“Heart Failure, Diabetes, Renal Dysfunction: time for a more unified approach” 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
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 of diabetes
Life expectancy is reduced by ~12 years in diabetes patients with previous CVD 60 yrs End of life No diabetes – 6 yrs Diabetes yrs – 12 Diabetes + MI The Emerging Risk Factors Collaboration. JAMA 2015;314:52
Life expectancy is reduced by multiple morbidities of diabetes, stroke and MI Age- and sex-adjusted HRs for mortality by baseline disease status Disease status at No. of No. of Person- Hazard ratio baseline participants deaths years (95% CI) 6.9 (5.7 – 8.3) Diabetes, stroke and MI 541 379 3584 3.5 (3.1 – 4.0) Stroke and MI 1836 1174 14,210 3.8 (3.5 – 4.2) Diabetes and stroke 1321 778 10,234 3.7 (3.3 – 4.1) Diabetes and MI 3233 1794 25,321 2.0 (1.9 – 2.2) MI 21,591 9636 216,081 2.1 (2.0 – 2.2) Stroke 8583 3814 82,208 1.9 (1.8 – 2.0) Diabetes 24,677 8087 254,608 None 627,518 103,181 8,772,977 1 [Reference] 4 1 2 8 16 Hazard ratio (95% CI) Adapted from Danesh et al. for ERFC JAMA 2015;314:52 – 60. 5
Diabetes is associated with a worse prognosis in patients with HF CV death or HHF in patients with or without diabetes based on EF category 60 Diabetes No diabetes HF r EF: unadjusted HR* 1.60 HF r EF (95% CI 1.44, 1.77); p <0.0001 Cumulative incidence (%) HF p EF: unadjusted HR* 2.0 (95% CI 1.70, 2.36); p <0.0001 40 HF p EF HF r EF 20 HF p EF 0 0 0.5 1 1.5 2 2.5 3 3.5 Follow-up (years) *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 6
Consequences of diabetic kidney disease
Kidney disease and increased mortality risk in type 2 diabetes 70 Standardised 10-year cumulative incidence of mortality 47.0% 60 50 23.9% 40 (95% CI) 17.8% 30 20 4.1% 10 0 No Kidney Disease Albuminuria Impaired GFR Albuminuria & Impaired GFR 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. Afkarian, et al. J Am Soc Nephrol. 2013;24:302-308.
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 x 2.1 Incidence per 100 patient-years x 1.7 x 2.5 x 2.2 Among patients with diabetes and CKD, the rate of cardiovascular events is more than twice that among patients with diabetes only Foley et al. J Am Soc Nephrol. 2005, 16,489 – 495
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
UKPDS: Intensive glycaemic control reduced microvascular but not macrovascular outcomes p = 0.44 6% All-cause mortality* p = 0.34 10% Diabetes-related death* p = 0.052 16% Myocardial infarction* p = 0.000054 Microalbuminuria † 33% p = 0.015 Retinopathy progression † 21% p = 0.0099 Microvascular complications* 25% p = 0.029 Any diabetes-related endpoint* 12% 0 10 20 30 40 Risk reduction (%) *Median follow-up, 10 years; † assessed as surrogate endpoints; follow-up, 12 years. UKPDS 33. Lancet 1998;352:837 – 53. 13
ADVANCE: intensive glycaemic control reduced microvascular but not macrovascular events Major macrovascular events Major microvascular events 14% risk Cumulative incidence (%) 25 25 reduction p = 0.32 p = 0.01 20 20 15 15 10 10 5 5 0 0 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) Follow-up (months) Standard control Intensive control Patel et al. N Engl J Med 2008;358:2560 – 72. 14
