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The EMPA-REG OUTCOME trial explored the effect of empagliflozin on improving heart failure outcomes across a variety of type 2 diabetes patients.
The effect of empagliflozin on improving heart failure outcomes extends across type 2 diabetes patients with a variety of characteristics, and with and without heart failure at baseline, according to results from the landmark EMPA-REG OUTCOME® trial.1
The study was published online in European Heart Journal.
“Consistent reductions [in hospitalization for heart failure or cardiovascular death] were observed across subgroups of patients defined by a variety of clinical characteristics, including the presence of heart failure at baseline and the use of medications commonly used in the treatment of patients with type 2 diabetes and/or heart failure, and between the two dose groups,” wrote lead author Silvio Inzucchi, MD, and colleagues.
“[P]rior to these findings, no glucose-lowering drug had been shown to improve heart failure outcomes in patients with type 2 diabetes,” they added.
Earlier results from the EMPA-REG OUTCOME trial showed that over a median of 3.1 years empagliflozin added to standard care significantly decreased the risk of CV death, non-fatal myocardial infarction, or nonfatal stroke by 14%, decreased all-cause mortality by 32%, decreased hospitalization for heart failure by 35%, and decreased CVD death by 38%, compared to placebo.2
In the study, researchers randomized 7020 patients to once daily empagliflozin at 10 mg or 25 mg doses, or placebo. Participants had the following characteristics: mean age of 63.1 years, mean BMI 30.6 kg/m2, 72% male, 25.9% with an eGFR <60 mL/min/1.73 m2, and 10.1% had heart failure at baseline. Ninety-seven percent of participants completed the study. Twenty-five percent discontinued empagliflozin early, mostly because of adverse events. Participants had a median treatment duration of 2.6 years.
• Heart failure hospitalization or cardiovascular death 34% lower with empagliflozin vs placebo (HR: 0.66 [95% confidence interval: 0.55–0.79], P < 0.001)
• Other heart failure outcomes:
♦ Hospitalization for or death from heart failure 39% lower with empagliflozin vs placebo (HR: 0.61 [0.47–0.79]; P < 0.001)
♦ Hospitalization for heart failure 35% lower with empagliflozin vs placebo (HR:0.65 [0.50–0.85]; P = 0.002)
♦ All-cause hospitalization 11% lower with empagliflozin vs placebo (HR: 0.89 (0.82–0.96); P = 0.003]
• Number needed to treat: 35 patients over 3 years to prevent one heart failure hospitalization or death
• The favorable effect of empagliflozin on heart failure hospitalization or CV death was consistent for patients with and without heart failure, and across doses, age, race, eGFR, as well as use of glucose-lowering agents (including insulin) and CVD drugs
• Serious adverse events and adverse events leading to discontinuation were similar with empagliflozin vs placebo
♦ Genital infections more common with empagliflozin
♦ Adverse events consistent with volume depletion similar with placebo (4.9%) vs empagliflozin (5.1%)
The authors noted several limitations, including the fact that the diagnosis of heart failure at baseline relied on investigator report, rather than cardiac function or biomarkers. In addition, whether or not the results apply to heart failure with reduced or preserved ejection fraction remains unknown because the study could not look at these issues.
The mechanisms underlying empagliflozin’s effect on heart failure and cardiovascular death are also unknown, they added. Possible factors include osmotic diuresis, effects on the cardio-renal, plasma volume and sodium retention, decreased arterial stiffness and decreased left ventricular afterload, decreased weight and blood pressure, decreased hyperglycaemia and insulin levels, and decreased uric acid.
Based on results from the EMPA-REG trial, in January 2016 the FDA accepted a supplemental new drug application for empagliflozin for lowering CV risk.3
• In the EMPA-REG OUTCOME® trial, empagliflozin lowered the risk of hospitalization for heart failure or cardiovascular death by 34%, as well as other measures of heart failure outcomes.
• The favorable effect of empagliflozin on heart failure outcomes was consistent for patients with and without heart failure, and across a variety of patient characteristics.
• Based on results from the EMPA-REG trial, in January 2016 the FDA accepted a supplemental new drug application for empagliflozin for lowering CV risk.
The study was sponsored by Boehringer Ingelheim and Eli Lilly and Company.
Stefan Hantel, Afshin Salsali, Odd Erik Johansen, Hans J. Woerle, and Uli C. Broedl are employees of Boehringer Ingelheim.
One or more authors reports personal fees, grants and/or nonfinancial support from one or more of the following: Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Sanofi, Merck & Co. B.Z., Eli Lilly and Company, Takeda, AstraZeneca, Janssen, Gilead Sciences, Regeron, Intarcia, Lexicon, and Poxel.
1. Fitchett D, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016 Jan 26. [epub ahead of print]
2. Zinman B, et al. EMPA REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128.
3. PR Newswire. U.S. FDA Accepts Filing of Cardiovascular Outcomes Data for Jardiance® (empagliflozin). Accessed February 11, 2016 at: http://prnewswire.sys-con.com/node/3647940.