(AGENPARL) - Roma, 23 Dicembre 2025 - (AGENPARL) – Tue 23 December 2025 T h e n e w e ng l a n d j o u r na l o f m e dic i n e
Original Article
Cardiovascular Outcomes with Tirzepatide
versus Dulaglutide in Type 2 Diabetes
S.J. Nicholls,1 I. Pavo,2 D.L. Bhatt,3 J.B. Buse,4 S. Del Prato,5 S.E. Kahn,6
A.M. Lincoff,7 D.K. McGuire,8,9 D. Miller,2 M.A. Nauck,10,11 H. Nishiyama,2
S.E. Nissen,12,13 N. Sattar,14 G. Weerakkody,2 R.J. Wiese,2 B. Zinman,15,16
S. Zoungas,1,17 J. Basile,18,19 M.J. Davies,20,21 F. Giorgino,22 M. Kellerer,23,24 L. Ji,25
T. Varkonyi,26 V. Menon,12,13 J.C. Broder,17,27 A. Herschtal,27 and D. D’Alessio,28
for the SURPASS-CVOT Investigators*​​
A BS T R AC T
BACKGROUND
Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucosedependent insulinotropic polypeptide receptors, has favorable effects on glycemic
control and body weight. The effects on cardiovascular outcomes are uncertain.
METHODS
We conducted an active-comparator–controlled, double-blind, noninferiority trial
in which patients with type 2 diabetes and atherosclerotic cardiovascular disease
were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection
of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown
to reduce the incidence of cardiovascular events. The primary end point was a
composite of death from cardiovascular causes, myocardial infarction, or stroke
and was tested for noninferiority of tirzepatide to dulaglutide with a margin of
1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An
upper limit of less than 1.00 was considered to indicate superiority of tirzepatide
to dulaglutide.
The authors’ full names, academic degrees,
and affiliations are listed at the end of the
article. Stephen J. Nicholls can be contacted at ­stephen​.­nicholls@​­monash​.­edu or at
the Victorian Heart Institute, Monash
University, 631 Blackburn Rd., Clayton,
VIC 3168, Australia.
*A complete list of the SURPASS-CVOT
Investigators is provided in the Supplementary Appendix, available at NEJM.org.
N Engl J Med 2025;393:2409-20.
Copyright © 2025 Massachusetts Medical Society.
RESULTS
A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-totreat population thus included 6586 patients in the tirzepatide group and 6579 in
the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years,
29.0% were women, the mean body-mass index (the weight in kilograms divided
by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin
level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and
862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority). The incidence
of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group.
CONCLUSIONS
Among patients with type 2 diabetes and atherosclerotic cardiovascular disease,
tirzepatide was noninferior to dulaglutide with respect to a composite of death
from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly;
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T h e n e w e ng l a n d j o u r na l o f m e dic i n e
A Quick Take
is available at
NEJM.org
herapies targeting incretin hormone receptors have an increasing role in
the management of type 2 diabetes and in
strategies to promote weight loss.1 Clinical trials
have shown that glucagon-like peptide-1 (GLP-1)
receptor agonists reduce the incidence of major
adverse cardiovascular events among patients with
high cardiovascular risk and type 2 diabetes,2-7
chronic kidney disease,8,9 or obesity.10 Clinical
guidelines have integrated the use of GLP-1 receptor agonists into the treatment of patients at
high cardiovascular risk.11-14
Tirzepatide is a dual agonist of the GLP-1 and
glucose-dependent insulinotropic polypeptide receptors.15 Clinical trials have shown that tirzepatide leads to incremental benefits with respect to
glycemic control, weight, atherogenic lipoprotein
levels, blood pressure, and kidney-related outcomes as compared with selective GLP-1 receptor agonists or other glucose-lowering agents.16-22
These benefits, if sustained over time, could also
have incremental effects on the incidence of atherosclerotic events. However, data from a randomized, clinical trial of the effect of tirzepatide
on cardiovascular outcomes have been lacking.
The established role of GLP-1 receptor agonists
in the management of type 2 diabetes in patients
with high cardiovascular risk2-7 precluded direct
comparison of tirzepatide with a placebo control
in a large, long-term clinical trial.23 We conducted
the Study of Tirzepatide Compared with Dulaglutide on Major Cardiovascular Events in Participants with Type 2 Diabetes (SURPASS-CVOT)
to determine the cardiovascular effects of tirzepatide as compared with those of the selective
GLP-1 receptor agonist dulaglutide in patients with
type 2 diabetes and established atherosclerotic
cardiovascular disease.24 Because dulaglutide has
been shown to reduce the incidence of cardiovascular events as compared with placebo,5 we sought
to determine whether tirzepatide was noninferior to dulaglutide with respect to cardiovascular
events, as well as whether tirzepatide was associated with a greater cardiovascular benefit.
