Efficacy and Safety of Incretin Therapy in Type 2 Diabetes: Systematic Review and Meta-Analysis

JAMA. 2007 Jul 11;298(2):194-206. doi: 10.1001/jama.298.2.194.

Abstract

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / therapeutic use
  • Adenosine Deaminase Inhibitors*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Exenatide
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glycoproteins / antagonists & inhibitors*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Liraglutide
  • Nitriles / therapeutic use
  • Peptides / therapeutic use
  • Pyrazines / therapeutic use
  • Pyrrolidines / therapeutic use
  • Sitagliptin Phosphate
  • Triazoles / therapeutic use
  • Venoms / therapeutic use
  • Vildagliptin

Substances

  • Adenosine Deaminase Inhibitors
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycoproteins
  • Hypoglycemic Agents
  • Nitriles
  • Peptides
  • Pyrazines
  • Pyrrolidines
  • Triazoles
  • Venoms
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Exenatide
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Vildagliptin
  • Adamantane
  • Sitagliptin Phosphate