Dr. Stephen Nicholls & Dr. C. Michael Gibson Discuss: SURPASS-CVOT

Live from AHA 2025, Dr. Stephen Nicholls joins Dr. C. Michael Gibson in this SnackableHealth discussion to unpack the SURPASS-CVOT, the first cardiovascular outcomes trial (CVOT) testing tirzepatide — a dual GIP and GLP-1 receptor agonist — against an active comparator, dulaglutide, rather than placebo. This design sets a new benchmark: not whether the drug beats nothing, but whether it outperforms one of cardiometabolic medicine’s best-in-class standards.

The trial enrolled patients with type 2 diabetes, established atherosclerotic cardiovascular disease (ASCVD), and a history of heart failure. Participants were randomized to tirzepatide or dulaglutide, with the primary endpoint being the composite of cardiovascular death, myocardial infarction, or stroke. The trial met its non-inferiority goal, with a hazard ratio of 0.92 and an upper confidence interval just above 1.0 — meaning tirzepatide was at least as safe as dulaglutide for major adverse cardiovascular events (MACE).

However, a pre-specified indirect comparison — matching SURPASS-CVOT tirzepatide patients to placebo participants from the REWIND trial (dulaglutide’s pivotal study) — revealed a statistically significant reduction in cardiovascular risk, suggesting that tirzepatide’s benefit extends beyond glycemic control.

Beyond MACE, tirzepatide also showed lower all-cause mortality (HR 0.84) and fewer events in the expanded composite endpoint (CV death, MI, stroke, or coronary revascularization). Moreover, renal outcomes favored tirzepatide, with a smaller eGFR decline among high-risk patients. Dr. Nicholls emphasized that these results may reflect tirzepatide’s broader metabolic effects — greater reductions in HbA1c, body weight, and other risk factors compared to traditional GLP-1 agents.

While superiority over dulaglutide was not formally met for the primary endpoint, the signal for multidimensional benefit — spanning cardiovascular, renal, and metabolic health — reinforces tirzepatide’s positioning as a next-generation cardiometabolic therapy. As Dr. Gibson summarized, it’s not just a win for glucose control, but a paradigm shift: “We’re no longer asking if a drug is safe — we’re asking how much more protection we can deliver.”