EMPA - REG trial - empagliflozin in type 2 diabetes patients with high cardiovascular risk (EMPAREG)

EMPA-REG

• this trial examined the effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk
• randomly assigned patients to receive 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, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina
• during the first twelve week glucose-lowering therapy was to remain unchanged, ie patients were on previous medication plus placebo or empagliflozin 10mg or 25mg during this 12 week period
  • after week 12, investigators were encouraged to adjust glucose lowering therapy at their discretion to achieve glycemic control according to local guidelines
• throughout the trial, investigators were encouraged to treat other cardiovascular risk factors (including dyslipidemia and hypertension) to achieve the best available standard of care according to local guidelines
• benefits were observed in a population with established cardiovascular disease in whom cardiovascular risk factors, including blood pressure and dyslipidemia, were well treated with the use of renin-angiotensin-aldosterone system inhibitors, statins, and acetylsalicylic acid. The reductions in the risk of cardiovascular death in the empagliflozin group were consistent across subgroups according to baseline characteristics
  
  
• results
  • total of 7020 patients were treated (median observation time, 3.1 years)
    • median duration for treatment was 2.6 years, and the median observation time was 3.1 years; both durations were similar in the pooled empagliflozin group and the placebo group
    • more than 99% of patients had established cardiovascular disease, and patients were well treated with respect to the use of lipid-lowering therapy and antihypertensive medications at baseline
    • primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group 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 to 0.99; P = 0.04 for superiority)
      • from analysis of individual outcomes, it is clear than the main drivers of the difference in the primary outcome were deaths from any cause, deaths from cardiovascular causes, and hospitalisation for heart failure, which were significantly different between empagliflozin and placebo:
        • death from any cause: 5.7% (269/4687) vs. 8.3% (194/2333); HR 0.68 (0.57 to 0.82); p < 0.001
        • death from cardiovascular causes: 3.7% (172/4687) vs. 5.9% (137/2333); HR 0.62 (0.49 to 0.77); p < 0.001
        • hospitalisation for heart failure: 2.7% (126/4687) vs. 4.1% (95/2333); HR 0.65 (0.50 to 0.85); p = 0.002
    • 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)
    • no significant between-group difference in the key secondary outcome (P = 0.08 for superiority)
      • key secondary outcome occurred in 599 of 4687 patients (12.8%) in the empagliflozin group and 333 of 2333 patients (14.3%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.78 to 1.01; P<0.001 for noninferiority and P = 0.08 for superiority)
    • among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events
      
      
  • glycaemic control
    
    
    • after 12 weeks, during which glucose-lowering therapy was to remain unchanged, the adjusted mean differences in the glycated hemoglobin level between patients receiving empagliflozin and those receiving placebo were -0.54 percentage points (95% CI, -0.58 to -0.49) in the 10-mg group and -0.60 percentage points (95% CI, -0.64 to -0.55) in the 25-mg group
    • after week 12, investigators were encouraged to adjust glucoselowering therapy at their discretion to achieve glycemic control according to local guidelines
    • at week 94, the adjusted mean differences in the glycated hemoglobin level between patients receiving empagliflozin and those receiving placebo were -0.42 percentage points (95% CI, -0.48 to -0.36) and -0.47 percentage points (95% CI, -0.54 to -0.41), respectively; at week 206, the differences were -0.24 percentage points (95% CI,-0.40 to -0.08) and -0.36 percentage points (95% CI, -0.51 to -0.20).
      
      
• 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

Reference:

• Zinman B, Wanner C, Lachin JM et al., Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; DOI: 10.1056/NEJMoa1504720