Journal name: Nature

Publishing date: February 24, 2022

Author: Naveed Sattar et.al

Meta-analysis on tirzepatide cardiovascular risk assessment showed no increased risk in participants with T2D on tirzepatide compared to controls.

Why does this study matter?

Glucagon-like peptide-1 receptor agonists are now considered the first choice of injectable therapy for many people with T2D, with several members of the class having proven cardiovascular efficacy. Now combined glucose-dependent insulinotropic polypeptide (GIP) and GLP-1RAs have been proposed as a novel therapeutic option for T2D.

Tirzepatide is one such molecule that has shown marked glycemia and weight benefits in a series of trials. For example, when compared to placebo, semaglutide 1 mg per week, dulaglutide 1.5 mg per week and insulin degludec or insulin glargine 100 U ml−1, tirzepatide was more effective in reducing glycated haemoglobin (HbA1c) and weight in people with T2D over a 26−52-week treatment period.

Tirzepatide might improve glycemic control beyond that of GLP-1RAs through direct and indirect actions on the pancreas and other tissues, including enhancing pancreatic β-cell insulin secretion, reducing glucose-adjusted glucagon secretion and improving insulin sensitivity beyond the levels usually explained by weight loss. Additionally, tirzepatide’s anorexigenic effect might exceed that of GLP-1RAs by integrating the activation signals of both central GIP and GLP-1 receptor pathways in the brain.

Tirzepatide is also associated with improvements in lipoprotein profiles (more than GLP-1RAs), blood pressure and several biomarkers of inflammation. Notably, glycemic and weight effects appear to be maintained for at least 2 years while receiving tirzepatide, the longest observation period for this drug.

This study presents the results of pre-specified cardiovascular safety meta-analyses and selected post hoc exploratory analyses of interest, based on prospectively collected and centrally adjudicated MACE (Major Adverse Cardiovascular Events) events.

Study Design

This pre-specified cardiovascular meta-analysis included all seven randomised 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 the first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke, and hospitalised 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 to 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 analysed.

Results and Conclusion

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.

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