Lipid Management in 2020:A Glimpse into the Future

Prof Kausik RayMBChB, MD, MPhil (Cantab), FRCP (Lon), FRCP (Ed),

FESC, FACC, FAHA

School of Public Health,Imperial College London, London, UK

CVD will still be a problem in 2020!

Why ?

• Public Health

• Lifestyle

• Increased life expectancy

• Awareness/ Knowledge

• Treating more advanced disease

• Lack of Screening

• Therapies

• Inadequate use of evidence based treatments

• Side effects of current Tx

• Treatment threshold has been reached

• Cost

59

65

41

49

68

40

61

48

83

31

51

4549 50

53

40

0

10

20

30

40

50

60

70

80

90

*Patients with ≥2 cardiovascular risk factors according to NCEP ATP III guidelines;

CEPHEUS, CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia,NCEP ATP, National Cholesterol Educational Program Adult Treatment Panel; JETF, Joint European Task Force

1. Hermans MP et al. Curr Med Res Opin 2010;26:445–454; 2. Park JE et al. Eur J Prev Cardiol 2012;19:781–794

Patients on lipid-lowering drugs for >3 months(stable medication >6 weeks)

CEPHEUS: about half of patients achieved LDL-C goals

% o

f p

atie

nts

at

LDL-

Cgo

al

Europe1

JETF guidelines

Asia2

NCEP ATP III guidelines*

What will change?

• Revolution in the management of FH

• Screening and Earlier Treatment to Prevent CVD

• More widespread understanding and use of absolute risk scores to

Familial Hypercholesterolaemia

Estimated millions of individuals worldwide with FH by WHO regions and by income groups

Nordestgaard BG et al. Eur Heart J 2013;34:3478-3490

Estimated % of individuals diagnosedwith FH in different countries/ territories, as a fraction of those theoretically predicted based on a frequency of 1/500 in the general population

Familial Hypercholesterolaemia

Nordestgaard BG et al. Eur Heart J 2013;34:3478-3490

Despite available treatment approaches, we still have a significant percentage of patients not at goal

• Pijlman AH et al. Atherosclerosis 2009;209:189–194

100

80

40

02

Att

ain

me

nt

of

targ

et

(%)

LDL-C target (mmol/l)

60

20

0 43 5 6 7 8 9 10

LDL-C burden in individuals with or without FH as a function of the age of initiation of statin therapy

Familial Hypercholesterolaemia

Nordestgaard BG et al. Eur Heart J 2013;34:3478-3490

Solutions

• Awareness/ Improve Knowledge

• Screening systematically

• Change Policy/ ICD codes

• Additional new therapies

www.eas-society.org

RUTHERFORD-2: LDL-Ca goal achievement <70 mg/dL at Week 12

Evolocumab is an investigational drug under clinical development. Raal et al Abstract No. 400-05, Featured Clinical Research, Oral Presentation, Saturday, March 29, 2:36 – 2:54 p.m. EDT

0

10

20

30

40

50

60

70

80

Pro

po

rtio

n o

f p

ati

en

ts (

%)

2%

68%

2%

63%

61%b

66%b

Placebo Q2W (N = 54)

Placebo QM (N = 55)

Evolocumab 140 mg Q2W (N = 110)

Evolocumab 420 mg QM (N = 110)

aDetermined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 40 mg/dL or triglyceride

levels were >400 mg/dL; bp<0.001; analyzed using CMH test, stratified by the stratification factors

Most heFH Patients Receiving Alirocumab on

Background Statin Other LLT Achieved LDL-C Goals

13

72.2%

81.4%

2.4%

11.3%

0

10

20

30

40

50

60

70

80

90

P<0.0001

% p

atie

nts

Placebo

†Very high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy.

Proportion of patients reaching LDL-C goal† at Week 24

FH I FH IIAlirocumab

Intent-to-treat (ITT) Analysis

Preserve Health vs Treating Disease

Ference BA et al. J Am Coll Cardiol 2012;60:2631–2639; Baigent C et al. Lancet 2005;366:1267–1278

Screen early, treat early,think about lifetime risk

rs12916

rs4299376

rs599839

rs11206510

rs2228671rs646776 rs6511720

rs4420638

rs11591147

1.00 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 11.010.0 12.013.0 14.015.016.017.0 18.0

10%

20%

30%

Lower LDL-C (mg/dL)

Pro

po

rtio

nal

Ris

k R

edu

ctio

n (

SE)

50%

40%

30%

20%

10%

0%

-10%

0.5 1.0 1.5 2.0

Reduction in LDL cholesterol (mmol/L)

Pro

po

rtio

nal

red

uct

ion

in e

ven

t ra

te (

SE)

Major vascular events

54.5% relative risk reductionper 1 mM/L (38.7mg/dL)

LDL-C lowering

22% relative risk reductionper 1 mmol/L (38.7mg/dL)

LDL-C lowering

Solutions

• Systematic Screening

• Exemplar NHS Vascular Health Checks being offered in the UK to everyone aged 40-70

Problems

• Visualising absolute risk in a n individual is poor

• Reluctance to use higher doses based on unfounded concerns

• Wait and watch approach

The Need for Absolute Risk Prediction for People on Statin

Therapy

0 1 2 3 4 5 6

8%-20% = 1.6% abs RR

-20% = 1.3% abs RR

-20% = 1% abs RR

-20% = 0.8% abs RR3.3%

Log

of

Ris

k

LDL-C mmoles

Relationship of LDL-C lowering and Risk Reduction with a statin~ 20% reduction in RR per mmol LDL-C

As abs risk

NNT

Consistent effect on relative risk; diminishing effect on absolute risk

• Bhatt JAMA REACH REGISTRY

• Bhatt JAMA REACH REGISTRYc

Other Therapies

CETP Inhibition HDL pathways Anti Inflammatory Tx

Other

Anacetrapib Apo A mimetics IL-1B inhibtion Target Lp(a)

Evacetrapib A1 Milano Methotrexate Target Apo C III

TA 8995 RVX 208 PPAR alpha agonists

High Dose fish oils

26 24 2520

9

1720 19 20

14 15 14

4340 42

13 14 1317

915

0

20

40

60

80

100

CHD Stroke CHD or stroke

Antiplatelet Beta-blockers ACEi or ARBs Diuretics BP-lowering Ca-channel blockers Statins

Overall rates of secondary prevention medication use for CVD is low worldwide

PURE study, 17 countries

PURE, Prospective Urban Rural Epidemiology; ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure

Yusuf S et al. Lancet 2011;378:1231–1243

% o

f p

atie

nts

wit

h t

reat

men

t

Conclusion

• All these emerging therapies will increase uptake of statins and other current Tx

• FH will be better detected (hope), better treated yes

• Screen and treat early

• Need to be more sophisticated about who we offer additional Tx to