Background: Recent clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors reported improved cardiovascular outcomes in patients with type 2 diabetes (T2D) with a high risk of cardiovascular events. However, the mechanisms of these clinical effects on endothelial function are not fully understood.

Methods: The EMBLEM trial in patients with T2DM and cardiovascular disease (CVD) demonstrated no effects of 24 weeks of empagliflozin treatment on endothelial function assessed by reactive hyperemia peripheral arterial tonometry. This secondary analysis of the EMBLEM trial included a detailed evaluation of the effect of empagliflozin treatment on endothelial function, its association with clinical variables, and the clinical characteristics of responders or non-responder to treatment.

Results: Among 47 patients randomized into the empagliflozin group, 21 (44.7%) patients showed increases in reactive hyperemia index (RHI) after 24 weeks of intervention, and no significant difference in clinical characteristics between patients whose RHI increased (at least >0) or did not increase. There was also no significant difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log-transformed RHI. No correlation was observed between changes in RHI and clinical variables, such as vital signs and laboratory parameters.

Conclusions: 24 weeks of empagliflozin treatment in patients with T2DM and established CVD did not affect peripheral endothelial function, and that was not associated with changes in clinical variables, including glycemic parameters. These findings emphasize that the improved cardiovascular outcomes observed in the recent trials on SGLT2 inhibitors are attributable, at least in the early phase, to mechanisms other than direct amelioration of endothelial function.


A. Tanaka: Consultant; Self; Kowa Company, Ltd. Research Support; Self; GlaxoSmithKline plc. Speaker’s Bureau; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. K. Node: None.


Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

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