Major adverse cardiovascular event risk dropped a relative 26% with
the novel glucagon-like peptide-1 (GLP-1) analogue semaglutide in
high-risk type 2 diabetes patients in SUSTAIN 6, the third such
cardiovascular safety outcomes trial to show benefit.
The drug
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.
A number needed to treat for 24 months to prevent one of the primary endpoint events was 45, as reported in the
New England Journal of Medicine and at the European Association for the Study of Diabetes in Munich.
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."
However, "I don't know if that's going to happen," cautioned
Bernard Zinman, MD, of the University of Toronto. Still, he suggested that such findings should heavily influence treatment choices.
"The
added value is they reduce cardiovascular death! My God, who ever
thought we'd have a diabetes therapy that reduces cardiovascular death?"
he told
MedPage Today. "We have three trials now with positive
outcomes as far as cardiovascular results, so they should be given
priority in the algorithm of drugs we would use to treat diabetes."
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, co-author
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.
The trial was funded by Novo Nordisk.
Marso disclosed relationships with Novo Nordisk, Abbott Vascular, and AstraZeneca.
Rydén
disclosed relationships with Amgen, Bayer, Boehringer-Ingelheim, MSD,
Sanofi, Merck, Novo Nordisk, the Swedish Heart-Lung Foundation, Swedish
Diabetes Foundation, Stockholm County Council, Swedish Medical Assembly,
and private donors.
Zinman disclosed relationships with AstraZeneca, Novo Nordisk, Merck, and Lily.
