SURPASS-CVOT Results: What Tirzepatide Did for the Heart, Explained
SURPASS-CVOT found tirzepatide (Mounjaro) noninferior to dulaglutide (Trulicity) for cardiovascular death, heart attack, or stroke: HR 0.92; 95.3% CI 0.83 to 1.01. Superiority was not met. A 16% lower all-cause death rate and kidney benefits were favorable but not statistically protected findings.
Semaglutides.org provides information only, not medical advice. Talk to a licensed provider about your own care before making changes. Some telehealth links are affiliate links and are labeled where they appear.
SURPASS-CVOT found that tirzepatide (Mounjaro) was noninferior to dulaglutide (Trulicity) for the risk of cardiovascular death, heart attack, or stroke in adults with type 2 diabetes and established atherosclerotic cardiovascular disease. It did not prove tirzepatide was better than dulaglutide for that combined heart outcome. The trial also showed favorable signals for all-cause death, kidney function, A1C, and weight, but those results were not protected by the strict statistical rules that guard the primary endpoint, so they are best read as supportive rather than confirmed [1][2][3].
The trial enrolled 13,299 people at 640 sites in 30 countries and ran about five years, with a median follow-up of four years, making it the largest and longest tirzepatide study to date according to Lilly [1][3][6]. Lilly announced topline results on July 31, 2025 [1]. Stephen J. Nicholls of Monash University presented the full results at the European Association for the Study of Diabetes (EASD) Annual Meeting 2025 [2][4]. The primary paper was published in the New England Journal of Medicine, with funding from Eli Lilly [3].
Who was in the trial, and how was it run?
SURPASS-CVOT (NCT04255433) was a Phase 3, randomized, double-blind trial with an active comparator rather than a placebo [1][3][4]. To join, participants had to be at least 40 years old, have type 2 diabetes, and have established atherosclerotic cardiovascular disease — coronary artery disease, cerebrovascular disease, or peripheral artery disease [4][6]. Screening HbA1c had to be between 7% and 10.5%, and BMI had to be at least 25 kg/m² [4][6].
People were excluded for reasons that included type 1 diabetes, hospitalization for heart failure within the prior 2 months, chronic New York Heart Association class IV heart failure, a personal or family history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma, and use of a GLP-1 receptor agonist or pramlintide within 3 months [4].
Enrollment ran from May 29, 2020 to June 27, 2022, with 16,979 people screened [6]. Of the 13,299 randomized, 134 were excluded because they were randomized in error, leaving a modified intention-to-treat population of 6,586 people on tirzepatide and 6,579 on dulaglutide [3][4].
Participants were randomized 1:1 to once-weekly injections of either tirzepatide at a maximum tolerated dose of 5, 10, or 15 mg, or dulaglutide at a fixed 1.5 mg [1][3]. Tirzepatide started at 2.5 mg and increased by 2.5 mg every 4 weeks until the maximum tolerated dose was reached; the dulaglutide arm received sham dose escalation so participants stayed blinded [1][2]. At 36 months, 72.7% of the tirzepatide group was on the 15 mg dose [4].
The average participant was 64.1 years old, had a BMI of 32.6, an HbA1c of 8.4%, and had lived with diabetes for 14.7 years; 29.0% were women [3]. Mean baseline weight was 92.6 kg (204.15 lbs) [1]. Study drug was added on top of standard care for cardiovascular disease, and glucose control could be adjusted during the trial with open-label non-incretin medications [2][4].
Why was tirzepatide compared to Trulicity instead of a placebo?
Dulaglutide 1.5 mg earned its comparator role in the REWIND trial (NCT01394952), a placebo-controlled study published in 2019 that showed dulaglutide reduced cardiovascular events. REWIND enrolled 9,901 participants across 24 countries, with a mean diabetes duration of 10.5 years and a median baseline A1C of 7.2% [1].
By the time SURPASS-CVOT was designed, GLP-1 therapies had become standard care for people with type 2 diabetes and high cardiovascular risk, which raised ethical concerns about giving that population a placebo, according to a commentary on the trial by Eldad Einav, MD [2]. So the researchers used a “preservation-of-effect” framework: if tirzepatide could be shown noninferior to dulaglutide, one could reasonably infer it carries the same protective effect dulaglutide showed in REWIND [2].
