the clinical unmet need in the patient with diabetes and acs · the clinical unmet need in the...
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The Clinical Unmet need in the patient with Diabetes and ACS
Professor Kausik Ray (UK)
BSc(hons), MBChB, MD, MPhil, FRCP (lon), FRCP (ed), FACC, FESC, FAHA
Diabetes is a global public health challenge and outcomes remain poor compared to those without
Diabetes
IDF diabetes atlas, 4th edition, 2009
2010 2030
Total number of people with diabetes (age 20-79)
285 million 438 million
Prevalence of diabetes (age 20-79)
6.6 % 7.8 %
Prevalence of diabetes in 2030
Coronary heart disease
Coronary death
Non-fatal MI
Cerebrovascular disease
Ischaemic stroke
Haemorrhagic stroke
Unclassified stroke
Other vascular deaths
2.00 (1.83–2.19)
2.31 (2.05–2.60)
1.82 (1.64–2.03)
1.82 (1.65–2.01)
2.27 (1.95–2.65)
1.56 (1.19–2.05)
1.84 (1.59–2.13)
1.73 (1.51–1.98)
HR (95% CI)
26,505
11,556
14,741
11,176
3799
1183
4973
3826
Number
of cases
64 (54–71)
41 (24–54)
37 (19–51)
42 (25–55)
1 (0–20)
0 (0–26)
33 (12–48)
0 (0–26)
I2 (95% CI)
11 2 4
HR (diabetes vs no diabetes)
Outcome
Diabetes doubles the risk of vascular disease
Data from 528,877 participants (adjusted for age, sex, cohort, SBP, smoking, BMI)
BMI, body mass index; CI, confidence interval; HR, hazard ratio; MI,
myocardial infarction; SBP, systolic blood pressure
Emerging Risk Factors Collaboration. Lancet 2010;375:2215
Diabetes is associated with significant loss of
life years
Seshasai et al. N Engl J Med
2011;364:829-415
.
0
7
6
5
4
3
2
1
040 50 60 70 80 90
Age (years)
Year
s o
f lif
e lo
st
Men7
6
5
4
3
2
1
040 50 60 70 80 900
Age (years)
Women
Non-vascular deaths
Vascular deaths
On average, a 50-year-old individual with diabetes and no history of vascular
disease will die 6 years earlier compared to someone without diabetes
Life expectancy is reduced by ~12 years in diabetes
patients with previous CVD*
6
* male, 60 years of age with history of MI or stroke
Modelling of Years of Life Lost by Disease Status of Participants at Baseline Compared With Those Free of Diabetes, Stroke, and MI
The Emerging Risk Factors Collaboration.
JAMA. 2015;314(1):52-60.
Life expectancy is reduced by 12 years in diabetes
patients* with previous CV disease
7
In this case, CV disease is represented by MI or stroke.*60 years of age.CV, cardiovascular; MI, myocardial infarction.
60 End of lifeyrs
-6 yrs
-12 yrs
No Diabetes
Diabetes
Diabetes +MI
The Emerging Risk Factors Collaboration.
JAMA. 2015;314:52–60.
Interventions that reduce cardiovascular disease
• Lipid lowering?
• Blood pressure?
• Glucose lowering?
-32
-24 -23 -22 -24
-31
-25
-44
-37
-8
-42
-19
-25
-18
-11
-60
-50
-40
-30
-20
-10
0R
R r
edu
ctio
n o
r h
azar
d
rati
o (
%)
Combined
Statin therapy has a pivotal role in reducing CV risk
9
6605659520,536415990144444N 10,001 17,802
Non-diabetes Diabetes
AFCAPS/TexCAPS5
4S1,2 LIPID1,2 CARE1,2 WOSCOPS4Trial HPS1,2TNT3 JUPITER6
Secondary prevention Primary preventionHigh risk
CARDS7 ALLHAT-LLT8
2838 10,355
1. Ryden et al. Eur Heart J 2007;28:88–136. 2. Libby. J Am Coll Cardiol 2005;46:1225–8. 3.
LaRosa et al. N Engl J Med 2005;352:1425–35. 4. Shepherd et al. N Engl J Med 1995;333:1301–
8. 5. Downs et al. JAMA 1998;279:1615–22.
6. Ridker et al. N Engl J Med 2008;359:2195. 7. Colhoun et al. Lancet 2004;364:685–96. 8.
ALLHAT-LLT. JAMA 2002;288:2998–3007.
