Physicians' Academy for Cardiovascular Education

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


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.’


Show references

Find this article online at J Am Coll Cardiol