ADVANCE-ON: intensive glycaemic control had significant benefit for end-stage renal disease End-stage renal disease 2 HR, 0.54 (95% CI, 0.34 – 0.85) Patients with event (%) p = 0.007 Standard control 1 Intensive control 0 0 2 4 6 8 10 Follow-up (years) No. at risk Intensive 5571 5402 5186 4124 3764 2811 Standard 5569 5400 5173 4041 3681 2683 Zoungas et al. N Engl J Med 2014;371:1392-406. 15
Intensive glycaemic control* has not shown impact on the risk of HF Number of events (yearly rate, %) DHbA1c HR (95% CI) (%) More Less intensive intensive Admission to hospital/fatal HF – 1.01 152 (0.90) 124 (0.75) ACCORD 1.18 (0.93, 1.49) – 0.72 220 (0.83) 231 (0.88) ADVANCE 0.95 (0.79, 1.14) – 0.66 8 (0.06) 6 (0.11) UKPDS 0.55 (0.19, 1.60) – 1.16 79 (1.80) 85 (1.94) VADT 0.92 (0.68, 1.25) – 0.88 459 446 Overall 1.00 (0.86, 1.16) ( Q= 3.59, p =0.31, I 2 =16.4%) 0.5 1.0 2.0 Favours more Favours less intensive control intensive control *Versus less-intensive glycaemic control HbA1c, glycated haemoglobin Turnbull FM et al. Diabetologia 2009;52:2288 16
Effect of SGLT2 inhibition on diabetic late complications EMPA REG Outcome Trial (CVOT)
EMPA REG OUTCOME: Trial design Stable background Background glucose-lowering therapy adjustment glucose-lowering therapy allowed to achieve glycaemic equipoise Placebo (n=2333) Randomised Empagliflozin 10 mg Screening and treated (n=2345) (n=11,531) (n=7020) Pooled 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-blinded • The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720 18
Primary outcome: 3-point MACE HR 0.86 (95.02% CI 0.74, 0.99) p =0.0382* 14% reduction 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) 19
CV death HR 0.62 (95% CI 0.49, 0.77) p <0.0001 38% reduction Cumulative incidence function. HR, hazard ratio 20
All-cause mortality HR 0.68 (95% CI 0.57, 0.82) p <0.0001 32% reduction Kaplan-Meier estimate. HR, hazard ratio 21
Hospitalisation for heart failure HR 0.65 (95% CI 0.50, 0.85) p =0.0017 35% reduction Cumulative incidence function. HR, hazard ratio 22
Lessons from the EMPA REG Outcome Trial Heart failure
HHF in patients with or without HF at baseline HR 0.59 HR 0.75 (95% CI 0.43, 0.82) (95% CI 0.48, 1.19) 14 12,3 12 10,4 Placebo 10 Patients (%) Empagliflozin 8 6 4 3,1 1,8 2 0 No HF at baseline HF at baseline Inzucchi SE et al. AHA 2015; Oral presentation 24
HHF or CV death HR 0.66 34% (95% CI 0.55, 0.79) p <0.001* No. of patients 4687 4614 4523 4427 3988 2950 2487 1634 395 Empagliflozin 2333 2271 2226 2173 1932 1424 1202 775 168 Placebo *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
HHF or CV death in patients with or without HF at baseline HR 0.63 HR 0.72 (95% CI 0.51, 0.78) (95% CI 0.50, 1.04) 25 20,1 20 Placebo 16,2 Patients (%) Empagliflozin 15 10 7,1 4,5 5 0 No HF at baseline HF at baseline Inzucchi SE et al. AHA 2015; Oral presentation 26
HHF or CV death by baseline characteristics Empagliflozin Placebo HR (95% CI) All patients 4687 2333 Age (years) <65 2596 1297 ≥65 2091 1036 eGFR (ml/min/1.73 m 2 ) ≥90 1050 488 60 to <90 2425 1238 <60 1212 607 0,25 0,50 1,00 2,00 Favours empagliflozin Favours placebo 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
HHF or CV death by baseline medications 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 No 4382 2197 Mineralocorticoid receptor antagonists Yes 305 136 0,25 0,50 1,00 2,00 Favours empagliflozin Favours placebo 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
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