CVD-REAL, the giant study of real-world evidence comparing sodium glucose co-transporter-2 (SGLT2) inhibitors with other glucose-lowering drugs to treat type 2 diabetes (T2D), found a 49% lower risk of all-cause death and a host of other benefits across 6 new, more diverse countries, the study’s lead author told a packed room Sunday at the 67th Scientific Session of the American College of Cardiology (ACC) in Orlando, Florida.
CVD-REAL 2, which was published simultaneously in the Journal of the American College of Cardiology, gathered registry and claims data from more than 400,000 patients in Japan, South Korea, Singapore, Israel, Australia, and Canada. Of the group, 74% did not have established cardiovascular disease (CVD).
Lead study author Mikhail Kosiborod, MD, of St. Luke’s Health System noted that the first CVD-REAL results, which were a surprise hit at ACC a year ago, showed SGLT2 inhibitors were associated with reduced risk of all-cause death and hospitalization for heart failure for T2D patients without established CVD. But the results had their limits.
“Most people with type 2 diabetes live outside the United States and Europe,” Kosiborod said, listing the areas that provides registries and claims for the first study. In Asia and the Middle East, he said, “there are important differences in patient characteristics, treatment patterns, and types of cardiovascular events experienced by patients in these regions.” In particular, stroke is much more common in Asia.
So, CVD-REAL 2 would take additional steps, and it found more. Patients with T2D who started an SGLT2 inhibitor for the first time, compared with another glucose-lowering drug, had:
- A 49% lower risk of all-cause death (hazard ratio [HR] 0.51, 95% CI 0.37—0.70; P <.001)
- A 36% lower risk of hospitalization for heart failure (0.64, 95% CI 0.50—0.82; P = 0.001)
- A 19% lower risk of myocardial infarction (HR 0.81, 95% CI 0.74—0.88; P <.00)
- A 32% lower risk of stroke (HR 0.68, 95% CI 0.55—0.84; P <.001).
Kosiborod presented data to show that the results were consistent across subgroups, across countries and included those with and without established CVD.
While most of the patients in the study were using dapagliflozin (Farxiga) at 75%, slices of the study population were using empagliflozin (Jardiance, 9%), ipragliflozin (Suglat, 8%) canagliflozin (Invokana, 4%), tofogliflozin (3%), and luseogliflozin (Lusefi, 1%), which Kosiborod said reflected the market dynamics in the various countries. In the first CVD-REAL trial, a small share of the patients was taking empagliflozin, with the rest evenly balanced between dapagliflozin and canagliflozin.
Not only did the first CVD-REAL results strongly suggest a class effect for SGLT2 inhibitors in the months before the release of CANVAS, the cardiovascular outcomes trial for canagliflozin, but the results for patients without established CVD suggested that the drugs might be able to prevent heart failure—something that is now being studied in clinical trials.
Kosiborod noted that, so far, the CVD-REAL trials provide a complement to the large cardiovascular outcomes trials that have been presented—empagliflozin (EMPA-REG) and CANVAS, although the EMPA-REG had no primary prevention patients and CANVAS had a relatively small number.
DECLARE, the outcomes trial for dapagliflozin, which is likely to be released this fall, has a much larger primary prevention population. “DECLARE is going to come at a critical juncture,” Kosiborod said.
AstraZeneca, manufacturer of dapagliflozin, sponsored the study.
Kosiborod M, Lam CSP, Kohsaka S, et al; CVD-REAL Investigators and Study Group. Lower cardiovascular risk associated with the SGLT2i in >400,000 patients: the CVD-REAL 2 study [published online March 11, 2018]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2018.03.009.