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Novel GLP-1 receptor agonist shows reduction in cardiovascular risk

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Delayed atherosclerosis may be mechanism in reduced outcomes

SUSTAIN-6 is a carefully planned, well-performed, and objectively reported trial that showed a meaningful reduction in the cardiovascular endpoint of first occurrence of cardiovascular death, nonfatal MI, or stroke of 26%.

Comparing the HbA1c attained across cardiovascular outcome trials of other antihyperglycemic drugs, semaglutide was more efficient in SUSTAIN-6 than in the two cardiovascular outcome trials that have thus far shown cardiovascular benefit, LEADER (N Engl J Med. 2016;375:311-32) in liraglutide and EMPA-REG (N Engl J Med. 2015;373:2117-128) in empagliflozin, lowering HbA1c to 7.3, compared with 7.7 and 8.0, respectively.

Michele G. Sullivan

Dr. Lars Rydén

However, that doesn’t explain the greater absolute risk reduction in the primary outcome of 2.6% in SUSTAIN-6, compared with LEADER (1.9%) and EMPA-REG (1.6), even with a shorter trial duration. But duration of action may hold the key. Semaglutide has a half-life of 7 days, compared with 13 hours for liraglutide and roughly 4 hours for lixisenatide, so perhaps it’s very important to cover the full day before you start to get the impact.

Considering the slow onset of action and the impact on stroke, myocardial infarction, and revascularization, the delay of progress, or regression of atherosclerosis, is likely the important mechanism.

Dr. Lars Rydén is a cardiologist at the Karolinska Institute in Stockholm. He has received research support from Amgen, Bayer AG, Boehringer-Ingelheim, Merck, and Novo Nordisk, the developer of semaglutide. He made these comments as designated discussant for the SUSTAIN-6 report.


AT EASD 2016


The novel glucagonlike peptide 1 (GLP-1) receptor agonist semaglutide may reduce the risk of cardiovascular events in patients with type 2 diabetes who are at elevated cardiovascular risk, according to data presented Sept. 16 at the annual meeting of the European Association for the Study of Diabetes and simultaneously published online in the New England Journal of Medicine.

“In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide,” wrote Steven P. Marso, MD, and his coinvestigators.

SUSTAIN-6 was a randomized, placebo-controlled, noninferiority trial in which 3,297 patients with type 2 diabetes, 85% of whom had established cardiovascular disease, were assigned to take either once-weekly semaglutide (0.5 mg or 1 mg) or placebo.

At the end of the 2-year study period, patients on semaglutide had a statistically significant, 26% lower risk of first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, the study’s primary composite outcome, compared with those on placebo (P less than .001), Dr. Marso and his associates wrote. This outcome occurred in 108 of 1,648 patients (6.6%) in the semaglutide group and in 146 of 1,649 patients (8.9%) in the placebo group.

Specifically, the study showed a 26% reduction in the risk of nonfatal MI (P = .12) and 39% reduction in nonfatal stroke (P = .04) with semaglutide, while the rates of cardiovascular death and heart failure hospitalizations were similar between the two arms of the study.

Overall, 60.5% of the patients in the study had a history of cardiovascular disease, and nearly one-third had a history of MI (N Engl J Med. 2016 Sep 16. doi: 10.1056/NEJMoa1607141).

“In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide,” wrote Dr. Marso of the Research Medical Center in Kansas City, Mo., and coauthors. “The beneficial effect of semaglutide on cardiovascular outcomes may relate to modification of the progression of atherosclerosis.”

Semaglutide has a longer duration of action than the approved GLP-1 receptor agonists – liraglutide, exenatide, albiglutide, dulaglutide, and lixisenatide – allowing for once-weekly subcutaneous injection.

Patients enrolled in the study were all on a standard care regimen, but those taking semaglutide showed significant and sustained reductions in hemoglobin A1c levels, compared with placebo, as well as a higher incidence of clinically meaningful and sustained weight loss, and reductions in systolic blood pressure.

The reductions in HbA1c, body weight, and systolic blood pressure may all have contributed to the observed reduction in cardiovascular risk with semaglutide,” the authors noted.

The study did observe significantly higher rates of diabetic retinopathy complications in patients taking semaglutide. The overall incidence of these complications occurred in 50 patients (3.0%) in the semaglutide group and 29 (1.8%) of the placebo patients, yielding a hazard ratio of 1.76 (P = .02). More patients in the semaglutide group required retinal photocoagulation or the use of an intravitreal agent, had a vitreous hemorrhage, or had developed diabetes-related blindness.

However, patients taking semaglutide also had a 36% lower incidence of new or worsening nephropathy (P = .005), and the frequency of serious adverse events was also lower in the semaglutide group than in the placebo patients.

“With the exception of complications of retinopathy, semaglutide had a safety profile similar to that of other GLP-1 receptor agonists,” the authors reported. The rates of malignant neoplasms were similar in both arms of the study, and the rate of pancreatic cancer, which is known to be an event of interest for this class of drugs, was lower in the semaglutide arm, compared with placebo.

Semaglutide is in development and not yet approved for the treatment of type 2 diabetes.

Starting in 2008, all new drug applications to the Food and Drug Administration for antihyperglycemic agents must include evidence that therapy will not increase the risk of cardiovascular events; SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects with Type 2 Diabetes) was designed to fill that need for semaglutide, and is being developed by Novo Nordisk.

The study was supported by Novo Nordisk. Thirteen authors declared consultancies, grants, fees, and other support from pharmaceutical companies, including Novo Nordisk, and three authors were employees of Novo Nordisk.

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