Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients - EMPA-REG OUTCOME

Contribution To Literature:

The EMPA-REG OUTCOME trial showed that empagliflozin is superior to placebo in improving glycemic control and reducing CV events including mortality in patients with DM2 and established CV disease.


The goal of the trial was to assess the cardiovascular (CV) safety of empagliflozin, a sodium–glucose cotransporter 2 (SGLT-2) inhibitor, in patients with type 2 diabetes mellitus (DM2) at high risk for CV events.

Study Design

Patients were randomized in a 1:1:1 fashion to either empagliflozin 10 mg (n = 2,345), 25 mg (n = 2,342), or matching placebo (n = 2,333).

  • Total number of enrollees: 7,028
  • Duration of follow-up: 3.1 years
  • Mean patient age: 63.1 years
  • Percentage female: 28%

Other salient features/characteristics:

  • White 72%, Asian 22%
  • Diagnosis of DM2 >10 years: 57%
  • History of myocardial infarction (MI): 47%, multivessel disease: 47%, coronary artery bypass grafting: 25%
  • Monotherapy at baseline: 29% (metformin 36%, insulin 46%)
  • Metformin + sulfonylurea: 43%, metformin + insulin: 45%
  • Statins: 77%

Inclusion criteria:

  • Age ≥18 years
  • DM2
  • Glycosylated hemoglobin (HbA1c) of ≥7.0% and ≤10% for patients on background therapy or HbA1c ≥7.0% and ≤9.0% for drug-naive patients
  • Background glucose-lowering therapy unchanged for ≥12 weeks prior to randomization or, in the case of insulin, unchanged by >10% from the dose at randomization in the previous 12 weeks
  • Body mass index ≤45 kg/m2
  • Glomerular filtration rate (GFR) >30
  • Established cardiovascular disease

Exclusion criteria:

  • Uncontrolled hyperglycemia with a glucose level >240 mg/dl after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
  • Indication of liver disease
  • Planned cardiac surgery or angioplasty within 3 months
  • Bariatric surgery within the past 2 years and other gastrointestinal surgeries that induce chronic malabsorption
  • Blood dyscrasias or any disorders causing hemolysis or unstable red blood cell (e.g., malaria, babesiosis, hemolytic anemia)
  • Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
  • Treatment with anti-obesity drugs (e.g., sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e., surgery, aggressive diet regimen, etc.) leading to unstable body weight
  • Current treatment with systemic steroids or any other uncontrolled endocrine disorder except DM2
  • Alcohol or drug abuse within the 3 months
  • Acute coronary syndrome, stroke, or transient ischemic attack within 2 months prior to informed consent

Principal Findings:

The primary outcome, CV death, nonfatal MI, or stroke for empagliflozin vs. placebo: 10.5% vs. 12.1%, hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99, p < 0.001 for noninferiority; p = 0.04 for superiority. For CV death: 3.7% vs. 5.9%, p < 0.001; all MI: 4.8% vs. 5.4%, p = 0.23; all stroke: 3.5% vs. 3.0%, p = 0.26. For the primary endpoint, results were similar for the two doses of empagliflozin vs. placebo.

Secondary outcomes:

  • All-cause mortality: 3.8% vs. 5.1%, p < 0.01
  • Congestive heart failure (CHF) hospitalization: 2.7% vs. 4.1%, p = 0.002 (results were similar in patients with and without CHF at baseline); time to first CHF episode: HR 0.70 (0.57-0.87)
  • CHF hospitalization or CV death: 5.7% vs. 8.5%, p < 0.001
  • All-cause hospitalization: 36.8% vs. 39.6%, p  = 0.003
  • Coronary revascularization: 7% vs. 8%, p = 0.11
  • Mean change in HbA1c at 12 weeks for 10 mg empagliflozin vs. placebo: -0.54%
  • Mean change in HbA1c at 12 weeks for 25 mg empagliflozin vs. placebo: -0.6%
  • Confirmed hypoglycemic event: 27.8% vs. 27.9%
  • Urinary tract infection: 18% vs. 18.1%, p > 0.05; genital infection: 6.4% vs. 1.8%, p < 0.001

Renal outcomes:

