Effect of Combination Therapy with SGLT2 Inhibitors and GLP-1 Receptor Agonists on Myocardial Infarction and Stroke in Type 2 Diabetes: A Systematic Review and Meta-Analysis
- Design
- Meta-analysis · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different population[Auto] Synthesis of studies conducted predominantly in people with type 2 diabetes.
- Could weight loss explain it?
- Possibly[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.
- Study tier
- Study tier 3[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).
- Assessment
- Version 1 · automatic, not yet reviewed by a person · Sep 13, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
[Auto, unreviewed; quoted from abstract conclusions] In adults with T2DM, SGLT2i and GLP-1RA combination therapy may be associated with lower risks of MI and stroke compared with their monotherapy. While the MI benefit appears primarily to be driven by GLP-1RA, combination therapy yields an additive reduction in stroke risk, particularly in older adults. Given the very low certainty of evidence, these hypothesis-generating findings require confirmation through dedicated prospective trials.
01Findings
What the study reported
- Drugs
- Class unspecified
- Comparator
- their combined use
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- 65 years
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Diabetes status
- type 2 diabetes present (all or most)
- Cvd status
- cardiovascular disease present in population (see abstract)
Study quality details
- Study design
- Meta-analysis
- Sample size
- not extracted
- Randomization
- n/a
- Blinding
- not stated
- Comparator
- not stated
- Follow up duration
- 65 years
- Outcome type
- hard
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI 0
- Risk of bias
- not assessed (auto)
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- None identified
- Sponsor role
- not reported in abstract
- Author conflicts
- Declarations. Author Contribution: Mohammad E. Khamseh contributed to the study conceptualization, supervision, and discrepancy resolution. Roya Ghafoury contributed to the study design and protocol development, literature search, and original draft preparation. Roya Ghafoury and Mobin Naghshbandi were both involved in study screening and selection, data extraction, risk of bias evaluation, and GRADE certainty of evidence assessment. Mobin Naghshbandi additionally performed the statistical analysis, meta-analysis, and software visualization. Faramarz Ismail-Beigi, Mojtaba Malek, Sanjay Kalra, and Mohammad E. Khamseh contributed to intellectual oversight and clinical data interpretation. All authors critically reviewed and edited the manuscript, approved the final version, and agree to be accountable for all aspects of the work. Funding: No funding or sponsorship was received for this study or publication of this article. Medical Writing/Editorial Assistance: ChatGPT (OpenAI, San Francisco, CA, USA) was used to assist with grammar and language editing during the preparation of this manuscript. No funding was received for this assistance. The authors reviewed and verified all content and take full responsibility for the integrity and accuracy of the work. Data Availability: This study is based on aggregate data from previously published studies; no new primary data were generated. All data supporting the findings are contained within the article and its tables. The extracted da
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[INTRODUCTION] Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardioprotection in type 2 diabetes mellitus (T2DM). We evaluated their monotherapy versus their combined use for prevention of myocardial infarction (MI) and stroke. [METHODS] Conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines, five databases were systematically searched through November 2025 for studies evaluating use of SGLT2i and GLP-1RA in combination versus their monotherapy in adults with T2DM. Hazard ratios (HRs) for MI and stroke were pooled utilizing random-effects models. Subgroup interaction testing and grading of recommendations assessment, development, and evaluation (GRADE) certainty assessments were performed. [RESULTS] Of the studies, eight comprising ten comparisons were included. Combination therapy was associated with a lower overall risk of MI (HR 0.79, 95% CI 0.70-0.88; I2 = 72.8%) and stroke (HR 0.85, 95% CI 0.77-0.93; I2 = 63.5%) compared with their monotherapy. For MI, combination therapy significantly outperformed SGLT2i monotherapy (HR 0.74, 95% CI 0.60-0.90) but not GLP-1RA monotherapy (HR 0.80, 95% CI 0.55-1.16). For stroke reduction, combination therapy outperformed both SGLT2i (HR 0.73, 95% CI 0.54-0.99) and GLP-1RA (HR 0.92, 95% CI 0.88-0.96) monotherapy. Cerebrovascular benefit appeared stronger in adults > 65 years (HR 0.50, 95% CI 0.37-0.68). Overall certainty of evidence was very low. [CONCLUSIONS] In adults with T2DM, SGLT2i and GLP-1RA combination therapy may be associated with lower risks of MI and stroke compared with their monotherapy. While the MI benefit appears primarily to be driven by GLP-1RA, combination therapy yields an additive reduction in stroke risk, particularly in older adults. Given the very low certainty of evidence, these hypothesis-generating findings require confirmation through dedicated prospective trials. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD420261320374 .