( JUL 6) University of Rochester School of Medicine and Dentistry: DPP-4 inhibitors: what may be the clinical differentiators? Researchers detail in ‘DPP Clinical and experimental evidence with the DPP-4 inhibitors .. Gerich, J. () DPP-4 inhibitors: What may be the clinical differentiators?. (1) they were RCTs comparing DPP-4 inhibitors plus metformin as initial combination Gerich J. Dpp-4 inhibitors: what may be the clinical differentiators?.
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Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria
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Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low differenfiators of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions.
One of the recently emerged interesting features of dipeptidyl peptidase-4 DPP-4 inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications.
Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Increasing prevalence of diabetes worldwide, leading to a steep rise of patients with chronic complications, represents one of the major health problems of the current medicine [ 1 ]. Since both micro- and macrovascular complications contribute in the increasing morbidity and mortality of patients with type 2 diabetes, novel antidiabetic therapies are intensively studied with respect to their possible beneficial effects on the long-term complications beyond their glucose-lowering properties [ 2 ].
Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain [ 3 ]. These therapeutics either increase concentrations of endogenous glucagon-like peptide-1 GLP-1 by the inhibition of its degradation dipeptidyl peptidase-4 inhibitors or directly stimulate GLP-1 receptor GLP-1 receptor agonists [ 4 ].
Stimulation of GLP-1 receptor in turn increases insulin secretion and suppresses excessive glucagon release leading to improved glucose control. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculoprotective actions and also numerous others pleiotropic positive effects such as neuroprotection and others [ 5 ].
One of the interesting possibilities that have emerged from experimental studies is the protective effect of DPP-4 inhibitors on the diabetic kidney disease [ 6 ]. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria. We will discuss potential mechanism of these effects, the differences between various DPP-4 inhibitors, and future perspectives of its use in patients with diabetic kidney disease.
We performed a primary Medline search using combinations of keywords: Due to a limited number of results, we performed secondary searches using combinations of additional keywords like diabetic kidney disease and nephropathy. CKD stage 1 is characterized by normal GFR and urine findings mostly albuminuria or structural abnormalities of the kidney.
Stages 2—5 are defined by specific values of GFR [ 7 ]. Patients with diabetic kidney disease, even in stage 1, have a markedly increased risk of cardiovascular complications and hypoglycemia compared to patients without DKD [ 89 ]. Numerous studies have shown that the risk of diabetic kidney disease is tightly linked to poor glucose control in both type 1 and type 2 diabetes [ 1011 ]. The adverse effects of hyperglycemia are generally mediated through diverse metabolic pathways including increased reactive oxygen species formation, excessive production of advanced glycation end products AGEsand the activation of polyol, protein kinase C PKCand hexosamine pathways, respectively [ 12 ].
Activation of these pathways leads to a complex dysregulation of various effector molecules resulting in cellular damage and dysfunction [ 12 ]. Experimental studies have shown that some of these pathophysiological mechanisms are potentially modifiable by DPP-4 inhibition [ 6 ].
Additional important players contributing to kidney damage especially in patients with type 2 diabetes include arterial hypertension and dyslipidemia that commonly cluster with glucose metabolism disturbances in these patients [ 15 ].
The presence of microalbuminuria represents an important early sign of kidney damage in patients with diabetes [ 16 ]. Associations between microalbuminuria, increased risk of cardiovascular complications, and progressive renal impairment are well described but the underlying pathophysiological mechanisms are only partially understood [ 16 ]. At the time of overt microalbuminuria, established glomerular structural changes are present in diabetic kidney [ 18 ]. Studies have shown that local changes in glomerular morphology and the extent of matrix accumulation in glomeruli and interstitium correlate with extent of albuminuria [ 19 ].
Glomerular filtration barrier is characterized by three-layer structure: Endothelial glycocalyx forms a barrier to protein permeability in both systemic and glomerular capillaries. The total systemic glycocalyx volume is reduced by acute hyperglycemia in humans [ 20 ].
Podocyte loss is one of the first changes contributing to increased glomerular permeability for albumin. Nevertheless, albuminuria may also occur in the complete absence of structural changes of podocytes [ 2122 ]. Its levels correlate with the degree of mesangial expansion, interstitial fibrosis, and renal dysfunction, but not with the extent of microalbuminuria [ 25 ]. Both of these cytokines are upregulated in patients with type 2 diabetes [ 2627 ].
