Initiation of SGLT2i therapy associated with decreased CV outcomes outside the US and Europe

Lower Cardiovascular Risk Associated with SGLT-2i in >400,000 Patients: The CVDREAL 2 Study

Literature - Kosiborod M, Lam CSP, Kohsaka S, et al. - J Am Coll Cardiol 2018; published online ahead of print

Introduction and Methods

Sodium-glucose cotransporter2 inhibitors (SGLT2i) are associated with a significant reduction in major adverse cardiovascular events (MACE), death and hospitalizations for heart failure (HHF) in patients with type 2 diabetes (T2DM) at high CV risk in the US and Europe [1-4]. However, it is not known, whether these effects are reproducible in real-world clinical practice of other world regions with patients who have different characteristics, and across a broader range of CV outcomes.

In this analysis of the Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors 2 (CVD-REAL 2), the relationship between the initiation of SGLT2i vs. initiation of other glucose-lowering drugs (oGLD) with a broad range of CV outcomes was studied in over 400,000 patients from three major world regions: Asia-Pacific (South Korea, Japan, Singapore, Australia), Middle East (Israel), and North America (Canada).

Anonymized health records were analyzed between 2016 and 2017 in each country, and T2DM patients, aged ≥18 years, and with >1 year data history in the database, who received a new SGLT-2i or oGLD prescription were identified. The two groups were matched using propensity scores. SGLT2i prescriptions included canagliflozin, dapagliflozin, empagliflozin, in all countries, as well as ipragliflozin in South Korea and Japan, and tofogliflozin and luseogliflozin in Japan. The outcomes included all-cause death, hospitalization for heart failure (HHF), the composite of ACD or HHF, myocardial infarction (MI), and stroke.

Main results

  • During 493,380 person-years of follow up, there were 5216 deaths by all causes, 1930 in the SGLT2i group and 3286 in the oGLD group (HR:0.51, 95%CI: 0.37-0.70, P<0.001).
  • During 441,357 person-years of follow up there were 5997 HHF events, 2646 in the SGLT2i group 3351 in the oGLD group (HR: 0.64, 95%CI 0.50–0.82, P=0.001), as well as 9788 HHF or all cause death events, 4118 in the SGLT2i group and 5670 in the oGLD group (HR: 0.60; 95%CI: 0.47–0.76; P<0.001).
  • During 443,307 person-years of follow up, there were 2249 MI events, 973 in the SGLT2i group and 1276 in the oGLD group (HR: 0.81; 95%CI: 0.74–0.88; P<0.001).
  • During 440,346 person-years of follow up, there were 6439 stroke events, 2791 in the SGLT2i group and 3648 in the oGLD group (HR: 0.68; 95%CI: 0.55–0.84; P<0.001).
  • There were no important interactions by patients’ demographic, clinical or treatment characteristics in all subgroups analyses, and for all outcomes.
  • SGLT2i therapy was associated with significantly lower risks of death, HHF, death or HHF, MI and stroke, in patients with and without established CVD at baseline.


The authors conclude that the initiation of SGLT2i as compared with oGLD was associated with significantly lower risks of CV outcomes, including death, heart failure, stroke and MI in T2DM patients from the Asia-Pacific, Middle East and North America.

Editorial comment

In his editorial article, Mc Murray [5] emphasized that only random assignment to therapy leads to credible evaluations of treatment effects. He criticized the study of Kosiborod et al. for using propensity scores to adjust for differences between the two groups using confounders that were not measured. He notes that a 50% reduction in mortality within one year is not realistic for a chronic therapy in real world conditions with questionable patient adherence. And he concluded: ‘We have seen this before. In another large and carefully conducted observational analysis using propensity matching and other methods of adjustment, Go et al. found that statin use was associated with a 30% to 40% lower mortality in patients with heart failure. Two subsequent large randomized controlled trials showed no effect of this treatment on mortality in heart failure. These and other examples reaffirm the unreliability of observational assessments of treatment “effects”……………..In summary, each of the observational studies and clinical trials are informative and valuable, and they are complementary, but only trials tell the truth about treatment effects.’


1. Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-657.

2. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117-28.

3. Mahaffey KW, Neal B, Perkovic V et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018;137:323-334.

4. Kosiborod M, Cavender MA, Fu AZ et al. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 2017;136:249-259.

5. Mc Murray JJV. Only Trials Tell the Truth About Treatment Effects. J Am Coll Cardiol 2018;71(23):2640-42

Find this article online at J Am Coll Cardiol

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