Randomized, “head‐to‐head” studies comparing different SGLT2 inhibitors are definitely needed

We appreciate the comments from Dr Patoulias and colleagues ¹ regarding our study investigating the effects of the sodium‐glucose cotransporter 2 (SGLT2) inhibitor, luseogliflozin, on arterial stiffness in patients with diabetes mellitus. ² The results of our single‐arm study did not show any favorable effect of luseogliflozin on arterial stiffness, measured using the cardio‐ankle vascular index (CAVI). ² As a measure of arterial stiffness, CAVI is relatively independent of blood pressure (BP) and is now widely used in cardiovascular research and clinical practice. ³ , ⁴ , ⁵ , ⁶ , ⁷

SGLT 2 inhibitors were primarily developed as antidiabetic agents, but are also considered as a new class of “antihypertensive drugs” due to their homeostatic mechanisms. These include regulation of body fluid volume by diuretic activity and attenuation of sympathetic nerve‐mediated salt sensitivity, which may be closely associated with the cardiorenal protective properties. ⁸ , ⁹ , ¹⁰

To date, three drugs in the SGLT2 inhibitor class (empagliflozin, canagliflozin, and dapagliflozin) have been shown to significantly reduce the rate of cardiovascular events and mortality compared with placebo. ¹¹ , ¹² , ¹³ In addition, significant attenuation of renal disease progression has been documented in controlled clinical trials with canagliflozin and empagliflozin. ¹¹ , ¹⁴ As Dr Patoulias and colleagues correctly point out, results with the newer agent ertugliflozin were less dramatic. ¹⁵ However, there was a trend toward lower rates of hospitalization for heart failure and the renal composite endpoint (although formal statistical testing was not performed due to the hierarchical nature of the statistical analysis and the lack of significance for the primary composite endpoint). Even results from studies with the same SGLT2 inhibitor agent are not consistent, with substantial reductions in cardiovascular mortality in the EMPA‐REG OUTCOME study with empagliflozin in patients with type 2 diabetes mellitus, ¹³ but no significant decrease in cardiovascular deaths during treatment with the same agent in the EMPEROR‐Reduced trial of patients with heart failure and reduced ejection fraction. ¹⁶ This suggests that other between‐trial differences and potential confounders could have contributed to the findings of different studies, and therefore, a class effect may still be possible. Certainly, SGLT2 inhibitors have a number of other beneficial actions that are likely to contribute to reductions in cardiovascular risk, including reductions in body weight and BP and improvement in glycemic control, ¹⁷ , ¹⁸ as were seen with luseogliflozin in our study. ²

We certainly agree with Dr Patoulias and colleagues that there is the possibility for differential effects of different SGLT2 inhibitors on markers of cardiorenal protection due to the significant difference in pharmacological properties between agents in this class. We also recommend future randomized, head‐to‐head comparisons between different SGLT2 inhibitors to provide robust comparative evidence in this field. In the meantime, the currently available cumulative data remain in favor of cardiorenal protection as a class effect of SGLT2 inhibitors, consistent with current guideline recommendations. ¹⁹ , ²⁰ , ²¹

CONFLICT OF INTEREST

Prof. K Kario has received research grants from Astellas Pharma Inc, Eisai Co., Otsuka Pharmaceutical Co., Sanofi KK, Shionogi & Co., Sanwa Kagaku Kenkyusho Co., Daiichi Sankyo Co., Sumitomo Dainippon Pharma Co., Takeda Pharmaceutical Co., Mitsubishi Tanabe Pharma Co., Boehringer Ingelheim Japan Inc, Pfizer Japan Inc, Bristol‐Myers Squibb KK, and Mochida Pharmaceutical Co. and lecture fees from Idorsia Pharmaceuticals Japan, Daiichi Sankyo Co., and Takeda Pharmaceutical Co. All other authors have no conflicts of interest to disclose.