Comparative efficacy of tirzepatide and glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in patients with type 2 diabetes: a systematic review and network meta-analysis.
This systematic review and frequentist network meta-analysis (NMA) examined the comparative cardiovascular efficacy of tirzepatide (a dual GIP/GLP-1 receptor agonist) versus GLP-1 receptor agonists (GLP-1RAs) and placebo in adults with type 2 diabetes (T2D) and established or high-risk atherosclerotic cardiovascular disease (ASCVD). Eleven randomized controlled trials were included — ten evaluating GLP-1RAs and one evaluating tirzepatide (SURPASS-CVOT). In the class-level analysis, the study found that tirzepatide was associated with statistically significant reductions in MACE, cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke compared to placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo and lixisenatide specifically, while appearing broadly comparable to other individual GLP-1RAs. Subgroup and leave-one-out sensitivity analyses were consistent with primary findings. A key limitation is that only one tirzepatide RCT (SURPASS-CVOT) was available, constraining direct head-to-head NMA comparisons between tirzepatide and individual GLP-1RAs and reducing the precision of tirzepatide-specific estimates. The authors concluded that tirzepatide may provide cardiovascular benefit at least comparable to established GLP-1RAs, though this inference is based on indirect comparisons.
Why this grade: The NMA synthesizes multiple large RCTs in humans with relevant clinical endpoints, but conclusions about tirzepatide specifically rest on a single contributing trial (SURPASS-CVOT), limiting confidence in indirect comparative estimates.
Background Glucagon-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. Methods We 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. Results Eleven 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. Conclusion Among 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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