Results of the EMPA-REG OUTCOME trial (1) have captured the attention of endocrinologists and cardiovascular physicians worldwide. The reason for this is that the use of empagliflozin, the sodium glucose cotransporter 2 (SGLT2) inhibitor investigated in the EMPA-REG OUTCOME trial, was associated with improved cardiovascular outcomes i.e. death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Brief description of the study – Zinman et al (1) randomly assigned patients to 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. 7,020 patients were included in the study and followed for a median time of 3.1 years. The primary outcome occurred in 490 of 4687 patients (10.5%) in the empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group; P=0.04 for superiority. There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant difference between groups regarding the key secondary outcome (P=0.08 for superiority). Apart from an increased rate of genital infection in patients receiving treatment with empagliflozin, there was no increase in other adverse events. The investigators concluded that “patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care”. (1)

This is the first time that a study of antidiabetic agents reports improved clinical outcomes beyond microvascular variables. The reasons for the improved outcome are currently been discussed but it looks as that the glucosuric effect of the SGLT2 inhibitor could have resulted in blood pressure lowering, which has been shown in many studies previously to improve cardiovascular outcome. In the EMPA-REG trial, empagliflozin caused a reduction in weight, waist circumference, and both systolic and diastolic blood pressure.

As a group, the SGLT2 inhibitors (i.e. empagliflozin, dapagliflozin and canagliflozin), reduce renal glucose reuptake, which lowers serum glucose and decreases blood pressure. The effects of these agents on blood pressure and weight, in addition to their glucose lowering actions, make them potentially attractive to cardiovascular physicians dealing with increased cardiovascular risk in diabetes. It remains to be seen, however, if the results of this important study (1) are enough to place SGLT2 inhibitors among established drug such as statins, aspirin, and ACE inhibitors, documented to improve cardiovascular outcomes. My impression is that there is a long way to go before these agents can be considered “established” therapy for reducing cardiovascular risk in patients with diabetes and some of the “barriers” they may encounter have been discussed in a recent article in Medscape (2). SGLT2 inhibitors however, based on the EMPA-REG OUTCOME trial results, represent a major advance in the battle to improve cardiovascular prognosis in diabetes and their development will most certainly be followed with extreme interest by the cardiovascular community.

References:

1. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D., David Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D., Michaela Mattheus, Dipl. Biomath., Theresa Devins, Dr.P.H., Odd Erik Johansen, M.D., Ph.D., Hans J. Woerle, M.D., Uli C. Broedl, M.D., and Silvio E. Inzucchi, M.D., for the EMPA-REG OUTCOME Investigators. N Engl J Med 2015; 373:2117-2128 – DOI: 10.1056/NEJMoa1504720

2. Empagliflozin a Diabetes ‘Game Changer’? Medscape. Mar 02, 2016