Lessons from EMPA REG Outcome Professor Per-Henrik Groop, MD DMSc - - PowerPoint PPT Presentation

SGLT2 inhibition & Heart Failure: Lessons from EMPA REG Outcome

Professor Per-Henrik Groop, MD DMSc FRCPE Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, and Folkhälsan Institute of Genetics, Helsinki, Finland, and Baker IDI Heart and Diabetes Institute, Melbourne, Australia ESC Heart Failure 2017 Paris, France 1.5.2017 “Heart Failure, Diabetes, Renal Dysfunction: time for a more unified approach”

Outline of the talk

• Cardiovascular consequences of diabetes
• Consequences of diabetic kidney disease
• Effect of glucose lowering on diabetic late complications
• Effect of SGLT2 inhibition on diabetic late complications
• Lessons from EMPA REG Outcome Trial: Heart failure
• Lessons from EMPA REG Outcome Trial: Renal endpoints
• Clinical implications of SGLT2-inhibition
• Take home messages

Cardiovascular consequences

• f diabetes

Life expectancy is reduced by ~12 years in diabetes patients with previous CVD

The Emerging Risk Factors Collaboration. JAMA 2015;314:52

60

End of life

yrs

–6

yrs

–12

yrs No diabetes

Diabetes Diabetes + MI

Disease status at baseline

• No. of

participants

• No. of

deaths Person- years Hazard ratio (95% CI) Diabetes, stroke and MI 541 379 3584 6.9 (5.7–8.3) Stroke and MI 1836 1174 14,210 3.5 (3.1–4.0) Diabetes and stroke 1321 778 10,234 3.8 (3.5–4.2) Diabetes and MI 3233 1794 25,321 3.7 (3.3–4.1) MI 21,591 9636 216,081 2.0 (1.9–2.2) Stroke 8583 3814 82,208 2.1 (2.0–2.2) Diabetes 24,677 8087 254,608 1.9 (1.8–2.0) None 627,518 103,181 8,772,977 1 [Reference]

Life expectancy is reduced by multiple morbidities

• f diabetes, stroke and MI

5

Adapted from Danesh et al. for ERFC JAMA 2015;314:52–60.

Age- and sex-adjusted HRs for mortality by baseline disease status

1 2 4 8 16 Hazard ratio (95% CI)

*HRs refer to the risk of CV death or HHF in patients with diabetes versus non-diabetes MacDonald MR et al. Eur Heart J 2008;29:1377

CV death or HHF in patients with or without diabetes based on EF category

Diabetes is associated with a worse prognosis in patients with HF

6

60 40 20 0.5 1 1.5 2 2.5 3 3.5 HFrEF: unadjusted HR* 1.60 (95% CI 1.44, 1.77); p<0.0001 HFpEF: unadjusted HR* 2.0 (95% CI 1.70, 2.36); p<0.0001 HFrEF HFpEF HFrEF HFpEF Cumulative incidence (%) Follow-up (years) No diabetes Diabetes

Consequences of diabetic kidney disease

Kidney disease and increased mortality risk in type 2 diabetes

Afkarian, et al. J Am Soc Nephrol. 2013;24:302-308.

10 20 30 40 50 60 70 No Kidney Disease Albuminuria Impaired GFR Albuminuria & Impaired GFR

Standardised 10-year cumulative incidence of mortality (95% CI)

4.1% 17.8% 23.9% 47.0%

The dashed line indicates mortality in persons without diabetes or kidney disease (the reference group). The numbers above bars indicate excess mortality above the reference group.

ADVANCE: Cardiovascular events

Ninomiya et al. J Am Soc Nephrol 2009;20:1813–21

Cardiovascular risk is greatest when both diabetes and CKD are present

Incidence per 100 patient-years

x 2.2 x 2.1 x 1.7 x 2.5

Foley et al. J Am Soc Nephrol. 2005, 16,489–495

Among patients with diabetes and CKD, the rate of cardiovascular events is more than twice that among patients with diabetes only

 Hypertension  Oxidative stress  Insulin resistance  Arterial calcification  Inflammation/immunity  Accumulation of uraemic toxins  Left ventricular hypertrophy  Endothelial dysfunction  Activation of the RAAS  Activation of the SNS  Anaemia

RAAS = renin-angiotensin aldosterone system; SNS = sympathetic nervous system

Effect of glucose lowering on diabetic late complications Glucose-lowering trials

Myocardial infarction* p = 0.052 16% Diabetes-related death* p = 0.34 10% All-cause mortality* p = 0.44 6%

10 20 30 40

Any diabetes-related endpoint* p = 0.029 12% Microvascular complications* p = 0.0099 25% Retinopathy progression† p = 0.015 21% Microalbuminuria† p = 0.000054 33%

Risk reduction (%)

UKPDS: Intensive glycaemic control reduced microvascular but not macrovascular outcomes

13

*Median follow-up, 10 years; †assessed as surrogate endpoints; follow-up, 12 years. UKPDS 33. Lancet 1998;352:837–53.

