Tirzepatide was noninferior to dulaglutide in reducing a composite of cardiovascular events in people with type 2 diabetes and existing heart disease.Both agents are currently approved for type 2 diabetes, but only dulaglutide also holds an indication for cardiovascular risk reduction.Patients on tirzepatide also experienced more metabolic benefits, such as greater reductions in weight and HbA1c, compared with dulaglutide.
The dual GIP/GLP-1 receptor agonist tirzepatide (Mounjaro, Zepbound) was just as cardioprotective as the GLP-1 drug dulaglutide (Trulicity) in patients with type 2 diabetes and atherosclerotic cardiovascular disease, a large randomized trial showed.
Over a median follow-up of 4 years, 12.2% of those randomized to tirzepatide and 13.1% of those assigned dulaglutide experienced a primary outcome event that included death from cardiovascular causes, myocardial infarction, or stroke (HR 0.92, 95.3% CI 0.83-1.01, P=0.003 for noninferiority), reported Stephen J. Nicholls, MD, PhD, of Monash University in Melbourne, Australia, and colleagues.
For each of these individual components, tirzepatide was also noninferior to dulaglutide:
Death from cardiovascular causes: 5.6% vs 6.2% (HR 0.89, 95% CI 0.77-1.02)Myocardial infarction: 4.7% vs 5.4% (HR 0.86, 95% CI 0.74-1.00)Stroke: 3.5% vs 3.8% (HR 0.91, 95% CI 0.76-1.09)
In a composite secondary endpoint that also included coronary revascularization, tirzepatide was favored over dulaglutide (16.5% vs 18.5%; HR 0.88, 95% CI 0.81-0.96).
“The noninferior effect of tirzepatide as compared with dulaglutide on the primary cardiovascular outcome provides additional evidence that targeting the incretin axis with multiple approaches has a favorable effect on cardiovascular risk in patients with type 2 diabetes,” Nicholls and team wrote in the New England Journal of Medicine.
“Although tirzepatide did not meet the criterion for superiority to dulaglutide with respect to the primary endpoint, a prespecified secondary analysis suggested a possible lower incidence of death from any cause and of death from noncardiovascular causes in the tirzepatide group than in the dulaglutide group,” the researchers wrote. “This finding should be considered exploratory and warrants further investigation.”
Death from any cause occurred in 8.6% and 10.2% of the tirzepatide and dulaglutide groups, respectively (HR 0.84, 95% CI 0.75-0.94), and 3% and 4% died from noncardiovascular causes (HR 0.75, 95% CI 0.63-0.91).
Tirzepatide currently holds indications for type 2 diabetes — supported by the SURPASS program — plus chronic weight management and obstructive sleep apnea. Meanwhile, dulaglutide holds indications for type 2 diabetes and cardiovascular risk reduction.
Tirzepatide-maker Eli Lilly stated plans to submit these data to global regulatory authorities by the end of this year.
The double-blind SURPASS-CVOT trial was conducted across 640 sites in 30 countries from May 2020 to June 2022. A total of 13,165 patients ages 40 and older with type 2 diabetes, an HbA1c between 7% to 10.5%, a body mass index (BMI) of at least 25, and established atherosclerotic cardiovascular disease in at least one vascular territory were included.
Participants were randomized 1:1 to receive weekly subcutaneous injections of tirzepatide at a dose adjusted up to 15 mg or dulaglutide at a dose of 1.5 mg. Tirzepatide was started at a dose of 2.5 mg. At 36 months, 72.7% of patients were on the 15-mg dose.
About a fifth of patients in both groups prematurely discontinued study drugs.
Average age was 64 years, 29% were women, average BMI was 32.6, and HbA1c was 8.4%. Most (65%) had coronary artery disease, 19.2% had a history of stroke, a quarter had peripheral artery disease, and 20.3% had a history of heart failure. Diabetes duration averaged 14.7 years.
At enrollment, most (81.4%) were on metformin, about half were receiving insulin, 30.6% were on an SGLT2 inhibitor, and 21.6% were on a sulfonylurea. Risk for the primary endpoint didn’t differ according to baseline SGLT2 use.
In addition to the endpoints described above, improvements in a host of metabolic factors also favored tirzepatide at 36 months:
HbA1c: -1.66 vs -0.88 percentage points with tirzepatide and dulaglutide, respectivelyBody weight: -11.6% vs -4.8%Systolic blood pressure: -6.2 vs -4.1 mmHg
There was also a greater decrease in triglyceride level with tirzepatide compared with dulaglutide at 24 months (-24.2% vs -10.2%). Change in LDL wasn’t significantly different.
“Additional analyses will be required to determine the contribution of different metabolic effects of tirzepatide and dulaglutide to the observed cardiovascular outcomes,” the team wrote. “These metabolic effects are factors that can be considered when clinicians and patients decide on the use of glucose-lowering therapies.”
In patients with high- or very-high-risk chronic kidney disease, estimated glomerular filtration rate dropped significantly more with dulaglutide at 36 months (-5.72 vs -8.90 mL/min/1.73 m2).
Rates of adverse events were generally comparable between the two agents, though gastrointestinal events were more common with tirzepatide (42.5% vs 35.9%). Severe hypoglycemia occurred in 0.7% of both groups, and acute kidney injury occurred in 3.4% of those on tirzepatide compared with 2.7% of those on dulaglutide. Medullary thyroid cancer occurred in two tirzepatide patients, and one tumor was positive for a RET proto-oncogene mutation.
Over 80% of participants were white, which may limit generalizability. The findings are also only applicable to people with type 2 diabetes, the researchers noted.