on top of the recommended standard treatment in patients with type 2 DM.14 Tsuprykov et al showed that linagliptin delays renal disease progression in a nondiabetic, nonglucose- dependent rodent CKD model.15 DPP-4 inhibition with linagliptin may therefore be a novel approach for the treatment of CKD in general.

Although no dose adjustment is required for patients with renal impairment, clinical study experience with linagliptin in patients with CKD is limited. Most of the studies showing the effects of linagliptin on renal progression were experimental studies on models of diabetic nephropathy.9,11,16 The potential beneficial effects of DPP-4 inhibitors, including linagliptin, in preventing and treating progression of kidney disease in patients with type 2 DM is supported by retrospective analyses of clinical trials.14,17 Therefore, the clinical implications of renoprotective effects of linagliptin in experimental studies are not clear. Our aim was to examine the effect of linagliptin on renal disease progression in only insulin dependent type 2 DM patients with CKD. Our study was the first to investigate effect of linagliptin on renal progression in only advanced stage of CKD patients.

The study population consisted of 164 patients with a mean age of 67.5±8.8 years. Patients were divided into two groups after enrollment (Fig. 1). Because of insufficient clinical data and lost to follow-up, 12 patient were excluded from group 2. In group 1, patients (n=90) received linagliptin plus insulin and in group 2, patients (n=74) received only insulin for treatment of diabetes mellitus. Baseline characteristics of the patients according to the groups were shown in Table 1. The patients in the 2 groups were similar with regard to gender, age, eGFR, renal and other laboratory parameters, and other medications; however, group 1 patients had higher HbA1C levels (p=0.004). No patient died during study period. No patients progressed to end-stage renal disease needing chronic dialysis in both groups. None of the patients experienced pancreatitis, hypersensitivity reaction or adverse events leading to study or drug discontinuation.

Fig. 1.

Flow chart of participants.

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At the end of 12 months follow-up, there was no significant HbA1C change in patients in groups 1 and 2 (Table 2) and HbA1C changes of patients during follow-up were shown in Fig. 2. eGFR significantly increased in group 1 patients (p=0.033), but decreased in group 2 patients (p=0.003). Total insulin dose increased significantly in group 2 (p<0.001), but no significant change was observed in group 1 (p=0.111). While uric acid levels significantly decreased in group 1 (p=0.014), no significant change was observed in group 2 (p=0.179). Proteinuria levels decreased in both groups, but there was no significant change.

Fig. 2.

HbA1C changes of patients during 12 month follow up.

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Logistic regression analysis was used to determine the relative risk of progression of renal disease. Only the variables with a statistically significant association in the simple logistic regression model were included in the multiple logistic regression model. Higher proteinuria, male gender emerged as the significant risk factors associated with renal progression in the multiple logistic regression analysis (OR=1.000, 95% CI: 1.000–1.001, p=0.018 and OR=1.755, 95% CI: 1.097–5.140, p=0.028; respectively) (Table 3). Moreover, the use of linagliptin was found to significantly reduce the risk of renal progression in multipl analysis (OR=0.253, 95% CI: 0.119–0.542, p<0.001).

Development of CKD is one of the major sequelae of type 2 DM.19 Because intensive glucose control per se has not been clearly associated with improvement in renal progression and insulin resistance contributes to the progression of renal disease,20 it is necessary to develop new strategies to improve renal progression. As a new hope in the treatment of diabetic nephropathy, we investigated the effects of linagliptin on renal progression. Patients with advanced CKD have largely been excluded from previous trials of glucose-lowering drugs, resulting in limited available information about use of these drugs in CKD population. This was not the case for the present trial, in which all patients had prevalent CKD. Present study demonstrated that administration of linagliptin markedly slow down renal progression and even improve renal disease in insulin dependent diabetes mellitus patients with CKD. Significantly less insulin was needed in patients using linagliptin. But, linagliptin was not found to be significant in terms of reducing albuminuria. Although patients receiving linagliptin had poorer glucose control at enrollment, a better renal improvement was achieved in patients receiving linagliptin at the end of one year follow up. HbA1c did not significantly change in both groups. The results of present study will provide further guidance on the role of anthyperglycemic therapies in patients with type 2 DM and their impact on the development and progression of diabetic nephropathy.

