The effect of SGLT2 inhibitors, GLP-1 receptor agonists, or
DPP-4 inhibitors on stroke risk in type 2 diabetes:
a nationwide longitudinal cohort study in Sweden with
contextualisation analysis
eClinicalMedicine
Oct 2026
https://pmc.ncbi.nlm.nih.gov/articles/PMC13634272/
Anastasios Mavridis,a,∗ Tamar Abzhandadze,a,b Dongni Buvarp,a,c,d Koen Simons,e Björn Eliasson,d,f Mia von Euler,g Adam Viktorisson,a,d and
Katharina S. Sunnerhagena,d
aDepartment of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg,
Sweden
bDepartment of Occupational Therapy and Physiotherapy, Sahlgrenska University Hospital, Gothenburg, Sweden
cDepartment of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
dThe Sahlgrenska University Hospital, Gothenburg, Sweden
eBiostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of
Gothenburg, Gothenburg, Sweden
fThe National Diabetes Register, Center of Registers, Gothenburg, Sweden
gSophiahemmet University, Stockholm, Sweden
Summary
Background
The impact of SGLT2 inhibitors (SGLT2i), GLP-1 receptor agonists (GLP-1RA), and DPP-4 inhibitors
(DPP-4i) on stroke risk in individuals with type 2 diabetes remains uncertain.
Meta-analyses of randomised controlled trials (RCTs) show a protective effect for GLP-1RA but neutral findings for SGLT2i and DPP-4i,
whereas observational studies often suggest broader stroke risk reductions.
This study aimed to estimate the associations of SGLT2i, GLP-1RA, and DPP-4i with stroke risk in nationwide longitudinal data, and to
contextualize these results within existing meta-analyses of RCTs and observational studies.
Methods
This was a nationwide longitudinal study including individuals with type 2 diabetes first registered in the
Swedish National Diabetes Register between January 1, 2013, and December 31, 2019. Individuals with a prior
stroke or insufficient data for multiple imputation were excluded. The primary outcome was ischemic stroke.
Treatments, comorbidities, and laboratory values were updated over time.
Marginal structural models with inverse probability of treatment weighting and weighted Cox regression were used to estimate hazard ratios (HRs) for
ischemic, hemorrhagic and total stroke pooled across five multiply imputed datasets. To contextualise the findings,
PubMed was searched from inception to June 23, 2026, for meta-analyses of randomised controlled trials and
observational studies reporting stroke outcomes for the three drug classes.
Findings
We included 171,917 individuals with type 2 diabetes [59.2% males, baseline mean (SD) age 62.7 (11.6),
mean (SD) follow-up 3.0 (1.9) years] contributing 1,617,462 clinical registrations.
During follow-up, 2734 (1.59%) ischemic and 428 (0.25%) hemorrhagic strokes occurred. GLP-1RA use was associated with a lower risk of
ischemic (HR 0.46, 95% CI 0.29–0.72) and total stroke (HR 0.51, 95% CI 0.33–0.79), whereas no clear
associations were observed for hemorrhagic stroke. SGLT2i and DPP-4i showed no clear associations with any
stroke outcome.
The contextualisation identified 91 meta-analyses. RCT meta-analyses generally showed a
protective effect for GLP-1RA and neutral effects for SGLT2i and DPP-4i, while observational meta-analyses
suggested protective associations for GLP-1RA and SGLT2i.
Interpretation In this nationwide study, GLP-1RA were associated with reduced stroke risk, while SGLT2i and DPP-
4i showed neutral effects. The overall direction of findings was consistent with evidence from RCT meta-analyses.
Future research should investigate how these therapies can be optimally incorporated into treatment strategies for
stroke prevention in individuals with type 2 diabetes.
Funding
Sahlgrenska University Hospital’s funds, the Swedish National Stroke Association, the Swedish Brain
Foundation, the Swedish Heart Lung Foundation, the Bygg-Göta Foundation for scientific research, the Winberg
foundation, and the Swedish state under the ALF agreement between the Swedish government and the county
councils.