  • Incident or worsening nephropathy for empagliflozin vs. placebo: 12.7% vs. 18.8%, HR 0.61, 95% CI 0.53-0.70; p < 0.001
  • Doubling of serum creatinine: 1.5% vs. 2.6%, p < 0.001
  • Progression to macroalbuminuria: 11.2% vs. 16.2%, p < 0.001
  • Initiation of renal replacement therapy: 0.3% vs. 0.6%, p = 0.04

Risk stratification for incident HF:

Using the Health ABC HF Risk Score, patients were categorized into low-to-average (<10%), high (10-20%), and very high (≥20%) risk for incident HF over 5 years. The incidence of HF per 100 patient-years for empagliflozin vs. placebo: low to average risk (1.2% vs. 1.68%), high (2.07% vs. 4.03%), and very high (3.8% vs. 7.0%) (p for interaction = 0.38).

Patients with established chronic kidney disease (CKD):

In both the empagliflozin and placebo groups, event rates for all outcomes presented were numerically higher in patients with estimated GFR <60 ml/min than in patients with ≥60 ml/min at baseline. The same trend was observed among patients with macroalbuminuria compared with normoalbuminuria. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of CV death by 29% compared with placebo (HR 0.71, 95% CI 0.52-0.98), the risk of all-cause mortality by 24% (HR 0.76, 95% CI 0.59-0.99), the risk of hospitalization for heart failure by 39% (HR 0.61, 95% CI 0.42-0.87), and the risk of all-cause hospitalization by 19% (HR 0.81, 95% CI 0.72-0.92). All interactions were nonsignificant (p > 0.05), including between patients with and without CKD, and among the different CKD subgroups.

Patients with established peripheral artery disease (PAD):

A total of 1,461 patients (20.8%) had established PAD. Event rates were higher among PAD patients compared with those without PAD. Among patients with PAD at baseline, empagliflozin reduced CV death by 43% (HR 0.57, 95% CI 0.37-0.88), all-cause mortality by 38% (HR 0.62, 95% CI 0.44-0.88), CV death/MI/stroke by 16% (HR 0.84, 95% CI 0.62-1.14), CV death/MI/stroke/unstable angina by 7% (HR 0.93, 95% CI 0.70-1.24), hospitalization for heart failure by 44% (HR 0.56, 95% CI 0.35-0.92), and incident or worsening nephropathy by 46% (HR 0.54, 95% CI 0.41-0.71) versus placebo, consistent with findings in patients without PAD (p for interaction for all endpoints > 0.05). Among all patients with PAD, lower-extremity amputations for empagliflozin vs. placebo were 5.5% vs. 6.3%, p > 0.05; major lower-extremity amputations: 1.3% vs. 3.3%. Among all patients without PAD, lower-extremity amputations for empagliflozin vs. placebo were 0.9% vs. 0.7%, p > 0.05; major lower-extremity amputations: 0.1% vs. 0.1%.

CV risk categories:

65% had a prior MI and/or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated CV risk according to TIMI risk score for secondary prevention (10-point TIMI Risk Score for Secondary Prevention [TRS 2°P]) (≤2, 3, 4, and ≥5 points, respectively). The reductions in risk of CV death, all-cause mortality, 3-point major adverse cardiac events, hospitalization for heart failure (HHF), and HHF or CV death with empagliflozin vs. placebo were consistent across subgroups by baseline TRS 2°P (p > 0.05 for randomized group-by-subgroup interaction tests).

Relationship of hypoglycemia and CV outcomes:

Hypoglycemia was broadly defined as symptomatic hypoglycemia with plasma glucose <70 mg/dl, hypoglycemic adverse event with plasma glucose <54 mg/dl, or severe hypoglycemic adverse event that required the assistance of another person.

This event occurred in 28% of each group and was associated with an increased risk for hospitalization for heart failure or MI. Hypoglycemia did not attenuate the improvement in CV outcomes from empagliflozin (p for interaction > 0.05).

Total HF events:

Empagliflozin reduced all HF events in patients with prior HF (relative risk 0.52, 95% CI 0.290-0.92) and those without prior HF (0.64, 95% CI 0.45-0.93) (p > 0.05 for interaction).


