Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Presenter: Michelle Lew, PharmD, BCPS
Mentor: Craig J. Beavers, PharmD, FAHA, AACC, BCPS (AQ-Cardiology), CACP
Trial Summary
The EMPA-REG OUTCOME trial was a randomized, double-blind, placebo controlled, multicenter trial in 590 sites in 42 countries. The trial aimed to examine the effects of empagliflozin, as compared with placebo, on cardiovascular morbidity and mortality in patients with type 2 diabetes and high risk for cardiovascular events.
Eligible patients included a diagnosis of type 2 diabetes mellitus, drug-naïve to anti-diabetic therapy, and with high cardiovascular risk. These patients were randomized 1:1:1 to empagliflozin 10 mg daily or 20 mg daily, or placebo. The primary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcome was the primary composite outcome plus hospitalization for unstable angina.
A total of 7,028 patients underwent randomization and were followed for a median of 2.6 years. The patient population for each of the 3 arms was similar in terms of age and cardiovascular risk factors. A large percentage of the population was also on standard of care of glucose-lowering therapy, anti-hypertensive agents, lipid-lowering therapy, as well as antiplatelet agents. The major efficacy and safety endpoints are listed in the table below.
Outcome / Placebo(N=2333) / Empagliflozin
(N=4687) / Hazard Ratio
(95% CI) / P-value
Death from cardiovascular causes, nonfatal myocardial infarction, or non fatal stroke (primary outcome) / 282 (12.1) / 490 (10.5) / 0.86 (0.74-0.99)
Noinferiority / <0.001
Superiority / 0.04
Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina (secondary outcome) / 333 (14.3) / 599 (12.8) / 0.89 (0.78-1.01)
Noninferiority / <0.001
Superiority / 0.08
Hospitalization for heart failure / 95 (4.1) / 126 (2.7) / 0.65 (0.50-0.85) / 0.002
Hospitalization for heart failure or death from cardiovascular causes excluding fatal stroke / 190 (8.5) / 265 (5.7) / 0.66 (0.55-0.79) / <0.001
Adverse Events / Placebo
(N=2333) / Empa 10 mg
(N=2345) / Empa 25 mg
(N=2342) / Pooled Empa
(N=4687)
Urinary tract infection / 423 (18.1) / 426 (18.2) / 416 (17.8) / 842 (18.0)
Male / 158 (9.4) / 180 (10.9) / 170 (10.1) / 350 (10.5)
Female / 265 (40.6) / 246 (35.5) / 246 (37.3) / 492 (36.4)
Complicated urinary tract infection / 41 (1.8) / 34 (1.4) / 48 (2.0) / 82 (1.7)
Genital infection / 42 (1.8) / 153 (6.5) / 148 (6.3) / 301 (6.4)
Male / 25 (1.5) / 89 (5.4) / 77 (4.6) / 166 (5.0)
Female / 17 (2.6) / 64 (9.2) / 71 (10.8) / 135 (10.0)
Diabetic Ketoacidosis / 1 (<0.1) / 3 (0.1) / 1 (<0.1) / 4 (0.1)
Although this was not a trial focused on glycemic control, it was reported that although there was a significant decrease in hemoglobin A1c within the first 12 weeks of the trial but that the majority of patients did not reach their A1c goal by the end of the trial.
The results of the EMPA-REG OUTCOME trial found the decrease in the primary composite outcome was driven by a significant reduction in death from cardiovascular causes, with no significant between-group difference in the risk of myocardial infarction or stroke. The cardiovascular benefits did not appear to be dose-dependent. The authors concluded that patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin had significantly lower rates of the primary composite cardiovascular outcome and of death from any cause than those in the placebo group when added to standard of care.
References:
1) Zinman, B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM 2015;373:2117-28.
Follow-Up Questions:
1)What was the difference in blood pressure lowering between the empagliflozin groups and placebo?
Patients in the empagliflozin 10 mg and 25 mg groups experienced a decrease in systolic blood pressure of about 4 mmHg in comparison to placebo that was sustained throughout the entire trial.
2)Based on the evidence and cost information of the medication, would you suggest adding empagliflozin to hospital formularies?
I would not recommend that empagliflozin be added to hospital formularies at this time. Although the results of this trial suggest empagliflozin is beneficial for heart failure patients, it is yet to be determined if they are useful in the acute setting.Furthermore, previous studies have shown an increase in urinary tract infections, genital mycotic infections, and diabetic ketoacidosis. The adverse event profile from the EMPA-REG OUTCOME trial did not appear to find a difference between among the three arms, pharmacists and other healthcare practitioners should still be cautious in using this agent in patients at risk for these adverse events.
3)Since these agents have been shown to increase HDL and lower triglyceride levels, is there any possibility that these may have added to the cardiovascular benefit?
The HDL levels in the empagliflozin arms did have a sustained increase in comparison to placebo seen in the figure below. It is arguable that the increase in HDL may have added to the cardiovascular benefit but osmotic diuresis effect of empagliflozin is more likely to be the primary mechanism for the benefit in cardiovascular mortality and hospitalizations for heart failure. Future studies may help give more insight into the underlying benefit in cardiovascular disease.