Conclusions
It has been nearly 100 years since insulin was introduced as the first pharmacologic agent for diabetes treatment and 20 years since the publication of the UKPDS documenting the benefits of intensive glycemic control on microvascular complications in patients with T2DM. We now have more than a dozen classes of agents to treat T2DM, but until now, we have not had any diabetes medication with proven benefits on CV and all-cause mortality. The enigma in the EMPA-REG OUTCOME study is that the CV/renal benefits occur as early as 3 months and that there is no reduction in traditional atherothrombotic CV events. A partial explanation for this enigma may lie in fuel energetics, with empagliflozin shifting myocardial and renal fuel metabolism away from fat/glucose oxidation to a more energy-efficient fuel like ketone bodies, thereby improving myocardial/renal work efficiency and function. Even small beneficial changes in energetics minute to minute can translate into large differences in efficiency over weeks to months. Furthermore, myocardial changes would benefit the kidney and vice versa. In addition to improved fuel metabolism, BP and natriuretic, diuretic, and neurohormonal/vascular effects could play a role but are unlikely to produce beneficial results within 3 months. Detailed physiologic and imaging studies need to be done to delineate mechanisms for CV/renal benefits.
