Glycemic Control Impact on Body Weight Potential to Reduce Cardiovascular Risk: Glucagon-like peptide 1 agonists

GIORGIO SESTI - T 2 diabetes are progressively increashe prevalence and incidence of type ing 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 incretinbased therapies, which include glucagonlike 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 b-cell apoptosis induced by toxic agents, and suppression of glucagon release from the a-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 (;12 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 receptor agonists (incretin mimetics) with longer half-life and 2) DPP-4 inhibitors (incretin enhancers) blocking GLP-1 degradation and thus preserving the endogenous secreted hormone. Among these, sitagliptin and saxagliptin were already approved for treatment by the U.S. Food and Drug Administration and European Medicines Agency (EMEA), and vildagliptin was approved for treatment by EMEA. At variance with DPP-4 inhibitors, GLP-1 receptor agonists provide a pharmacological dose of a GLP-1 mimetic, designed to resist degradation. Among these, exenatide and liraglutide have been approved for treatment by the U.S. Food and Drug Administration and EMEA. Although GLP-1 receptor agonists and DPP-4 inhibitors are both related to antidiabetic properties of incretins, they represent different approaches to type 2 diabetes therapy. In this article, we will discuss their clinical value, with special c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c Exenatide Exenatide was the first GLP-1 receptor agonist approved by regulatory agencies for human clinical use. Exenatide is a synthetic form of the naturally occurring peptide found in the saliva of the Gila monster (Heloderma suspectum). It has 53% amino acid homology to human GLP-1 and is a potent agonist of human GLP-1 receptor. Because exenatide contains a glycine residue at position 2, it is less susceptible to DPP-4 degradation than the native molecule and is suitable for twice-daily dosing. In a 24-week study carried out in 232 antidiabetic drug-naive patients with type 2 diabetes, twice-daily exenatide monotherapy was associated with a significant reduction in glycosylated hemoglobin (HbA1c) (8). At the end of the study, the changes from baseline HbA1c were 20.7% in the exenatide 5-mg group (P = 0.003) and 20.9% (0.1%) in the exenatide 10-mg group (P , 0.001), compared with 20.2% with placebo. The improvement in HbA1c was associated with a significant decrease in body weight in both groups treated with exenatide. Weight changes from baseline were 22.8 kg in the exenatide 5-mg group (P = 0.004) and 23.1 kg in the exenatide 10-mg group (P , 0.001) compared with 21.4 kg with placebo. Mean systolic blood pressure (SBP) decreased from baseline by 23.7 mmHg in both 5- and 10-mg exenatide groups (both P = 0.037) compared with 20.3 mmHg with placebo. Mean diastolic blood pressure (DBP) decreased from baseline by 20.8 mmHg in the exenatide 5-mg group (P = NS) and 22.3 mmHg in the exenatide 10-mg group (P = 0.046) compared with 20.3 mmHg with placebo. Changes in fasting total cholesterol, HDL cholesterol, and LDL cholesterol from baseline were not significantly different between the exenatide 5- and 10-mg groups and the placebo group. Three phase III clinical trials, each of 30 weeks duration, have examined the effect of exenatide on glycemic control in patients inadequately controlled with maximally effective doses of sulfonylurea monotherapy, metformin monotherapy, or sulfonylurea + metformin combination therapy (911). In patients on background metformin monotherapy, the reduction in HbA1c from baseline was 20.78, 20.40, and 20.08% for patients treated with 10 mg exenatide, 5 mg exenatide, and placebo, respectively (P , 0.002) (9). During the study, patients treated with exenatide exhibited progressive weight loss regardless of baseline BMI. The reduction in body weight from baseline was 22.8 kg (P , 0.001 vs. placebo), 21.6 kg (P , 0.05 vs. placebo), and 20.3 kg for patients treated with 10 mg exenatide, 5 mg exenatide, and placebo, respectively. No changes in plasma lipids, heart rate, blood pressure, or electrocardiogram variables were observed between treatment groups. In patients on background sulfonylurea monotherapy, the reduction in HbA1c from baseline was 20.86, 20.46, and 20.12% for patients treated with 10 mg exenatide, 5 mg exenatide, and placebo, respectively (P , 0.001) (10). Patients treated with 10 mg exenatide showed a progressive weight reduction with an end-of-study loss of 21.6 kg from baseline (P , 0.05 vs. placebo), whereas subjects treated with 5 mg exenatide had an end-of-study weight loss of 20.9 kg from baseline (NS vs. placebo), and subjects in the placebo arm had an end-of-study weight loss of 20.6 kg from baseline. There were small reductions in LDL (P , 0.05 for pair-wise comparisons) and apolipoprotein B (P , 0.05 for pairwise comparisons) concentrations in the exenatide groups compared with placebo. However, other lipid parameters (total cholesterol, triglycerides, and LDL-toHDL ratios) did not differ significantly among treatment groups. In patients on background sulfonylurea + metformin combination therapy, the reduction in HbA1c from baseline was 20.80, 20.60, and 0.2% for patients treated with 10 mg exenatide, 5 mg exenatide, and placebo, respectively (P , 0.001 vs. placebo) (11). Subjects treated with exenatide exhibited progressive weight reduction ove (...truncated)