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

Mikhail Kosiborod, Carolyn S.P. Lam, Shun Kohsaka, Dae Jung Kim, Avraham Karasik, Jonathan Shaw, Navdeep Tangri, Su Yen Goh, Marcus Thuresson, Hungta Chen, Filip Surmont, Niklas Hammar, Peter Fenici, CVD-REAL Investigators and Study Group

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Abstract

Background: 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. 

Objectives: 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. 

Methods: 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. 

Results: 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. 

Conclusions: 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. 

Original languageEnglish
Pages (from-to)2628-2639
Number of pages12
JournalJournal of the American College of Cardiology
Volume71
Issue number23
DOIs
Publication statusPublished - 12 Jun 2018
Externally publishedYes

Keywords

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

Cite this

Kosiborod, M., Lam, C. S. P., Kohsaka, S., Kim, D. J., Karasik, A., Shaw, J., Tangri, N., Goh, S. Y., Thuresson, M., Chen, H., Surmont, F., Hammar, N., Fenici, P., & CVD-REAL Investigators and Study Group (2018). Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study. Journal of the American College of Cardiology, 71(23), 2628-2639. https://doi.org/10.1016/j.jacc.2018.03.009