1. 2015.11.11 R1. 이정미 / prof. 이상열

2. INTRODUCTION Type 2 diabetes is a major risk factor for cardiovascular disease The presence of both type 2 diabetes and cardiovascular disease increases the risk of death. Glucose lowering  reducing the rates of cardiovascular events. BUT death has not been convincingly shown Intensive glucose lowering or the use of specific glucose-lowering drugs  may be associated with adverse cardiovascular outcomes.

3. INTRODUCTION Inhibitors of sodium–glucose cotransporter 2 - decreasing renal glucose reabsorption - thereby increasing urinary glucose excretion  Reduce rates of hyperglycemia in patients with type 2 diabetes Empagliflozin - Selective inhibitor of sodium glucose cotransporter 2 - Weight loss, Reductions in BP without increases in heart rate. -An increase in levels of both LDL & HDL cholesterol - The most common side effects : UTI & genital infection

4. INTRODUCTION In the EMPA-REG OUTCOME trial, -Examine the effects of empagliflozin - cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events who were receiving standard care.

5. METHODS(1) - STUDY DESIGN Randomized, Double-blind, Placebo-controlled trial At 590 sites in 42 countries. Once-daily empagliflozin at a dose of either 10 mg or 25 mg versus placebo. The trial continued until an adjudicated primary outcome event had occurred in at least 691 patients.

6. METHODS(2) – STUDY PATIENT Type 2 diabetes adults (≥18 years of age) BMI ≤ 45 eGFR ≥ 30 ml/min/1.73 m 2 BSA, according to MDRD All the patients had established cardiovascular disease No glucose-lowering agents for at least 12 weeks before randomization glycated hemoglobin level of at least 7.0% - 9.0% OR Stable glucose- lowering therapy for at least 12 weeks before randomization and had a glycated hemoglobin level of at least 7.0% - 10.0%

7. METHODS(3) – STUDY PROCEDURE Randomly assigned in a 1:1:1 ratio - 10 mg or 25 mg of empagliflozin or placebo qd For the first 12 weeks after randomization - Background glucose-lowering therapy was to remain unchanged After week 12 - Investigators were encouraged to adjust glucose lowering therapy Throughout the trial, To treat other cardiovascular risk factors (including dyslipidemia and hypertension) to achieve the best available standard of care.

8. METHODS(4) – STUDY OUTCOMES The primary outcome - A composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction), or nonfatal stroke. The secondary outcome - Primary outcome + Hospitalization for unstable angina.

9. RESULTs(1) – STUDY PATIENTS A total of 7020 patients underwent randomization from September 2010 through April 2013. The median observation time was 3.1 years

10. RESULTs(1) – CARDIOVASCULAR OUTCOME 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%]) (P<0.001 for noninferiority and P = 0.04 for superiority)

13. After 12 weeks, during which glucose-lowering therapy was to remain unchanged, Mean differences in the glycated hemoglobin level between Empagliflozin & placebo 10mg group : −0.54 % points (95% CI, −0.58 to −0.49) 25mg group : −0.60 % points (95% CI,−0.64 to −0.55) Mean differences in the glycated hemoglobin level between Empagliflozin & placebo 10mg group : −0.42 %points (95% CI,−0.48 to −0.36) 25mg group : −0.47 %points (95% CI,−0.54 to −0.41)