BACKGROUND: Evidence 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.
METHODS: Patients 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.
RESULTS: Between 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.
DISCUSSION: EMPA-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 REGISTRATION: Clinicaltrials.gov NCT01131676.