Renoprotection Provided by Dipeptidyl Peptidase-4 Inhibitors in Combination with Angiotensin Receptor Blockers in Patients with Type 2 Diabetic Nephropathy

Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

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Dipeptidyl peptidase-4 inhibitors in type 2 diabetic elderly patient

Gériatrie et Psychologie Neuropsychiatrie du Viellissement ◽

10.1684/pnv.2011.0281 ◽

2011 ◽

Vol 9 (2) ◽

pp. 157-162

Author(s):

Jean Doucet ◽

Bernard Bauduceau ◽

Jean-Frédéric Blicklé

Keyword(s):

Elderly Patient ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Type 2 Diabetic

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Dipeptidyl Peptidase‐4 Inhibitors Attenuate Endothelial Function as Evaluated by Flow‐Mediated Vasodilatation in Type 2 Diabetic Patients

Journal of the American Heart Association ◽

10.1161/jaha.112.003277 ◽

2013 ◽

Vol 2 (1) ◽

Cited By ~ 86

Author(s):

Makoto Ayaori ◽

Naotsugu Iwakami ◽

Harumi Uto‐Kondo ◽

Hiroki Sato ◽

Makoto Sasaki ◽

...

Keyword(s):

Endothelial Function ◽

Dipeptidyl Peptidase ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Type 2 Diabetic

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ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study

Vascular Medicine ◽

10.1177/1358836x0501000114 ◽

2005 ◽

Vol 10 (1_suppl) ◽

pp. S97-S102 ◽

Cited By ~ 14

Author(s):

Rainer H Böger ◽

Edzard Schwedhelm ◽

Renke Maas ◽

Sabine Quispe-Bravo ◽

Cord Skamira

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Vascular Function ◽

Angiotensin Receptor Blockers ◽

Angiotensin Receptor ◽

Endogenous Inhibitor ◽

Receptor Blockers ◽

Circulating Levels

The renin angiotensin system has been shown to be involved in the patho genesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mel litus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium- mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in com parison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the poten tial pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2α (8-iso-PGF 2α). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF 2α has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dys functional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.

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