Exenatide as a treatment for diabetes and obesity: Implications for cardiovascular risk reduction

Abstract

Among the challenges in improving outcomes in patients with diabetes is effectively implementing existing pharmacotherapies. However, current therapies for diabetes are often limited by adverse effects such as edema, hypoglycemia, and weight gain. Understanding the role of the incretin effect on the pathophysiology of diabetes has led to the development of new therapeutic agents. Exenatide is the first in a new class of agents termed "incretin mimetics," which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1. In clinical trials, patients with type 2 diabetes treated with exenatide demonstrate sustained improvements in glycemic control, with reductions in fasting and postprandial glucose levels and improvements in glycosylated hemoglobin levels. Improvements in glycemic control with exenatide are coupled with reductions in body weight. Lipid parameters, blood pressure, and C-reactive protein have been shown to improve favorably in patients treated with exenatide. The sustained glycemic improvements and progressive reduction in body weight with exenatide treatment support a shift toward a more favorable cardiovascular risk profile and may have a positive impact on decreasing the risk of associated long-term complications.

Evidence-Based Practice Use of Incretin-Based Therapy in the Natural History of Diabetes

“…41,42 The reported CV effects included reduced total and lowdensity lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglyceride levels; increased high-density lipoprotein cholesterol (HDL-C); reduced high-sensitivity C-reactive protein; lowered systolic and diastolic blood pressure; improved endothelial function in patients with T2DM who had established coronary heart disease (CHD); improved left ventricular (LV) function in patients with acute myocardial infarction (MI); enhanced sodium excretion 43 ; improved cardiomyocyte viability after ischemia-reperfusion injury; improved systolic function; peripheral vasodilation; and reduced vascular inflammation. 41,[44][45][46][47][48][49] Patients with acute MI with or without diabetes who received a 72-hour infusion of GLP-1 added to standard therapy after successful primary angioplasty showed significant improvements in LV ejection fraction (LVEF; from 29 ± 2% to 39 ± 2%; P , 0.01 vs controls). 46 In addition, GLP-1 infusion peri-MI reduced infarct size.…”

Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss

“…However, treatment with insulin and most oral hypoglycaemic agents is often associated with weight gain [13,14], which makes glucose control in type 2 diabetes more difficult. In contrast, metformin has only a minimal effect on body weight [14,15], the dipeptidyl peptidase (DPP‐IV) inhibitors, such as sitagliptin, are considered weight neutral [16] and exenatide has been shown to affect modest weight loss [17].…”

Obesity Epidemic

“…‐ 65 The satiation actions of GLP‐1 stemming from the variety of aforementioned mechanisms have been seen in both animal models and human studies 65 . ‐ 67 These actions are further demonstrated with long‐acting GLP‐1 pharmacotherapy for diabetes mellitus, which results in not only improvement in glucose control but also meaningful weight loss 68 . Several other satiation/satiety signaling molecules, such as glicentin, GLP‐2, glucagon, oxyntomodulin, peptide tyrosine tyrosine, apolipoprotein A‐IV, and enterostatin, have been described and have recently been reviewed 24 …”

“…[65][66][67] These actions are further demonstrated with long-acting GLP-1 pharmacotherapy for diabetes mellitus, which results in not only improvement in glucose control but also meaningful weight loss. 68 Several other satiation/satiety signaling molecules, such as glicentin, GLP-2, glucagon, oxyntomodulin, peptide tyrosine tyrosine, apolipoprotein A-IV, and enterostatin, have been described and have recently been reviewed. 24 Although satiation signals are dependant on the intake of nutrients, "adiposity" signals are directly related to the amount of body fat present in the host organism.…”