diabetes and renal impairment · more facts and figures diabetes and heart failure framingham: dm...
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Challenges in heart failure managementDiabetes and Renal Impairment
Martin R CowieProfessor of Cardiology
National Heart & Lung Institute
Imperial College London (Royal Brompton Hospital Campus)
@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 patient76M; T2DM; CABG; LVEF 15%; CRT-D; ‘Optimal’ medical therapy
Tight rope between “too dry” and “too wet”
Admitted for IV diuretics
Admitted for observation
“too dry”
Admitted for IV diuretics
eGFR: 51 ml/min/1.73m2
eGFR:
20 ml/min/1.73m2
ACEI
BB
MRA
Renal function in incident heart failureThe 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 HFHillingdon Study (incident heart failure)
Creat < 113 mol/l
Creat ≥ 113 mol/l
P < 0.0005
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/1.73m2]
• 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 HF25 prospective studies
Finlay A. McAlister et al. Circ Heart Fail. 2012;5:309-314
N=15 962 N= 4 792
8
Kidney disease and diabetes mellitus are common
co-morbidities in patients with cardiovascular disease
Prevalence of CKD and diabetes mellitus
in patients in the USA with STEMI (n = 19 029)
and NSTEMI (n = 30 462)2
30,5
22,5
42,9
33,9
0
10
20
30
40
50
CKD Diabetes
Pre
va
len
ce
(%
)
STEMI
NSTEMI
41
29
0
10
20
30
40
50
CKD Diabetes
Pre
va
len
ce
(%
)
Prevalence of CKD and diabetes mellitus
in patients in Europe with heart failure
(N = 3226)1
CKD, chronic kidney disease; NSTEMI, non ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction
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 8
Diabetes
mellitus
Diabetes
mellitus
Diabetes
mellitus
DM prevalence in HF admissionsEuroheart Survey
21%
26% 23%
18%
35%
23%
18% 36%
37%
29%
32%
23%
EHJ 2003; 24: 442 – 463
More facts and figuresDiabetes 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
PARADIGM HFrEF 2014 “Entresto”Sacubitril valsartan
35% N=8442
TOPCAT HFnEF 2013 Spironolactone 32% N=3445
EMPHASIS HFrEF 2011 Eplerenone 31% N=2737
SHIFT HFrEF 2010 Ivabradine 30% N=6558
HF risk is related to diabetic control
10
1
0.55 6 7 8 9 10
Updated Mean HbA1C Concentration (%)
Haz
ard
Rat
io
p=0.021
16% decrease per 1% reduction in HbA1C
Heart Failure
Based on UKPDS Study. BMJ 2000; 321: 405 – 412
Is better TIDM control associated with lower HF risk?Swedish National Registry
Lind M et al. Lancet 2011; 378: 140 – 146
20 985 adults with T1DM
Mean age 38.6 yrs
Median FU 9 yrs
Endpoint: HF admission
HR 3.98 [2.23-7.14] for those withHbA1c ≥ 10.5% cf. HbA1c < 6.5%
20
15
10
5
0
40
30
20
10
0
Ad
just
ed
Inci
den
ce p
er
10
00
Pat
ien
ts (
yrs)
Updated Mean HbA1C (%)
0 6 7 8 9 10 11
A.
B.
What is associated with HF risk in T1DM?Multivariable analysis from national Swedish Registry
Hazard Ratio (95% CI) P-value
HbA1c (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/m2 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
TrialsNo. of Events (annual event rate, %)
ΔHbA1C (%)Favors More
IntensiveFavors Less Intensive
Hazard Ratio(%% 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)
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)
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)
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)
Does improving T2DM control reduce the HF risk?
0.5 1.0 2.0Hazard Ratio (95% CI)
(Q=1.32, p=0.72, I2=0.0%)
(Q=0.40, p=0.94, I2=0.0%)
(Q=2.25, p=0.52, I2=0.0%)
(Q=3.59, p=0.31, I2=16.4%)
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 OUTCOMEZinman 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