The EMPA-REG OUTCOME trial: Design and results. David Fitchett, MD University of Toronto, Canada

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1 The EMPA-REG OUTCOME trial: Design and results David Fitchett, MD University of Toronto, Canada Asian Cardio Diabetes Forum April 23 24, 2016 Kuala Lumpur, Malaysia

2 Life Expectancy Is Reduced by ~12 Years in Diabetes Patients with Previous CVD 60 yrs End of life No diabetes Diabetes 6 yrs Diabetes + MI 12 yrs The Emerging Risk Factors Collaboration. JAMA 2015;314:52

3 Glucose Lowering Trials Superiority Results June 2016 EMPA-REG Outcome (n=7020) 771 MACE 3 Johansen OE. World J Diabetes 2015; in press 3

4 SGLT2 Inhibition Reduces Renal Glucose Reabsorption Glucose filtration Glomerulus SGLT2 Proximal tubule S1 SGLT1 S3 Distal tubule Collecting duct Glucose reabsorption 90% SGLT2 inhibitor 10% Loop of Henle Increased Minimal glucose excretion glucose excretion Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18; Lee YJ et al. Kidney Int Suppl. 2007;106:S27-S35; Han S. Diabetes. 2008;57: g/day ( Kcal/day)

5 Active (SGLT2) and Passive (GLUT2) Glucose Transport in a Renal Proximal Tubule Cell Tubular lumen Interstitium Na + Glucose SGLT2 Na + Glucose GLUT2 K + Na + /K + ATPase Pump Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42.

6 SGLT2 Inhibitors: Potential Risks & Benefits BENEFITS Insulin-independent glucose lowering (irrespective of DM duration) Low risk of hypoglycemia Modest weight, BMI, WC Modest BP Albumin:Cr Ratio Modest TGs Small HDL-C RISKS Genital mycotic infections UTIs DKA Polyuria/ Dehydration Reversible GFR Small Hgb/Hct Small LDL-C Urinary Ca+ losses Kim Y et al. Diabetes Metab Syndr Obes. 2012;5: Inzucchi SE et al. Diabetes Care 2015;38:

7 CV outcome trials for SGLT2 Inhibitors in Diabetes Empagliflozin CANVAS (n = 4339) DECLARE-TIMI 58 (n = 17,150) Dapagliflozin Ertugliflozin CVOT (n = 3900) Established CVD Triple MACE 691 events Canagliflozin Established CVD or > 2 CVD risk ff Triple MACE 420 events High risk for CVD Established CVD Triple MACE 1390 events

8 Zinman et al N Engl J Med 2015 DOI: /NEJMoa

9 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 Zinman et al N Engl J Med 2015 DOI: /NEJMoa

10 Long-term CV safety of empagliflozin is being evaluated in a large, multicentre Phase III trial (EMPA-REG OUTCOME ) Europe 41% North America / Western Pacific * 20% 4% Africa 19% Asia 15% 42 Countries 7020 Patients Latin America 592 Clinical sites Countries with study centres involved in the EMPA-REG OUTCOME trial *Cumulative percentage for North America, Australia and New Zealand. 1. Zinman et al. Cardiovasc Diabetol 2014;13: NCT

11 Inclusion Criteria Insufficient glycemic control Plus A 1 C 7 10% ( 7-9% if glycemic agent naïve) High risk for CV events Myocardial infarction (more than 2 months) Multivessel CAD Single vessel CAD & +ve stress ECG or UA in past 1 yr Stroke (more than 2 months) Occlusive peripheral vascular disease Zinman et al N Engl J Med 2015 DOI: /NEJMoa

12 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 Glycemic control unchanged for 12 weeks then adjusted to maintain A1C to local target On treatment median 2.6 years Observation median 3.2 years 97% patients completed study Vital status in 99.3% Zinman et al N Engl J Med 2015 DOI: /NEJMoa

13 EMPA-REG OUTCOME: statistical considerations Primary endpoint time to the first occurrence of 1. CV death (including fatal stroke and fatal MI) 2. Non-fatal MI (excluding silent MI) 3. Non-fatal stroke Target number of events: 691 Non-inferiority and superiority of empagliflozin versus placebo With 691 events, 90% power to demonstrate non-inferiority defined as an upper limit of a 1-sided 95% CI below the non-inferiority margin of 1.3 Hierarchical testing for superiority will follow for the primary and key secondary outcomes Zinman et al. Cardiovasc Diabetol

