Challenges in heart failure management Diabetes and Renal Impairment Martin R Cowie Professor of Cardiology National Heart & Lung Institute Imperial College London (Royal Brompton Hospital Campus) m.cowie@imperial.ac.uk @ProfMartinCowie
Declaration of Interests • Research grants administered by Imperial College London from Bayer, Boston Scientific, St Jude Medical, and ResMed • Consultancy and speaker fees from ResMed, Servier, Novartis, Pfizer, Bayer, Medtronic, Boston Scientific, St Jude Medical, Alere, Daiichi-Sankyo, Bristol Myers Squibb, Roche, Amgen, MSD, Respicardia, Sorin • Non-Executive Director of the National Institute for Health and Care Excellence (NICE) in England but opinions are my own
A ‘typical’ CHF patient 76M; T2DM; CABG; LVEF 15%; CRT- D; ‘Optimal’ medical therapy Tight rope between “too dry” and “too wet” Admitted for IV diuretics Admitted for IV diuretics eGFR: 20 ml/min/1.73m 2 eGFR: 51 ml/min/1.73m 2 Admitted for observation “too dry” ACEI BB MRA
Renal function in incident heart failure The Hillingdon Study Serum Creatinine Median 113 mol/l N=220 38% had [creatinine] > 125 mol/l 20% had [creatinine] > 150 mol/l Cowie et al. Eur Heart J 1999
Renal function and prognosis in HF Hillingdon Study (incident heart failure) P < 0.0005 Creat < 113 mol/l Creat ≥ 113 mol/l
Worsening renal function during HF hospitalisation Prospective Outcomes Study in Heart Failure • 299 patients admitted with HFrEF to 8 EU centres • Average age 69 (74% male) Median serum creatinine 137 mol/l (1.58 mg/dl) • = eCreat clearance 56ml/min [90% range 19-113 ml/min/1.73m 2 ] • 29% developed WRF (rise in serum creatinine by at least 26 mol/l (0.3mg/dl)) during admission • Factors independently associated with risk of WRF: – baseline serum creatinine – pulmonary oedema on chest x-ray – history of atrial fibrillation • WRF had no impact on mortality (after adjustment for co-morbidity), but prolonged length of stay up by 2 days Cowie & Komajda (POSH Investigators). Eur Heart J 2006; 27: 1216-22
MAGGIC meta-analysis in Chronic HF 25 prospective studies N=15 962 N= 4 792 Finlay A. McAlister et al. Circ Heart Fail. 2012;5:309-314
Kidney disease and diabetes mellitus are common co-morbidities in patients with cardiovascular disease Prevalence of CKD and diabetes mellitus Prevalence of CKD and diabetes mellitus in patients in Europe with heart failure in patients in the USA with STEMI (n = 19 029) (N = 3226) 1 and NSTEMI (n = 30 462) 2 50 50 40 40 42,9 Prevalence (%) Prevalence (%) 41 30 30 33,9 30,5 29 STEMI 20 20 NSTEMI 22,5 10 10 0 0 CKD Diabetes CKD Diabetes Diabetes Diabetes Diabetes mellitus mellitus mellitus CKD, chronic kidney disease; NSTEMI, non ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction 8 8 Data from 1. van Deursen VM et al. Eur J Heart Fail 2014;16:103 – 11; 2. Fox CS et al. Circulation 2010;121:357 – 65
DM prevalence in HF admissions Euroheart Survey 23% 26% 21% 18% 35% 23% 36% 18% 29% 23% 37% 32% EHJ 2003; 24: 442 – 463
More facts and figures Diabetes and heart failure Framingham: DM increases risk of HF by 1.82 ♂ and 3.15 ♀ CV Health Study (retired population): 33% of diabetic men and 45% of diabetic women develop HF in 5.5 years Hospitalisation databases suggest that 11.8% of patients with diabetes have HF (vs. 4.5% of non-diabetics) 44% of acute HF admissions (USA) are coded as diabetic Voors AA and van der Horst ICC. Heart 2011; 97: 774 – 780 Cleland JGF et al. Eur Heart J 2003; 24: 442 – 463