The noninferiority margin of about 1.05 came from a Bayesian meta-analysis of six GLP-1 cardiovascular outcomes trials, and it was chosen so that at least 50% of dulaglutide’s benefit would be preserved and tirzepatide’s superiority to a putative placebo would be ensured [2][4].
The framework has limits, though. Einav noted that dulaglutide’s effect in REWIND was modest (HR 0.88; 95% CI 0.79–0.99) and came mostly from a primary prevention population, while SURPASS-CVOT was entirely secondary prevention with wider use of modern drugs like SGLT2 inhibitors. The dosing also favored tirzepatide, which was titrated up to 15 mg, while dulaglutide stayed at a fixed 1.5 mg [2].
At the EASD press conference, Nicholls said the trial “demonstrates that tirzepatide is cardioprotective” in this population. Whether the results lead to an FDA cardiovascular risk-reduction indication is uncertain, according to the commentary [2].
What was the primary endpoint result?
The primary endpoint was time to the first occurrence of MACE-3: cardiovascular death, heart attack (myocardial infarction), or stroke [1][3][4]. A primary endpoint event occurred in 801 of 6,586 people (12.2%) on tirzepatide versus 862 of 6,579 (13.1%) on dulaglutide [3][4].
The hazard ratio was 0.92, with a 95.3% confidence interval of 0.83 to 1.01 [1][3]. Noninferiority was met (P = 0.003). Under the trial’s preservation-of-effect design, the margin was set so that meeting noninferiority would preserve at least half of dulaglutide’s benefit and ensure tirzepatide’s superiority to a putative placebo — an inference that depends on cross-trial assumptions [2][4]. Superiority to dulaglutide was not met: the NEJM abstract reports P = 0.09, and Lilly’s table and the EASD presentation show p = 0.086 [1][2][3].
The rules were set in advance: noninferiority required the upper bound of the 95.3% confidence interval to stay below 1.05, and superiority required it to stay below 1.00 [1][3][4]. The upper bound landed at 1.01, so the trial cleared the first bar but not the second. Lilly framed the result as an 8% lower rate of MACE-3, consistent across all three components of the composite [1].
The trial was powered assuming 1,616 adjudicated primary events for 90% power, a projected dulaglutide event rate of 3.5% per year, and projected relative risk reductions of 10.5% for noninferiority and 15% for superiority [4].
| Measure | Tirzepatide | Dulaglutide | Result |
|---|---|---|---|
| MACE-3 events | 801 (12.2%) | 862 (13.1%) | HR 0.92; 95.3% CI 0.83–1.01 [3][4] |
| Noninferiority (margin <1.05) | — | — | Met, P = 0.003 [2][3] |
| Superiority (upper bound <1.00) | — | — | Not met, P = 0.09 [3] |
What about the 16% lower death rate?
All-cause death was 16% lower on tirzepatide: HR 0.84, with a 95.0% confidence interval of 0.75 to 0.94, and p = 0.002 [1][2]. Lilly highlighted this number, but it comes with an important caveat: it was not controlled for multiplicity-adjusted type 1 error [1].
That matters because the trial’s key secondary endpoints were designed to be tested with a graphical alpha-spending approach only after primary superiority was met — and primary superiority was not met [4]. So the death result, along with other secondary findings, sits outside the trial’s statistically protected conclusions.
The commentary also noted that the mortality signal was not accompanied by a clear reduction in cardiovascular death or MACE, so a direct cardiovascular explanation is uncertain, and non-cardiovascular drivers or chance are possible [2]. Non-cardiovascular deaths were 175 (2.7%) on tirzepatide versus 228 (3.5%) on dulaglutide [4].
Other secondary endpoints, reported as hazard ratios with confidence intervals, included the expanded composite of cardiovascular death, heart attack, stroke, or coronary revascularization (95% CI 0.81–0.96, favoring tirzepatide), heart attack (HR 0.86; 95% CI 0.74–1.00), stroke (HR 0.91; 95% CI 0.76–1.09), cardiovascular death (HR 0.89; 95% CI 0.77–1.02), and cardiovascular death or heart failure hospitalization or urgent visit (HR 0.91; 95% CI 0.81–1.03) [2].
