- A total of 7020 patients were randomized to 10 or 25 mg of empagliflozin or placebo and followed for a median 3.1 years. The primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke occurred in 10.5% of the empagliflozin group compared with 12.1% of the placebo group. There were significant differences in death from cardiovascular causes with empagliflozin (38% lower relative risk), hospitalization for heart failure (35% relative risk reduction), and death from any cause (32% relative risk reduction) but no significant between-group differences in the rates of myocardial infarction or stroke.
- “The EMPA-REG OUTCOME results may force us to change the way we look at type 2 diabetes. It has been a long time since we’ve had a trial in diabetes that showed cardiovascular benefits. There have now been multiple studies with neutral results, so the EMPA-REG results should make professional associations consider how they will affect treatment guidelines for type 2 diabetes.”
ARYAN'S BLOG 
This study evaluated empagliflozin, an SGLT2 inhibitor, in terms of long-term safety and efficacy in type 2 diabetes patients with vascular disease. There were three arms in this study: empagliflozin 10 mg (n = 2345); empagliflozin 25 mg (n = 2342); and placebo (usual care; n = 2333).
The primary outcomes were CV death, MI, and stroke. The doses showed benefit individually, and, when pooled together, empagliflozin had 14% reduction in the primary outcome (HR, 0.86) and empagliflozin reduced CV death by 38% and total death by 32% in just 3 years. The curves separated early, and they continue to diverge to the end of the study. There was also a 35% reduction in hospitalization for heart failure.
This is the first study of a glucose-lowering medication that has shown a benefit in terms of death rate reduction compared with usual care. There are many theories as to why this might be. For example, the empagliflozin patients did have lower A1cs, reduced blood pressure, and reduced weight and abdominal adiposity. This may have contributed to the benefits; however, such risk factors usually take time to show benefits; yet the curves diverge quickly in this study. Perhaps the SGLT2 is reducing arterial wall stiffness, which, in turn, is reducing sympathetic nerve activation, and thereby reducing albuminuria or glucose variability. As a result, there are fewer ups and downs of glucose and less stress on the heart. No one knows the true answer; but for now, the results speak for themselves.
Guideline writers will have to grapple with how this study will change the order of our recommended treatments and whether this is a drug-specific or a class effect. As more studies are completed in the future, the answers to these questions will become clearer.
For our patients, there is great optimism. On top of statin and ACE/ARB treatments, the total death reduction was 32%. Treating 39 patients would prevent 1 death over a 3-year period. The only real penalty to be paid was a slight increase in yeast infections. There were no bone fractures and no renal failures or complications. However, we must remember that renal function must be good for these medications to work. Almost three-quarters of the patients in this study had eGFR >60 ml/min/1.73m.2
Perhaps empagliflozin will usher in an era when CV protections will be the norm; but, for now, in the right patients, we can postpone death.