Cardiovascular Outcomes - 26 Nov 15

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 373;22 nejm.org November 26, 2015 2117

From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) and the Divisions of Endocrinology (B.Z.) and Cardiology (D.F.), University of Toronto all in Toronto; the Depart-ment of Medicine, Division of Nephrolo-gy, Wrzburg University Clinic, Wrzburg (C.W.), Boehringer Ingelheim Pharma, Biberach (E.B., S.H.), and Boehringer Ingelheim Pharma, Ingelheim (M.M., H.J.W., U.C.B.) all in Germany; the Bio-statistics Center, George Washington University, Rockville, MD (J.M.L.); Boeh-ringer Ingelheim Pharmaceuticals, Ridge-field, CT (T.D.); Boehringer Ingelheim Norway, Asker, Norway (O.E.J.); and the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.). Address reprint requests to Dr. Zinman at Mount Sinai Hospital, 60 Mur-ray St., Suite L5-024, Box 17, Toronto, ONT M5T 3L9, Canada, or at zinman@ lunenfeld . ca.

This article was published on September 17, 2015, at NEJM.org.

N Engl J Med 2015;373:2117-28.DOI: 10.1056/NEJMoa1504720Copyright 2015 Massachusetts Medical Society.

BACKGROUNDThe effects of empagliflozin, an inhibitor of sodiumglucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.

METHODSWe randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascu-lar causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary compos-ite outcome was the primary outcome plus hospitalization for unstable angina.

RESULTSA total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empa-gliflozin 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). There were 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). There was no significant between-group difference in the key secondary outcome (P = 0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.

CONCLUSIONSPatients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary com-posite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)

A BS TR AC T

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D., David Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D.,

Michaela Mattheus, Dipl. Biomath., Theresa Devins, Dr.P.H., Odd Erik Johansen, M.D., Ph.D., Hans J. Woerle, M.D., Uli C. Broedl, M.D., and Silvio E. Inzucchi, M.D., for the EMPA-REG OUTCOME Investigators

Original Article

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n engl j med 373;22 nejm.org November 26, 20152118


Type 2 diabetes is a major risk factor for cardiovascular disease,1,2 and the pres-ence of both type 2 diabetes and cardio-vascular disease increases the risk of death.3 Evidence that glucose lowering reduces the rates of cardiovascular events and death has not been convincingly shown,4-6 although a modest cardio-vascular benefit may be observed after a prolonged follow-up period.7 Furthermore, there is concern that intensive glucose lowering or the use of specific glucose-lowering drugs may be associat-ed with adverse cardiovascular outcomes.8 There-fore, it is necessary to establish the cardiovascu-lar safety benefits of glucose-lowering agents.9

Inhibitors of sodiumglucose cotransporter 2 reduce rates of hyperglycemia in patients with type 2 diabetes by decreasing renal glucose re-absorption, thereby increasing urinary glucose excretion.10 Empagliflozin is a selective inhibitor of sodium glucose cotransporter 211 that has been approved for type 2 diabetes.12 Given as either monotherapy or as an add-on therapy, the drug is reported to reduce glycated hemoglobin levels in patients with type 2 diabetes, including those with stage 2 or 3a chronic kidney dis-ease.13-20 Furthermore, empaglif lozin is associ-ated with weight loss and reductions in blood pressure without increases in heart rate.13-20 Empagliflozin also has favorable effects on mark-ers of arterial stiffness and vascular resistance,21 visceral adiposity,22 albuminuria,20 and plasma urate.13-19 Empaglif lozin has been associated with an increase in levels of both low-density lipoprotein (LDL)14 and high-density lipoprotein (HDL) cholesterol.13-16 The most common side effects of empagliflozin are urinary tract infec-tion and genital infection.12

In the EMPA-REG OUTCOME trial, we exam-ined the effects of empagliflozin, as compared with placebo, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events who were receiv-ing standard care.

Me thods

Study Oversight

The trial was designed and overseen by a steer-ing committee that included academic investiga-tors and employees of Boehringer Ingelheim. The role of Eli Lilly was limited to cofunding the trial. Safety data were reviewed by an independent aca-

demic data monitoring committee every 90 days or at the discretion of the committee. Cardiovas-cular outcome events and deaths were prospec-tively adjudicated by two clinical-events commit-tees (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 Harmonisa-tion Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participat-ing center. All the patients provided written in-formed 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, Boeh-ringer 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 Univer-sity of Freiburg conducted an independent statis-tical analysis of cardiovascular outcomes (Section B in the Supplementary Appendix). The manu-script 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 dia-betes at high cardiovascular risk against a back-ground 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

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Empagliflozin in Type 2 Diabetes

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, ac-cording 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 hemo-globin 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 randomiza-tion 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-la-bel, placebo run-in period in which background glucose-lowering therapy was unchanged. Patients meeting the inclusion criteria were then ran-domly 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 hemo-globin level at screening (

n engl j med 373;22 nejm.org November 26, 20152120


the primary outcome was determined if the up-per boundary of the two-sided 95.02% confi-dence 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 KaplanMeier esti-mates are presented. Because of the declining numbers of patients at risk, cumulative-inci-dence 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 pa-tients 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 de-scribed in the Section F in the Supplementary Appendix. We analyzed the changes from base-line in glycated hemoglobin level, weight, waist circumference, systolic and diastolic blood pres-sure, 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.

R esult s

Study Patients

A total of 7028 patients underwent randomiza-tion from September 2010 through April 2013. Of these patients, 7020 were treated and in-cluded in the primary analysis (Fig. S1 in Section G in the Supplementary Appendix). Reasons for premature discontinuation are provided in Table S1 in Section H in the Supplementary Appendix. Overall, 97.0% of patients completed the study, with 25.4% of patients prematurely discontinu-ing a study drug. Final vital status was available for 99.2% of patients.

At baseline, demographic and clinical charac-teristics were well balanced between the placebo group and the empagliflozin group (Table S2 in Section I in the Supplementary Appendix). Ac-

cording to the inclusion criteria, more than 99% of patients had established cardiovascular dis-ease, and patients were well treated with respect to the use of lipid-lowering therapy and antihy-pertensive medications at baseline. The median duration of treatment was 2.6 years, and the median observation time was 3.1 years; both durations were similar in the pooled empa-gliflozin group and the placebo group (Table S3 in Section J in the Supplementary Appendix).

Cardiovascular Outcomes

The primary outcome occurred in a significantly lower percentage of patients in the empagliflozin group (490 of 4687 [10.5%]) than in the placebo group (282 of 2333 [12.1%]) (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval [CI], 0.74 to 0.99; P


Empagliflozin in Type 2 Diabetes

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Cardiovascular Outcomes - 26 Nov 15