Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis

Abstract

Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57-1.11) for MACE-4; 0.90 (95% CI, 0.50-1.61) for cardiovascular death; and 0.80 (95% CI, 0.51-1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls.

Trial registration: ClinicalTrials.gov NCT03131687 NCT03954834 NCT03987919 NCT03882970 NCT03730662 NCT04039503 NCT03861052.

Conflict of interest statement

N.S. has consulted for or received lecture fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer and Sanofi and received grant support from AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics through his institution, the University of Glasgow. D.K.M. reports personal fees from Boehringer Ingelheim, Janssen Research and Development, Sanofi US, Merck & Co., Merck Sharp & Dohme, Eli Lilly and Company, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon Pharmaceuticals, Eisai, Pfizer, Metavant, Applied Therapeutics, Afimmune, Bayer and Esperion. S.Z. reports participation in advisory boards, expert committees or educational meetings on behalf of Monash University for Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Servier, AstraZeneca, Novo Nordisk and Merck Sharp & Dohme Australia, outside of the submitted work. N.S., D.K.M. and S.Z. sit on the steering committee for the SURPASS-CVOT. I.P., R.J.W., G.J.W. and H.N. are employees and shareholders of Eli Lilly and Company.

© 2022. The Author(s).

Figures

Fig. 1. Primary and secondary cardiovascular outcomes confirmed by central-blinded adjudication.

Data are point estimates of HR (illustrated by the diamond symbol) and range of two-sided 95% CI of the HR. aStrata size adjusted estimate. Strata are defined as trial-level cardiovascular risk (SURPASS-4 forms one stratum, and all other trials form one stratum) bDeath due to cardiovascular cause includes adjudication-confirmed death due to cardiovascular or undetermined cause. cMACE-3 includes death due to cardiovascular or undetermined cause, MI and stroke. Note: P values were based on the Wald chi-square test. n, number of participants in the specified category.

Fig. 2. Adjusted Kaplan–Meier plot of pooled tirzepatide versus pooled comparator effect on time to first occurrence of adjudication-confirmed MACE-4 (primary outcome).

Gray bars represent the planned follow-up period for trials GPGB (30 weeks); SURPASS-1, SURPASS-2 and SURPASS-5 (44 weeks); SURPASS-3 and SURPASS J-mono (56 weeks); and SURPASS-4 (56–108 weeks). Note: P values were based on the Wald chi-square test.

Fig. 3. Time to first occurrence of adjudication-confirmed MACE-4 by trial groupings.

Adjusted Kaplan–Meier estimates. a, Time to first occurrence of composite MACE-4, pooled tirzepatide versus insulin glargine, insulin degludec and placebo combined and mITT population. Gray bars represent the planned follow-up period for trials GPGB (30 weeks); SURPASS-1 and SURPASS-5 (44 weeks); and SURPASS-3 (56 weeks). b, Time to first occurrence of adjudicated-confirmed MACE-4, pooled tirzepatide versus insulin glargine, SURPASS-4 only and mITT population. Gray bar represents the planned follow-up period for SURPASS-4 (56–108 weeks). Note: P values were based on the Wald chi-square test.

Fig. 4. Other adjudication-confirmed cardiovascular outcomes.

Data are point estimates of HR (illustrated by the diamond symbol) and range of two-sided 95% CI of the HR. aStrata size adjusted estimate. Strata are defined as trial-level cardiovascular risk (SURPASS-4 forms one stratum, and all other trials form one stratum). bMACE-6 includes MACE-3 and all other adjudication-confirmed cardiovascular outcomes: HUA, HHF and coronary revascularization. n, number of participants in the specified category.

Fig. 5. Subgroup analyses of the effects of tirzepatide on the adjudication-confirmed composite MACE-4.

Data are point estimates of HR (illustrated by the diamond symbol) and range of two-sided 95% CI of the HR. aStrata size adjusted estimate. Strata are defined as trial-level cardiovascular risk (SURPASS-4 forms one stratum, and all other trials form one stratum). bDerived from a Cox proportional hazards model with treatment (pooled tirzepatide versus pooled comparator), the subgroup variable and the treatment-by-subgroup interaction term as fixed effects, stratified by study-level cardiovascular risk (SURPASS-4 forms one stratum, and all other trials form one stratum) for subgroups other than stratum. Pre-specified subgroup analyses were by sex, age and baseline HbA1c; the rest of the analyses were post hoc. P value is from the Wald chi-square test. N, number of participants in the subgroup in population; n, number of participants in the specified category.

Extended Data Fig. 1. Time-to-event analyses of composite adjudication-confirmed MACE-4.

Data are point estimate of HR (illustrated by the diamond symbol) and range of 2-sided 95% CI of the HR. aStrata size adjusted estimate. Strata are defined as trial-level cardiovascular risk (SURPASS-4 forms one stratum, and all other trials form one stratum). Abbreviations: CI = confidence interval; HR = hazard ratio; iDeg = insulin degludec; iGlar = insulin glargine; MACE = major adverse cardiovascular events; n = number of participants in the specified category; PBO = placebo; TZP = tirzepatide.