The risk of renal progression in CKD is determined by many factors. Among these, hyperglycemia and uncontrolled hypertension represent the 2 most frequently studied classic risk factors. On the other hand, strict glycemic control was not associated with any significant changes in renal parameters, such as GFR or urinary albumin excretion, or risk for commencing dialysis in advanced CKD.21–23 These findings suggest that intensive glycemic control may not suffice to prevent renal progression in CKD patients. Similarly, our analysis did not support a direct relationship between renal progression and glucose control. Some other factors could have a stronger impact on renal progression in advanced CKD. Until recently, renal-protective effects of renin-angiotensin system blockers (RASB) were thought to represent a major therapeutic strategy for the management of patients with renal diseases.24 Despite the use of RASB, renal disease continues to progress, and many patients remain proteinuric under treatment. These observations have raised the necessity of an additional strategy in treatment of diabetic patients with CKD. In present study, antihypertensive therapies at enrollment were well balanced between the two treatment groups and significant improvement in renal progression was only detemined in patients using linagliptin at the end of 12 months follow-up. Our results suggest that linagliptin may provide additional benefit in addition to RASB in renal protection.

Compared to other DPP-4 inhibitors, linagliptin is extensively protein bound10 and is mainly eliminated by a biliary route.25 Therefore does not require dose adjustment in patients with CKD.26,27 Although the pharmacokinetics and pharmacodynamics of linagliptin suggests that it will be an ideal agent for patients with CKD, the drug has not adequately been studied in this population.

The mechanism by which linagliptin, which was unable to completely normalize the glucose level, is able to positively modulate kidney function is unknown. Compared to other tissues, the kidneys express the highest level of DPP-4 and it is likely that the presence of DPP-4 in the glomerular endothelium and proximal renal tubules contributes importantly to sodium retention, tubular injury and glomerular injury. Renoprotective effect of linagliptin was probably the result of the inhibition of DPP-4 activity and the enhancement of active glucagon-like peptide-1 (GLP-1) level, which activated GLP-1 receptors, resulting in antioxidative and antiapoptotic effects. The GLP-1 receptor agonist exendin-4 exerts renoprotective effects through its anti-inflammatory action via GLP-1 receptor without glucose control.11 In the Alter et al.’s study, similar effects were achieved by inhibition of DPP-4, which resulted in highly increased plasma GLP-1 levels. In different studies, the renoprotective effect of linagliptin has been associated with various markers, such as osteopontin, cyclophilin A, stromal cell-derived factor-1.6,12,28 Several other experimental studies showed beneficial effects of sitagliptin and vildagliptin on albuminuria and renal function in models of diabetic nephropathy.4,8,11 These preclinical findings raise the possibility of a renal class effect of DPP-4 inhibitors, independent of a glucose-lowering effect. But, it is not possible to extrapolate the results from animal studies into human clinical conditions due to some discrepancies. Prospective, randomized, controlled clinical trials were needed to assess the renal effects of DPP-4 inhibitors in patients with type 2 diabetes. Our study provides very important information in this regard.

Linagliptin significantly reduced albuminuria in Groop et al.’s study.14 Although they found no clinically meaningful change in eGFR during 24 weeks of treatment, our study showed that eGFR improved in patients receiving linagliptin. MARLINA Trial demonstrated the efficacy of linagliptin in improving glycemia in patients with type 2 DM and early diabetic kidney disease, although significant effects on albuminuria were not demonstrated.29 Similarly, our study did not show any effect of linagliptin on proteinuria. These results were unexpected compared to findings in Groop et al.’s study. This difference could have arisen from the limitations of the pooled analysis or differences in the populations.

