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Systematic Review and Meta-analysis

Renee E. Amori, MD; Joseph Lau, MD; Anastassios G. Pittas, MD, MSc

JAMA. 2007;298:194-206.

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.

Author Affiliations: Division of Endocrinology, Diabetes and Metabolism (Drs Amori and Pittas) and Institute for Clinical Research and Health Policy Studies (Dr Lau), Tufts-New England Medical Center, Boston, Massachusetts.

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