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Research in context
Evidence before this study
We searched PubMed from inception to June 23, 2026, for
meta-analyses of randomised controlled trials (RCTs) and
observational studies using the terms (sodium-glucose
cotransporter 2 OR SGLT2 OR SGLT-2 OR GLP1 OR GLP-1 OR
glucagon-like peptide-1 OR DPP4 OR DPP-4 OR dipeptidyl
peptidase-4) AND (stroke OR “cerebral infarction” OR
“intracerebral hemorrhage”) AND diabetes, filtered for Meta-
Analyses. Of 274 abstracts and 102 full texts screened, meta-
analyses of RCTs for SGLT2 inhibitors consistently showed no
effect on stroke risk (effect sizes 0.84–1.30), whereas
observational meta-analyses suggested a protective
association (0.75–0.87).
For GLP-1 receptor agonists, both
RCTs and observational studies showed a consistent
protective effect (0.80–0.91).
For DPP-4 inhibitors, RCTs
indicated a neutral effect (0.77–1.03), and only one meta-
analysis including observational data was identified, which
also reported a neutral effect.
Observational studies that
consider time-varying treatment patterns and confounding
in routine clinical data may help contextualize differences
between trial and real-world findings.
Added value of this study
This was a nationwide, real-world longitudinal study using
data from the Swedish National Diabetes Register, including
171,917 individuals with up to 7 years of follow-up and
1,617,462 clinical registrations. We applied inverse
probability of treatment weighting to address time-varying
confounding, treatment switching, and
treatment–confounder feedback.
To our knowledge, this is
one of the largest nationwide register-based studies to
examine stroke risk with modern glucose-lowering therapies
under routine clinical use.
Treatment use and clinical
characteristics were updated throughout follow-up to reflect
routine clinical practice.
GLP-1RA use was associated with a
lower risk of ischemic stroke (HR 0.46, 95% CI 0.29–0.72)
and total stroke (HR 0.51, 95% CI 0.33–0.79), whereas no
clear associations were observed for hemorrhagic stroke.
SGLT2i and DPP-4i showed no clear associations with
ischemic, hemorrhagic, or total stroke.
Implications of all the available evidence
Our findings together with existing meta-analyses support a
protective association between GLP-1RA use and stroke risk,
while showing no clear association for SGLT2i or DPP-4i. By
accounting for evolving treatment use, treatment switching,
and time-varying confounding, this study extends existing
evidence by characterizing stroke risk under the dynamic
treatment patterns encountered in routine clinical practice.
Future research should determine how these findings can be
translated into personalised glucose-lowering strategies that
optimise stroke prevention in type 2 diabetes.
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From condensed
Discussion
This study aimed to examine stroke risk associated with
SGLT2i, GLP-1RA, and DPP-4i use in individuals with
type 2 diabetes, using nationwide longitudinal data. In a
cohort of 171,917 individuals with type 2 diabetes, GLP-
1RA were associated with lower risk of both ischemic
and total stroke, while SGLT2i and DPP-4i showed no
clear associations with stroke risk. These findings are
directionally consistent with results reported in RCTs,
providing complementary real-world evidence on the
cerebrovascular benefits of GLP-1RA and the neutral
effects of SGLT2i and DPP-4i.
Several placebo-controlled RCTs have examined the
effect of GLP-1RA on stroke risk and consistently
demonstrated a 10–20% reduction.7–9,73,79 A meta-
analysis of real-world studies reported similar bene-
fits.114 However individual observational analyses have
been inconsistent, with estimates ranging from a 70%
reduction in stroke hazard,116 to non-significant find-
ings.117,118 In the present study, GLP-1RA use was
associated with lower hazards of ischemic stroke. While
the magnitude of the observed association was greater
than that reported in most RCTs, the direction of effect
was consistent with the overall evidence base. For
SGLT2i, placebo-controlled RCTs have generally
reported neutral effects on stroke,7–9,53 while meta-
analyses of observational studies often suggest a pro-
tective effect, particularly in comparisons with other
glucose-lowering agents.12,14,15 Other real-world studies
comparing SGLT2i directly with GLP-1RA have typi-
cally found no significant differences.10,11 In our anal-
ysis, SGLT2i showed neutral effects, in line with the
RCT evidence. DPP-4i have likewise been consistently
neutral in RCTs,7–9 although some observational studies
have suggested protective effects.16,17 Real-world evi-
dence was included in only one107 of the identified meta-
analyses, which also incorporated RCTs and reported a
neutral effect. In the present study, DPP-4i showed no
clear association with ischemic stroke, consistent with
trial evidence.
