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however, it is not included in the NMA.33 Liraglutide, though widely studied, is less potent than Semaglutide and is associated with higher rates of gastrointestinal adverse events, as shown in STEP-8 and corroborated in observational cohorts.26,34 Cagrilintide, in contrast, is generally better tolerated but achieves smaller reductions in weight and metabolic outcomes, suggesting a niche role for patients prioritizing tolerability over maximum efficacy.35 Safety outcomes across trials show broadly comparable rates of SAEs between active agents and placebo, consistent with prior GLP-1 receptor agonist meta-analyses.36 However, gastrointestinal adverse events, particularly nausea, vomiting, and diarrhea, remain the primary tolerability issue and a major driver of discontinuation.37 Higher discontinuation rates with semaglutide and liraglutide reflect the well-established dose-dependent relationship between incretin therapies and gastrointestinal side effects.38 These symptoms often peak during dose escalation, especially at higher maintenance doses or in combination regimens.39 Although structured titration schedules in trials help mitigate intolerance, real-world adherence to these protocols may be variable, contributing to greater symptom burden and higher discontinuation rates

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doi: 10.1016/j.mce.2021.111239 [DOI] [PubMed] [Google Scholar] 14