Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study

Ann Intern Med. 2022 Jul;175(7):927-937. doi: 10.7326/M21-4012. Epub 2022 May 24.


Background: Evidence on the risk for cardiovascular events associated with use of first-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited.

Objective: To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin.

Design: Population-based cohort study.

Setting: Claims data from 2 large U.S. commercial and Medicare databases (April 2013 to March 2020).

Participants: Patients with T2D aged 18 years and older (>65 years in Medicare) initiating treatment with SGLT-2i or metformin during April 2013 to March 2020, without any use of antidiabetic medications before cohort entry, were identified. After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported.

Intervention: First-line SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin.

Measurements: Primary outcomes were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Safety outcomes including genital infections were assessed.

Results: Among 8613 first-line SGLT-2i initiators matched to 17 226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months. Initiators receiving SGLT-2i showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality compared with metformin. Initiators receiving SGLT-2i had a higher risk for genital infections (HR, 2.19; CI, 1.91 to 2.51) and otherwise similar safety as those receiving metformin.

Limitation: Treatment selection was not randomized.

Conclusion: As first-line T2D treatment, initiators receiving SGLT-2i showed a similar risk for MI/stroke/mortality, lower risk for HHF/mortality and HHF, and a similar safety profile except for an increased risk for genital infections compared with those receiving metformin.

Primary funding source: Brigham and Women's Hospital and Harvard Medical School.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Cardiovascular Diseases* / chemically induced
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / prevention & control
  • Cohort Studies
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Female
  • Glucose / therapeutic use
  • Heart Failure*
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Medicare
  • Metformin* / adverse effects
  • Myocardial Infarction* / chemically induced
  • Myocardial Infarction* / epidemiology
  • Risk Factors
  • Sodium / therapeutic use
  • Sodium-Glucose Transporter 2 Inhibitors* / adverse effects
  • Stroke* / chemically induced
  • Stroke* / epidemiology
  • Stroke* / prevention & control
  • United States


  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors
  • Metformin
  • Sodium
  • Glucose