Albuminuria also positively correlates with markers of endothelial dysfunction and chronic low-grade inflammation including C-reactive protein [ 2829 ].
DPP-4 inhibitors: what may be the clinical differentiators?
DPP-4 inhibitors are known to exert also GLP-1 independent effects as DPP-4 cleaves a wide range of other substrates such as neuropeptides, hormones, cytokines, and chemokines [ 630 ].
DPP-4 is also bound on the surface of many cell types including kidney proximal tubular cells and endothelial cells [ 31 ]. Microvesicle-bound DPP-4 secreted from tubular epithelial cells is found in urine and may be an early marker of renal damage before the onset of albuminuria [ 31 ].
Upregulation of DPP-4 expression in renal glomeruli occurs during inflammation and usually accompanies the development of diabetes-induced glomerulosclerosis [ 6 ]. In addition to pancreas, GLP-1 receptor GLP-1R is expressed in other numerous tissues including glomerular endothelial cells, mesangial cells, podocytes and also proximal tubular cells. Its expression was decreased in diabetic compared with nondiabetic mice [ 32 ]. Nevertheless, their exact role and importance in renoprotective effects of DPP-4 inhibitors has not yet been tested [ 38 ].
Preclinical data suggesting nephroprotective effects of DPP-4 inhibitors are available for sitagliptin [ 46 ], vildagliptin [ 47 ], and linagliptin [ 48 ]. The study with sitagliptin administration assessed its effects on metabolic profile and renal lesions in a rat model of type 2 diabetic nephropathy [ 46 ].
Diabetic and controls rats were treated with sitagliptin or vehicle for 6 weeks. Sitagliptin treatment of diabetic rats lowered glycemia and ameliorated glomerular, tubulointerstitial, and vascular lesions. It also reduced kidney lipid peroxidation as measured by decreased malondialdehyde content. The study with vildagliptin was performed on rats with streptozotocin-induced diabetes.
In this insulinopenic model, vildagliptin increased GLP-1 levels but did not affect blood glucose levels [ 47 ]. Light and electron microscopies of renal tissue revealed that vildagliptin treatment dose dependently inhibited interstitial expansion, glomerulosclerosis, and thickening of the glomerular basement membrane [ 47 ]. Expression of GLP-1R was demonstrated by immunohistochemical analysis in both glomeruli and tubules. The week duration of hyperglycemia in untreated diabetic rats resulted in decrease of GLP-1R staining [ 47 ].
This decrease was prevented by treatment with vildagliptin. Streptozotocin-induced diabetes was used also in an experimental study with linagliptin [ 48 ].
Diabetes was induced in endothelial nitric oxide synthase eNOS knockout mice which were used as an experimental model of nephropathy [ 48 ]. The effect of linagliptin on the progression of nephropathy alone and in combination with the angiotensin receptor blocker telmisartan was tested.
After 12 weeks of administration, linagliptin or telmisartan had no effect on glycemic control, while telmisartan reduced systolic blood pressure by 5. Combined treatment with linagliptin and telmisartan significantly reduced albuminuria compared with untreated diabetic mice, while monotherapy with either telmisartan or linagliptin had no effect. In this study, vildagliptin was administered intravenously 15 minutes before surgery, and animals were sacrificed after 2, 12, and 48 hours of reperfusion.
These data suggest that the nephroprotection by DPP-4 inhibition was mediated by antiapoptotic, anti-inflammatory, and antioxidative changes. In addition to experimental data for DPP-4 inhibitors, animal studies suggest also possible nephroprotective effects of GLP-1R agonists. Both exendin-4 [ 35 ] and liraglutide [ 50 ] ameliorated albuminuria decreased oxidative stress and inflammatory cytokines in a rat model of diabetic nephropathy.
In the exendin-4 study, glomerular macrophage infiltration was prevented by suppression of ICAM-1 production on glomerular endothelial cells and by inhibition of proinflammatory cytokine release from macrophages.
