Treatment of hyperlipidaemia

Lipid Lowering DrugsLipid Lowering Drugs

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Pathways of Lipid Transport & Pathways of Lipid Transport & Inherited HyperlipidemiasInherited Hyperlipidemias

Familial HyperTriGlyceridemia Familial HyperTriGlyceridemia – LPL deficiency etc. RARE– LPL deficiency etc. RARE

Familial Combined Hypertriglyceridemia Familial Combined Hypertriglyceridemia – Polygenic. VERY COMMON – Polygenic. VERY COMMON

(ApoB) Remnant Removcal Disease – Remnant Removcal Disease – ApoE deficiency. UNCOMMON ApoE deficiency. UNCOMMON

Familial Hypoalphalipoproteinemia Familial Hypoalphalipoproteinemia (Tangier’s Disease) – HDL low. RARE(Tangier’s Disease) – HDL low. RARE

Familial Hyper- Familial Hyper- cholesterolemia – LDL cholesterolemia – LDL receptor deficiency. receptor deficiency. COMMON. COMMON. Heterozygotes ~1:500.Heterozygotes ~1:500.

X

X = HMG-coA Reductase step – blocked by Statins


Endemic Hyperlipidemias Endemic Hyperlipidemias

66% UK population have a Total cholesterol >5.2 mmol/L

Reflects high dietary fat, obesity and genotype

Secondary causes should be excluded* but explains only a minority of cases

* Liver or biliary disease, hypothyroidism, diabetes, nephrotic syndrome or drug-induced (etretinate, HAART, thiazides, OC, glucocorticoids, -blockade and ciclosporin)


Management StrategyManagement Strategy Who to treat?

Primary – 10 yr risk of event 30%

Secondary - Established IHD or CVD

What degree of hyperlipidemia should trigger intervention? Total cholesterol > 5mmol/L (or LDL >3)

What are the specific interventions Correct secondary causes – if possible

Dietary modification – in all subjects

Drug Rx – for vast majority a statin www.freelivedoctor.com

Dietary InterventionDietary Intervention

Step II diet has <30% of calories as fat, <7% as saturated fat and <200mg cholesterol/day.

Can achieve a fall in LDL-C of 8-15% … but long-term compliance a problem.

Has useful 2ary benefits Weight reduction BP reduction Reduced insulin resistance Improve intake vitamins & fresh fruit/vegetables

(folate and antioxidants)


General points about StatinsGeneral points about Statins

They competitively and potently inhibit HMG-CoA reductase (in nM range) leading to 2ary upregulation of surface LDL receptors

They have short half-lives (~2 hours except atorvastatin at 14h) but effective with once daily administration

All have slightly higher efficacy if given at night

All except pravastatin are metabolised through CYP enzymes in the liver (usually 3A4) which is the source of important interactions

Major side effects – hepatitis (stop if ALT rises > 3x ULN) and myositis


Clinical Trials in Primary and Secondary Clinical Trials in Primary and Secondary Prevention of IHDPrevention of IHD

Study

No. ofPatients

Follow-up(yrs) Drug

LDL/HDLChange (%)

Total Mortality(%)

CHD Death,Nonfatal MI (%)

PTCA, Bypass(%)

Primary prevention

LRC-CPPT[4] 3806 7.4 BAS -13/2 -7 -19 NR

AFCAPS/TexCAPS[14]

6605 4.8 Lovastatin -25/6 NR -40 -33

WOSCOPS[13] 6595 4.9 Pravastatin

-26/5 -22 -31 -37

HHS[8] 4081 5 Gemfibrozil

-10/10 0 -34 NR

Secondary prevention

CDP[7] 1119 15 Niacin -10/NA -11 NR NR

4S[12] 4444 5.4 Simvastatin

-35/8 -30 -34 -34

CARE[11] 4159 5 Pravastatin

-28/2 -9 -24 -27

LIPID[10] 9014 6 Pravastatin

-25/6 -22 -24 -20

PostCABG[16] 1351 4.3 + 3a Lovastatin -40/4 -35 -31 -30

VA-HIT[9] 2531 5.1 Gemfibrozil

0/6 -11 -22 -9

BIP[5] 3090 6.2 Bezafibrate

-7/18 +6 -11 -4

POSCH[6] 838 14.7 Surgery -38/4 -25 -40 -69

LRC-CPPT = Lipid Research Clinics-Coronary Primary Prevention Trial; BAS = bile acid sequestrant; NR = not reported; AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; WOSCOPS = West of Scotland Coronary Prevention Study; HHS = Helsinki Heart Study; CDP = Coronary Drug Project; NA = not applicable; 4S = Scandinavian Simvastatin Survival Study; CARE = Cholesterol and Recurrent Events; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; PostCABG = Post Coronary Artery Bypass Graft Trial; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial; BIP = Bezafibrate Infarction Prevention Study; POSCH = Program on the Surgical Control of Hyperlipidemias.www.freelivedoctor.com

