Gastrointestinal adverse events with insulin glargine/lixisenatide fixed‐ratio combination versus GLP‐1 RAs in people with type 2 diabetes mellitus: a network meta‐analysis

Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long-term persistence is suboptimal, and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed-ratio combination GLP-1 RA/insulin therapies may improve GLP-1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP-1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira. Materials and methods The PICO framework was used to identify studies from MEDLINE, Embase, and CENTRAL searches using a proprietary, web-based, standardised tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta-analysis (NMA), using fixed and random effects for each recommended dose (treatment-specific NMA) and class (drug-class NMA). Results Treatment-specific NMA included 17 trials (n=9030; 3665 event-weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 mcg twice-daily (rate ratio: 0.32; 95% credible interval: 0.15, 0.66), once-daily lixisenatide 20 mcg (0.35; 0.24, 0.50), and liraglutide 1.8 mg once-daily (0.48; 0.23, 0.98). Rates were numerically, but not statistically, lower versus once-weekly semaglutide 1 mg (0.60; 0.30, 1.23) and dulaglutide 1.5 mg (0.60; 0.29, 1.26), and numerically, but not statistically, higher versus once-weekly exenatide (1.91; 0.91, 4.03). Sensitivity analysis results were similar. In a naive pooled analysis, vomiting was lower with iGlarLixi versus other GLP-1 RAs. Conclusions During the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single-agent GLP-1 RAs. Enhanced gastrointestinal tolerability with fixed-ratio combinations may favour treatment persistence. This article is protected by copyright. All rights reserved.