Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data

Kamlesh Khunti, Mikhail Kosiborod, Dae Jung Kim, Shun Kohsaka, Carolyn S.P. Lam, Su Yen Goh, Chern En Chiang, Jonathan Shaw, Matthew A. Cavender, Navdeep Tangri, Josep Franch-Nadal, Reinhard W. Holl, Marit Eika Jørgensen, Anna Norhammar, Johan G. Eriksson, Francesco Zaccardi, Avraham Karasik, Dianna J. Magliano, Marcus Thuresson, Hungta ChenEric Wittbrodt, Johan Bodegård, Filip Surmont, Peter Fenici, Mikhail Kosiborod, Matthew A. Cavender, John P. Wilding, Kamlesh Khunti, Anna Norhammar, Bendix Carstensen, Reinhard W. Holl, Carolyn S.P. Lam, Rachel Kendrick, Wesley Belli, Eric T. Wittbrodt, Josep Franch-Nadal, Yusuke Noguchi, Avraham Karasik, Navdeep Tangri, Shun Kohsaka, Dae Jung Kim, Jonathan Shaw, Karolina Andersson-Sundell, Su Yen Goh, Chern En Chiang, Johan G. Eriksson, Francesco Zaccardi, Peter Fenici, Johan Bodegård, on behalf of the CVD-REAL Investigators and Study Group, Marit Eika Jørgensen (Member of author group)

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BACKGROUND: Randomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics.

METHODS: De-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects.

RESULTS: Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58-0.75; p < 0.001), ACD (HR: 0.52, 95%CI 0.45-0.60; p < 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53-0.68; p < 0.001), MI (HR: 0.85, 95%CI 0.78-0.92; p < 0.001), and stroke (HR: 0.78, 95%CI 0.72-0.85; p < 0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region.

CONCLUSIONS: This CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically diverse population, and across multiple subgroups. Trial registration NCT02993614.

Original languageEnglish
Article number159
JournalCardiovascular Diabetology
Issue number1
Publication statusPublished - 31. Jul 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).


  • Aged
  • Blood Glucose/drug effects
  • Cardiovascular Diseases/diagnosis
  • Diabetes Mellitus, Type 2/blood
  • Female
  • Glycemic Control
  • Hospitalization
  • Humans
  • Male
  • Middle Aged
  • Protective Factors
  • Risk Assessment
  • Risk Factors
  • Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
  • Time Factors
  • Treatment Outcome


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