Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.

CONTEXT: Pharmacotherapies that augment the incretin pathway have recently become available, but their role in the management of type 2 diabetes is not well defined. OBJECTIVE: To assess the efficacy and safety of incretin-based therapy in adults with type 2 diabetes based on randomized controlled trials published in peer-reviewed journals or as abstracts. DATA SOURCES: We searched MEDLINE (1966-May 20, 2007) and the Cochrane Central Register of Controlled Trials (second quarter, 2007) for English-language randomized controlled trials involving an incretin mimetic (glucagonlike peptide 1 GLP-1 analogue) or enhancer (dipeptidyl peptidase 4 DPP4 inhibitor). We also searched prescribing information, relevant Web sites, reference lists and citation sections of recovered articles, and abstracts presented at recent conferences. STUDY SELECTION: Randomized controlled trials were selected if they were at least 12 weeks in duration, compared incretin therapy with placebo or other diabetes medication, and reported hemoglobin A (1c) data in nonpregnant adults with type 2 diabetes. DATA EXTRACTION: Two reviewers independently assessed trials for inclusion and extracted data. Differences were resolved by consensus. Meta-analyses were conducted for several efficacy and safety outcomes. RESULTS: Of 355 potentially relevant articles identified, 51 were retrieved for detailed evaluation and 29 met the inclusion criteria. Incretins lowered hemoglobin A (1c) compared with placebo (weighted mean difference, -0. 97% 95% confidence interval CI, -1. 13% to -0. 81% for GLP-1 analogues and -0. 74% 95% CI, -0. 85% to -0. 62% for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. Glucagonlike peptide 1 analogues resulted in weight loss (1. 4 kg and 4. 8 kg vs placebo and insulin, respectively) while DPP4 inhibitors were weight neutral. Glucagonlike peptide 1 analogues had more gastrointestinal side effects (risk ratio, 2. 9 95% CI, 2. 0-4. 2 for nausea and 3. 2 95% CI, 2. 5-4. 4 for vomiting). Dipeptidyl peptidase 4 inhibitors had an increased risk of infection (risk ratio, 1. 2 95% CI, 1. 0-1. 4 for nasopharyngitis and 1. 5 95% CI, 1. 0-2. 2 for urinary tract infection) and headache (risk ratio, 1. 4 95% CI, 1. 1-1. 7). All but 3 trials had a 30-week or shorter duration; thus, long-term efficacy and safety could not be evaluated. CONCLUSIONS: Incretin therapy offers an alternative option to currently available hypoglycemic agents for nonpregnant adults with type 2 diabetes, with modest efficacy and a favorable weight-change profile. Careful postmarketing surveillance for adverse effects, especially among the DPP4 inhibitors, and continued evaluation in longer-term studies and in clinical practice are required to determine the role of this new class among current pharmacotherapies for type 2 diabetes.