Time to first major cardiovascular event in patients with
diabetes
*CHD death, non-fatal non-procedure-related MI, resuscitated cardiac arrest, fatal or non-fatal stroke. CV, cardiovascular
Shepherd J et al. Diabetes Care 2006;29:1220
HR=0.75
(95% CI 0.58–0.97)
p=0.026Atorvastatin 10 mg
Atorvastatin 80 mg
0 1 2 3 4
5 6
Time (years)
0.2
0
0.1
0
0.1
5
0.0
5
0
Cu
mu
lati
ve
in
cid
en
ce
of
majo
rC
V e
ven
ts*
Relative risk reduction = 25%
7 Year Risk of Cardiovascular death, MI, documented unstable angina
requiring rehospitalization, coronary revascularization (≥30 days), or
stroke in IMPROVE IT
34,7
45,5
30,832,7
40
30,2
Overall DM No DM
LDL-C ~68mg/dl LDL-C~53mg/dl
Cannon Et al NEJM 2015
Interventions that reduce cardiovascular disease
• Lipid lowering?
• Blood pressure?
• Glucose lowering?
10 mmHg reduction in SBP reduces all-cause mortality, macrovascular and
microvascular outcomes in T2D
13
Meta-analysis of 40 large scale, randomised, controlled trials of BP-lowering treatment including patients with diabetes (n=100,354 participants).
Stroke
Outcome
All-cause mortality
Macrovascular disease
CV disease
CHD
Stroke
Heart failure
Microvascular disease
Renal failure
Retinopathy
Albuminuria
0.5 1.0 2.0
Favours BP lowering Favours control
Relative risk (95% CI)
Emdin et al. JAMA 2015;313:603–15.
ACCORD
110
120
130
140
0 1 2 3 4 5 6 7 8
SB
P (
mm
Hg
)
Years post-randomisation
Intensive Standard
Int. N = 2174 1973 1150 156
Std. N = 2208 2077 1241 201
ACCORD Study Group. N Engl J Med 2010;362:1575
Average after 1st year: 133.5 Standard,
119.3 Intensive; Delta = 14.2
Primary and secondary outcomes
Intensive
events
(%/yr)
Standard
events
(%/yr)
HR (95% CI) p
Primary 208 (1.87) 237 (2.09) 0.88 (0.73–1.06) 0.20
Total mortality 150 (1.28) 144 (1.19) 1.07 (0.85–1.35) 0.55
CV death 60 (0.52) 58 (0.49) 1.06 (0.74–1.52) 0.74
Non-fatal MI 126 (1.13) 146 (1.28) 0.87 (0.68–1.10) 0.25
Non-fatal
stroke34 (0.30) 55 (0.47) 0.63 (0.41–0.96) 0.03
Total stroke 36 (0.32) 62 (0.53) 0.59 (0.39–0.89) 0.01
ACCORD Study Group. N Engl J Med 2010;362:1575
Interventions that reduce cardiovascular disease
• Lipid lowering?
• Blood pressure?
• Glucose lowering?
Effects of more- vs less-intensive control of
glucose on non-fatal MI, CHD, stroke and mortality
Ray KK et al. Lancet 2009;373:1765. *Included non-fatal MI and death from all-cardiac mortality; †Included only non-fatal strokes
I2=0% (95% CI 0-69.3%), p=0.61
Overall
ADVANCE
ACCORD
PROactive
VADT
UKPDS
21.86
28.86
9.44
21.81
0.83 (0.75, 0.93)
0.98 (0.78, 1.23)
0.78 (0.64, 0.95)
0.83 (0.64, 1.06)
0.81 (0.58, 1.15)
0.78 (0.62, 0.98)
100.00
28.86
18.03
1.4 .6 .8 1.2 1.4 1.6 1.8 2
Odds Ratio
Study
Intensive therapy better Standard therapy better
Weight
(%)
Odds ratio
(95% CI)
Non-fatal MI
I2=0% (95% CI 0-53%), p=0.78
Overall
UKPDS
PROactive*
Study
ACCORD
ADVANCE
VADT
0.85 (0.77, 0.93)
Odds ratio
(95% CI)
100.00
20.22
25.68
36.48
9.03
0.75 (0.54, 1.04)
0.81 (0.65, 1.00)
0.82 (0.68, 0.99)
0.92 (0.78, 1.07)
0.85 (0.62, 1.17)
8.59
Weight
(%)
1.4 .6 .8 1.2 1.4 1.6 1.8 2
Odds RatioIntensive therapy better Standard therapy better
CHD
I2=0% (95% CI 0-62%), p=0.70
Overall
ACCORD
ADVANCE
PROactive†
UKPDS
VADT†
0.93 (0.81, 1.06)
1.05 (0.76, 1.46)
0.91 (0.51, 1.61)
0.78 (0.47, 1.28)
16.21
5.18
0.97 (0.81, 1.16)
0.81 (0.60, 1.08)
100.00
51.38
20.47
6.76
1.4 .6 .8 1.2 1.4 1.6 1.8 2
Odds RatioIntensive therapy better Standard therapy better