The results of this trial indicate that empagliflozin is superior to placebo in improving glycemic control and reducing CV events in patients with DM2 and established CVD. Further, it appears to have a salutary effect on renal outcomes too, including the need to initiate renal replacement therapy. There was also a significant mortality benefit with empagliflozin. It reduced HF and all-cause hospitalizations among patients with and without baseline HF.

Hypoglycemia can occur; however, this did not appear to attenuate the improvement in CV outcomes from empagliflozin. Unlike canagliflozin, there was no safety signal, regarding increased amputations, even among patients with established PAD. Findings were independent of baseline renal function. These are really important findings and suggest that agents such as liraglutide and empagliflozin with documented CV benefits may need to be considered as second-line therapy in similar high-risk patients going forward.

Empagliflozin is a novel drug for the treatment of DM2 and functions as an SGLT2 inhibitor. These drugs reduce hyperglycemia in patients with DM2 by reducing renal glucose reabsorption and thus increasing urinary glucose excretion.

Following the much publicized CV safety concerns with rosiglitazone, the Food and Drug Administration mandated that all new diabetes drugs conduct studies demonstrating CV safety. The upper limit of the 95% confidence interval for the hazard ratio had to be <1.8 for premarketing studies and <1.3 for postmarketing studies. This trial thus establishes the CV safety profile of empagliflozin for use in patients with DM2, and is in fact, one of the first large-scale DM2 trials to show an improvement in hard CV outcomes with simultaneous improvements in glycemic control in a high-risk population. The mechanisms for this benefit will need to be established in future trials.

Other trials with SGLT-2 inhibitors are ongoing and will help establish whether this is a class effect. There was no increase (and in fact this trial showed a significant reduction) in CHF hospitalizations with empagliflozin, as was previously noted with saxagliptin and some of the other dipeptidyl peptidase-4 (DPP-4) inhibitors.


Fitchett D, Inzucchi SE, Wanner C, et al., on behalf of the EMPA-REG OUTCOME Trial Investigators. Relationship Between Hypoglycaemia, Cardiovascular Outcomes, and Empagliflozin Treatment in the EMPA-REG OUTCOME Trial. Eur Heart J 2020;41:209-17.

Editorial: Solis-Herrera C, Sheikh O, Chilton R. A New Perspective on Lowering CV Risk From Hypoglycaemia. Eur Heart J 2020;41:218-20.

Presented by Stefan D. Anker at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.

Presented by Dr. David Fitchett at the European Society of Cardiology Congress, Paris, France, August 31, 2019.

Fitchett D, Inzucchi SE, Cannon CP, et al. Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation 2019;138:1384-95.

Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME. Circulation 2017;137:405-7.

Presented by Dr. Subodh Verma at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.

Wanner C, Lachin JM, Inzucchi SE, et al., on behalf of the EMPA-REG OUTCOME Investigators. Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes, Established Cardiovascular Disease and Chronic Kidney Disease. Circulation 2017;137:119-29.

Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME trial. Eur Heart J 2018;39:363-70.

Presented by Dr. Javed Butler at the European Society of Cardiology Congress, Barcelona, Spain, August 28, 2017.

Presented by Dr. David Fitchett at the European Society of Cardiology Congress, Rome, Italy, August 28, 2016.

Wanner C, Inzucchi SE, Lachin JM, et al., on behalf of the EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016;375:323-34.

Editorial: Ingelfinger JR, Rosen CJ. Cardiac and Renovascular Complications in Type 2 Diabetes — Is There Hope? N Engl J Med 2016;375:380-2.

Fitchett D, Zinman B, Wanner C, et al., on behalf of the EMPA-REG OUTCOME Trial Investigators. 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;37:1526-34.

Zinman B, Wanner C, Lachin JM, et al., on behalf of the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

Presented by Dr. Silvio E. Inzucchi at the American Heart Association Scientific Sessions, Orlando, FL, November 9, 2015.

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Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: AHA Annual Scientific Sessions, AHA19, Diabetes Mellitus, Type 2, Glucose, Heart Failure, Glycated Hemoglobin A, Hyperglycemia, Hypoglycemic Agents, Insulin, Kidney Diseases, Metabolic Syndrome, Metformin, Myocardial Infarction, Primary Prevention, Stroke, Sulfonylurea Compounds, AHA Annual Scientific Sessions, AHA17, ESC Congress, ESC2017, ESC Congress, ESC 19

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