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Comparative cardiovascular risks of canagliflozin and selective SGLT2 inhibitors in type 2 diabetes

Edy Kornelius1,2, Shih-Chang Lo2, Yi-Sun Yang1,2

  • 1Chung Shan Medical University, School of Medicine, Taichung, Taiwan.

Frontiers in Pharmacology
|November 5, 2025
PubMed
Abstract

Insights

Canagliflozin, a dual SGLT1/2 inhibitor, showed a higher risk of major adverse cardiovascular events and mortality compared to selective SGLT2 inhibitors in type 2 diabetes patients. Further research is needed to confirm these real-world findings.

Area of Science:

  • Cardiovascular Medicine
  • Endocrinology
  • Pharmacology

Background:

  • Dual inhibition of sodium-glucose cotransporter (SGLT) 1 and 2 with canagliflozin may offer distinct metabolic benefits.
  • Comparative cardiovascular safety of canagliflozin versus selective SGLT2 inhibitors in real-world settings is not well-established.

Purpose of the Study:

  • To compare the risks of major adverse cardiovascular events (MACE) and all-cause mortality between canagliflozin and selective SGLT2 inhibitors.
  • To investigate cardiovascular associations of dual SGLT1/2 inhibition versus selective SGLT2 inhibition in patients with type 2 diabetes.

Main Methods:

  • Retrospective cohort study utilizing a multicenter electronic health record database of over 118 million patients.
  • Included adults with type 2 diabetes and new use of SGLT inhibitors (canagliflozin vs. other SGLT2 inhibitors) from January 2016 to December 2023.
  • 24,078 patients were propensity score matched (1:1); MACE (myocardial infarction, stroke, all-cause mortality) was the primary outcome.

Main Results:

  • Canagliflozin was associated with a significantly higher risk of MACE (HR, 1.23; 95% CI, 1.14-1.33) compared to selective SGLT2 inhibitors.
  • Higher risk of all-cause mortality (HR, 1.49; 95% CI, 1.33-1.68) and hemorrhagic stroke (HR, 1.35; 95% CI, 1.02-1.79) was observed with canagliflozin.
  • Risks of ischemic stroke and myocardial infarction were similar between the groups.

Conclusions:

  • Initiation of canagliflozin was linked to higher observed event rates for MACE and all-cause mortality in a large real-world cohort.
  • These findings are exploratory and hypothesis-generating, requiring cautious interpretation due to the observational design.
  • Further research is necessary to elucidate potential differences in cardiovascular outcomes among SGLT2 inhibitors in clinical practice.
Keywords:
MACESGLT1SGLT2diabetesmortality

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