StudyOdds ratio
(95% CI)
Weight
(%)
Stroke
I2=58% (95% CI 0-84%), p=0.049
Overall
ADVANCE
ACCORD
UKPDS
VADT
PROactive
1.02 (0.87, 1.19)
0.93 (0.82, 1.05)
1.28 (1.06, 1.54)
1.09 (0.81, 1.47)
0.96 (0.77, 1.19)
29.38
23.64
10.05
15.46
21.47
0.79 (0.53, 1.20)
100.00
1.4 .6 .8 1.2 1.4 1.6 1.8 2
Odds RatioIntensive therapy better Standard therapy better
Study
Odds ratio
(95% CI)Weight
(%)
All-cause mortality
Cardiovascular risk reduction requires multiple interventions
including blood pressure and lipid management
-12,5
-8,2
-2,9
-14
-12
-10
-8
-6
-4
-2
0
Nu
mb
er
of
CV
e
ven
ts*
pre
ven
ted
*Comprised non-fatal MI, CHD, stroke and all-cause mortality
Ray KK et al. Lancet 2009;373:1765
Per 4 mmHg
lower SBP
Per 1 mmol/l
lower LDL-C
Per 0.9%
lower HbA1c
Benefit of different interventions per 200 diabetic patients treated for 5
years
DDP 4 inhibitors do not reduce CVD
Abbas A & Ray KK. Diabetes Obesity Metabolism 2015
Other novel treatments for DM
• SGLT2 (empagliflozin) only reduced CV death and HF hospitalization in
stable chronic patients
• GLP1 agonist (liraglutide) only reduced CV death in stable CAD patients
• GLP-1 lixisenatide did not affect CV death NF MI or stroke composite in
people with DM after an ACS
Other novel treatments for reducing CVD
• PCSK9 monoclonal Ab
• Direct inhibition of IL-1 beta (inflammation) CANTOS trial
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
LDL
Ch
ole
ste
rol (
mg/
dl)
Weeks
Evolocumab(median 30 mg/dl, IQR 19-46 mg/dl)
Placebo
59% mean reduction (95%CI 58-60), P<0.00001
Absolute reduction: 56 mg/dl (95%CI 55-57)
LDL Cholesterol
0%
2%
4%
6%
8%
10%
12%
14%
16%
Primary Endpoint
Evolocumab
Placebo
Months from Randomization
CV
Dea
th, M
I, S
tro
ke,
Ho
sp f
or
UA
, or
Co
rR
evas
c
0 6 12 18 24 30 36
Hazard ratio 0.85(95% CI, 0.79-0.92)
P<0.0001 12.6%
14.6%
Reducing CV risk in T2D may need a multifactorial approach
CV, cardiovascular; T2D, Type 2 Diabetes.*Includes smoking cessation. Rydén L, et al. Eur Heart J. 2013;34:3035–3087.
CV risk
Control of dyslipidaemia
Antiplatelet therapy
Antihypertensive therapy
Glycaemic control
Weight loss and lifestyle
intervention*
Targeting additional pathways
(inflammation, complement
activation,
Activated vasculature
Reverse cholesterol transport
What else is perturbed and which could be a target for therapy ?
Ray JACC 2005
Perturbed Vasculature
A perturbed vasculature predicts recurrent events Post ACS
Ray AJC 2006
Ray AJC 2006
The risk from a perturbed vasculature may be attenduatedby treaments that reduce LDL-C and inflammtion
The presence of heightened inflammation or a perturbed vascular is associated with greater risk in those with DM vs
those without – OPUS TIMI 16
Ray EHJ 2012
Validation of the greater impact of inflammtion on adverse outcomes among those with DM vs those
without DM in TACTICS-TIMI 18
Ray EHJ 2012
Potential mechanism of increased risk is an interaction between dysglycaemia and inflammation in DM
Ray EHJ 2012
Targeting the high risk patient with an unmet need
• ACS patient
• DM
• A low HDL-C
• Heightened inflammation
One target but multiple effects in the right patient
Summary• T2D is a major public health challenge
• CV events are highest in patients with T2D, ACS, a low HDL and heightened inflammation
• Beyond current therapies targeting several novel pathways known to be perturbed post ACS may offer novel solutions to current unmet need