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Comparative Study
. 2025 Mar 1;185(3):302-313.
doi: 10.1001/jamainternmed.2024.7357.

Comparative Effectiveness of Individual Sodium-Glucose Cotransporter 2 Inhibitors

HoJin Shin  1   2   3 , Julie M Paik  1   4   5 , Brendan M Everett  6 , Elyse DiCesare  1 , Caroline Alix  1 , Robert J Glynn  1 , Deborah J Wexler  7 , Elisabetta Patorno  1
Affiliations
Comparative Study

Comparative Effectiveness of Individual Sodium-Glucose Cotransporter 2 Inhibitors

HoJin Shin et al. JAMA Intern Med. .

Abstract

Importance: Evidence on cardiovascular benefits and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors is mainly from placebo-controlled trials. Therefore, the comparative effectiveness and safety of individual SGLT-2 inhibitors remain unknown.

Objective: To compare the use of canagliflozin or dapagliflozin with empagliflozin for a composite outcome (myocardial infarction [MI] or stroke), heart failure hospitalization, MI, stroke, all-cause death, and safety outcomes, including diabetic ketoacidosis (DKA), lower-limb amputation, bone fracture, severe urinary tract infection (UTI), and genital infection and whether effects differed by dosage or cardiovascular disease (CVD) history.

Design, setting, and participants: This comparative effectiveness study using target trial emulation included adults with type 2 diabetes (T2D) using 3 US claims databases using data from August 2014 through June 2020. The study was conducted from August 2023 to July 2024, with a follow-up period of up to 8 years, and the analysis was completed in July 2024.

Exposures: First dispensing of canagliflozin, dapagliflozin, or empagliflozin without any use of SGLT-2 inhibitors during the prior 365 days.

Main outcomes and measures: Database-specific models were weighted using propensity score matching-weights to adjust for 129 confounders. Hazard ratios and 95% CIs for outcomes were estimated using weighted Cox proportional hazards models. HRs were pooled across databases using a fixed-effect meta-analysis.

Results: : Across the databases, 232 890 patients receiving canagliflozin, 129 881 patients receiving dapagliflozin, and 295 043 patients receiving empagliflozin were identified. Compared with empagliflozin initiators, those receiving canagliflozin or dapagliflozin were less likely to have diabetes-related conditions or a history of CVD at baseline. For MI/stroke risk, both canagliflozin (HR, 0.98; 95% CI, 0.91-1.05) and dapagliflozin (HR, 0.95; 95% CI, 0.89-1.03) were comparable to empagliflozin. For heart failure hospitalization, dapagliflozin initiators had a higher risk (HR, 1.19; 95% CI, 1.02-1.39), particularly at the low dose of 5 mg (HR, 1.30; 95% CI, 1.12-1.50). These findings were consistent across subgroups of CVD history. For safety events, compared with empagliflozin, canagliflozin initiators had a lower risk of genital infections (HR, 0.94; 95% CI, 0.91-0.97) but a higher risk of severe UTIs (HR, 1.13; 95% CI, 1.03-1.24), and dapagliflozin initiators had lower risks of genital infections (HR, 0.92; 95% CI, 0.89-0.95) and DKA (HR, 0.78; 95% CI, 0.68-0.90).

Conclusions and relevance: This study found that individual SGLT-2 inhibitors demonstrated comparable cardiovascular effectiveness at clinically effective doses, though low-dose dapagliflozin showed a reduced benefit for heart failure hospitalization compared with empagliflozin.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Everett reported grants from Novo Nordisk for site coinvestigator, personal fees from Novo Nordisk for endpoint adjudication, grants from the Patient-Centered Outcomes Research Institute, principal investigator of a grant to Brigham and Women's Hospital, and personal fees from Kowa not clearly relevant to the work; personal fees from Ipsen Pharmaceuticals for consulting, and personal fees from NIDDK outside the submitted work; and consulting (editorial board member) for the American Heart Association journal Circulation, and royalties for peer review of UptoDate articles. Dr Glynn reported grants from Amarin to employer, grants from Kowa to employer, and grants from Novartis to employer outside the submitted work. Dr Wexler reported personal fees from Novo Nordisk for data monitoring committee service, SOUL and FLOW trials of semaglutide outside the submitted work. Dr Patorno reported grants from Patient Centered Outcomes Research Institute (DB-2020C2-20326) during the conduct of the study; grants from National Institute of Diabetes and Digestive and Kidney Diseases ((R01DK138036), grants from the Food and Drug Administration (5U01FD007213), and grants from Boehringer Ingelheim to the Brigham and Women’s Hospital outside the submitted work. No other disclosures were reported.

References

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