Recent CHF trials Trial HF type Year Drug Hx of DM Pts enrolled “ Entresto ” 35% N=8442 PARADIGM HFrEF 2014 Sacubitril valsartan TOPCAT HFnEF 2013 Spironolactone 32% N=3445 31% N=2737 EMPHASIS HFrEF 2011 Eplerenone SHIFT HFrEF 2010 Ivabradine 30% N=6558
HF risk is related to diabetic control Heart Failure 10 p=0.021 Hazard Ratio 1 16% decrease per 1% reduction in HbA 1C 0.5 5 6 7 8 9 10 Updated Mean HbA 1C Concentration (%) Based on UKPDS Study. BMJ 2000; 321: 405 – 412
Is better TIDM control associated with lower HF risk? Swedish National Registry A. 20 Adjusted Incidence per 1000 Patients (yrs) 20 985 adults with 15 T1DM 10 Mean age 38.6 yrs Median FU 9 yrs 5 Endpoint: HF 0 admission B. 40 HR 3.98 [2.23-7.14] 30 for those with HbA 1c ≥ 10.5% cf. 20 HbA 1c < 6.5% 10 0 0 6 7 8 9 10 11 Updated Mean HbA 1C (%) Lind M et al. Lancet 2011; 378: 140 – 146
What is associated with HF risk in T1DM? Multivariable analysis from national Swedish Registry Hazard Ratio (95% CI) P-value HbA 1c (1% increase) 1.30 (1.21 – 1.40) <0.0001 Men vs women 1.14 (0.97 – 1.35) 0.10 Age (10 yr increase) 1.64 (1.46 – 1.83) <0.0001 DM duration (10 yr increase) 1.34 (1.21 – 1.49) <0.0001 Smoking (across dose) -- <0.0001 BMI (1 kg/m 2 increase) 1.05 (1.03 – 1.08) <0.0001 SBP (10 mmHg increase) 1.15 (1.09 – 1.22) <0.0001 DBP (10 mmHg increase) 1.10 (0.98 – 1.24) 0.10 AF 1.89 (1.42 – 2.50) <0.0001 Myocardial infarction 6.42 (5.41 – 7.62) <0.0001 Ischaemic heart disease 2.9 (1.53 – 5.45) 0.001 Lind M et al. Lancet 2011; 378: 140 – 146
Does improving T2DM control reduce the HF risk? No. of Events (annual event rate, %) Favors More Hazard Ratio Trials Δ HbA 1C (%) Favors Less Intensive Intensive (%% CI) More Intensive Less intensive MAJOR CARDIOVASCULAR EVENTS ACCORD 352 (2.11) 371 (2.29) -1.01 0.90 (0.78-1.04) ADVANCE 557 (2.15) 590 (2.28) -0.72 0.94 (0.84-1.06) UKPDS 169 (1.30) 87 (1.60) -0.66 0.80 (0.62-1.04) VADT 116 (2.68) 128 (2.98) -1.16 0.90 (0.70-1.16) (Q=1.32, p =0.72, I 2 =0.0%) OVERALL 1.194 1.176 -0.88 0.91 (0.84-0.99) STROKE ACCORD 73 (0.43) 70 (0.42) -1.01 1.00 (0.72-1.39) ADVANCE 238 (0.91) 246 (0.94) -0.72 0.97 (0.81-1.16) UKPDS 35 (0.26) 17 (0.31) -0.66 0.85 (0.48-1.52) VADT 32 (0.71) 37 (0.82) -1.16 0.87 (0.54-1.39) OVERALL 378 370 -0.88 0.96 (0.83-1.10) (Q=0.40, p =0.94, I 2 =0.0%) MYOCARDIAL INFARCTION ACCORD 198 (1.18) 245 (1.51) -1.01 0.77 (0.64-0.93) ADVANCE 310 (1.18) 337 (1.28) -0.72 0.92 (0.79-1.07) UKPDS 150 (1.20) 76 (1.40) -0.66 0.81 (0.62-1.07) VADT 72 (1.65) 87 (1.99) -1.16 0.83 (0.61-1.13) OVERALL 730 745 -0.88 0.85 (0.76-0.94) (Q=2.25, p =0.52, I 2 =0.0%) HOSPITALISED/FATAL HEART FAILURE 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) (Q=3.59, p =0.31, I 2 =16.4%) Hazard Ratio (95% CI) 0.5 1.0 2.0 Turnbull FM et al. Diabetologia 2009; 52: 2288 – 2298
American Diabetes Association 2017 Standards of Care. Diabetes Care 2017; 40 (Suppl 1)
https://www.nice.org.uk/guidance/ng28/resources/algorithm-for-blood-glucose-lowering-therapy-in-adults-with-type-2-diabetes-2185604173
EMPA-REG OUTCOME Zinman B et al. N Engl J Med 2015; 373: 2117 – 28
Zinman B et al. N Engl J Med 2015; 373: 2117 – 28
Conclusions Diabetes (and renal dysfunction) are VERY common in patients with heart failure Strong association between poorer diabetic control and poorer micro- and macro-vascular outcome, including heart failure Until recently tightening up diabetic control appears to have had only modest effects on CV outcome The game may have changed with EMPA-REG
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