Research highlights
Obesity
SELECT shows cardiovascular risk reduction
with weight-loss drug semaglutide in people
without diabetes
Treatment with the glucagon-like peptide
1 receptor (GLP1R) agonist semaglutide,
administered subcutaneously at a dose of
2.4 mg once per week, reduces the risk
of major cardiovascular events by 20%
compared with placebo in patients who are
overweight or obese and with pre-existing
cardiovascular disease but without diabetes
mellitus and who were already receiving
guideline-directed therapy. This finding
from the SELECT trial was presented at the
AHA Scientific Sessions 2023.
“There was uncertainty in the field about
whether any approved weight-loss drug
would show meaningful benefit on cardio-
vascular outcomes given the chequered
history of harm or no benefit in trials of
agents tested in the past,” comments Naveed
Sattar from the University of Glasgow in
the UK, who was not involved in the SELECT
trial. “However, GLP1R agonists were shown
repeatedly to lower adverse cardiovascular
outcomes in patients with diabetes and
thus there was more optimism that SELECT
would show similar benefit in those without
diabetes but who were living with obesity or
a high BMI,” he adds.
SELECT was a multicentre, double-blind,
randomized, placebo-controlled, event-
driven superiority trial designed to assess
whether addition of semaglutide (2.4 mg
once per week) to standard care would
reduce the excess cardiovascular risk that is
associated with being overweight or obese
in patients with no history of diabetes.
The trial included a total of 17,604 patients
nature reviews cardiology
https://doi.org/10.1038/s41569-023-00970-3
with pre-existing cardiovascular disease
and a BMI of ≥27 kg/m2 but without diabetes
(mean age 61.6 years; 72.3% men). Of note,
approximately 66% of the patients had
pre-diabetes (defined as a mean glycated
haemoglobin level of 5.7–6.4%).
After a mean treatment duration
of 34.2 months and a mean follow-up of
39.8 months, semaglutide was superior to
placebo in reducing the risk of the primary
cardiovascular end point (a composite of
death from cardiovascular causes, non-fatal
myocardial infarction or non-fatal stroke),
with a primary cardiovascular event occur-
ring less frequently in the semaglutide group
than in the placebo group (6.5% versus 8.0%;
HR 0.80, 95% CI 0.72–0.90, P < 0.001). Inter-
estingly, the effects of semaglutide occurred
early after the treatment initiation.
The incidence of death from cardio­
vascular causes (the first confirmatory
secondary end point) was not significantly
different between the semaglutide and
placebo groups (2.5% versus 3.0%). As the
between-group difference did not meet
the required P value for hierarchical testing,
superiority was not tested for the rest of
the confirmatory secondary end points
(heart failure composite and death from any
cause). Nevertheless, semaglutide reduced
the risk of the heart failure composite by 18%
and the risk of all-cause death by 19% com-
pared with placebo, and directionally con-
sistent effects were observed for supportive
secondary end points. In addition, the
effects of semaglutide on the primary end
point were similar across all p
­ respecified
subgroups.
Consistent with the known metabolic
effects of GLP1R agonists, patients receiving
semaglutide had a mean decrease in body
weight of 9.4% (versus 0.9% with placebo).
With regard to the safety profile of the drug,
adverse events leading to permanent discon-
tinuation of the treatment occurred in 16.6%
of patients in the semaglutide group and
8.2% in the placebo group (P < 0.001). The
majority of adverse events with semaglutide
were gastrointestinal, including d ­ iarrhoea,
nausea and gastrointestinal upset.
“These trial results will
meaningfully expand the
options available to doctors
to help to lower future
adverse cardiovascular
outcomes in people with
previous cardiovascular
disease”
“These trial results will meaningfully
expand the options available to doctors to
help to lower future adverse cardiovascular
outcomes in people with previous cardio-
vascular disease,” says Sattar. “Crucially,
this new option has the advantage over
other treatments for secondary prevention
of c
­ ardiovascular disease, as it also leads to
lower body weight and improves quality
of life, with hints of reductions in the risk of
other chronic diseases (such as diabetes
and heart failure) and all-cause death,” he
adds. “Such effects might be competitive
in the landscape of secondary prevention
of cardio­vascular disease, as many patients
would be pleased to lose weight intention-
ally at the same time as being protected
from further cardiovascular events.”
Credit: SCIENCE PHOTO LIBRARY/Getty
Irene Fernández-Ruiz
Original article: Lincoff, A. M. et al. Semaglutide and
cardiovascular outcomes in obesity without diabetes. N. Engl.
J. Med. https://doi.org/10.1056/NEJMoa2307563 (2023)
Related article: Ussher, J. R. & Drucker, D. J. Glucagon-like
peptide 1 receptor agonists: cardiovascular benefits and
mechanisms of action. Nat. Rev. Cardiol. 20, 463–474 (2023)