Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes
Nicholls SJ, Bhatt DL, Buse JB, Prato SD, Kahn SE, Lincoff AM, McGuire DK, Nauck MA, +4 more
New England Journal of Medicine (2025) · n=13,165
SURPASS-CVOT randomized 13,299 T2D patients with established atherosclerotic cardiovascular disease to tirzepatide versus dulaglutide; the MACE composite occurred in 12.2% on tirzepatide versus 13.1% on dulaglutide (HR 0.92, 95.3% CI 0.83–1.01), meeting non-inferiority but not demonstrating superiority.
SURPASS-CVOT is the dedicated cardiovascular outcomes trial for tirzepatide, uniquely designed as an active-comparator non-inferiority trial rather than the placebo-controlled standard that defined the GLP-1-receptor-agonist CVOT generation (LEADER, SUSTAIN-6, REWIND, SELECT). Nicholls and colleagues randomized 13,299 adults with type 2 diabetes and established atherosclerotic cardiovascular disease in a 1:1 ratio to once-weekly subcutaneous tirzepatide (titrated to maximum tolerated dose, up to 15 mg) or dulaglutide (1.5 mg, the approved Trulicity dose at trial initiation), on top of standard care. The modified intention-to-treat population was 6,586 on tirzepatide and 6,579 on dulaglutide. Primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE).
The primary composite occurred in 801 tirzepatide patients (12.2%) and 862 dulaglutide patients (13.1%), corresponding to a hazard ratio of 0.92 (95.3% confidence interval, 0.83 to 1.01). The trial met its prespecified non-inferiority criterion (P=0.003) but did not demonstrate superiority of tirzepatide over dulaglutide (P=0.09). Secondary endpoints including all-cause mortality, expanded MACE composites, and heart-failure hospitalization were directionally consistent with the primary finding. Gastrointestinal adverse events were more common on tirzepatide than on dulaglutide; overall adverse-event incidence and discontinuation rates were similar between groups. The trial was sponsored by Eli Lilly.
The active-comparator design positions SURPASS-CVOT as a different kind of question than the placebo-controlled CVOTs. Dulaglutide had already demonstrated MACE benefit versus placebo in REWIND, so a tirzepatide-versus-dulaglutide trial that meets non-inferiority implicitly establishes tirzepatide's cardiovascular benefit relative to standard care — without requiring a placebo arm in a population where placebo would now be ethically constrained. The narrow miss on superiority (upper CI of 1.01) means the field cannot conclude that tirzepatide is cardiovascularly superior to a GLP-1-only agonist, but it can conclude that tirzepatide does not appear cardiovascularly inferior despite its more aggressive metabolic profile.
Active-comparator non-inferiority trials produce different inferential structure than placebo-controlled superiority trials. The reassurance from SURPASS-CVOT runs through a non-inferiority logic chain — tirzepatide is non-inferior to dulaglutide, which was previously superior to placebo, therefore tirzepatide is presumptively superior to placebo. That logic is regulatory-acceptable but is weaker than a direct placebo-controlled MACE superiority demonstration would have been. The narrow miss on the superiority endpoint (HR 0.92, upper CI just above 1.0) is the headline ambiguity: tirzepatide may be modestly superior, equivalent, or marginally inferior to dulaglutide on hard cardiovascular outcomes, and SURPASS-CVOT cannot reliably distinguish between those possibilities.
The trial's population — T2D plus established atherosclerotic cardiovascular disease — is high-risk and event-rich, which served the trial's power calculation but constrains generalizability to the broader real-world tirzepatide population, which now includes off-label obesity use without established CV disease. The non-diabetic obesity equivalent of SURPASS-CVOT (SURMOUNT-MMO) had not read out as of mid-2026 and is the trial that would answer the cardiovascular question for the larger off-label user base.
Industry sponsorship by Eli Lilly is disclosed; the trial design, conduct, and endpoint adjudication were regulatory-grade and consistent with FDA cardiovascular safety guidance. The choice of dulaglutide 1.5 mg as the active comparator reflects the dose approved at trial design; the field has subsequently moved toward higher GLP-1 doses (semaglutide 2.4 mg, dulaglutide 4.5 mg in some settings), and whether a head-to-head against those higher doses would tell a different story is unknown. The trial's null superiority finding does not change real-world prescribing decisions for tirzepatide — which are driven primarily by metabolic efficacy and tolerability — but it does constrain marketing claims about cardiovascular superiority over the GLP-1 class.
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