Many diabetic patients develop diabetic kidney disease despite intensive efforts to achieve optimal control of blood pressure and glycemia. In addition to being a marker of renal damage, albuminuria has emerged as a predictive marker of increased risk of cardiovascular disease [ 51 ]. According to current guidelines, the primary intervention in patients with detected albuminuria is the blockade of renin-angiotensin-aldosterone system RAAS with an angiotensin-converting enzyme inhibitor ACEi or angiotensin II receptor blocker ARB [ 52 ].
Proven additive effect of any antihyperglycemic agent on albuminuria lowering would be therefore of a high interest. First study indicating possible beneficial effect of a DPP-4 inhibitor on the kidney in Man was a small observational study with sitagliptin [ 53 ]. Sitagliptin significantly lowered HbA1c and systolic and diastolic blood pressure.
After 6 months of sitagliptin treatment, albuminuria measured by urinary albumin creatinine ratio UACR significantly decreased both in the patients with relatively modest microalbuminuria and the patients with more pronounced microalbuminuria at baseline.
Albuminuria was also one of secondary endpoints in the study of Harashima et al. The primary endpoint was a change in HbA1c. After 52 weeks sitagliptin treatment reduced HbA1c by 0. Ina comprehensive analysis of randomized, double-blind, placebo-controlled trials duration 24—52 weeks with linagliptin was published [ 55 ].
The analysis included studies with both linagliptin monotherapy or add-on therapy to various glucose-lowering agents. The analysis included patients treated with linagliptin and 59 patients on placebo, respectively.
The endpoint of the analysis was the percentage change in geometric mean of UACR after 24 weeks of treatment compared to baseline values. Interestingly, the degree of microalbuminuria reduction did not correlate with the magnitude of change in HbA1c suggesting that the effects may have been independent of improvement in glycemic control.
In a recently published meta-analysis of 13 linagliptin trials including patients focused on composite renal outcome, the hazard ratio of 0. The risk ratios for individual renal endpoints were 0. Although none of the studies was primarily designed to test the effect of linagliptin on microalbuminuria and renal function, they collectively suggest its possible nephroprotective effects.
Furthermore, two small studies with sitagliptin and the experimental studies described previously open the possibility that nephroprotection might be a class effect of DPP-4 inhibition. On the other hand, DPP-4 inhibitors have different pharmacokinetics, and their nonglucose lowering effects may vary in man due to different concentrations in various organs and due to distinct substrate selectivity of binding to DPP-4 enzyme [ 57 ].
In general, all long-term studies with antidiabetic agents suggest that good glucose control can prevent or delay the development of microvascular complications in both type 1 and type 2 diabetes [ 1011 ]. In short-term studies, the specific influence of different antidiabetic medications on microalbuminuria might differ substantially.
In a week, open-label, cardiac safety study comparing rosiglitazone to glyburide, only the rosiglitazone group showed a significant reduction of albuminuria from baseline [ 59 ]. For patients with microalbuminuria at baseline, reductions in UACR did not correlate with reductions in HbA1c or fasting plasma glucose but showed strong correlation with changes in mean 24 h systolic and diastolic blood pressures in rosiglitazone-treated patients.
Another small randomized study comparing pioglitazone versus metformin in patients with baseline albuminuria treated with RAAS blockade showed similar effects [ 60 ]. These results suggest that metformin does not share the albuminuria-lowering potential of thiazolidinediones and incretin-based therapies [ 60 ].
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Collectively, these data suggest a possibility of specific and glucose-lowering independent effects of incretin-based therapies and thiazolidinediones on inhibitros renal damage in patients with diabetes. Nevertheless, larger trials designed primary on testing renal outcomes are necessary to confirm this interesting possibility.
The results of published preclinical and clinical studies suggest that DPP-4 inhibitors may have a potential to lower albuminuria and to also possess other more complex nephroprotective properties. Mat mechanisms underlying these effects include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction in the kidney. At the moment, the data are too scarce and incomplete to make definite conclusions with respect to DPP-4 inhibitors induced nephroprotection.
Ongoing studies, such as the MARLINA study comparing, prospectively, the effects of linagliptin to placebo on albuminuria may shed some light in this field [ 61 ]. Furthermore, numerous ongoing long-term cardiovascular trials with DPP-4 inhibitors can bring novel crucial information about relationships among glucose control and macrovascular and microvascular complications and further elucidate the role of albuminuria in these processes.