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J Am Coll Cardiol. 2018 Jun 12;71(23):2628-2639. doi: 10.1016/j.jacc.2018.03.009. Epub 2018 Mar 11.

Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study.

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Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri. Electronic address:
National Heart Centre, Singapore and SingHealth Duke-NUS, Singapore; University Medical Centre Groningen, Groningen, the Netherlands.
Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea.
Institute of Endocrinology, Tel Aviv University and Maccabi Healthcare Israel, Tel Aviv, Israel.
Clinical and Population Health, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Endocrinology, Singapore General Hospital, Singapore.
Statisticon AB, Uppsala, Sweden.
AstraZeneca, Gaithersburg, Maryland.
AstraZeneca, Luton, United Kingdom.
Karolinska Institutet, Stockholm, Sweden; AstraZeneca, Gothenburg, Sweden.
AstraZeneca, Cambridge, United Kingdom.



Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe.


The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions.


New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis.


After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease.


In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614).


SGLT-2 inhibitor; death; diabetes mellitus; heart failure; observational studies; sodium glucose cotransporter-2 inhibitors

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