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ObjectiveThis study aims to evaluate and compare the gastrointestinal adverse effects associated with different GLP-1 receptor agonists (GLP-1RAs) and multi-target analogs in patients with type 2 diabetes mellitus (T2DM) using a Bayesian network meta-analysis.MethodsA systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients. Inclusion criteria included adult patients with confirmed T2DM receiving any GLP-1RA, with the outcomes focused on gastrointestinal adverse events such as nausea, vomiting, diarrhea, constipation, dyspepsia, and reduced appetite. Bayesian network meta-analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the comparison of gastrointestinal side effects among different GLP-1RAs.ResultsA total of 48 RCTs involving 27,729 participants were included in the analysis. The overall incidence of gastrointestinal adverse events was 11.66%, with nausea being the most frequent (21.49%) and reduced appetite the least frequent (5.49%). Tirzepatide had the highest risk of inducing nausea and diarrhea, while dulaglutide and lixisenatide had the lowest risks. Exenatide exhibited the highest incidence of vomiting, while dulaglutide showed a lower risk. Semaglutide demonstrated a significantly higher risk of diarrhea compared to other GLP-1RAs.ConclusionThis study highlights significant differences in the gastrointestinal adverse event profiles of various GLP-1RAs. Tirzepatide exhibited the highest risk of gastrointestinal side effects, whereas dulaglutide and exenatide showed relatively better tolerability. These findings provide valuable insights for clinicians to make informed treatment decisions, emphasizing the importance of individualized therapy based on patient tolerance.Systematic review registrationCRD42024592308.

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BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used therapies for cardiovascular risk reduction in type 2 diabetes (T2D). With the emergence of the SURPASS-CVOT trial, tirzepatide (a dual GIP/GLP-1 receptor agonist) has entered the therapeutic landscape; however, its comparative effect on cardiovascular outcomes compared to placebo and individual GLP-1RAs remains undefined.MethodsWe conducted a systematic review and frequentist network meta-analysis (NMA) of RCTs enrolling adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular (CV) risk. Eligible RCTs evaluated tirzepatide or GLP-1RAs and reported major adverse cardiovascular events (MACE), CV mortality, all-cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke. A class-level NMA was conducted to estimate the incremental benefit of tirzepatide and GLP-1RAs over placebo, and an agent-level NMA was conducted to explore differences between tirzepatide and individual GLP-1RA agents. Subgroup analyses, including established cardiovascular disease populations, and leave-one-out sensitivity analyses were performed.ResultsEleven trials met inclusion criteria (10 GLP-1RA trials and 1 tirzepatide trial [SURPASS-CVOT]). In the class-level analysis, tirzepatide significantly reduced MACE (HR 0.79, 95% CI 0.69-0.91), CV mortality (HR 0.77, 95% CI 0.66-0.90), all-cause mortality (HR 0.74, 95% CI 0.65-0.83), non-fatal MI (HR 0.77, 95% CI 0.61-0.97), and non-fatal stroke (HR 0.79, 95% CI 0.64-0.97) compared to placebo. Formal statistical comparisons between tirzepatide and the GLP-1RA class could not be performed within the constraints of the NMA; however, point estimates across outcomes numerically favored tirzepatide compared with placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo (HR 0.81, 95% CI 0.70-0.94) and lixisenatide (HR 0.79, 95% CI 0.65-0.97). Subgroup and sensitivity analyses did not substantially change point estimates.ConclusionAmong adults with T2D and established ASCVD or high CV risk, class-level analysis demonstrated that tirzepatide significantly reduced the risk of cardiovascular events compared to placebo; at the agent-level, tirzepatide demonstrated comparable efficacy to individual GLP-1RAs. These findings suggest that tirzepatide provides cardiovascular benefit at least comparable to established GLP-1RAs, supporting its emerging role in cardiovascular risk reduction in T2D.

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IntroductionIncreased risk of suicidality has been reported in association with glucagon-like peptide receptor agonist (GLP-1 RA) prescription. Herein, we conducted a comprehensive review evaluating reports of GLP-1 RA prescription and suicidality.MethodsRelevant articles were retrieved from OVID (Medline, EMBASE, AMED, PsycINFO, JBI EBP Database), PubMed, and Web of Science from inception to May 20, 2024. Primary research examining the association between GLP-1 RAs (i.e., dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, tirzepatide) and suicidality were included for analysis.ResultsOur findings indicate liraglutide (reported odds ratio [ROR] = 3.26, 95% CI = 2.53, 4.22) and semaglutide (ROR = 1.73; 95% CI = 0.30, 0.80) are significantly associated with a greater odds ratio of reported suicidal ideation. Similarly, tirzepatide was associated with greater odds of reported suicidal ideation; however, this was nonsignificant (ROR = 1.49; 95% CI = -0.41, 1.21). Similarly, semaglutide (ROR = 8.81; 95% CI = 3.69, 21.04) and liraglutide (ROR = 3.74; 95% CI = 1.23, 11.38) are also associated with a greater odds ratio of reported suicidal depression. No significant association between other GLP-1 RAs and suicidality was observed.DiscussionReports of aspects of suicidality and exposure to select GLP-1 RAs exist; notwithstanding, no causality between GLP-1 RA exposure and suicidality is apparent.

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