Efficacy and Safety of Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Compared with Exenatide Twice Daily and Sitagliptin in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Background: Long-acting glucagon-like peptide-1 receptor agonists (LA-GLP-1RAs) may deliver additional therapeutic benefits over other available incretin-based therapies. Objective: To pool results of randomized controlled trials comparing the efficacy and safely of maximum dose LA-GLP-1RAs (liraglutide, exenatide once weekly) with exenatide twice daily and dipeptidyl-peptidase-IV inhibitors in patients with type 2 diabetes. Methods: We searched PubMed, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE (all from inception-December 2010), and abstracts presented at the American Diabetes Association Scientific Sessions in 2009 and 2010 to identify English-language reports of studies of at least 24 weeks' duration. The primary endpoint was mean change in hemoglobin A1c (A1C) from baseline to study endpoint. Weighted mean differences or odds ratios and their 95% confidence intervals for each outcome relative to control were calculated as appropriate. Results: A1C was reduced favoring LA-GLP-1RAs compared with exenatide twice daily and sitagliptin (weighted mean difference [WMD] –0.47% [95% CI –0.69 to –0.25] and WMD –0.60% [95% CI –0.75 to –0.45], respectively). Odds ratios greater than 1 favored LA-GLP-1RAs for reaching the A1C target goal of less than 7%. Fasting plasma glucose (FPG) was reduced and favored the LA-GLP-1RA–based regimens. Exenatide demonstrated significantly greater reductions in postprandial glucose (PPG) after the morning and evening meals, compared with LA-GLP-1RAs. Body weight was reduced similarly between LA-GLP-1RAs and exenatide, but favored LA-GLP-1RAs in the sitagliptin comparator trials. LA-GLP-1RA therapy was not associated with severe hypoglycemia or acute pancreatitis. Compared with exenatide twice daily, vomiting was reduced significantly with LA-GLP-1RAs (OR 0.55; 95% CI 0.34 to 0.89); there was a trend toward decreased nausea (OR 0.58; 95% CI 0.32 to 1.06) and no difference in the incidence of diarrhea (OR 1.03; 95% CI 0.67 to 1.58). Conclusions: Compared with other incretin-based therapies, LA-GLP-1RAs produce greater improvement in A1C and FPG. They provide lesser effect on PPG, similar reduction in body weight, and result in a potentially favorable adverse event profile compared with exenatide twice daily.