1. Empagliflozin
Empagliflozin is a highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2) in the kidney
Glucose reduction occurs by reducing renal glucose reabsorption and thus increasing urinary glucose excretion
In patients with type 2 diabetes, empagliflozin leads to1:
Significant reductions in HbA1c
Weight loss
Reductions in blood pressure without increases in heart rate
1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93

2. Empagliflozin modulates several factors related to CV risk
BP
Arterial stiffness
Other
Albuminuria
Uric acid
Glucose
Insulin
Sympathetic nervous system activity
↑LDL-C
↑HDL-C
Triglycerides
Weight
Visceral adiposity
Oxidative stress
Adapted from Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100

3. EMPA-REG OUTCOME®
Randomised, double-blind, placebo-controlled CV outcomes trial
Objective To examine the long-term effects of empagliflozin versus placebo, in addition to standard of care, on CV morbidity and mortality in patients with type 2 diabetes and high risk of CV events
CV, cardiovascular

4. Trial design John M Lachin, ScD
Professor of Biostatistics and Epidemiology, and Statistics, The George Washington University, Rockville, USA

5. Disclosure Consultations
Boehringer Ingelheim, Merck and Co., Gilead, Janssen, Novartis, AstraZeneca

6. Participating countries
590 sites in 42 countries
Participating countries (42):
Argentina
Australia
Austria
Belgium
Brazil
Canada
Colombia
Croatia
Czech Republic
Denmark
Estonia
France
Georgia
Greece
Hong Kong
Hungary
India
Indonesia
Israel
Italy
Japan
Korea
Malaysia
Mexico
Netherlands
New Zealand
Norway
Peru
Philippines
Poland
Portugal
Romania
Russia
Singapore
South Africa
Spain
Sri Lanka
Taiwan
Thailand
Ukraine
United Kingdom
United States
North America, Australia, New Zealand
Latin America
Asia
Africa
Europe

7. Randomised and treated
Trial design
Placebo (n=2333)
Screening
(n=11531)
Randomised and treated
(n=7020)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Study medication was given in addition to standard of care
Glucose-lowering therapy was to remain unchanged for first 12 weeks
Treatment assignment double masked
The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event

8. Timeline September 15th 2010: First patient entered
April 13th 2013: Last patient entered
December 15th 2014: Closeout (final visits) started
April 13th 2015: Last patient out
Efforts were made to track outcomes and vital status for all patients, including those who discontinued trial medication

9. Patient disposition Placebo Empagliflozin 10 mg Empagliflozin 25 mg
Intent-to-treat population
2333 (100)
2345 (100)
2342 (100)
Discontinued study drug prematurely
683 (29.3)
555 (23.7)
542 (23.1)
Completed study or died
2266 (97.1)
2264 (96.5)
Vital status available
2316 (99.3)
2324 (99.1)
2327 (99.4)
6809 (97%) completed study or died
1780 (25%) discontinued study drug prematurely, more in placebo
All but 214 (3%) completed study or died
Vital status assessed in 99%

10. Key inclusion and exclusion criteria
Key inclusion criteria
Adults with type 2 diabetes
BMI ≤45 kg/m2
HbA1c 7–10%*
Established cardiovascular disease
Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease
Key exclusion criteria
eGFR <30 mL/min/1.73m2 (MDRD)
BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease *No glucose-lowering therapy for ≥12 weeks prior to randomisation or no change in dose for ≥12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation

11. Pre-specified primary and key secondary outcomes
Primary outcome
3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke
Key secondary outcome
4-point MACE: Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina
CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event

12. Further pre-specified outcomes
CV death
Non-fatal MI
Non-fatal stroke
Hospitalisation for heart failure
All-cause mortality
All CV and neurological events were adjudicated by independent, masked, clinical event committees
CV, cardiovascular; MI, myocardial infarction

13. Additional analyses Changes from baseline in: HbA1c Weight
Waist circumference
Systolic and diastolic blood pressure
Heart rate
LDL cholesterol
HDL cholesterol
Safety and tolerability
Adverse events
HDL, high density lipoprotein; LDL, low density lipoprotein

14. Statistical testing strategy for MACE
Analysis compared empagliflozin 10 mg and 25 mg (pooled) versus placebo
Hierarchy to be used:
Test of non-inferiority for 3-point MACE
Test of non-inferiority for 4-point MACE
Test of superiority for 3-point MACE
Test of superiority for 4-point MACE
Each tested at =0.0249, allowing for penalty for inclusion of interim data in NDA to FDA
Non-inferiority was concluded if two-sided upper bound of % CI was <1.3
Superiority was concluded if two-sided p≤0.0498
MACE; Major Adverse Cardiovascular Event; NDA, New Drug Application; FDA, Food and Drug Administration

15. Statistical analysis
Analyses of CV outcomes were based on a Cox proportional hazards model
Patients who did not have an event were censored on the last day they were known to be free of the outcome
Cumulative incidence functions were corrected for mortality as a competing risk (except for all-cause mortality)
The primary analysis was conducted in patients treated with ≥1 dose of study drug (intent-to-treat population)
The CV outcome analyses were independently validated by statisticians at the University of Freiburg, Germany

16. Further pre-defined analyses of the primary outcome
Secondary analyses:
Comparisons of empagliflozin 10 mg versus placebo and empagliflozin 25 mg versus placebo
Sensitivity analyses:
To assess the robustness of the outcomes, we used three subsets of the data set (two on-treatment sets and one per-protocol set)
Subgroup analyses based on baseline characteristics