Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium–Glucose Cotransporter-2 Inhibitors Versus Metformin

TO THE EDITOR: Shin and colleagues carried out a cohort study (1) and drew the key conclusion that use of first-line treatment with sodium–glucose cotransporter-2 inhibitors (SGLT-2i) versus metformin significantly decreased hospitalization for heart failure (HHF) and the composite outcome of HHF or all-cause mortality (HHF/mortality) in patients with type 2 diabetes (T2D). Although the authors conducted subgroup analyses stratified by history of cardiovascular disease (CVD), they did not mention any content related to subgroup analyses in the conclusion of their article. I am interested in the results of subgroup analyses on heart failure– associated outcomes. As shown in Figure 4 of Shin and colleagues' article, SGLT-2i versus metformin significantly reduced HHF (hazard ratio [HR], 0.63 [95% CI, 0.40–0.99]) and HHF/mortality (HR, 0.60 [CI, 0.41– 0.88]) in patients with T2D without CVD but did not reduce HHF (HR, 0.86 [CI, 0.67–1.10]) and HHF/mortality (HR, 0.92 [CI, 0.74– 1.15]) in those with CVD even though P values for subgroup differences were slightly more than and approximate to 0.050, respectively. These results suggest that, compared with metformin, SGLT-2i are more effective in patients with T2D without CVD than in those with CVD for the prevention of heart failure–associated events. In other words, first-line SGLT-2i may be used in patients with earlystage T2D (namely, T2D without CVD) to better prevent heart failure events. Amentionof this in theDiscussion sectionwouldhavegreatly increased the clinical importance of Shin and colleagues' article. As previously noted, relevant subgroup analyses in Shin and colleagues' cohort study (1) revealed that first-line SGLT-2i significantly reduced HHF and HHF/mortality in patients with T2D without CVD but not those with CVD. On the contrary, 2 meta-analyses (2, 3) based on large cardiovascular outcome trials of SGLT-2i showed that these agents significantly reduced HHF, HHF/cardiovascular mortality, or both in both T2D subgroups. To address this inconsistency, there is a need for future studies with sufficient statistical power to assess heart failure outcomes with first-line SGLT-2i in these 2 T2D subgroups. Addressing this point in Shin and colleagues' Discussion sectionwould have promptedmore studies of importance.