14 Baseline Characteristics (n= 7034) Age 63.1 (9% > 75 yrs) Male 72% Current / ex smoker 46% Diabetes > 10yrs 57% egfr 74 ml/min/1.73m 2 26 % ml/min/1.73m 2 Coronary disease 75% Prior MI 47% Multivessel CAD 47% CABG 25% Stroke 23% Heart failure 10.5% Zinman et al N Engl J Med 2015 DOI: /NEJMoa

15 Baseline Characteristics (n= 7034) ASA 85% Statins 77% ACE inhibitor 81% Beta blockers 65% Insulin 49% Metformin 74% SU 43% TZD 4.2% BP 135 / 77 LDL C 2.2 mmol/l Zinman et al N Engl J Med 2015 DOI: /NEJMoa

16 HbA1c Placebo Empagliflozin 10 mg Empagliflozin 25 mg All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements 16

17 Adjusted mean (SE) systolic blood pressure (mmhg) Mean adjusted blood pressure parameters Systolic BP Heart rate (ECG) Placebo Empagliflozin 10 mg Empagliflozin 25 mg Diastolic BP Week Week Placebo Placebo EMPA 10 mg EMPA 10 mg EMPA 25 mg EMPA 25 mg All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent to treat) X-axis: time points with reasonable amount of data available for prescheduled measurements BP, blood pressure; ECG, electrocardiogram; EMPA, empagliflozin Zinman B et al. N Engl J Med 2015;doi: /NEJMoa

18 Weight Placebo Empagliflozin 10 mg Empagliflozin 25 mg Placebo Empagliflozin 10 mg Empagliflozin 25 mg All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat). X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements 18

19 Primary outcome: 3-point MACE Cardiovascular Mortality, Non-fatal MI, Non-fatal Stroke HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* * Two-sided tests for superiority were conducted (statistical significance was indicated if p ) 19

20 CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI Favours empagliflozin Favours placebo Zinman et al N Engl J Med 2015 DOI: /NEJMoa

21 CV death HR 0.62 (95% CI 0.49, 0.77) p< Cumulative incidence function. CI, confidence interval; HR, hazard ratio. Zinman et al. N Engl J Med 2015:373:

22 CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p= Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77) p= Cumulative incidence function. CI, confidence interval; HR, hazard ratio. Zinman et al. N Engl J Med 2015:373:

23 CV death: subgroup analyses Empagliflozin Placebo HR (95% CI) p-value All patients for interaction Age, years 0.21 < Sex 0.32 Male Female Race 0.43 White Asian Black/African-American HbA1c, % 0.51 < Body mass index, kg/m < egfr, ml/min/1.73m to < < Favours empagliflozin Favours placebo Zinman et al N Engl J Med 2015 DOI: /NEJMoa

24 Categories of CV death Placebo (n=2333) Pooled empagliflozin (n=4687) Patients with CV death 137 (5.9) 172 (3.7) Sudden death 38 (1.6) 53 (1.1) Worsening of heart failure 19 (0.8) 11 (0.2) Acute MI 11 (0.5) 15 (0.3) Stroke 11 (0.5) 16 (0.3) Cardiogenic shock 3 (0.1) 3 (0.1) Other CV death 55 (2.4) 74 (1.6) Data are n (%) Zinman et al. N Engl J Med 2015:373:

25 All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) p= Empagliflozin 25 mg HR 0.67 (95% CI 0.54, 0.83) p= HR 0.68 (95% CI 0.57, 0.82) p< Kaplan-Meier estimate. CI, confidence interval; HR, hazard ratio. Zinman et al. N Engl J Med 2015:373:

26 All-cause mortality, CV death and non-cv death Patients with event/analysed Empagliflozin Placebo HR 95% CI p-value All-cause mortality 269/ / (0.57, 0.82) < CV death 172/ / (0.49, 0.77) < Non-CV death 97/ / (0.60, 1.16) Favours empagliflozin Favours placebo Cox regression analysis. CI, confidence interval; HR, hazard ratio. Zinman et al. N Engl J Med 2015:373:

