Sodium‐Glucose Cotransporter 2 Inhibitors, All‐Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta‐Analysis and Meta‐Regression
Open accessAbstract
Background: This study aimed to assess the effectiveness of sodium‐glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results: We conducted a Bayesian meta‐analysis of randomized controlled trials comparing sodium‐glucose cotransporter 2 inhibitors with placebo. We used meta‐regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty‐three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63–0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69–1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72–1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61–1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63–1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71–1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all‐cause and cardiovascular mortality. There was no association between treatment effects for all‐cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%–95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions: Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause and cardiovascular mortality versus placebo. Treatment effects of sodium‐glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.
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SGLT2i and GLP1ra are widely endorsed by clinical practice guidelines.
“Sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) are novel classes of medications for type 2 diabetes that significantly reduce cardiovascular deaths independent of their effect on hyperglycemia and are widely endorsed by clinical practice guidelines.4–11”
From Disparities in Use of Novel Diabetes Medications by Insurance: A Nationally Representative Cohort Study (2024) · cites this paper as [4]
The Discussion (page not provided) says current guidelines recommend SGLT-2 inhibitors for adults with established cardiovascular disease or high cardiovascular risk, and cites a European guideline recommending them for secondary prevention. It does not address guideline endorsement of GLP-1 receptor agonists, so it supports only the SGLT2i part of the claim. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSGLT2i and GLP1ra significantly reduce cardiovascular deaths independent of their effect on hyperglycemia.
“Sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) are novel classes of medications for type 2 diabetes that significantly reduce cardiovascular deaths independent of their effect on hyperglycemia and are widely endorsed by clinical practice guidelines.4–11”
From Disparities in Use of Novel Diabetes Medications by Insurance: A Nationally Representative Cohort Study (2024) · cites this paper as [4]
The Results (All-Cause and Cardiovascular Mortality; page unavailable) report evidence of reduced cardiovascular mortality for three SGLT2 inhibitors, but little evidence for two others. The paper does not establish that the mortality benefit is independent of glucose lowering, and it does not evaluate GLP-1 receptor agonists. Its Discussion addresses guideline recommendations for SGLT2 inhibitors, not both drug classes. (LLM, conf=0.88)
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References 72 · Cited by 29
- Authors
- Odutayo, A., da Costa, B. R., Pereira, T. V., Garg, V., Iskander, S., Roble, F., Lalji, R., Hincapié, C. A., Akingbade, A., Rodrigues, M., Agarwal, A., Lawendy, B., Saadat, P., Udell, J. A., Cosentino, F., Grant, P. J., Verma, S., & Jüni, P.
- Affiliations
- St. Michael's Hospital (CA)
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael’s HospitalUniversity of Toronto Canada
- University of Toronto (CA)
- University of Zurich (CH)
- Queen's University (CA)
- McMaster University (CA)
- Karolinska University Hospital (SE)
- University of Leeds (GB)
- Corresponding author
- Jüni, Peter
- ORCID
- Venue
- Journal of the American Heart Association
- Published
- 2021-09-21
- Volume
- 10
- Issue
- 18
- Pages
- e019918-e019918
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC8649541
- OpenAlex
- W3199553988
- Cited by
- 29
- References
- 72
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 5 · 2022: 4
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Yale University
- University of Toronto
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- SGLT2 inhibitors, type 2 diabetes, all-cause mortality, cardiovascular mortality, heart failure, acute myocardial infarction, empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, sotagliflozin, cardiovascular risk, meta-regression
- MeSH terms
- Canagliflozin, Bayes Theorem, Diabetes Mellitus, Type 2, Glucose, Humans, Sodium, Stroke
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