MUNICH -- A type 2 diabetes regimen that included the novel glucagon-like peptide-1 (GLP-1) analogue semaglutide reduced the risk of major adverse cardiovascular events compared with usual care in an FDA-mandated cardiovascular safety outcomes trial, SUSTAIN 6.

In a high cardiovascular risk population, semaglutide lowered the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke to 6.6% compared with 8.9% in the placebo group getting usual care (HR 0.74, 95% CI 0.58-0.95, P<0.001 for noninferiority).

"This lower risk was principally driven by a significant (39%) decrease in the rate of nonfatal stroke and a nonsignificant (26%) decrease in nonfatal MI, with no significant difference in the rate of cardiovascular death," Steven P. Marso, MD, of HCA Midwest Health Research Medical Center in Kansas City, Mo., and colleagues reported.

The number needed to treat for 24 months to prevent one of the primary endpoint events was 45 in the findings presented here at the European Association for the Study of Diabetes and simultaneously online in the New England Journal of Medicine.

Although the trial was not powered for nor had a prespecified analysis to look for superiority of semaglutide, Marso noted to applause at the session that more events than expected occurred and superiority was seen at P=0.02. In that, semaglutide joined a select group agents reporting a cardiovascular outcome benefit.



Last year, the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) showed a relative 14% reduction in the same major adverse cardiovascular event (MACE) composite compared with placebo in the EMPA-REG trial, although an FDA advisory panel was split on giving it an indication for reducing risk of cardiovascular mortality. Earlier this year, the GLP-1 drug liraglutide (Victoza) was shown to cut major cardiovascular event rates by 13% in the LEADER trial.

But while both of those trials showed significant reductions in cardiovascular mortality and all-cause mortality as individual endpoints with their respective diabetes drugs, SUSTAIN 6 found no such advantage with semaglutide. Rates of death from cardiovascular causes were similar with the drug as with placebo.

The impact on nonfatal MI, which included silent infarcts, was not statistically significant either (2.9% on semaglutide versus 3.9% on placebo, HR 0.74, P=0.12). But for nonfatal stroke, the difference between semaglutide and placebo was significant (1.6% versus 2.7%, HR 0.61, P=0.04).

The impact on the composite was "meaningful" and "quite substantial," discussant Lars Rydén, MD, PhD, an emeritus professor of cardiology at the Karolinska Institute in Stockholm, told attendees. "We are, in the cardiology field, looking at new platelet-stabilizing drugs and we get much smaller impact on the actual reduction of problems than we are having with that."

He agreed with the researchers that cardiovascular impact of semaglutide might be by delaying or otherwise modifying progression of atherosclerosis.

Even more exciting, Rydén suggested, is the potential for combining both classes that have shown a cardiovascular impact -- GLP-1 and SGLT2 -- "which I think is the most fascinating thought for a new trial."

SUSTAIN 6 included 3,297 patients with type 2 diabetes on a standard diabetes care regimen randomized to once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 2.1 years. Among them, 83% qualified for the high-risk criteria by being age 50 or older with established cardiovascular disease and 17% by being age 60 or older with at least one cardiovascular risk factor.

Overall, fewer serious adverse events but more treatment discontinuations (mainly due to GI effects) occurred with semaglutide in a safety profile similar to that of other GLP-1 receptor agonists.

While new or worsening nephropathy was less common with semaglutide, rates of retinopathy complications -- vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation -- were significantly and "unexpectedly" higher (HR 1.76, 95% CI 1.11-2.78).

"An association between rapid glucose lowering and worsening of retinopathy has been reported in patients with type 1 diabetes," the researchers noted. "The applicability of such an association to our finding is unclear, and a direct effect of semaglutide cannot be ruled out."

At the session, coauthor Tina Visbøll, MD, of the University of Copenhagen, pointed out to continued murmurs of the gathered crowd over this risk that the effect was almost entirely accounted for among patients with pre-existing retinopathy at baseline.

Rydén pointed out that LEADER also showed a 15% relative increase in risk of retinopathy, although not significant with few events.

Pancreatic cancer was actually less common with semaglutide, and pancreatitis rates were similarly low in both groups. No medullary thyroid carcinomas occurred in the trial.

"There's been considerable interest in baseline heart rate for the GLP-1 agonists" Marso noted, and there was an increase that at end of trial was 2.1 and 2.4 bpm over placebo for the lower and higher dose groups, respectively.