Tirzepatide gained an FDA cardiovascular indication after SURPASS-CVOT showed noninferiority to dulaglutide in high-risk adults.
The FDA has expanded the indication for
“While a large portion of type 2 diabetes care is focused on glucose control, mitigating cardiovascular risk is essential and can be overlooked,” David A. D’Alessio, MD, study coauthor and director of the Division of Endocrinology and Metabolism at Duke University School of Medicine, said in the press release.1
The expanded indication was based on data from
Participants were randomly assigned 1:1 to receive once-weekly subcutaneous tirzepatide, titrated to 15 mg or the maximum tolerated dose, or dulaglutide 1.5 mg. The primary end point was time to first 3-point major adverse cardiovascular event, defined as cardiovascular death, myocardial infarction, or stroke.
During a median follow-up of 210.1 weeks, tirzepatide met the prespecified criterion for noninferiority to dulaglutide. The hazard ratio for the primary end point was 0.92 (95.3% CI, 0.83-1.01), corresponding to an 8% lower relative event rate with tirzepatide.¹ Superiority over dulaglutide was not established.
That distinction is clinically important. SURPASS-CVOT showed that cardiovascular outcomes with tirzepatide were no worse than those with an active comparator already known to reduce cardiovascular risk; it did not demonstrate that tirzepatide was superior. The company announcement did not provide absolute event rates, numbers needed to treat, or subgroup results, limiting assessment of the magnitude and consistency of benefit.
Cardiovascular risk remains central to type 2 diabetes management. An analysis of US adults found a substantial burden of subclinical cardiovascular disease among people with diabetes, including disease not previously recognized clinically.³ Dulaglutide and other agents with cardiovascular outcome data already form part of the treatment landscape, making the active-comparator design relevant to therapeutic decision-making.
Tirzepatide is a once-weekly peptide that activates glucose-dependent insulinotropic polypeptide and GLP-1 receptors. Its metabolic effects include glucose-dependent insulin secretion, reduced glucagon concentrations, delayed gastric emptying, and reduced food intake.⁴ The cardiovascular indication adds an outcomes-based use to its established glycemic indication.
Safety findings in SURPASS-CVOT were described as consistent with tirzepatide’s known profile. Gastrointestinal events were most common, were generally mild to moderate, and occurred primarily during dose escalation. The prescribing information also warns about pancreatitis, hypoglycemia when used with insulin or sulfonylureas, acute kidney injury associated with dehydration, severe gastrointestinal reactions, gallbladder disease, hypersensitivity, and aspiration risk during anesthesia or deep sedation. Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.⁴
Remaining questions include absolute cardiovascular benefit, comparative effects across patient subgroups, treatment discontinuation, and applicability to patients without established atherosclerotic cardiovascular disease. Although the FDA indication covers adults considered at high cardiovascular risk, the pivotal trial specifically enrolled patients with established disease.
