Just over a month after Novo Nordisk announced positive top-line results for liraglutide (Victoza, Novo Nordisk), showing that it significantly reduced the risk of major adverse cardiovascular events in the LEADER Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial, the company has announced another positive study of a similar agent — both are glucagonlike peptide-1 (GLP-1) agonists for the treatment of type 2 diabetes; this time it is a once-weekly product called semaglutide, which is not yet approved anywhere.
The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes(SUSTAIN-6) examines the long-term cardiovascular and other safety outcomes of 0.5-mg and 1.0-mg semaglutide, which was administered subcutaneously once weekly and compared with placebo, both in addition to standard of care, in approximately 3300 people with type 2 diabetes treated for 104 weeks.
"The trial achieved its primary end point of showing noninferiority of major cardiovascular events (MACE) with semaglutide compared with placebo, as well as a statistically significant reduction in cardiovascular risk," Novo Nordisk says in a press statement.
In the trial, around 250 MACE were accrued. The primary end point of the study was defined as the composite outcome of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
The safety profile of semaglutide in SUSTAIN 6 "was as expected and consistent with previous semaglutide clinical studies," the company notes.
SUSTAIN-6 Will Be Presented, but Not at ADA
Full results of SUSTAIN-6 will be presented at an upcoming meeting, but asked whether this was likely to be the American Diabetes Association conference in New Orleans in June, a spokesperson told Medscape Medical News this was "not realistic."
The company is already gearing up to present the full results of LEADER at the ADA meeting, which are hotly anticipated by endocrinologists.
Although a prior trial, ELIXA, demonstrated no safety concerns with the GLP-1 agonist lixisenatide (Lyxumia, Sanofi), LEADER will be the first trial in which a GLP-1 agonist has shown cardiovascular benefit in the patient population — those with type 2 diabetes at high risk of cardiovascular events.
Liraglutide, a GLP-1 agonist administered by daily subcutaneous injection, has been on the market for some time for the treatment of type 2 diabetes and was more recently approved, at a higher dose, for the treatment of obesity (as Saxenda).
Liraglutide is now the third glucose-lowering agent to show cardiovascular benefit and the first of the GLP-1 class.
The first glucose-lowering drug to show a cardiovascular benefit was the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) trial, reported at the European Association for the Study of Diabetes (EASD) meeting in Stockholm in September 2015.
And pioglitazone (Actos, Takeda Pharmaceuticals), also available generically now, demonstrated cardiovascular benefit over a decade ago in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) and more recently in in the IRIS study in patients with insulin resistance but not diabetes. However, the agent is also associated with higher rates of edema, weight gain, and heart failure, and there is still a question over its potential association with bladder cancer.
Filings for Semaglutide by Year-end; Oral Version in Development
Novo Nordisk says it expects to file the once-weekly subcutaneous form of semaglutide for regulatory review in the United States and European Union in the fourth quarter of 2016.
"We are very encouraged by the potential for reduction of CV risk in people with type 2 diabetes with semaglutide based on the results of SUSTAIN-6. In addition to the strong efficacy profile, we have also established the safety profile for semaglutide by concluding the six SUSTAIN trials," Mads Krogsgaard Thomsen, executive vice president and chief science officer of Novo Nordisk, added in the statement. "With the strong results from SUSTAIN-6, we look forward to the regulatory filing of semaglutide."
Semaglutide is one of a number of once-weekly subcutaneous GLP-1 agonists available or in development.
Semaglutide is also being developed in an oral tablet version for treatment of type 2 diabetes — encouraging phase 2 results were reported with this formulation at the recent ENDO 2016 meeting. And semaglutide is being developed as a once-daily subcutaneous injection for the treatment of type 2 diabetes and weight management, the company adds.
SUSTAIN-6 is the culmination of a global phase 3 clinical development program for semaglutide injection, comprising six trials and encompassing more than 7000 people with type 2 diabetes.
The other trials were: