Gastrointestinal adverse events of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a systematic review and network meta-analysis

Abstract

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a new class of drugs used in the treatment of type 2 diabetes mellitus (T2DM). Gastrointestinal (GI) adverse events (AEs) are the most frequently reported treatment-related AEs for GLP-1 RAs. We aim to evaluate the effect of GLP-1 RAs on the incidence of GI AEs of T2DM.

Materials and methods: The overview of the GI events of GLP-1 RAs has been performed on relevant publications through the literature search, such as MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov The manufacturer was contacted regarding unpublished data. We analyzed direct and indirect comparisons of different treatments using Bayesian network meta-analysis.

Results: Taspoglutide 30 mg once weekly (TAS30QW) and lixisenatide 30 μg twice daily (LIX30BID) were ranked the top two drugs in terms of GI AEs versus placebo. The odds ratios of nausea and vomiting for TAS30QW were 11.8 (95% confidence interval [CI], 2.89, 46.9) and 51.7 (95% CI, 7.07, 415), respectively, and that of diarrhea was 4.93 (95% CI, 1.75, 14.7) for LIX30BID.

Conclusions: Our study found all GLP-1 RA dose regimens significantly increased the incidence of GI AEs, compared with placebo or conventional treatment. The occurrence of GI AEs was different with diverse dose regimens of GLP-1 RAs. TAS30QW had the maximum probability to occur nausea and vomiting, whereas LIX30BID had the maximum probability to cause development of diarrhea versus other treatments.

FIG. 1.

Flow diagram of the included studies. GLP-1, glucagon-like peptide-1; RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus.

FIG. 2.

Evidence structure of eligible comparisons of nausea. The numbers along the link lines indicate the number of trials or pairs of trial arms. Lines connect the interventions that have been studied in head-to-head (direct) comparisons in the eligible randomized controlled trials. The width of the lines represents the cumulative number of randomized controlled trials for each pairwise comparison, and the size of every node is proportional to the number of randomized participants (sample size). Albi30Q2W, albiglutide 30 mg once biweekly; Albi30QW, albiglutide 30 mg once weekly; Albi50Q2W, albiglutide 50 mg once biweekly; Albi50QM, albiglutide 50 mg once monthly; EX10BID, exenatide 10 μg twice daily; EX2QW, exenatide 2 mg once weekly; EX5BID, exenatide 5 μg twice daily; LIR0.6QD, liraglutide 0.6 mg once daily; LIR1.2QD, liraglutide 1.2 mg once daily; LIR1.8QD, liraglutide 1.8 mg once daily; LIX20BID, lixisenatide 20 μg twice daily; LIX20QD, lixisenatide 20 μg once daily; LIX30BID, lixisenatide 30 μg twice daily; LIX30QD, lixisenatide 30 μg once daily; LY0.5/1.0, LY2189265 0.5 mg once weekly for 4 weeks, then 1.0 mg once weekly for 12 weeks; LY1.0/1.0, 1.0 mg once weekly for 16 weeks; LY1.0/2.0, 1.0 mg once weekly for 4 weeks, then 2.0 mg once weekly for 12 weeks; Met, metformin; SU, sulfonylureas; TAS20Q2W, taspoglutide 20 mg once biweekly; TAS20QW, taspoglutide 20 mg once weekly; TAS30QW, taspoglutide 30 mg once weekly; TZD, thiazolidinedione. Color images available online at www.liebertonline.com/dia

FIG. 3.

Network meta-analysis about the impact of glucagon-like peptide-1 receptor agonists on gastrointestinal adverse events versus placebo: (A) nausea, (B) vomiting, and (C) diarrhea. Albi30Q2W, albiglutide 30 mg once biweekly; Albi30QW, albiglutide 30 mg once weekly; Albi50Q2W, albiglutide 50 mg once biweekly; Albi50QM, albiglutide 50 mg once monthly; CI, confidence interval; EX10BID, exenatide 10 μg twice daily; EX2QW, exenatide 2 mg once weekly; EX5BID, exenatide 5 μg twice daily; LIR0.6QD, liraglutide 0.6 mg once daily; LIR1.2QD, liraglutide 1.2 mg once daily; LIR1.8QD, liraglutide 1.8 mg once daily; LIX20BID, lixisenatide 20 μg twice daily; LIX20QD, lixisenatide 20 μg once daily; LIX30BID, lixisenatide 30 μg twice daily; LIX30QD, lixisenatide 30 μg once daily; LY0.5/1.0, LY2189265 0.5 mg once weekly for 4 weeks, then 1.0 mg once weekly for 12 weeks; LY1.0/1.0, 1.0 mg once weekly for 16 weeks; LY1.0/2.0, 1.0 mg once weekly for 4 weeks, then 2.0 mg once weekly for 12 weeks; Met, metformin; OR, odds ratio; SU, sulfonylureas; TAS20Q2W, taspoglutide 20 mg once biweekly; TAS20QW, taspoglutide 20 mg once weekly; TAS30QW, taspoglutide 30 mg once weekly; TZD, thiazolidinedione.