Starting
a
GLP-1
receptor
agonist
was
associated
with
significantly
lower
risks
of
death
and
cardiovascular
events
in
adults
with
serious
mental
illness
(SMI),
a
target
trial
emulation
showed.

Among
195,184
propensity
score-matched
pairs
of
adults
with
SMI,
GLP-1
drug
initiators
had
a
24%
lower
4-year
mortality
risk
compared
with
SGLT2
inhibitor
initiators
(HR
0.76,
95%
CI
0.74-0.78).
Death
occurred
in
4.91%
and
6.45%
of
groups,
respectively,
equating
to
an
absolute
risk
difference
of
-1.54
percentage
points.

At
year
1,
all-cause
mortality
risk
was
49%
lower
among
GLP-1
initiators
compared
with
SGLT2
inhibitor
initiators
(HR
0.51,
95%
CI
0.49-0.53,

P<0.001),
Roger
McIntyre,
MD,
of
the
University
of
Toronto,
and
colleagues
reported
in


JAMA
Psychiatry.

This
association
persisted
across
sensitivity
analyses.
A
review
of
semaglutide
(Ozempic,
Wegovy)
initiators
who
had
SMI
and
type
2
diabetes
indicated
that
the
relationship
was
largely
driven
by
risk
reductions
in
cardiovascular
outcomes
(all

P<0.001):

• 3-point
  major
  adverse
  cardiovascular
  events
  (MACEs):
  HR
  0.77,
  95%
  CI
  0.76-0.79
• 5-point
  MACEs:
  HR
  0.76,
  95%
  CI
  0.75-0.77
• Myocardial
  infarction:
  HR
  0.71,
  95%
  CI
  0.69-0.73
• Stroke:
  HR
  0.89,
  95%
  CI
  0.86-0.92
• Heart
  failure:
  HR
  0.73,
  95%
  CI
  0.72-0.74
• Coronary
  artery
  bypass
  grafting:
  HR
  0.77,
  95%
  CI
  0.70-0.85

The
findings
“may
represent
a
treatment
option
to
narrow
the
cardiovascular
mortality
gap
in
persons
living
with
SMI”
and
support
“a
broad
cardiometabolic
benefit
rather
than
an
isolated
outcome-specific
signal,”
the
authors
wrote.

Life
expectancy
for
individuals
with
SMI
is
roughly
10
to
25
years
shorter
than
the
general
population,
primarily
due
to

cardiovascular
disease.

“The
excess
cardiovascular
morbidity
and
mortality
in
SMI
reflects
the
convergence
of
elevated
cardiometabolic
risk
factor
burden,
psychopharmacotherapy-related
metabolic
effects,
and
systemic
disparities
in
preventive
care
delivery,
chronic
disease
screening,
and
guideline-concordant
treatment,”
the
researchers
wrote.

Underlying
mechanisms
driving
this
risk
reduction
may
include
anti-inflammatory
and
anti-atherogenic
effects
of
GLP-1
drugs,
alongside
possible
influence
on
motivation,
behavior,
cognitive
organization,
and
mitigation
of
risk
factors
like
alcohol
use
disorder,
they
suggested.

The
findings
didn’t
come
as
a
surprise
as
GLP-1
drugs
reduce
cardiovascular
mortality
in
the
general
population,
McIntyre
told

MedPage
Today.

“The
impetus
to
conduct
our
study
was
provided
by
the
observation
that
people
living
with
serious
mental
illness
—
such
as
major
depressive
disorder,
bipolar
disorder,
or
schizophrenia
—
not
only
have
a
significantly
higher
rate
of
mortality
with
consequently
shorter
lifespan,
but
the
cause
contributing
most
to
excess
mortality
in
this
population
is
cardiovascular
disease,”
McIntyre
explained.

He
argued
the
drug
class
could
be
“potentially
transformative
in
the
psychiatric
population,”
noting
“currently
no
FDA-approved
treatment
has
been
shown
to
reduce
mortality…
to
the
extent
to
which
we
have
just
observed
with
GLP-1
receptor
agonists.”

The
retrospective
target
trial
emulation
utilized
TriNetX
electronic
health
record
data
through
March
2026.
Using
a
new-user,
active-comparator
design,
1,528,230
adults
were
classified
into
SMI
and
non-SMI
categories
and
propensity-score
matched,
with
a
mean
age
of
approximately
60.5
years
in
the
SMI
cohort.

At
4
years,
mortality
was
significantly
reduced
in
type
2
diabetes
patients
with
SMI
who
started
semaglutide
(HR
0.76)
or
tirzepatide
(Mounjaro,
Zepbound;
HR
0.49).
Older
GLP-1
drugs
—
dulaglutide
(Trulicity),
liraglutide
(Victoza,
Saxenda),
exenatide
(Byetta,
Bydureon),
lixisenatide
(Adlyxin),
and
albiglutide
(now
discontinued)
—
showed
no
consistent
survival
advantage
over
SGLT2
inhibitors.

In
10-year
exploratory
analyses
of
individuals
with
type
2
diabetes,
semaglutide
was
associated
with
lower
mortality
across
SMI
subgroups,
including
major
depressive
disorder
(HR
0.75),
bipolar
disorder
(HR
0.76),
and
schizophrenia
(HR
0.85,
all

P<.001).

The
emulation
could
not
fully
control
for
unmeasured
medication
adherence,
lifestyle,
socioeconomic
factors,
or
psychiatric
severity,
the
authors
acknowledged.
The
findings
may
not
apply
to
all
populations,
as
cost
barriers
and
inequities
in
GLP-1
drug
access
disproportionately
affect
those
with
SMI.

“Our
results
provide
the
impetus
for
careful
mechanistic
studies
to
better
understand
how
they
offer
this
anti-mortality
effect
and
also
provide
a
compelling
line
of
evidence
to
justify
considering
these
agents
as
part
of
the
integrated
care
of
people
with
mental
illness
with
an
aim
to
improve
health
span
and
lifespan,”
McIntyre
concluded.

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