SUSTAIN 6

SUSTAIN 6. It was a pivotal, multi-national, randomized, double-blind, placebo-controlled cardiovascular outcomes trial designed to assess the long-term cardiovascular safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with type 2 diabetes at high cardiovascular risk. The trial was a critical component of the regulatory requirements established by the U.S. Food and Drug Administration and the European Medicines Agency for new antidiabetic medications. Its primary aim was to demonstrate that semaglutide did not increase the risk of major adverse cardiovascular events compared to placebo, building upon the safety profile established in earlier phase 3 trials of the SUSTAIN clinical trial program.

Background and rationale

Following concerns raised by the rosiglitazone controversy and subsequent mandates from the U.S. Food and Drug Administration, all new antidiabetic drugs were required to demonstrate cardiovascular safety in large, dedicated outcomes trials. This regulatory landscape emerged from the RECORD study and led to a series of trials for newer drug classes, including those for SGLT2 inhibitors like empagliflozin in the EMPA-REG OUTCOME trial and glucagon-like peptide-1 receptor agonists. The SUSTAIN clinical trial program, conducted by Novo Nordisk, was designed to evaluate the efficacy and safety of semaglutide, with SUSTAIN 6 specifically mandated to address the cardiovascular safety question. The rationale was to provide definitive evidence for clinicians and regulators, ensuring that the glycemic control benefits of semaglutide were not offset by unforeseen cardiovascular harms.

Study design and participants

SUSTAIN 6 was a randomized, double-blind, placebo-controlled trial conducted across multiple countries. A total of 3,297 participants with type 2 diabetes who were at high risk for cardiovascular events were enrolled. High risk was defined as being age 50 or older with established cardiovascular disease, chronic kidney disease, or congestive heart failure, or being age 60 or older with at least one cardiovascular risk factor such as microalbuminuria, hypertension, or dyslipidemia. Participants were randomized to receive either once-weekly subcutaneous semaglutide or matching placebo, in addition to their standard care. The trial's primary endpoint was a composite of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The median follow-up duration was 2.1 years, which was relatively short for a cardiovascular outcomes trial but deemed sufficient to assess safety signals.

Results and outcomes

The trial met its primary objective, demonstrating that semaglutide was noninferior to placebo with respect to the primary composite cardiovascular endpoint. Furthermore, semaglutide showed a statistically significant reduction in the primary endpoint, with a hazard ratio of 0.74. This benefit was driven primarily by significant reductions in nonfatal stroke and nonfatal myocardial infarction; there was no significant difference in the rate of cardiovascular death. Semaglutide also led to greater reductions in glycated hemoglobin, body weight, and systolic blood pressure compared to placebo. However, rates of diabetic retinopathy complications, a prespecified secondary endpoint, were higher in the semaglutide group, a finding that prompted further investigation. The results were first presented at the European Association for the Study of Diabetes annual meeting and subsequently published in *The New England Journal of Medicine*.

Significance and impact

The results of SUSTAIN 6 had an immediate and profound impact on the management of type 2 diabetes. It provided robust evidence that semaglutide not only controlled blood sugar and promoted weight loss but also offered cardiovascular protection, a highly desirable combination for a high-risk population. This positioned semaglutide favorably against other drug classes and influenced updates to major clinical guidelines from organizations like the American Diabetes Association and the European Society of Cardiology. The trial's success significantly bolstered the commercial prospects for Novo Nordisk's product, Ozempic, and reinforced the strategic importance of cardiovascular outcomes trials in the pharmaceutical industry. It also contributed to the evolving paradigm in diabetology, where cardiovascular and renal benefits became key differentiators among therapeutic options.

Criticisms and limitations

Despite its positive findings, SUSTAIN 6 faced several criticisms and had acknowledged limitations. The trial duration of 2.1 years was considered short for a definitive assessment of long-term cardiovascular outcomes, especially compared to longer trials like LEADER for liraglutide. The higher incidence of diabetic retinopathy complications, though potentially linked to rapid glycemic control, raised safety concerns that required clarification in post-marketing studies. Furthermore, the trial was not powered to assess individual components of the primary endpoint or to detect differences in heart failure hospitalization or renal outcomes, areas where other drug classes like SGLT2 inhibitors had shown benefit. Some statisticians also noted that the early termination of the trial for efficacy may have led to an overestimation of the treatment effect.

Category:Clinical trials Category:Diabetes Category:Cardiology