Understanding SGLT2 Inhibitor Effect on CV Events

December 11, 2015

Getting to the bottom of why an SGLT2 inhibitor produced a reduction in cardiovascular events is part of the challenge and excitement of medicine.

Empagliflozin (Jardiance, Boehringer-Ingelheim) surprised the medical world this past September when the EMPA-REG study demonstrated for the first time that a diabetes therapeutic agent significantly reduced cardiovascular (CV) events.1 A total of 7020 patients with type 2 diabetes (T2DM) and CV disease (MI, CVA, or PAD) received standard of care for dyslipidemia and hypertension, along with optimal diabetes agents other than SGLT2 inhibitors, including, if warranted, insulin. The participants were then randomized to one of two doses of empagliflozin (10 mg or 25 mg) or placebo.

The primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal CVA occurred in 490 of 4687 patients (10.5%) in the empagliflozin group (pooled for both doses) and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74-0.99; P=0.04 for superiority). Those on empagliflozin had a relative risk reduction of 38% in death from cardiovascular disease (3.7% in the pooled empagliflozin group vs. 5.9% in the placebo group), and were 32% less likely to die from any cause over the 3 years of the study (5.7% and 8.3%, respectively). Heart failure hospitalizations were significantly decreased (2.7% and 4.1%, respectively; 35% relative risk reduction). Strikingly, the rates of non-fatal myocardial infarction and cerebrovascular accident did not reach statistical significance.

Here are some interesting, and as yet, unanswered questions:

1. What’s the mechanism behind this medication’s CV effects?

Could it be lowering blood pressure? Or what about a reduction in HbA1c? Given the trial’s duration, it would appear unlikely that either would be a putative underlying mechanism. What about this medication’s diuretic effect? This property, along with other unknown effects, such as cardiac remodeling, may have a role.

2. Is this a class effect?

This is a crucial question - and the short answer is, “We don’t know (yet).” Studies are currently underway for the other SGLT2 inhibitors, canagliflozin (Invokana), and dapagliflozin (Farxiga). The Canagliflozin Cardiovascular Assessment Study (CANVAS), which is examining approximately 4000 patients with T2DM on canagliflozin 100 mg or 300 mg daily or placebo, has an anticipated completion date of 2017. The DECLARE-TIMI 58 study of dapagliflozin will randomize over 17,000 T2DM patients on dapagliflozin 10 mg per day or placebo, with a completion date slated in 2019.

3. How generalizable are the results to other populations?

Why would empagliflozin decrease CV mortality, yet appear not to have an impact on MI and CVA? Would low-CV risk patients with T2DM demonstrate similar benefits with empagliflozin?3 This study was a secondary, and not primary, prevention trial. What about T1DM patients?3 These and other questions are as intriguing as they are important, and await further study. To me, the further questions are part of the limitless complex challenges, as well as the boundless excitement, of medicine.


1. Zinman B, et al. Empagliglozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.

2. McMuray J. EMPA-REG - the “diuretic hypothesis”. J Diabetes Complications. 2015 Oct 21 [Epub ahead of print].

3. Kalra S. One small step for empagliflozin, one giant leap for diabetology. Diabetes Therapy. 2015 Nov 4 [Epub ahead of print].