What did the trial show for kidneys?
A pre-specified exploratory analysis of SURPASS-CVOT looked at a composite kidney outcome: persistent macroalbuminuria, a persistent eGFR decline of 50% or more, end-stage kidney disease (eGFR below 15 or chronic kidney replacement therapy), or death from kidney disease [6].
Of the 13,299 randomized, 2,948 had high-risk chronic kidney disease at baseline [6]. Overall, the composite kidney outcome occurred in 396 people (6.0%) on tirzepatide versus 498 (7.6%) on dulaglutide — a 23% lower risk, with HR 0.77 (95% CI 0.68–0.88), p = 0.0002 [6].
| Kidney population | Tirzepatide | Dulaglutide | Hazard ratio |
|---|---|---|---|
| Overall | 396 (6.0%) | 498 (7.6%) | 0.77 (95% CI 0.68–0.88), p = 0.0002 [6] |
| Low-to-moderate-risk CKD | 195 (4.0%) | 283 (5.6%) | 0.70 (95% CI 0.58–0.84), p = 0.0001 [6] |
| High-risk CKD | 185 (12.2%) | 203 (14.5%) | 0.79 (95% CI 0.64–0.96), p = 0.018 [6] |
The benefit was driven mainly by less new-onset persistent macroalbuminuria in people with low-to-moderate-risk kidney disease and a slower eGFR decline in people with high-risk kidney disease [6]. The annual eGFR decline was slower on tirzepatide by 0.29 mL/min/1.73 m² overall (95% CI 0.17–0.41, p < 0.0001) and by 0.93 mL/min/1.73 m² in the high-risk group (95% CI 0.65–1.22, p < 0.0001) [6].
Lilly also reported a key secondary endpoint of eGFR change at 36 months in participants with high or very-high risk chronic kidney disease, starting from a mean baseline of 53.4 mL/min/1.73 m²: −4.97 on tirzepatide versus −8.51 on dulaglutide, a difference of 3.54 mL/min/1.73 m² (95.0% CI 2.57–4.50), p < 0.001 — though this was not controlled for multiplicity-adjusted type 1 error [1].
At baseline, 32.0% of participants with measurements had microalbuminuria, 11.5% had macroalbuminuria, and 22.5% had an eGFR below 60 [6]. Kidney function was assessed with the CKD-EPI creatinine-cystatin C 2021 equation, and kidney risk categories followed KDIGO 2025 guidance [1][4][6]. One measurement caveat comes from the SUMMIT trial analysis: baseline eGFR based on cystatin C ran about 9 mL/min/1.73 m² lower than creatinine-based eGFR, and the two formulas can disagree during weight loss and body-composition change [7].
How did weight, A1C, and blood pressure change?
At 36 months, from a mean baseline A1C of 8.39%, tirzepatide lowered A1C by 1.73 percentage points versus 0.90 for dulaglutide — a treatment difference of −0.83% (95.0% CI −0.88 to −0.78), p < 0.001, not controlled for multiplicity [1].
Weight fell 12.06% on tirzepatide (−11.43 kg, or −25.20 lbs) versus 4.95% on dulaglutide (−4.65 kg, or −10.25 lbs), from a mean baseline of 92.6 kg. The difference was −7.1% (95.0% CI −7.4 to −6.8), p < 0.001 [1]. Tirzepatide also produced greater improvements in lipids and systolic blood pressure than dulaglutide, again not multiplicity-controlled [1][2].
What is the “imputed placebo” analysis?
Because there was no placebo arm, the researchers ran a prespecified indirect comparison: they multiplied the hazard ratio for tirzepatide versus dulaglutide from SURPASS-CVOT by the hazard ratio for dulaglutide versus placebo from REWIND, with propensity-score adjustment for population differences [5]. The analysis used 2,055 of the 9,901 REWIND participants — those who would have been eligible for SURPASS-CVOT — plus all 13,165 SURPASS-CVOT participants [5].
