MILAN —New analyses from the SURPASS-CVOT trial suggest that differences between tirzepatide and dulaglutide in people with type 2 diabetes (T2D) and established cardiovascular disease (CVD) may extend beyond traditional cardiovascular outcomes, with signals emerging in favor of tirzepatide for lower noncardiovascular mortality and improvements in patient-reported health and daily functioning.

The findings prompted discussion here at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting about whether the benefits of incretin-based therapies should increasingly be considered beyond conventional cardiovascular and metabolic outcomes.

"I think we've been cardiovascular-centric," said session moderator, Naveed Sattar, MD, PhD, professor of cardiometabolic medicine at the University of Glasgow, Scotland, highlighting infection, quality of life, and kidney outcomes among effects that also matter to patients.

Primary Analysis 

SURPASS-CVOT randomized 13,299 adults with T2D and established atherosclerotic CVD to tirzepatide (2.5 mg titrated up to a maximum of 15 mg) or dulaglutide 1.5 mg once weekly, on top of standard care. Participants were followed for a median of approximately 4 years.

The primary analysis previously showed that tirzepatide was noninferior, but not superior, to dulaglutide — an established GLP-1 receptor agonist with demonstrated cardiovascular benefit for the primary three-point major adverse cardiovascular events (MACE) endpoint.

MACE occurred in 801 of 6586 participants (12.2%) receiving tirzepatide and 862 of 6579 (13.1%) receiving dulaglutide (hazard ratio [HR], 0.92; 95% CI, 0.83-1.01; P = .003 for noninferiority and P =.09 for superiority).

However, tirzepatide produced substantially greater reductions in A1c and body weight than dulaglutide over the trial.

Looking Beyond MACE 

In one of the current analyses of the trial, presented at the meeting by Stefano Del Prato, MD, professor of endocrinology at Sant'Anna School of Advanced Studies, Pisa, Italy, researchers looked at differences in time to cardiovascular death, time to death of any cause, and rates of noncardiovascular mortality, among other secondary endpoints. 

All-cause mortality was lower with tirzepatide than dulaglutide (HR, 0.84; 95% CI, 0.75-0.94), as was noncardiovascular mortality (HR, 0.76; 95% CI, 0.63-0.91; nominal P = .003), Del Prato reported; however, there was no clear difference between in cardiovascular mortality (HR, 0.92; 95% CI, 0.76-1.10).

The difference in noncardiovascular mortality appeared largely attributable to infection-related deaths. Infection-related deaths occurred in 78 (1.2%) participants receiving tirzepatide vs 138 (2.1%) receiving dulaglutide (HR, 0.56; 95% CI, 0.42 - 0.74). When the analysis was restricted to infection-related deaths unrelated to a COVID diagnosis, the difference persisted (HR, 0.48; 95% CI, 0.34-0.68; P < .001).

There was no corresponding difference in deaths from malignancy, which occurred in 72 participants receiving tirzepatide and 75 receiving dulaglutide (HR, 0.95; 95% CI, 0.69-1.31; P = .76).

Immune Function and Obesity 

Discussing the findings, Samuel Klein, MD, of Washington University School of Medicine in St Louis, questioned whether the lower infection-related mortality observed with tirzepatide could reflect improved immune function accompanying greater weight loss, better glycemic control, or potentially improved blood flow within adipose tissue as fat mass decreases.

Klein noted that obesity is characterized by increased immune activity and inflammation but, paradoxically, reduces effectiveness of the immune system in combating viral, bacterial, and fungal infections. He pointed to evidence linking greater obesity with an increased risk for serious infections requiring hospital treatment, particularly skin and soft-tissue infections. 

He also questioned which types of infections accounted for the difference, noting that although COVID contributed, it did not fully explain the signal. The trial, however, was not designed to establish a mechanism for the infection finding.

Interpreting Mortality Findings 

An audience member questioned how the secondary outcomes should be interpreted because tirzepatide had not demonstrated superiority to dulaglutide for the trial's primary MACE endpoint. 

The differences "were nominal, so you can't say they're statistically significant," said Sattar, describing the findings as "hypothesis-generating."

Patients Report Better Daily Function 

A second analysis presented by Steven E. Kahn, MBChB, of the University of Washington, Seattle, shifted the focus from clinical events to how patients perceived their own health and functioning.