The number of clinical studies evaluating the renal effects of DPP-4 inhibitors is quite few and the results of these studies were scarce. A randomized study compared sitagliptin with the sulfonylurea in patients with type 2 DM and moderate to severe renal impairment showed that sitagliptin was associated with an increase in UPCR from baseline.30 Ryuge et al.31 found that liraglutide, GLP-1 analog, was not associated with any changes in renal function in patients with diabetic nephropathy. Cooper et al.32 concluded a pooled analysis in patients with type 2 DM and showed that linagliptin was associated with a significant reduction in clinically relevant kidney disease end points (albuminuria, reduction in kidney function). Kim et al demonstrated that DPP-4-inhibitor treatment could ameliorate diabetic nephropathy, by reducing urine albumin excretion and mitigating the reduction of eGFR in T2DM patients.33 But the potential of this drug to improve kidney disease was not clearly established in these studies. Preclinical evidence suggests that the potential renoprotective effects of linagliptin may mostly result from chronic changes in renal physiology rather than acute changes in renal hemodynamics.29,34 Thus, the duration of some studies might not have been sufficient to demonstrate clinically relevant effects on renal function. It is not known whether long-term administration (≥2 years) is required before renal benefits become apparent, as cardiovascular outcomes studies of antihyperglycemic agents. However, our study had a 1-year follow-up and renal functions improved with linagliptin.

CARMELINA trial, a randomized noninferiority trial, evaluated the effects of linagliptin on renal outcomes in patients with type 2 DM and generally more advanced CKD than subjects enrolled in MARLINA trial.35 Unlike our study, CARMELINA trial showed that there was no significant benefit of linagliptin compared with placebo for the incidence of the secondary kidney composite outcome (first occurrence of adjudicated death due to renal failure, end stage renal disease, or sustained 40% or higher decrease in eGFR from baseline). But, present study has important differences from CARMELINA trial. In CARMELINA trial, 38% of study participants did not have low eGFR. But, all patients in our study had prevalent CKD. Another difference was that all of our patients were using insulin. But in the CARMELINA trial, approximately 57% of patients were using insulin. Therefore, our study included a more homogeneous group of CKD patients than the CARMELINA trial. As in our study, notably fewer patients in the linagliptin group initiated or increased doses of preexisting insulin therapy in CARMELINA trial.

Only male gender and proteinuria emerged as significant risk factors for renal progression in our multiple regression analysis at the end of 1-year follow up. Similar to our study, a number of studies suggested that renal disease progression is faster in men and proteinuric patients.36 No significant relationship was found between total insulin dose and renal progression, but the use of linagliptin was found to significantly reduce the risk of renal progression. This result suggests that the improvement in renal function in linagliptin group is not due to the decrease in insulin dose but the use of linagliptin. Possible interactions between renal progression and linagliptin should be investigated in randomized controlled studies.

The rate of progression of CKD shows considerable inter-individual variability and is affected by several factors, such as classic factors (eg, age, gender, ethnicity, family history of CKD, diabetes mellitus, metabolic syndrome, proteinuria and hypertension) or other factors (asymmetric dimethylarginine, fibroblast growth factor 23, calcium–phosphate metabolism, and adiponectin).37,38 Therefore, the major limitation of the present study is that not all factors related to renal progression have been studied. Therefore, this analysis cannot provide conclusive evidence for improved long-term renal outcomes with linagliptin. Another limitation is that UPCR assessments were based on a single urine specimen; this may have reduced the precision of the results because urinary protein excretion shows considerable intraindividual variability.

In conclusion, we have shown that linagliptin in DM patients with CKD was able to improve renal progression without significant effect on proteinuria and glucose control. Despite the availability of many modern therapies for glycemic control, many diabetic patients still progressed to severe renal damage. With regard to treating diabetic nephropathy, blockade of the DPP-4 system may offer a new therapeutic approach.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

No conflicts of interest are declared by any of the authors.