ADVANCE: intensive glycaemic control reduced microvascular but not macrovascular events

14

Patel et al. N Engl J Med 2008;358:2560–72.

Standard control Intensive control

Major microvascular events Major macrovascular events

p = 0.32 25 6 Cumulative incidence (%) 20 15 10 5 18 24 30 36 42 48 66 Follow-up (months) 25 6 20 15 10 5 18 24 30 36 42 48 Follow-up (months) p = 0.01 12 54 60 66 12 54 60 14% risk reduction

HR, 0.54 (95% CI, 0.34–0.85) p = 0.007 2 Patients with event (%) 1 4 6 10 Follow-up (years) 2 8

ADVANCE-ON: intensive glycaemic control had significant benefit for end-stage renal disease

15

Zoungas et al. N Engl J Med 2014;371:1392-406.

Standard control Intensive control

End-stage renal disease

• No. at risk

Intensive 5571 5402 5186 4124 3764 2811 Standard 5569 5400 5173 4041 3681 2683

Intensive glycaemic control* has not shown impact on the risk of HF

16

Number of events (yearly rate, %) DHbA1c (%) HR (95% CI) More intensive Less intensive Admission to hospital/fatal HF ACCORD 152 (0.90) 124 (0.75) –1.01 1.18 (0.93, 1.49) ADVANCE 220 (0.83) 231 (0.88) –0.72 0.95 (0.79, 1.14) UKPDS 8 (0.06) 6 (0.11) –0.66 0.55 (0.19, 1.60) VADT 79 (1.80) 85 (1.94) –1.16 0.92 (0.68, 1.25) Overall 459 446 –0.88 1.00 (0.86, 1.16)

0.5 1.0 2.0 (Q=3.59, p=0.31, I2=16.4%)

*Versus less-intensive glycaemic control HbA1c, glycated haemoglobin Turnbull FM et al. Diabetologia 2009;52:2288

Favours more intensive control Favours less intensive control

Effect of SGLT2 inhibition on diabetic late complications

EMPA REG Outcome Trial (CVOT)

EMPA REG OUTCOME: Trial design

• Study medication was given in addition to standard of care

– Glucose-lowering therapy was to remain unchanged for first 12 weeks

• Treatment assignment double-blinded
• The trial was to continue until at least 691 patients experienced an

adjudicated primary outcome event

18 Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

Screening (n=11,531) Randomised and treated (n=7020) Pooled

Stable background glucose-lowering therapy Background glucose-lowering therapy adjustment allowed to achieve glycaemic equipoise

Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Placebo (n=2333)

Primary outcome: 3-point MACE

19

HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382*

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

14% reduction

CV death

20

HR 0.62 (95% CI 0.49, 0.77) p<0.0001

Cumulative incidence function. HR, hazard ratio

38% reduction

All-cause mortality

21

HR 0.68 (95% CI 0.57, 0.82) p<0.0001

Kaplan-Meier estimate. HR, hazard ratio

32% reduction

Hospitalisation for heart failure

22

HR 0.65 (95% CI 0.50, 0.85) p=0.0017

Cumulative incidence function. HR, hazard ratio

35% reduction

Lessons from the EMPA REG Outcome Trial

Heart failure

3,1 12,3 1,8 10,4 2 4 6 8 10 12 14 No HF at baseline HF at baseline

Inzucchi SE et al. AHA 2015; Oral presentation

24

Placebo Empagliflozin Patients (%) HR 0.75 (95% CI 0.48, 1.19) HR 0.59 (95% CI 0.43, 0.82)

HHF in patients with or without HF at baseline

HHF or CV death

*Nominal p-value. Graph shows time to first occurrence – cumulative incidence function Fitchett D et al. Eur Heart J 2016; doi:10.1093/eurheartj/ehv728

25

• No. of patients

Empagliflozin Placebo 4614 2271 4523 2226 4427 2173 3988 1932 2950 1424 2487 1202 1634 775 395 168 4687 2333

HR 0.66 (95% CI 0.55, 0.79) p<0.001*

34%

7,1 20,1 4,5 16,2 5 10 15 20 25 No HF at baseline HF at baseline

HHF or CV death in patients with or without HF at baseline

26

HR 0.72 (95% CI 0.50, 1.04) HR 0.63 (95% CI 0.51, 0.78) Placebo Empagliflozin Patients (%)

Inzucchi SE et al. AHA 2015; Oral presentation

Empagliflozin Placebo HR (95% CI) All patients 4687 2333 Age (years) <65 2596 1297 ≥65 2091 1036 eGFR (ml/min/1.73 m2) ≥90 1050 488 60 to <90 2425 1238 <60 1212 607