The agreement between our SGLT2i findings and
randomized trial evidence, despite contrasting with
several observational meta-analyses, may partly reflect
differences in methodology. The majority of prior real-
world studies have relied on baseline-only adjustment,
which is suitable for an analysis of initial treatment
akin to intention-to-treat analysis. However, adjustment
for baseline variables may not adequately capture con-
founding of dynamic treatment regimes that evolve
during follow-up. When exposures and covariates
change over time, such static approaches can yield
biased estimates.29,119 As treatment switching is com-
mon in clinical practice, an intention-to-treat estimator
has limited information for long-term follow-up and
does not directly address the question “what is the ef-
fect if individuals actually fill prescriptions?” Differ-
ences in length of follow-up, type of estimand,
treatment adherence and persistence, study pop-
ulations, outcome ascertainment, and residual con-
founding may all contribute to differences between
observational studies and randomized trials. By incor-
porating longitudinal data with repeated measures, the
present study explicitly considers treatment changes
and evolving clinical characteristics that may influence
observational estimates.
The stronger association observed for GLP-1RA
compared with most randomized trials may have
several explanations. Most trials report intention-to-treat
analyses, which estimate the effect of treatment assign-
ment regardless of subsequent adherence or treatment
changes. In contrast, the present analysis incorporated
treatment use throughout follow-up, including treat-
ment discontinuation and switching. As a result, the
estimated associations are not directly comparable and
may differ when adherence changes over time. Differ-
ences in study populations, treatment patterns, residual
confounding, and effect modification may also
contribute. Consequently, the larger effect estimates
observed in the present study should not be attributed to
any single explanation and should not be interpreted as
evidence that GLP-1RA are more effective in routine
clinical practice than suggested by randomized trials.
Several biological mechanisms may explain the
observed reduction in ischemic stroke risk associated
with GLP-1 receptor agonists.120–122 Beyond glucose
lowering, GLP-1RA exert multiple cardiometabolic ef-
fects that influence established cerebrovascular risk
pathways, including reductions in systolic blood pres-
sure, body weight, and post-prandial lipaemia, as well
as improvements in endothelial function and vascular
inflammation.120 Experimental and clinical studies also
suggest anti-atherosclerotic effects mediated through
reduced oxidative stress, improved nitric oxide
bioavailability, and modulation of macrophage activity
within atherosclerotic plaques, which may contribute to
stabilization of vulnerable vascular lesions.120 In addi-
tion to systemic vascular effects, GLP-1 receptors are
expressed in the central nervous system, and preclinical
models indicate potential direct neuroprotective prop-
erties, including attenuation of excitotoxicity, reduced
neuroinflammation, decreased apoptotic signalling,
and promotion of angiogenesis.120,122 In contrast, DPP-4
inhibitors increase endogenous incretin levels only
modestly and do not appear to produce the same
magnitude of metabolic or vascular effects as GLP-
1RA.123 Similarly, SGLT2 inhibitors produce substantial
cardiovascular and renal benefits through mechanisms
including osmotic diuresis, natriuresis, reductions in
blood pressure and arterial stiffness, and improved
cardiac loading conditions124,125; however, these effects
In this nationwide longitudinal study, GLP-1RA
were associated with a reduced risk of stroke, while
SGLT2i and DPP-4i showed no clear effects.
These findings are consistent with results from RCTs and
provide complementary evidence from routine clinical
care. Overall, GLP-1RA may be considered as part of
strategies to reduce cerebrovascular risk in individuals
with type 2 diabetes. At the same time, the established
benefits of SGLT2i and DPP-4i for other cardiovascular
and renal outcomes should remain central in clinical
decisions. It may be most appropriate for treatment
choices to be informed by the totality of available evi-
dence, recognizing that the benefits and limitations of
each drug class should be thoughtfully weighed in de-
cisions affecting both individuals and public health
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