Patient-reported outcomes included the EQ-5D-5L health status index, the EQ visual analogue scale (VAS), the Ability to Perform Physical Activities of Daily Living (APPADL) questionnaire, and the Impact of Weight on Self-Perception questionnaire.

Self-rated health measured by EQ VAS improved more with tirzepatide than dulaglutide, with scores increasing from baseline by 3.9 vs 1.5 points at 24 months and by 2.5 vs 0.5 points at the final visit. 

The APPADL results also favored tirzepatide. At 24 months, the APPADL score had increased by 2.9 points from baseline with tirzepatide compared with a 0.4-point decrease with dulaglutide. At the final visit, scores remained 1.1 points above baseline with tirzepatide but had fallen by 2.6 points with dulaglutide. 

Patient-reported outcomes generally deteriorate over time in people with multimorbidity, noted Khan, adding that he found the APPADL results particularly compelling because the two treatment groups moved in opposite directions.

Weight-related self-perception also improved with both treatments but to a greater extent with tirzepatide (13.4 vs 9.3 points at the final visit). Participants receiving tirzepatide also lost substantially more weight, with 85% achieving at least 5% weight loss compared with 47% receiving dulaglutide at 156 weeks. 

Greater weight loss with tirzepatide appeared to be associated with greater improvements in several patient-reported outcomes, although Kahn cautioned that the analyses could not establish whether weight loss itself accounted for the differences. He also stressed that statistically significant differences in questionnaire scores do not necessarily translate into clinically meaningful changes, but said the divergent APPADL trajectories made that particular finding more compelling.

Assessing Incretin-Based Therapies 

The findings raised a broader question about how the benefits of incretin-based therapies should be assessed. Tirzepatide produced substantially greater improvements in body weight and glycemic control than dulaglutide without demonstrating superiority for the primary cardiovascular endpoint. Yet the newer analyses point to potential differences in outcomes ranging from infection-related mortality to patients' perceptions of their health and daily functioning.

"These drugs have multiple effects," Kahn said during the discussion. "Weight loss is one of them; it's not the only one." 

The active comparator is also important to interpreting SURPASS-CVOT, panelists noted. Rather than being tested against placebo, tirzepatide was compared with dulaglutide, a GLP-1 receptor agonist with established cardiovascular benefit. This set a relatively high bar for demonstrating additional cardiovascular benefit: Despite substantially greater reductions in body weight, A1c, and systolic blood pressure with tirzepatide, any incremental cardiovascular advantage over an already effective therapy may have been relatively small and therefore more difficult to demonstrate during the trial.

Taken together, the analyses suggest that the clinical effects of incretin-based therapies may need to be evaluated across a broader range of outcomes than MACE and weight loss alone, the panelists agreed, adding, however, that the mortality findings in particular remain exploratory and require confirmation.

Sattar reports consulting for and/or receiving speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gan & Lee, Hanmi Pharmaceuticals, Kailera, Metsera, Novo Nordisk, Pfizer, Regeneron, Roche, and Verdiva Bio. 

Kahn declares Altimmune, Amgen, Biomea Fusion, Convergence Therapeutics, Corcept Therapeutics, Eli Lilly, General Medicines, Hoffman La-Roche, Kailera Therapeutics, Neurocrine, Novo Nordisk. 

Del Prato reports advisory-board fees from Abbott, Amgen, Dexcom, Eli Lilly, Hoffmann-La Roche, Innovent, Menarini International, Nephris, Novo Nordisk, Structure Therapeutics, and Sun Pharma; and speaking fees from Abbott, Boehringer Ingelheim, Dexcom, Eli Lilly, Laboratori Guidotti, Menarini International, and Novo Nordisk. 

Klein reported serving on scientific advisory boards for Merck, Boehringer Ingelheim, Regeneron, Eli Lilly, and AbbVie.

Becky McCall, PhD, is a UK-based medical journalist and researcher at University College London. Her research and academic publications focus on antimicrobial resistance and the use of digital storytelling to understand patients' and clinicians' experiences of healthcare. She has reported on medicine and health for more than 20 years, including from major international medical conferences, and writes primarily for Medscape Medical News. Her work has also appeared in The Lancet, Nature Medicine, Re:solve Global Health, The Times, and other publications.