Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence

Abstract

An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti-diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose-lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications.

Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy

“…Experimental studies have shown that incretin-based therapies have valuable effects on diabetic complications, independent of their glucose-lowering abilities, mainly mediated by their antiinflammatory and antioxidative stress properties. 44 However, in a pilot study in patients with type 2 diabetes and mild to moderate DPN, 18 months of treatment with exenatide, compared with glargine, had no effect on neuropathy. 45 In a meta-analysis of data from 10 studies, there was greater remission and lower risks for microvascular and macrovascular disease and mortality in the bariatric surgery group as compared to a nonsurgical treatment group in patients with type 2 diabetes after at least 5 years of follow-up.…”

Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease

“…Activation of GLP-1 receptor stimulates adenylate cyclase to drive the production of cAMP and protein kinase A (PKA) activation, primary effectors of GLP-1-mediated insulin secretion. Findings from small clinical studies as well as large cardiovascular safety trials with GLP-1 receptor agonists suggest its renoprotective effects, mainly in patients with macroalbuminuria [69][70][71]. However, no change was observed in renal hard endpoints, possibly due to low the incidence of renal death.…”

Diabetic Peripheral Neuropathy: Epidemiology, Physiopathology, Diagnosis and Treatment

“…Experimental studies have shown that incretin-based therapies have valuable effects on diabetic complications, independent of their glucose-lowering abilities, mainly mediated by their anti inflammatory and anti oxidative stress properties. 50 However, in a pilot study in patients with type 2 diabetes and mild to moderate DPN, 18 months of treatment with exenatide, compared with glargine, had no effect on neuropathy. 51 In a meta-analysis of data from 10 studies, there was greater remission and lower risks for microvascular and macro vascular disease and mortality in the bariatric surgery group as compared to a non-surgical treatment group in patients with type 2 diabetes after at least 5 years of follow-up.…”