Background: Tirzepatide is a dual-acting glucagon-like peptide-1 analog and a glucose-dependent insulinotropic polypeptide analog. The disease-specific weight-reducing effects associated with tirzepatide use are well established, but its adverse effects have not been systematically assessed and may not be disease-specific. This systematic review aimed to assess the adverse effects associated with tirzepatide use compared with placebo in patients at increased risk of cardiovascular events.
Methods: We searched six electronic databases and other sources from inception to June 16, 2025. Randomized clinical trials comparing tirzepatide with placebo in patients at increased risk of cardiovascular events were eligible for inclusion. The literature search identified 8866 records after removal of duplicates. Two review authors screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with Cochrane Risk of Bias tool - version 2; an eight-step procedure was used to assess whether thresholds for statistical significance were crossed, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs). Secondary outcomes included non-serious adverse events (nsAEs).
Results: The analysis included 21 trials, randomizing 8043 participants to tirzepatide versus placebo. Beta-binomial regression showed no evidence of a difference when assessing all-cause mortality (odds ratio 1.02, 95% CI 0.57 to 1.81; p = 0.95; 21 trials; TSA: underpowered meta-analysis; very low certainty of evidence) or SAEs (odds ratio 0.98, 95% CI 0.82 to 1.17; p = 0.80; 21 trials; TSA: sufficiently powered meta-analysis; moderate certainty of evidence). Meta-analysis showed that tirzepatide increased the risk of several nsAEs, primarily gastrointestinal nsAEs such as nausea, diarrhea, decreased appetite, and vomiting.
Conclusions: Current evidence indicates that tirzepatide does not appear to influence the risk of serious adverse events. A meta-analysis of all-cause mortality showed no evidence of a difference; however, this finding was based on sparse data and is associated with very low certainty. Tirzepatide use is associated with an increased risk of several gastrointestinal nsAEs. Further trials designed for investigating the effects of tirzepatide compared with placebo on all-cause mortality are needed.
Trial registration: PROSPERO, CRD42024599035.
Keywords: Meta-analysis; Placebo; Safety; Systematic review; Tirzepatide; Trial Sequential Analysis.
© 2026. The Author(s).