Patients with type 2 diabetes at high risk for cardiovascular (CV) events who received empagliflozin (Jardiance) plus standard care had a significantly reduced risk for hospitalization for heart failure as well as CV death and all-cause mortality, according to results from the EMPA-REG OUTCOME study presented at EASD 2015.
“Empagliflozin was associated with a reduction in hemoglobin A1c without an increase in hypoglycemia, a reduction in weight and blood pressure, but small increases in LDL cholesterol and HDL cholesterol,” said study author Bernard Zinman, MD, who is a professor of medicine and director of the Diabetes Centre at the University of Toronto in Canada.
“We looked at two doses of empagliflozin and found a similar magnitude of reduction with both doses for CV death, all-cause mortality and hospitalization for heart failure.”
Zinman, who presented the study findings at the annual meeting of the European Association for the Study of Diabetes, said empagliflozin was associated with an increase in genital infections. However, it was otherwise well tolerated.
The current study included 7,020 adults with type 2 diabetes, BMI less than 45, an estimated glomerular filtration rate of at least 30 mL per minute per 1.73 m2 of body surface area and an established history of CVD. Patients had received no glucose-lowering agents for 12 weeks prior and had glycated hemoglobin levels of at least 7.0% and no more than 9.0% or they had received stable glucose-lowering therapy for 12 weeks prior and had glycated hemoglobin levels of at least 7.0% and no more than 10.0%.
Median observation time was 3.1 years.
In this current study, the researchers randomly assigned patients to receive empagliflozin 10 mg or 25 mg or placebo once daily. Death from CV causes, nonfatal myocardial infarction (MI) or nonfatal stroke, as evaluated in the pooled empagliflozin group vs. the placebo group, served as the primary composite outcome.
According to the data, the primary outcome occurred in 490 (10.5%) of the 4,687 patients in the pooled empagliflozin group, compared with 282 (12.1%) of the 2,333 patients in the placebo group (HR=0.86; 95.02% CI, 0.74-0.99). There also appeared to be no significant between-group differences in the rate of MI or stroke.
Additionally, patients who received empagliflozin had significantly lower rates of death from CV causes, as compared with those who received placebo (3.7% vs. 5.9%, translating to a 38% relative risk reduction). They also had lower rates of hospitalization for heart failure (2.7% vs. 4.1%, translating to a 35% relative risk reduction) and death from any cause (5.7% vs. 8.3%, translating to a 32% relative risk reduction) than those who received placebo.
The researchers also found no significant between-group differences in the key secondary composite outcome, which was comprised of the primary outcome plus hospitalization for unstable angina (P=.08 for superiority). There also appeared to be no differences between the groups in terms of confirmed hypoglycemic adverse events, acute renal failure, diabetic ketoacidosis, thromboembolic events and bone fracture, as well as overall rates of urinary tract infection, complicated urinary tract infection or pyelonephritis. However, urosepsis was reported in 0.4% of patients in the empagliflozin group compared with 0.1% in the placebo group.
“Empagliflozin reduced hospitalization for heart failure by 35%. Empagliflozin reduced cardiovascular death by 38% and empagliflozin improved survival by reducing all-cause mortality by 32%,” said Zinman.
“There are certain features of this trial that are worthy to note. The population studied was a high cardiovascular risk population with modest hyperglycemia on standard glucose-lowering and cardiovascular therapy. Follow-up and retention were noteworthy. Ninety-seven percent of patients completed the study and vital status was available for 99.2% of all participants.”
Empagliflozin is a sodium–glucose co-transporter 2 (SGLT2) inhibitor and is associated with weight loss and reductions in blood pressure without increases in heart rate. Previous studies have also demonstrated that it has a favorable effect on markers of arterial stiffness, vascular resistance and visceral adiposity.
The study researchers noted that there have been concerns about renal safety with long-term use of SGLT2 inhibitors. However, this study showed the percentage of patients with acute renal failure, including acute kidney injury, was lower in the empagliflozin groups than in the placebo group.
The findings of this study were also simultaneously published in the New England Journal of Medicine.
- Walker M et al. RESULTS OF THE EMPA-REG OUTCOME™ STUDY. Presented at: EASD 2015; Sept. 14-18, 2015; Stockholm.
- Zinman B et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1504720.