Study Oversight

The trial was designed and overseen by a steering committee that included academic investigators and employees of Boehringer Ingelheim. The role of Eli Lilly was limited to cofunding the trial. Safety data were reviewed by an independent academic data monitoring committee every 90 days or at the discretion of the committee. Cardiovascular outcome events and deaths were prospectively adjudicated by two clinical-events committees (one for cardiac events and the other for neurologic events), as recommended by the Food and Drug Administration (FDA) guidelines.9 A list of investigators and committee members is provided in Sections A and B, respectively, in the Supplementary Appendix, which is available with the full text of this article at NEJM.org.

The trial was conducted in accordance with the principles of the Declaration of Helsinki and the the International Conference on Harmonisation Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

All the authors were involved in the study design and had access to the data, which were analyzed by one of the study sponsors, Boehringer Ingelheim. All the authors vouch for the accuracy and completeness of the data analyses and for the fidelity of the study to the protocol, available at NEJM.org. Members of the University of Freiburg conducted an independent statistical analysis of cardiovascular outcomes (Section B in the Supplementary Appendix). The manuscript was drafted by the first and last authors and revised by all the authors. Medical writing assistance, which was paid for by Boehringer Ingelheim, was provided by Fleishman-Hillard Group.

Study Design

As described previously,23 this was a randomized, double-blind, placebo-controlled trial to assess the effect of once-daily empagliflozin (at a dose of either 10 mg or 25 mg) versus placebo on cardiovascular events in adults with type 2 diabetes at high cardiovascular risk against a background of standard care. Patients were treated at 590 sites in 42 countries. The trial continued until an adjudicated primary outcome event had occurred in at least 691 patients.

Study Patients

Eligible patients with type 2 diabetes were adults (≥18 years of age) with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 45 or less and an estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m2 of body-surface area, according to the Modification of Diet in Renal Disease criteria. All the patients had established cardiovascular disease (as defined in Section C in the Supplementary Appendix) and had received no glucose-lowering agents for at least 12 weeks before randomization and had a glycated hemoglobin level of at least 7.0% and no more than 9.0% or had received stable glucose-lowering therapy for at least 12 weeks before randomization and had a glycated hemoglobin level of at least 7.0% and no more than 10.0%. Other key exclusion criteria are provided in Section D in the Supplementary Appendix.

Study Procedures

Eligible patients underwent a 2-week, open-label, placebo run-in period in which background glucose-lowering therapy was unchanged. Patients meeting the inclusion criteria were then randomly assigned in a 1:1:1 ratio to receive either 10 mg or 25 mg of empagliflozin or placebo once daily. Randomization was performed with the use of a computer-generated random-sequence and interactive voice- and Web-response system and was stratified according to the glycated hemoglobin level at screening (<8.5% or ≥8.5%), body-mass index at randomization (<30 or ≥30), renal function at screening (eGFR, 30 to 59 ml, 60 to 89 ml, or ≥90 ml per minute per 1.73 m2), and geographic region (North America [plus Australia and New Zealand], Latin America, Europe, Africa, or Asia).

Background glucose-lowering therapy was to remain unchanged for the first 12 weeks after randomization, although intensification was permitted if the patient had a confirmed fasting glucose level of more than 240 mg per deciliter (>13.3 mmol per liter). In cases of medical necessity, dose reduction or discontinuation of background medication could occur. 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. Patients were instructed to attend the clinic at prespecified times, which included a follow-up visit 30 days after the end of treatment. Patients who prematurely discontinued a study drug were to be followed for ascertainment of cardiovascular outcomes, and attempts were made to collect vital-status information for any patient who was lost to follow-up, as allowed by local guidelines.

Study Outcomes

The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction), or nonfatal stroke. The key secondary outcome was a composite of the primary outcome plus hospitalization for unstable angina. Definitions of the major clinical outcomes are provided in Section E in the Supplementary Appendix.

Safety was assessed on the basis of adverse events that occurred during treatment or within 7 days after the last dose of a study drug and were coded with the use of the Medical Dictionary for Regulatory Activities, version 18.0. Adverse events of special interest included confirmed hypoglycemic adverse events (plasma glucose level, ≤70 mg per deciliter [3.9 mmol per liter] or an event requiring assistance), and adverse events reflecting urinary tract infection, genital infection, volume depletion, acute renal failure, bone fracture, diabetic ketoacidosis, and thromboembolic events.

Statistical Analysis

The primary hypothesis was noninferiority for the primary outcome with empagliflozin (pooled doses of 10 mg and 25 mg) versus placebo with a margin of 1.3 for the hazard ratio.9 We used a four-step hierarchical-testing strategy for the pooled empagliflozin group versus the placebo group in the following order: noninferiority for the primary outcome, noninferiority for the key secondary outcome, superiority for the primary outcome, and superiority for the key secondary outcome.

Since interim data from the trial were included in a new-drug application submitted to the FDA, under the Haybittle–Peto rule, a two-sided P value of 0.0498 or less was considered to indicate statistical significance in the final analyses.23 For the test of noninferiority for the primary outcome with a margin of 1.3 at a one-sided level of 0.0249, at least 691 events were required to provide a power of at least 90% on the assumption of a true hazard ratio of 1.0. Noninferiority for the primary outcome was determined if the upper boundary of the two-sided 95.02% confidence interval was less than 1.3. Analyses were based on a Cox proportional-hazards model, with study group, age, sex, baseline body-mass index, baseline glycated hemoglobin level, baseline eGFR, and geographic region as factors. Estimates of cumulative-incidence function were corrected for death as a competing risk,24 except for death from any cause, for which Kaplan–Meier estimates are presented. Because of the declining numbers of patients at risk, cumulative-incidence plots have been truncated at 48 months. We calculated the number of patients who would need to be treated to prevent one death on the basis of the exponential distribution.

We performed the primary analysis using a modified intention-to-treat approach among patients who had received at least one dose of a study drug. Data for patients who did not have an event were censored on the last day they were known to be free of the outcome. Secondary analyses included comparisons of the 10-mg dose of empagliflozin versus placebo and the 25-mg dose versus placebo. Sensitivity analyses are described in the Section F in the Supplementary Appendix. We analyzed the changes from baseline in glycated hemoglobin level, weight, waist circumference, systolic and diastolic blood pressure, heart rate, LDL and HDL cholesterol, and uric acid using a repeated-measures analysis as a mixed model. Subgroup analyses are described in Section F in the Supplementary Appendix.