Against this imputed (putative) placebo, tirzepatide showed a 28% lower risk of MACE-3: HR 0.72 (95% CI 0.55–0.94), with p = 0.02 reported at EASD [1][2][5]. Cardiovascular death or heart failure events showed HR 0.70 (95% CI 0.51–0.96), and all-cause death showed a 39% lower risk: HR 0.61 (95% CI 0.45–0.82) [1][5]. Sensitivity analyses using unadjusted data, the full REWIND cohort, and GLP-1 receptor agonist meta-analysis data were generally consistent [5].
This is not a randomized placebo-controlled result. The authors themselves label it an indirect prespecified exploratory comparison, and the trial commentary describes it as model-based supportive evidence, not conclusive proof, because it stitches together two different trials with extra statistical assumptions and room for bias [2][5].
What side effects were most common, and how many people quit?
Serious adverse events occurred in roughly 32% of both groups [2]. The most common treatment-emergent side effects were gastrointestinal: nausea affected 25.1% of the tirzepatide group versus 22.4% of the dulaglutide group, and diarrhea affected 24.8% versus 19.1% [2].
The NEJM paper reports that adverse event incidence appeared similar overall, with more gastrointestinal events on tirzepatide [3]. Lilly said the gastrointestinal events were generally mild to moderate and mostly resolved after dose escalation was complete [1].
Discontinuation due to adverse events was higher on tirzepatide: 874 people (13.3%) stopped the drug for that reason versus 671 (10.2%) on dulaglutide [1][4]. Median study drug exposure was long in both arms — 47.6 versus 47.7 months — and vital status was known for 99.7% of participants in each group [4].
Does this apply to people taking Zepbound without diabetes?
No. Every participant in SURPASS-CVOT had type 2 diabetes plus established atherosclerotic cardiovascular disease, so the results do not extend to people with obesity who do not have diabetes [3][4][6].
In the United States, tirzepatide is approved as Mounjaro for adults with type 2 diabetes to improve glycemic control, and as Zepbound for adults with obesity, or overweight with at least one weight-related medical problem, and for moderate-to-severe obstructive sleep apnea with obesity. Both are to be used with diet and exercise [1].
Lilly lists studies of tirzepatide in chronic kidney disease and in morbidity and mortality in obesity as ongoing [1]. The obesity trial is registered as SURMOUNT-MMO (NCT05556512), “A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With Obesity” [8].
What about heart failure?
SURPASS-CVOT’s secondary endpoint of cardiovascular death or heart failure hospitalization or urgent visit showed HR 0.91 (95% CI 0.81–1.03), which is not a statistically protected benefit [2].
Separate evidence comes from the SUMMIT trial (NCT04847557), which randomized 731 patients with heart failure with preserved ejection fraction (HFpEF) and BMI of 30 or greater, enriched for chronic kidney disease, to tirzepatide or placebo for a median of 104 weeks. It assessed cardiovascular death or worsening heart failure events and change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 52 weeks [7].
In that trial, chronic kidney disease did not alter the relative benefit of tirzepatide on major adverse heart failure events or the KCCQ score, though the absolute risk reduction was numerically greater in patients with CKD. Tirzepatide increased eGFR at 52 weeks by both creatinine-based and cystatin C-based formulas, with discordance between the two in individual patients, and produced an eGFR decline at 12 weeks by the creatinine formula only [7].
What is still not known?
What SURPASS-CVOT established is that tirzepatide is noninferior to a GLP-1 drug with proven cardiovascular benefit, that its cardiovascular safety is confirmed, and that superiority over dulaglutide for MACE-3 was not demonstrated [1][2][3]. The favorable findings on all-cause death, eGFR, A1C, and weight were not controlled for multiplicity-adjusted type 1 error, and the kidney composite was labeled a pre-specified exploratory analysis [1][6].
Lilly said it planned to submit the data to global regulators by the end of 2025 [1]. The open question, per the trial commentary, is whether noninferiority to an active cardioprotective GLP-1 is enough to infer conclusive cardiovascular protection or support an FDA indication [2].
