Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients - EMPA-REG OUTCOME
The goal of the trial was to assess the cardiovascular (CV) safety of empaglifozin, a sodium–glucose cotransporter 2 (SGLT-2) inhibitor, in patients with type 2 diabetes mellitus (DM2) at high risk for CV events.
Contribution to the Literature: The EMPA-REG OUTCOME trial showed that empaglifozin is superior to placebo in improving glycemic control and reducing CV events including mortality in patients with DM2 and established CV disease.
Patients were randomized in a 1:1:1 fashion to either empaglifozin 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%
- Age ≥18 years
- 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 >30
- Established cardiovascular disease
- 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
The primary outcome, CV death, nonfatal MI, or stroke for empaglifozin 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 empaglifozin vs. placebo.
- 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
- HbA1c at 12 weeks for 10 mg empaglifozin vs. placebo: -0.54%; at 206 weeks: -0.24%
- HbA1c at 12 weeks for 25 mg empaglifozin vs. placebo: -0.6%; at 206 weeks: -0.36%
- 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
- Incident or worsening nephropathy for empaglifozin 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
The results of this trial indicate that empaglifozin 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 empaglifozin. These are really important findings and suggest that agents such as liraglutide and empaglifozine with documented CV benefits may need to be considered as second-line therapy in similar high-risk patients going forward.
Empaglifozin 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 empaglifozin 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 empaglifozin, as was previously noted with saxagliptin and some of the other dipeptidyl peptidase-4 (DPP-4) inhibitors.
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;Jan 26:[Epub ahead of print].
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.
Keywords: Diabetes Mellitus, Type 2, Glucose, Hemoglobin A, Glycosylated, Hyperglycemia, Hypoglycemic Agents, Insulin, Metabolic Syndrome X, Metformin, Myocardial Infarction, Primary Prevention, Stroke, Sulfonylurea Compounds, AHA Annual Scientific Sessions, ESC Congress
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