Response by Kosiborod et al to Letters Regarding Article, “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)”

Regarding the comments about our article1 from Koh, we agree that the results from recent randomized clinical trials of several glucose-lowering compounds (including sodium-glucose cotransporter-2 inhibitors [SGLT-2i] and glucagon-like peptide-1 receptor agonists), complemented by large observational studies, such as CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors), should drive a paradigm shift in the management of type 2 diabetes mellitus, from a narrow focus on hemoglobin A1c, to a broader focus on reducing the risk of adverse cardiovascular events (including heart failure), especially for those with established cardiovascular disease. As evidenced by the recent Standards of Care for Diabetes,2 just released by the American Diabetes Association, this shift is already occurring, and is likely to accelerate in the near future. We would also caution against overinterpretation of hazard ratios generated by the subgroup analyses from the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) and CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Specifically, in regard to the impact of empagliflozin and canagliflozin on cardiovascular outcomes across racial subgroups, the interaction P values were nonsignificant in both studies, indicating consistent effects with no significant heterogeneity.3,4 Regarding the comments from Jin-shan and Xue-bin: first, the CVD-REAL study was not designed to explore the mechanisms behind the cardiovascular benefits associated with SGLT-2i. Nevertheless, it is unlikely that these are directly …