Impact of GLP-1 receptor agonists on major gastrointestinal disorders for type 2 diabetes mellitus: a mixed treatment comparison meta-analysis

Abstract

Aim: We aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM).

Methods: RCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration ≥4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed.

Results: All GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 μg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed.

Conclusions: Our MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance.

Figure 1

Flow diagram of included studies.

Figure 2

Evidence of structure of GI AEs for MTC meta-analysis. 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 RCTs. The width of the lines represents the cumulative number of RCTs for each comparison, and the size of every node is proportional to the number of randomized participants (sample size). CT: conventional treatment. EX5BID: exenatide 5 μg twice daily; EX10BID: exenatide 10 μg twice daily; EX2QW: exenatide 2 mg once weekly; LIR0.6: liraglutide 0.6 mg once daily; LIR1.2: liraglutide 1.2 mg once daily; LIR1.8: liraglutide 1.8 mg once daily.

Figure 3

Plots for ranking probability of different dosing of GLP-1 on GI AEs. EX5BID: exenatide 5 μg twice daily; EX10BID: exenatide 10 μg twice daily; EX2QW: exenatide 2 mg once weekly; LIR0.6: liraglutide 0.6 mg once daily; LIR1.2: liraglutide 1.2 mg once daily; LIR1.8: liraglutide 1.8 mg once daily. Ranking: probability of being the worst treatment, of being the second worst, the third worst and so on, among the 8 comparisons. CT: conventional treatment. SUCRA: surface under the cumulative ranking curve. For rankogram, on the horizontal axis are the eight possible ranks and on the vertical axis the probability of a treatment to achieve each rank. For SUCRA plot, on the horizontal axis is the possible rank of each treatment (from the first best rank to worse according to the outcome). On the vertical axis is the cumulative probability for each treatment to be the best option, among the best two options, among the best three options, and so on.