Sources
- Eli Lilly and Company. Lilly’s Mounjaro (tirzepatide) demonstrated cardiovascular protection in head-to-head trial. July 31, 2025.
- Healio. Tirzepatide similar to dulaglutide for CV outcomes but tied to lower rates of death.
- PubMed. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.
- Eli Lilly and Company. The Cardiovascular Outcomes in Participants on Tirzepatide Versus Dulaglutide of the SURPASS-CVOT. September 18, 2025.
- PubMed. Estimating the True MACE Benefits From Tirzepatide in SURPASS-CVOT Using an Imputed Placebo Analysis of REWIND.
- PubMed. A comparison of the effects of tirzepatide and dulaglutide on major kidney events in people with type 2 diabetes: SURPASS-CVOT analyses.
- PubMed. Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial.
- ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With Obesity. NCT05556512.
- PubMed. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.
- PubMed. Semaglutide and tirzepatide effects on cardiovascular outcomes in people with overweight or obesity in the real world (STEER).
- PubMed. Comparative real-world outcomes of tirzepatide vs semaglutide in patients with obesity and type 2 diabetes: A retrospective propensity-matched cohort study.
Frequently asked questions
Did tirzepatide beat dulaglutide for heart attacks and strokes, or just tie?
It was a statistical tie on the primary outcome. Tirzepatide was noninferior to dulaglutide for cardiovascular death, heart attack, or stroke (HR 0.92; 95.3% CI 0.83–1.01; P = 0.003 for noninferiority), but superiority was not met (P = 0.09). Events occurred in 12.2% on tirzepatide versus 13.1% on dulaglutide.
What does the 16% lower death rate really mean and why is it caveated?
All-cause death was 16% lower on tirzepatide (HR 0.84; 95.0% CI 0.75–0.94, p = 0.002). But this secondary endpoint was not controlled for multiplicity-adjusted type 1 error, and it was not accompanied by a clear reduction in cardiovascular death or MACE, so non-CV drivers or chance are possible explanations.
Why was there no placebo group?
GLP-1 therapies became standard care for type 2 diabetes with high cardiovascular risk, creating ethical concerns about a placebo arm. Instead, tirzepatide was tested against dulaglutide, which beat placebo in the REWIND trial, using a preservation-of-effect framework with a noninferiority margin of about 1.05.
Why is the confidence interval 95.3% instead of 95%?
The 95.3% confidence interval reflects a type 1 error rate adjusted for an efficacy interim analysis. Noninferiority required the upper bound to stay below 1.05; superiority required it below 1.00. The upper bound was 1.01, so noninferiority passed and superiority did not.
Does SURPASS-CVOT apply to Zepbound users without diabetes?
No. Every participant had type 2 diabetes plus established atherosclerotic cardiovascular disease, so the results do not extend to people with obesity but no diabetes. Lilly lists a tirzepatide study on morbidity and mortality in obesity as ongoing, registered as SURMOUNT-MMO (NCT05556512).
What did the trial show for kidneys?
In a pre-specified exploratory analysis, the composite kidney outcome was 23% lower on tirzepatide: 6.0% versus 7.6% of participants, HR 0.77 (95% CI 0.68–0.88), p = 0.0002. In high-risk kidney disease, eGFR decline at 36 months was slower by 3.54 mL/min/1.73 m² (95.0% CI 2.57–4.50).
How much did weight and A1C change in the trial?
At 36 months, weight fell 12.06% on tirzepatide (about 25.20 lbs) versus 4.95% on dulaglutide (about 10.25 lbs), a difference of −7.1%. A1C dropped 1.73 points versus 0.90 from a baseline of 8.39%. Both results were favorable but not controlled for multiplicity-adjusted type 1 error.
What side effects were most common and how many people quit?
Nausea affected 25.1% on tirzepatide versus 22.4% on dulaglutide, and diarrhea 24.8% versus 19.1%; events were generally mild to moderate. Discontinuation due to adverse events was 13.3% on tirzepatide versus 10.2% on dulaglutide. Serious adverse events were about 32% in both groups.
This article summarizes FDA labeling, published research and company information current as of September 14, 2026. It is not medical advice and does not replace a conversation with your own healthcare provider. How we research and verify.