IPM Take
Cardiometabolic trials have spent years asking whether newer diabetes medicines prevent heart attacks and strokes.
SURPASS-CVOT raises a different question: what if some of the clinically important effects sit outside MACE?
The original trial enrolled 13,299 people with type 2 diabetes and established atherosclerotic cardiovascular disease and compared tirzepatide directly with dulaglutide, an active GLP-1 receptor agonist with established cardiovascular benefit. Tirzepatide was noninferior, but not superior, for cardiovascular death, myocardial infarction or stroke. The primary endpoint occurred in 12.2% versus 13.1% of participants, respectively, with a hazard ratio of 0.92.
At EASD 2026, however, researchers showed something different.
All-cause mortality was lower with tirzepatide, while the largest apparent difference in noncardiovascular mortality came from infection-related deaths. Participants also reported better physical functioning and self-rated health.
That does not turn a non-superior cardiovascular trial into a superior one.
But it does challenge an increasingly outdated idea that the value of cardiometabolic therapy can be captured entirely by MACE, HbA1c and kilograms lost.
Executive Summary
SURPASS-CVOT randomised 13,299 adults with type 2 diabetes and established atherosclerotic cardiovascular disease to weekly tirzepatide or dulaglutide on top of standard care, with median follow-up of approximately four years. Tirzepatide met the trial’s primary objective of cardiovascular noninferiority but did not establish superiority.
At EASD 2026, investigators presented secondary analyses showing:
- All-cause mortality: HR 0.84, 95% CI 0.75-0.94.
- Noncardiovascular mortality: HR 0.76, 95% CI 0.63-0.91.
- Infection-related deaths: 78 with tirzepatide versus 138 with dulaglutide, HR 0.56.
- When COVID-related deaths were excluded, the infection signal persisted, HR 0.48.
- Cardiovascular mortality itself did not clearly differ, HR 0.92.
- Deaths from malignancy were also similar between groups.
Separate patient-reported analyses showed greater improvement with tirzepatide in self-rated health, physical activities of daily living and weight-related self-perception. At 24 months, APPADL scores increased by 2.9 points with tirzepatide but fell by 0.4 points with dulaglutide.
The major caveat is statistical. Because superiority was not established for the primary cardiovascular endpoint, investigators described the mortality analyses as nominal and hypothesis-generating, rather than confirmatory evidence of a mortality benefit.
Why it matters
- HTA bodies: The findings reinforce the case for looking beyond HbA1c, weight and conventional cardiovascular composites when assessing cardiometabolic therapies. Physical function and health status can matter greatly to patients, but exploratory mortality signals require confirmation before being incorporated as established comparative benefits.
- Payers: Tirzepatide already delivers greater weight and glycaemic reductions than dulaglutide. If future research confirms benefits in hospitalisation, infection or functional outcomes, value assessments could broaden considerably. For now, those additional benefits should not be priced in as proven.
- Industry / innovation partners: Active-comparator CVOTs are raising the evidentiary bar. New incretin therapies may increasingly need to demonstrate value against drugs that already protect the cardiovascular system, making broader outcomes such as kidney disease, function, quality of life and other complications more relevant to differentiation.
SURPASS-CVOT did not deliver a clean cardiovascular superiority story.
That may be precisely why its secondary findings are interesting.
The landmark trial directly compared tirzepatide with dulaglutide in people who already had both type 2 diabetes and atherosclerotic cardiovascular disease. This was not a placebo-controlled study. Dulaglutide already has evidence of cardiovascular benefit, meaning tirzepatide was being tested against an effective cardiometabolic therapy rather than an inactive comparator.
The result was reassuring but not dominant.
Three-point MACE occurred in 801 of 6,586 people receiving tirzepatide and 862 of 6,579 receiving dulaglutide. Tirzepatide satisfied the prespecified noninferiority criterion, but the P value for superiority was 0.09.
Yet the treatments separated much more clearly on weight and glycaemic control.
And now the EASD analyses suggest they may also differ elsewhere.
The unexpected infection signal
The most striking finding involved deaths from infection.
There were 78 infection-related deaths in the tirzepatide group compared with 138 with dulaglutide, corresponding to a hazard ratio of 0.56. Excluding deaths attributed to COVID did not remove the signal.
Why might that happen?
One hypothesis is that larger reductions in body weight and improved glycaemic control could influence immune function. Obesity and diabetes are both associated with altered immune responses and greater vulnerability to severe infections. Investigators also raised possible effects related to inflammation and adipose-tissue physiology.
But SURPASS-CVOT was not designed to determine the mechanism, and the infection result was not the trial’s primary endpoint.
Independent epidemiological research strengthens the biological plausibility without proving causation. A large multicohort analysis published in 2026 found obesity associated with greater risk of severe infection and infection-related mortality across multiple populations.
A separate 2026 BMJ real-world study comparing tirzepatide with sitagliptin also reported fewer serious infections and lower infection-related mortality among tirzepatide users, although the observational design leaves residual confounding possible.
The convergence is interesting.
It is not yet confirmation.
Patients also reported functioning better
The second EASD analysis asks a more patient-centred question.
Did people actually feel or function differently?
Participants completed measures including the EQ-5D-5L, EQ visual analogue scale and Ability to Perform Physical Activities of Daily Living questionnaire.
At 24 months, self-rated health improved by 3.9 points from baseline with tirzepatide versus 1.5 with dulaglutide. APPADL scores improved by 2.9 points with tirzepatide while decreasing by 0.4 points with dulaglutide. By the final visit, the groups continued to move in different directions on physical functioning.
The investigators appropriately cautioned that a statistically significant questionnaire difference is not automatically a clinically meaningful one.
Greater weight loss also correlated with greater improvements in several patient-reported outcomes, but the analysis could not establish that weight loss caused those improvements.
MACE is still central, but perhaps no longer sufficient
The findings fit a broader transformation in cardiometabolic medicine.
Historically, diabetes drugs were judged predominantly by glucose control and cardiovascular safety. Newer incretin therapies affect weight, kidney disease, heart failure, sleep apnoea, physical function and other health domains.
The updated 2026 ADA/EASD consensus report reflects that expansion, discussing cardiometabolic treatment according to cardiovascular, kidney, weight and other disease-specific benefits rather than glucose lowering alone. It also records SURPASS-CVOT as demonstrating cardiovascular noninferiority to dulaglutide.
That does not mean endpoints should simply multiply until every therapy looks beneficial.
Quite the opposite.
As trials measure more outcomes, the distinction between prespecified confirmatory endpoints and exploratory findings becomes more important.
SURPASS-CVOT’s infection and mortality results are therefore valuable because they generate a new question, not because they settle it.
Tirzepatide did not prove superior cardiovascular protection to dulaglutide in the trial’s primary analysis.
But the EASD data suggest the clinical effects of modern cardiometabolic medicines may extend into areas that traditional cardiovascular trials were never designed to place centre stage.
The next challenge is proving which of those signals are real.