domized, active-comparator–controlled trial at
640 sites in 30 countries (additional details are
provided in the Supplementary Appendix, available at NEJM.org). The trial was designed by the
sponsor, Eli Lilly, in collaboration with the academic executive committee. The protocol was
approved by the ethics committee at each participating site. The sponsor oversaw the conduct
of the trial, undertook site monitoring, collected
the data, and performed the initial statistical
analysis. Subsequently, the database was transferred to Monash University, Melbourne, VIC,
Australia, and statisticians affiliated with the university validated the data analyses. An independent data and safety monitoring committee reviewed the safety and efficacy data during the
trial. The first author wrote the first draft of the
manuscript, which was edited and approved by
all the authors. The sponsor reviewed the manuscript and suggested revisions, but the final decision on content was reserved for the first author,
who made the decision to submit the manuscript
for publication. The first author vouches for the
accuracy and completeness of the data and for the
fidelity of the trial to the protocol and the statistical analysis plan.
Trial Population
Patients at least 40 years of age were eligible if
they had type 2 diabetes with a glycated hemoglobin level between 7.0% (53 mmol per mole)
and 10.5% (91 mmol per mole), a body-mass index (BMI; the weight in kilograms divided by the
square of the height in meters) of at least 25, and
established atherosclerotic cardiovascular disease
in at least one vascular territory. Among the exclusion criteria were any cardiovascular event
in the 60 days before screening, use of a GLP-1
receptor agonist or pramlintide in the 3 months
before screening, planned treatment for diabetic
retinopathy or macular edema, chronic advanced
heart failure, a history of pancreatitis, a clinically significant abnormality in gastric emptying
or previous bariatric surgery, active liver disease
(not including metabolic dysfunction–associated
steatohepatitis), an estimated glomerular filtraMe thods
tion rate (eGFR) of less than 15 ml per minute
Trial Organization and Oversight
per 1.73 m2 of body-surface area or use of long24
The trial design has been described previously, term dialysis, or a family or personal history of
and the trial protocol and statistical analysis plan multiple endocrine neoplasia or medullary thyroid
are available with the full text of this article at carcinoma. All the patients provided written inNEJM.org. We conducted this double-blind, ran- formed consent. Additional details with regard
n engl j med 393;24
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Cardiovascular Outcomes with Tirzepatide
to inclusion and exclusion criteria, as well as
criteria for established atherosclerotic cardiovascular disease, are provided in the Supplementary
Appendix.
Randomization and Trial Regimen
Eligible patients were randomly assigned in a 1:1
ratio to receive weekly subcutaneous injections
of tirzepatide at a dose adjusted up to 15 mg or
dulaglutide at a dose of 1.5 mg. Randomization
was stratified according to country and the use
of sodium–glucose cotransporter 2 (SGLT2) inhibitors at baseline. Tirzepatide was initiated at
a dose of 2.5 mg and increased by 2.5 mg every
4 weeks to a maximum of 15 mg or to the maximum tolerated dose. Because the dose of dulaglutide remained at 1.5 mg throughout the trial, a
sham dose-escalation scheme was used to maintain trial blinding. Discontinuation of dipeptidyl
peptidase 4 inhibitors was recommended at the
time of randomization. The glucose-control regimen was adjusted during the trial, at the discretion of the site investigator, with the use of
open-label nonincretin agents in accordance
with national guidelines for glycemic control.
Adjustment of the blinded trial medication dose
was permitted at the discretion of the investigator. Patients were monitored at trial visits every
4 weeks for the first 24 weeks and every 3
months thereafter (Fig. S1 in the Supplementary
Appendix).
Trial End Points
The primary end point was a composite of death
from cardiovascular causes, myocardial infarction,
or stroke, assessed in a time-to-first-event analysis. Key secondary end points included death
from cardiovascular causes; myocardial infarction;
stroke; death from any cause; a composite of death
from cardiovascular causes, myocardial infarction,
stroke, or coronary revascularization; a composite of death from cardiovascular causes or hospitalization or urgent visit for heart failure; the
change from baseline to 36 months in the eGFR
according to the Chronic Kidney Disease Epidemiology Collaboration creatinine–cystatin equation 202125 in patients with high-risk or veryhigh-risk chronic kidney disease as defined by
the Kidney Disease: Improving Global Outcomes
2024 guideline (an eGFR of ≥60 ml per minute
per 1.73 m2 and a urinary albumin-to-creatinine
ratio of >300 [with albumin measured in miln engl j med 393;24
ligrams and creatinine measured in grams], an
eGFR of 45 to 30, or
an eGFR of