SGLT2 Based Treatments and Cardiovascular Effects - Are all the Same?

Published in 2015, the Empa-Reg Outcome was the first cardiovascular outcome study (CVOT) to demonstrate both cardiovascular safety and benefit of an anti-hyperglycemic medication. A significant 14% reduction in major adverse cardiovascular events (including cardiovascular death, myocardial infarction, and stroke-MACE) was noted with a robust 38% reduction in cardiovascular death and 35% reduction in hospitalization for heart failure (HHF) in subjects treated with empagliflozin in patients with diabetes and established cardiovascular disease (CVD).  In 2017 the results of the CANVAS/CANVAS-R CVOT were published showing a similar 14% reduction in MACE  and a 33% reduction in HHF with canagliflozin but without a clear and significant benefit on mortality. The study included a different population- as opposed to the Empa-Reg population only 66% of subjects in the CANVAS trial had prior established CVD. Moreover, canagliflozin is less selective than empagliflozin, exerting some inhibition of SGLT-1 as well as SGLT-2. Its clinical efficacy and observed adverse event profile differ from that described with both empagliflozin and dapagliflozin. Two other CVOT studies are underway with highly selective SGLT-2 inhibitors- dapagliflozin and ertugliflozin. The DECLARE- TIMI 58 study examining the cardiovascular safety of dapagliflozin includes two distinct populations- subjects with established CVD and subjects with diabetes, age greater than 55(men)/60(women) and 1 additional risk factor (dyslipidemia, hypertension or tobacco use). Results from this study may shed light on the utility of SGLT-2 inhibitors in the primary prevention of CVD in patients with diabetes. The VERTIS-CV is a smaller study of ertugliflozin, mirroring the study population examined in the Empa-Reg Outcome study.  In the interim, real-world data studies including the CVD-REAL 1 and 2 suggest a mortality and HHF benefit for treatment with various SGLT-2 inhibitors (mostly dapagliflozin and canagliflozin are represented in these HMO database studies)  in patients with diabetes with and without established CVD.  While the clinical profile with regards to glycemic efficacy and safety, of the highly selective SGLT-2 inhibitors (ertugliflozin, dapagliflozin, and empagliflozin) is similar, whether their cardiovascular effect is the same is yet to be answered. However, acknowledging the almost identical effect on MACE reduction and HHF observed in the Empa-Reg and CANVAS studies, and the real world data it would be surprising to observe large differences in the results of the upcoming CVOTs.