Glycemic Control Impact on Body Weight Potential to Reduce Cardiovascular Risk

Abstract

The prevalence and incidence of type 2 diabetes are progressively increasing because of a concomitant rise in the prevalence of obesity. Intentional weight loss in patients with type 2 diabetes has been associated with a 25% reduction in total mortality and a 28% reduction in cardiovascular disease and diabetes mortality (1). Weight gain is not only a risk factor for development of type 2 diabetes, but it is also the undesirable feature of several current antidiabetic treatments such as thiazolidinediones, sulfonylureas, and insulin, with an estimated 2-kg weight gain for every 1% decrease in HbA1c (2,3). Reasons for this include defensive snacking to treat or prevent hypoglycemia, decreased glucosuria, decreased basal metabolic rate, and expansion in adipose tissue and fluid retention. Recently, novel therapeutic agents were developed for the treatment of type 2 diabetes. Among these are the incretin-based therapies, which include glucagon-like peptide (GLP)-1 receptor agonists and inhibitors of the protease dipeptidyl peptidase (DPP)-4. Both classes of drugs use the antidiabetic properties of GLP-1, an incretin hormone that potentiates insulin secretion in a glucose-dependent manner (4). In addition, GLP-1 exerts many beneficial effects on pancreatic islet function, including stimulation of (pro)-insulin biosynthesis, reduction in β-cell apoptosis induced by toxic agents, and suppression of glucagon release from the α-cells, resulting in reduced hepatic glucose output (5). GLP-1 also decreases the rate of gastric emptying, which slows the entry of nutrients into the circulation after meals, reduces appetite, and promotes satiety, leading to weight loss upon chronic exposure (6). However, GLP-1 has a short half-life (∼1–2 min), since it is rapidly degraded through NH2-terminal cleavage by the protease DPP-4; therefore, a continuous infusion would be required to achieve a clinical effect in diabetic patients (7). Two approaches were used to overcome these limitations: 1 ) GLP-1 …