27 Hospitalisation for heart failure HR 0.65 (95% CI 0.50, 0.85) p= Cumulative incidence function. HR, hazard ratio 27

28 Investigator-reported heart failure Patients with event/analyzed Empagliflozin Placebo HR (95% CI) p-value Investigator-reported heart failure* 204/ / (0.56, 0.87) Investigator-reported serious heart failure* 192/ / (0.55, 0.86) Favors empagliflozin Favors placebo Cox regression analysis. *Based on narrow standardized MedDRA query cardiac failure. Reported as serious adverse events by investigator. HR, hazard ratio; CI, confidence interval. 28

29 Hospitalization for HF in patients with HF vs without HF at baseline HR 0.59 (95% CI 0.43, 0.82) HR 0.75 (95% CI 0.48, 1.19) Patients hospitalized for heart failure (%) Cox regression analysis. CI, confidence interval; HR, hazard ratio Inzucchi SE. AHA Oral presentation 29

30 All-cause hospitalization Hospitalization Empa Placebo HR (95% CI) For HF 126/4687 (2.7%) For non-hf cause 1695/4687 (36.2%) All-cause 1725/4687 (36.8%) 95/2333 (4.1%) 911/2333 (39.0%) 925/2333 (39.6%) 0.65 (0.50, 0.85) 0.89 (0.82, 0.96) 0.89 (0.82, 0.96) Nominal p-value Cumulative incidence function. CI, confidence interval; CV, cardiovascular; HR, hazard ratio Inzucchi SE. AHA Oral presentation 30

31 Adverse events consistent with genital infection Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate n (%) Rate n (%) Rate Events consistent with genital infection 42 (1.8%) (6.5%) (6.3%) 2.55 Events leading to discontinuation 2 (0.1%) (0.8%) (0.6%) 0.23 Rate = per100 patient-years Genital infections: Mycotic (candida species) Men Balanitis Women Vulvo-Vaginiitis Zinman et al N Engl J Med 2015 DOI: /NEJMoa

32 Other adverse events Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Confirmed hypoglycaemic adverse events n (%) n (%) n (%) 650 (27.9%) 656 (28.0% 647 (27.6%) Events requiring assistance 36 (1.5%) 33 (1.4%) 30 (1.3%) Diabetic ketoacidosis* 1 (<0.1%) Acute kidney injury 155 (6.6%) Bone fractures 91 (3.9%) 3 (0.1%) 121 (5.2%) 92 (3.9%) 1 (<0.1%) 125 (5.3%) 87 (3.7%) Rate = per100 patient-years Patients treated with 1 dose of study drug *Based on 4 MedDRA preferred terms. Based on 1 standardised MedDRA query Based on 8 MedDRA preferred terms. **Based on 1 standardised MedDRA query Zinman et al N Engl J Med 2015 DOI: /NEJMoa

33 EMPA-REG OUTCOME : Therapeutic considerations Empagliflozin, as used in this trial, for 3 years in 1,000 patients with type 2 diabetes at high CV risk: 25 lives saved (82 vs 57 deaths) 22 fewer CV deaths (59 vs 37) 14 fewer hospitalisations for heart failure (42 vs 28) Similar benefit in patients with and without prior HF 53 additional genital infections (22 vs 75) 33

34 Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk Simvastatin 1 for 5.4 years Ramipril 2 for 5 years Empagliflozin for 3 years High CV risk 5% diabetes, 26% hypertension Pre-statin era High CV risk 38% diabetes, 46% hypertension Pre-ACEi/ARB era <29% statin T2DM with high CV risk 92% hypertension >80% ACEi/ARB >75% statin S investigator. Lancet 1994; 344: , 2. HOPE investigator N Engl J Med 2000;342:145-53, 34

35 Canadian Diabetic Association 2016 Interim Update Pharmacological Management of Type 2 Diabetes 4. In people with clinical cardiovascular disease in whom glycemic targets are not met, an SGLT2 inhibitor with demonstrated cardiovascular outcome benefit should be added to antihyperglycemic therapy to reduce the risk for cardiovascular and all-cause mortality (Grade A, Level 1A for empagliflozin) Canadian Journal of Diabetes

36 Prevention of Cardiovascular Disease In Patients with Diabetes Multifaceted risk reduction remains first line Lifestyle modification LDL C reduction BP reduction Tight glycemic control (especially in newly diagnosed DM) RAAS inhibition Safety / Benefit of glucose lowering agent Metformin: limited safety / efficacy data Uncertainty about safety of SUs (and? TZDs) Recent trials show safety of DPP4i and GLP1A Empagliflozin reduces mortality and heart failure in patients with T2 DM and CVD 36