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

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-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