HHF or CV death by baseline characteristics

Cox regression analysis; All patients treated with at least one dose of study drug Fitchett D et al. Eur Heart J 2016; doi:10.1093/eurheartj/ehv728

27

0,25 0,50 1,00 2,00

Favours empagliflozin Favours placebo

Empagliflozin Placebo HR (95% CI) All patients 4687 2333 Insulin No 2435 1198 Yes 2252 1135 ACEis/ARBs No 889 465 Yes 3798 1868 Diuretics No 2640 1345 Yes 2047 988 Loop diuretics No 3962 1969 Yes 725 364 β-blockers No 1631 835 Yes 3056 1498 Mineralocorticoid receptor antagonists No 4382 2197 Yes 305 136

HHF or CV death by baseline medications

Cox regression analysis; All patients treated with at least one dose of study drug Fitchett D et al. Eur Heart J 2016; doi:10.1093/eurheartj/ehv728

28

0,25 0,50 1,00 2,00

Favours empagliflozin Favours placebo

HHF or death from HF

*Nominal p-value. Graph shows time to first occurrence – cumulative incidence function Inzucchi SE et al. AHA 2015; Oral presentation Fitchett D et al. Eur Heart J 2016; doi:10.1093/eurheartj/ehv728

29

• No. of patients

Empagliflozin Placebo 4614 2271 4523 2226 4427 2173 3988 1932 2950 1424 2487 1202 1634 775 395 168 4687 2333

39%

HR 0.61 (95% CI 0.47, 0.79) p<0.001*

Time to first introduction of loop diuretics

*Nominal p-value; Graph shows time to first occurrence – cumulative incidence function Patients treated with at least one dose of study drug Fitchett D et al. Eur Heart J 2016; doi:10.1093/eurheartj/ehv728 (Supplementary data)

30

• No. of patients

Empagliflozin Placebo 3834 1882 3746 1817 3638 1740 3267 1523 2387 1120 2030 934 1351 597 320 129 3962 1969

HR 0.62 (95% CI 0.53, 0.73) p=0.001*

Patients with event/analysed HR (95% CI) Empagliflozin Placebo n with event/n % n with event/n % HHF or CV death All patients 265/4687 5.7 198/2333 8.5 0.66 (0.55, 0.79) HF at baseline No 190/4225 4.5 149/2089 7.1 0.63 (0.51, 0.78) Yes 75/462 16.2 49/244 20.1 0.72 (0.50, 1.04) CV death All patients 172/4687 3.7 137/2333 5.9 0.62 (0.49, 0.77) HF at baseline No 134/4225 3.2 110/2089 5.3 0.60 (0.47, 0.77) Yes 38/462 8.2 27/244 11.1 0.71 (0.43, 1.16)

0,25 0,50 1,00 2,00

Outcomes were consistent in patients with and without HF at baseline

Cox regression analysis. Patients treated with at least one dose of study drug Fitchett D et al. Eur Heart J 2016; doi:10.1093/eurheartj/ehv728

31

Favours placebo Favours empagliflozin HHF All patients 126/4687 2.7 95/2333 4.1 0.65 (0.50, 0.85) HF at baseline No 78/4225 1.8 65/2089 3.1 0.59 (0.43, 0.82) Yes 48/462 10.4 30/244 12.3 0.75 (0.48, 1.19) All-cause mortality All patients 269/4687 5.7 194/2333 8.3 0.68 (0.57, 0.82) HF at baseline No 213/4225 5.0 159/2089 7.6 0.66 (0.51, 0.81) Yes 56/462 12.1 35/244 14.3 0.79 (0.52, 1.20)

Lessons from the EMPA REG Outcome Trial

Pre-specified renal endpoints

New onset or worsening diabetic kidney disease

Empagliflozin is not indicated for CV risk reduction or kidney disease. Kaplan-Meier

• estimate. Treated set (≥1 dose of study drug)

*Nominal p-value. CI, confidence interval; CV, cardiovascular; HR, hazard ratio

33

• No. of patients

Empagliflozin Placebo 3994 1946 3848 1836 3669 1703 3171 1433 2279 1016 1887 833 1219 521 290 106 4124 2061

39%

*

Wanner et al. NEJM 2016

Doubling of serum creatinine*, initiation of renal replacement therapy, or death due to renal disease

Kaplan-Meier estimate in patients treated with ≥1 dose of study drug. Hazard ratios are based on Cox regression analyses. *Accompanied by eGFR [MDRD] ≤45 ml/min/1.73m2. HR, hazard ratio; CI, confidence interval. Post-hoc analyses.

