Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™)

Abstract

BackgroundEvidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.MethodsPatients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.ResultsBetween Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m2, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m2. The study is expected to report in 2015.DiscussionEMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.Trial registrationClinicaltrials.gov NCT01131676

Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes

“…Only one large non-inferiority trial, the EMPA-REG OUTCOME trial, was designed to examine difference in a composite outcome defined as the first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke in adults with type 2 diabetes and high cardiovascular risk (49).…”

“…Moderate-quality evidence suggests that empagliflozin reduces all-cause mortality (7,11,40,44,46,47,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61) and increases the rates of diabetes control without increasing the risk of serious adverse effects and hypoglycemia when compared with placebo in adults with type 2 diabetes ( Table 1) (50,51,70). The increase in rates of glycemic improvement starts at the dose of 10 mg/day (150 attributable events per 1,000 treated, Figure 1) and increases to 210 attributable events per 1,000 treated after the larger dose of empagliflozin (25 mg/day, Figure 1).…”

“…NNT is calculated as 1/absolute risk difference; attributable events per 1,000 treated as the number of excessive or avoided events per 1,000 treated that are attributed to active treatment; attributable events per 1,000 treated are calculated as absolute rate difference multiplied by 1,000. *, composite outcome of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction), or nonfatal stroke death in adults at high risk of cardiovascular disease or with established cardiovascular disorder; **, results from EMPA-REG OUTCOME trial (49,(57)(58)(59)68), the only RCT designed to examine differences in cardiovascular mortality and morbidity; ‡ , favors empagliflozin. HbA1c, hemoglobin A1c; CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HR, hazard ratio; NNT, number needed to treat to achieve an outcome in one patient; NNTp, number needed to treat to prevent an outcome in one patient (when the outcome is more probable with control intervention); RCT, randomized controlled trial; RR, relative risk.…”

“…The increase in rates of glycemic improvement starts at the dose of 10 mg/day (150 attributable events per 1,000 treated, Figure 1) and increases to 210 attributable events per 1,000 treated after the larger dose of empagliflozin (25 mg/day, Figure 1). Low-quality evidence suggests that empagliflozin reduces cardiovascular mortality, the risk of hospitalization for any cause (73), and hospitalizations for heart failure (59), as well as the risk of developing heart failure (73), developing or worsening of nephropathy (58), and the risk of treatment discontinuation due to lack of efficacy, at the expense of higher risk of adverse effects (Table 1) (7,11,40,44,46,47,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)70,(75)(76)(77). The observed improvement in patient outcomes is attributable to the largest RCT, EMPA-REG OUTCOME, which enrolled patients with established orally, once daily; comparator: placebo.…”

Empagliflozin/linagliptin single‐tablet combination: first‐in‐class treatment option

“…While a clinical impact is not yet clear, patients on empagliflozin should be monitored for lipid changes. A large cardiovascular outcomes trial ( n  =   7034) in patients with T2DM and a heightened risk of cardiovascular disease is investigating the long‐term cardiovascular safety profile and the potential cardiovascular protective effects of empagliflozin 49.…”