Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data
Authors: Khunti Kamlesh , Kosiborod Mikhail , Kim Dae Jung , Kohsaka Shun , Lam Carolyn S. P. , Goh Su-Yen , Chiang Chern-En , Shaw Jonathan E. , Cavender Matthew A. , Tangri Navdeep , Franch-Nadal Josep , Holl Reinhard W. , Jørgensen Marit E. , Norhammar Anna , Eriksson Johan G. , Zaccardi Francesco , Karasik Avraham , Magliano Dianna J. , Thuresson Marcus , Chen Hungta , Wittbrodt Eric , Bodegård Johan , Surmont Filip , Fenici Peter ,   the CVD-REAL Investigators and Study Group, Kosiborod Mikhail , Cavender Matthew A. , Wilding John P. , Khunti Kamlesh , Norhammar Anna , Birkeland Kåre , Jørgensen Marit Eika , Holl Reinhard W. , Lam Carolyn S. P. , Gulseth Hanne Løvdal , Carstensen Bendix , Bollow Esther , Franch-Nadal Josep , Rodríguez Luis Alberto García , Karasik Avraham , Tangri Navdeep , Kohsaka Shun , Kim Dae Jung , Shaw Jonathan , Arnold Suzanne , Goh Su-Yen , Chiang Chern-En , Eriksson Johan G. , Zaccardi Francesco , Fenici Peter , Bodegård Johan , Chen Hungta , Surmont Filip , Kendrick Rachel , Belli Wesley , Wittbrodt Eric T. , Saathoff Matthias , Noguchi Yusuke , Tan Donna , Williams Maro , Lee Hye Won , Greenbloom Maya , Kaidanovich-Beilin Oksana , Andersson-Sundell Karolina , Yeo Khung Keong , Bee Yong Mong , Khoo Joan , Koong Agnes , Lau Yee How , Gao Fei , Tan Wee Boon , Kadir Hanis Abdul , Ha Kyoung Hwa , Lee Jinhee , Chodick Gabriel , Cohen Cheli Melzer , Whitlock Reid , Soriano Lucia Cea , Cantero Oscar Fernándex , Menzin Jordan A. , Guthrie Matthew , Ilomaki Jennie , Magliano Dianna , Hoti Fabian , Christopher Solomon , Vehkala Minna 
Published: August 2021

Abstract
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