46%

Empagliflozin Placebo n with event/ N analyzed Hazard ratio (95% CI) p-value Incident or worsening nephropathy 525/4124 388/2061 0.61 (0.53, 0.70) <0.0001 New onset macroalbuminuria 459/4091 330/2033 0.62 (0.54, 0.72) <0.0001 Doubling of serum- creatinine* 70/4645 60/2323 0.56 (0.39, 0.79) 0.0009 Initiation of renal replacement therapy 13/4687 14/2333 0.45 (0.21, 0.97) 0.0409

Incident or worsening diabetic kidney disease and its components

35

*Accompanied by eGFR (MDRD) ≤45 mL/min/1.73m2. Cox regression analyses. 0,13 0,25 0,50 1,00 2,00 Favors empagliflozin Favors placebo 1 2 0.5

New onset or worsening diabetic kidney disease in patients with prevalent kidney disease*

(eGFR <60 ml/min and/or ACR >300 mg/g)

Empagliflozin is not indicated for CV risk reduction or kidney disease. Kaplan–Meier estimates in patients with prevalent kidney disease treated with ≥1 dose of study drug; HRs are based on Cox regression analyses; Post hoc analyses. *Defined as eGFR (MDRD) <60 ml/min/1.73 m2 and/or macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline; †Nominal p-value. CI, confidence interval; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease; HR, hazard ratio.

36 952 462 895 425 836 377 694 302 516 206 420 172 273 102 69 23 988 507

• No. of patients

Empagliflozin Placebo

42%

†

Wanner et al. NEJM 2016

eGFR (CKD-EPI formula) over 192 weeks

Empagliflozin is not indicated for CV risk reduction or kidney disease. Pre-specified mixed model repeated measures analysis in all patients treated with ≥1 dose of study drug (OC-AD). All participants in the study were able to reach the study visit at week 94 and patient numbers declined thereafter based on study design.

37 66 68 70 72 74 76 78 Adjusted mean (SE) eGFR (ml/min/1.73 m2) Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg 12 0 4 28 52 94 108 80 122 66 136 150 164 178 192

2323 2322 2322 2267 2264 2269 2205 2235 2216 2121 2162 2156 2064 2114 2111 1927 2012 2006 1981 2064 2067 1763 1839 1871 1479 1540 1563 1262 1314 1340 1123 1180 1207 977 1024 1063 731 785 838 448 513 524 2295 2290 2288

Empagliflozin 10 mg Empagliflozin 25 mg Placebo

7020 6996 6931 6864 6765 6696 6651 6068 5114 4443 3961 3488 2707 1703 7020

• No. in follow-up for adverse/outcome events
• No. analysed

Total

Wanner et al. NEJM 2016

Doubling of serum creatinine ESRD All cause mortality

0.75 1.02 0.72

0.1 0.4 0.7 1.0 1.4

RENAAL (losartan vs placebo)

21.6% vs 26.0% 19.6% vs 25.5% 21% vs. 20.3%

Hospitalisation for heart failure

11.9% vs. 16.7%

0.68

Doubling of serum creatinine ESRD All cause mortality 0.1 0.4 0.7 1.0 1.4

IDNT (irbesartan vs placebo)

0.67 0.92 0.77

Hospitalisation for heart failure

0.78

Doubling of serum creatinine ESRD All cause mortality 0.1 0.4 0.7 1.0 1.4

EMPA-REG (empagliflozin vs placebo)

0.56 0.68

Hospitalisation for heart failure

0.65 0.45

Clinical implications of SGLT2 inhibition - as important as RAAS inhibition?

0.16- 0.12- 0.08- 0.04- 0.00-

Cardiovascular mortality

Placebo ACEi

0.16- 0.12- 0.08- 0.04- 0.00-

I I I I I 0 12 24 36 48

RRR = 37% (21 to 51) ARR = 3.5% NNT 29 (for 4.5 years) 9.7% 6.2%

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators Lancet (2000)

0.16- 0.12- 0.08- 0.04- 0.00-

Cardiovascular mortality

Placebo ACEi

0.16- 0.12- 0.08- 0.04- 0.00-

I I I I I 0 12 24 36 48

SGLT2i Placebo

RRR = 38% (23 to 51) ARR = 2.1% NNT 45 (for 2.6 years) 5.8% 3.7%

Zinman et al NEJM 2015

Heart Outcomes Prevention Evaluation (HOPE) Study

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators Lancet (2000)

Heart Outcomes Prevention Evaluation (HOPE) Study

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators Lancet (2000)

EMPA-REG Outcome Study

Zinman et al NEJM 2015 18.8

Take home messages

• Diabetes is associated with increased risk of cardiovascular

disease and remarkably shortened life expectancy

• Diabetic kidney disease is a common complication with grim

consequences

• The SGLT2-inhibitor empagliflozin on top of standard care

reduces risk of CV death, hospitalization due to heart failure and risk of progression of diabetic kidney disease

• SGLT2-inhibition may be an as important innovation as RAAS

inhibition