ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1686851
This article is part of the Research TopicCardiometabolic Crosstalk: Mechanisms, Modulators, and Therapeutics in Diabetes-Induced Cardiovascular DiseaseView all articles
Comparative Cardiovascular Risks of Canagliflozin and selective SGLT2 Inhibitors in Type 2 Diabetes
Provisionally accepted
- 1Chung Shan Medical University, Taichung, Taiwan
- 2Chung Shan Medical University Hospital, Taichung, Taiwan
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Aims Dual inhibition of sodium-glucose cotransporter (SGLT) 1 and 2 with canagliflozin may offer additional metabolic effects beyond selective SGLT2 inhibition; however, its comparative cardiovascular associations remain uncertain. This study compared the risks of major adverse cardiovascular events (MACE) and all-cause mortality between canagliflozin and selective SGLT2 inhibitors in routine clinical practice. Methods and Results We conducted a retrospective cohort study using a multicenter electronic health record database including over 118 million patients. Adults with type 2 diabetes, no prior cardiovascular disease, and new use of an SGLT inhibitor between January 2016 and December 2023 were identified. After applying strict exclusion criteria and 1:1 propensity score matching, 24,078 patients (mean age, 57 years; 47% women) were included: 12,039 initiated canagliflozin and 12,039 initiated other SGLT2 inhibitors. The primary outcome was MACE (composite of myocardial infarction, stroke, or all-cause mortality). Compared with other SGLT2 inhibitors, canagliflozin was associated with higher risk of MACE (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.14–1.33) and all-cause mortality (HR, 1.49; 95% CI, 1.33–1.68). Hemorrhagic stroke risk was also elevated (HR, 1.35; 95% CI, 1.02–1.79), while risks of ischemic stroke and myocardial infarction were similar. Conclusion In this large real-world cohort, patients initiating canagliflozin had higher observed event rates for a composite of myocardial infarction, stroke, or all-cause mortality compared with those initiating selective SGLT2 inhibitors. These associations should be interpreted as exploratory and hypothesis-generating, given the observational design and differences from randomized trial evidence. Further research is needed to clarify potential differences among SGLT2 inhibitors in routine practice.
Keywords: SGLT1, SGLT2, MACE, Mortality, diabetes
Received: 16 Aug 2025; Accepted: 06 Oct 2025.
Copyright: © 2025 Kornelius, Lo, Yang, Wang and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Edy Kornelius, korn3lius82@gmail.com
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