Steven E. Nissen, MD, MACC

Tirzepatide Outperforms Dulaglutide in Cardiorenal Outcomes, With Steven Nissen, MD

Tirzepatide treatment resulted in a substantial reduction in a broad 6-component composite of cardiovascular and kidney endpoints compared to dulaglutide, according to a post hoc analysis of the SURPASS-CVOT trial.

American College of Cardiology (ACC) Scientific Sessions 2026

 in New Orleans, Louisiana, by Steven Nissen, MD, chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic and professor of medicine at the Lerner College of Medicine.

“What this tells us is that targeting 2 incretins, which is what tirzepatide does, is actually a better strategy in terms of reducing major morbidity and mortality than just targeting GLP-1 alone,” Nissen told 

 in an exclusive interview. “We’re moving beyond the simple GLP-1 agonists – we’re moving to these more complex therapies that involve targeting more than 1 of the gut hormones.”

SURPASS-CVOT was an active-comparator-controlled, double-blind, noninferiority trial comparing tirzepatide and dulaglutide for cardiovascular outcomes in patients with 

atherosclerotic cardiovascular disease (ASCVD)

. Patients were eligible if they were ≥40 years old with T2D, a glycated hemoglobin level between 7% and 10.5%, a body mass index (BMI) of ≥25, and established ASCVD. Patients were excluded if they had any cardiovascular event within 60 days before screening, had used a GLP-1 RA within 3 months before screening, or had chronic advanced 

Eligible patients were randomized in a 1:1 ratio to either weekly subcutaneous tirzepatide 15 mg or dulaglutide 1.5 mg. Patients were monitored at trial visits every 4 weeks for the first 24 weeks and every 3 months thereafter. A total of 6586 patients entered the tirzepatide arm and 6579 entered the dulaglutide arm. The primary endpoint was a composite of cardiovascular mortality, myocardial infarction, or stroke.

Among the 13,165 patients enrolled in the original trial, the mean age was 64 years (standard deviation [SD], 8.8), and mean hemoglobin A1c was 8.4% (SD, 0.93). A primary endpoint event occurred in 801 patients (12.2%) in the tirzepatide arm and 862 (13.1%) in the dulaglutide arm. Adverse event incidence was similar between the 2 groups, although tirzepatide recipients saw more gastrointestinal adverse events.

In the present analysis, Nissen and colleagues crafted an additional primary endpoint composed of 6 potential events, including all-cause mortality, myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure, and a composite of several adverse kidney outcomes.

This 6-point composite endpoint occurred in 1559 patients (23.7%) receiving tirzepatide and 1803 patients (27.4%) receiving dulaglutide (HR, 0.84; 95% CI, 0.79-0.9; 

 <.001) after a median treatment duration of 46.9 months (interquartile range [IQR], 34.6-50.6). Sensitivity analyses showed similar hazard ratios for a 5-component endpoint excluding kidney outcomes (HR, 0.86; 95% CI, 0.8-0.93).

Nissen noted the limited structure of the trial, given its status as a post hoc analysis. Tirzepatide’s explicit superiority in this particular patient cohort cannot be assumed based on these data.

“It’s important to remember that this is a secondary analysis of a trial,” Nissen said. “I happen to be the chair of the study SURMOUNT-MMO, which is studying tirzepatide compared to placebo in both primary and secondary prevention patients without diabetes. We’ll find out in a much broader population whether targeting with a dual incretin therapy really is superior to placebo.”

Editors’ Note: Nissen reports disclosures with Amgen, AstraZeneca, Bristol Myers Squibb, Novartis, Medtronic, Eli Lilly, and others.

Nissen SE, Wolski K, D’Alessio D, et al. Cardiorenal Outcomes With Tirzepatide Compared With Dulaglutide in Patients With Diabetes and Cardiovascular Disease: A Post Hoc Analysis of the SURPASS-CVOT Randomized Clinical Trial. 

. March 28, 2026. Accessed April 10, 2026. 

Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with Tirzepatide versus dulaglutide in type 2 diabetes. 

Videos

Nissen discusses his post-hoc analysis of the SURPASS-CVOT trial, comparing the 2 drugs for a 6-component composite endpoint of cardiorenal outcomes.

The ALPACA trial demonstrated lepodisiran, a long-acting small interfering RNA therapy, significantly and durably reduces lipoprotein(a) [Lp(a)] levels, with effects lasting up to 18 months.

American College of Cardiology (ACC) 2025 Annual Scientific Sessions

, with Eli Lilly and Company announcing the therapy’s progression to the phase 3 ACCLAIM-Lp(a) trial.

“Nearly a quarter of the world’s population has elevated Lp(a), increasing cardiovascular risk, yet no approved therapies exist,” said Steve Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at the Cleveland Clinic. “These findings suggest siRNA approaches like lepodisiran could offer durable benefits with long-term dosing.”

Conducted across 66 sites on 5 continents, ALPACA randomized 320 patients with elevated Lp(a) to receive placebo or one of several lepodisiran regimens. The primary outcome of the trial was time-averaged percent change in Lp(a) from day 60 to 180. Results suggested patients receiving lepodisiran achieved reductions of 40.8%, 75.2%, and 93.9% for the 16 mg, 96 mg, and pooled 400 mg dose groups, respectively.

Additionally, those receiving 400 mg at baseline and day 180 maintained a 74.2% reduction in Lp(a). Secondary outcome analyses revealed the 400 mg group also experienced sustained reductions in apolipoprotein B, with decreases of 14.1% at day 60 and 13.7% at day 180.

Safety data showed treatment-emergent adverse events in 1% of placebo recipients, 3% of the 16 mg group, 12% of the 96 mg group, and 14% of the 400 mg group. No serious adverse events were linked to lepodisiran, though one death occurred in the 16 mg group due to chronic coronary disease complications.

For more on the trial and its implications, check out our interview with principal investigator Nissen.

Lepodisiran, ALPACA, and Lp(a), with Steve Nissen, MD

Relevant disclosures for AbbVie, Inc., Amgen, arrowhead, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Encarda, Esperion Therapeutics, Medtronic, Mineralys, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics.

Nissen SE, Ni W, Shen X, et al. Lepodisiran — A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). 

. Published online March 30, 2025. doi: 10.1056/nejmoa2415818

Eli Lilly and Company. Lilly’s lepodisiran reduced levels of genetically inherited heart disease risk factor, lipoprotein(a), by nearly 94% from baseline at the highest tested dose in adults with elevated levels | Eli Lilly and Company. Eli Lilly and Company. Published March 30, 2025. Accessed March 30, 2025. 

https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart

Steve Nissen, MD, discusses the phase 2 ALPACA trial and how it informs the potential of lepodisiran for lowering Lp(a). 

Steven E. Nissen, MD, MACC

Articles