What the SURPASS-CVOT post-hoc analysis tells us about tirzepatide and cardiorenal outcomes

SURPASS-CVOT (ClinicalTrials.gov NCT04255433) was the first cardiovascular outcome trial (CVOT) to use an active incretin-based comparator rather than placebo. It enrolled 13,165 patients with type 2 diabetes and established cardiovascular disease at 640 centers globally. The primary outcome was a 3-component composite: cardiovascular death, myocardial infarction (MI), or stroke.

Tirzepatide was compared to dulaglutide (Trulicity), a GLP-1 receptor agonist with an established cardiovascular benefit from the REWIND trial. The regulatory requirement was to show noninferiority.

The primary 3-component MACE result: HR 0.92 (95% CI 0.83–1.01) — noninferior to dulaglutide, but not superior.

If you need background on the drug itself, see tirzepatide explained (Mounjaro and Zepbound).

The JAMA Cardiology post-hoc analysis expanded to a 6-component composite endpoint: all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure, and a composite of adverse kidney outcomes.

The rationale: the narrow 3-component endpoint was chosen for regulatory reasons specific to the trial design. In practice, GLP-1 therapies have demonstrated effects across a broader range of cardiorenal outcomes in other trials. The post-hoc analysis asked whether a broader look would reveal a signal not captured by the primary endpoint.

After a median (IQR) treatment duration of 46.9 (34.6–50.6) months:

6-component cardiorenal composite:

• Tirzepatide: 23.7% (1,559 of 6,586 patients)
• Dulaglutide: 27.4% (1,803 of 6,579 patients)
• HR: 0.84 (95% CI 0.79–0.90); P<.001
• Number needed to treat to prevent 1 event: 27

Individual components (all numerically favoring tirzepatide):

• All-cause mortality: 8.6% vs 10.2% (HR 0.84, 95% CI 0.75–0.94)
• Myocardial infarction: 4.7% vs 5.4% (HR 0.86)
• Stroke: 3.5% vs 3.8% (HR 0.91)
• Coronary revascularization: 8.0% vs 9.4% (HR 0.84)
• Heart failure hospitalization: 3.0% vs 3.1% (HR 0.96)
• Composite kidney endpoint: 4.9% vs 6.1% (HR 0.79, 95% CI 0.68–0.91)

Adverse events: Gastrointestinal events were more common with tirzepatide (42.5%) than dulaglutide (35.9%).

The key distinction: the primary SURPASS-CVOT endpoint showed tirzepatide was noninferior but not superior to dulaglutide for the 3-component composite. This post-hoc analysis of the broader endpoint showed statistical superiority for the 6-component composite.

These are not contradictory. The primary trial was powered and designed for the 3-component endpoint. The post-hoc analysis used roughly double the number of events (because the composite is broader) and found a more pronounced signal.

An accompanying editorial by Fonarow and McMurray in JAMA Cardiology noted that the broader endpoint better reflects the full burden of cardiorenal disease in this population — but post-hoc analyses remain post-hoc. The statistical findings are compelling, but they don't carry the same regulatory standing as a pre-specified primary outcome.

• Whether these results would replicate in a dedicated superiority trial with the 6-component endpoint as the pre-specified primary outcome
• Whether the benefit reflects tirzepatide's dual GIP/GLP-1 mechanism, its greater weight loss effect, or some combination
• How these results compare to placebo-controlled trials — this is an active-comparator study
• Whether the all-cause mortality signal (HR 0.84) reflects a treatment benefit or differences in patient characteristics or dropout patterns

• How does the SURPASS-CVOT post-hoc analysis fit into the broader evidence for tirzepatide's cardiorenal effects?
• Given my specific cardiovascular risk profile, does this data change how you think about tirzepatide vs. another GLP-1?
• What do you make of the active-comparator design vs. the placebo-controlled GLP-1 trials?
• Is a prospective cardiovascular outcome trial for tirzepatide in obesity without diabetes planned?

The SURPASS-CVOT post-hoc analysis adds meaningful evidence to the picture of tirzepatide's cardiorenal effects — particularly for patients with type 2 diabetes and established cardiovascular disease. The HR of 0.84 for the 6-component endpoint is statistically strong and consistent across individual components.

But it is a post-hoc analysis, funded by Eli Lilly, comparing two active GLP-1 treatments rather than placebo. It does not by itself change prescribing guidelines, and it does not tell any individual patient that tirzepatide is the right choice for their cardiovascular risk management.

Bring these findings to your cardiology appointment as context for a conversation — not as a directive.

Medical disclaimer: This content is for educational purposes only and is not medical advice. Always consult a licensed healthcare professional before starting, stopping, or changing any treatment.

Sources

• Nissen SE et al. Cardiorenal outcomes with tirzepatide compared with dulaglutide: a post hoc analysis of the SURPASS-CVOT randomized clinical trial. JAMA Cardiology, March 28, 2026. doi:10.1001/jamacardio.2026.0767. jamanetwork.com
• ClinicalTrials.gov NCT04255433. clinicaltrials.gov
• Fonarow GC, McMurray JJV. Exploring additional cardiorenal outcomes [editorial]. JAMA Cardiology, 2026. jamanetwork.com