ELIGIBILITY: MRC/BHF Heart Protection Study ELIGIBILITY: MRC/BHF Heart Protection Study (HPS)*(HPS)*

Increased risk of CHD death due to prior disease:

Myocardial infarction or other coronary heart disease;

Occlusive disease of non-coronary arteries; or

Diabetes mellitus or treated hypertension

Age 40-80 years

Total cholesterol 3.5 mmol/l ( 135mg/dl)

Statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors

* Lancet 2002;360:7-22


http://www-clinpharm.medschl.cam.ac.uk/publications/Lancet_HPS.pdf

PRIOR DISEASE at BASELINEPRIOR DISEASE at BASELINE

Prior disease Number Percentage

Any MI 8510 41%Other CHD 4876 24%No CHD* 7150 35% Cerebrovascular 1820 Peripheral vascular 2701 Diabetes 3982

ALL PATIENTS 20,536 100%

* Overlap between categories within “No CHD” group


TOTAL & LDL CHOLESTEROLTOTAL & LDL CHOLESTEROLterciles at BASELINEterciles at BASELINE

Baseline lipids Number Percentage

LDL cholesterol (mmol/l)<3.0 (116 mg/dl) 6793 33%3.0 <3.5 5063 25%3.5 (135 mg/dl) 8680 42%

Total cholesterol (mmol/l)<5.0 (193 mg/dl) 4072 20%5.0 <6.0 7883 38%6.0 (232 mg/dl) 8581 42%


SIMVASTATIN 40mg daily:SIMVASTATIN 40mg daily: Muscle symptoms Muscle symptoms

Muscle pain orweakness

SIMVASTATIN(10,269)

PLACEBO(10,267)

P-value

Ever reported 3380 (33%) 3410 (33%) NS

Stopped tablets 49 (0.5%) 50 (0.5%) NS


SIMVASTATIN 40mg daily:SIMVASTATIN 40mg daily: Safety monitoring Safety monitoring

Blood enzymes (x upper limit of normal)

SIMVASTATIN (10,269)

PLACEBO (10,267)

Liver: ALT >4 x ULN 43 (0.42%) 32 (0.31%)

Muscle: CK 4 –10 x ULN 19 (0.09%) 13 (0.05%)

CK >10 x ULN 11 (0.11%) 6 (0.06%)

Myopathy* 10 (0.10%) 4 (0.04%)

*Muscle symptoms with CK >10 x ULN


Fatal Rhabdomyolysis with StatinsFatal Rhabdomyolysis with Statins• Rare – probably a class effect• Appears to be dose-dependent

– implications for superstatins• Risk increased by combination with fibrate

– Fibrates especially for gemfibrozil/cerivastatin– Nicotinic acid– Protease Inhibitors (HAART therapy)– Interacting drugs affecting metabolism through CYP pathway

FDA 2001 DataFDA 2001 Data Lova-Lova- Prava-Prava- Simva-Simva- Fluva-Fluva- Atorva-Atorva- Ceriva-Ceriva- AllAll

Cases 19 3 14 0 6 31 73

Total Scripts 99.2 81.4 116 37.4 140 9.8 484

Rate/million scripts 0.19 0.04 0.12 0 0.04 3.16 0.15


SIMVASTATIN: CORONARY EVENTSSIMVASTATIN: CORONARY EVENTS & REVASCULARISATION& REVASCULARISATION

(10269) (10267)

SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO better

Major coronary event

357 574Non-fatal MI587 707Coronary death

(8.7%) (11.8%)27% SE 4reduction

898 1212

(2P<0.00001)

CORONARY EVENTS

Revascularisation

513 725Coronary450 532Non-coronary

(9.1%) (11.7%)24% SE 4reduction

939 1205

(2P<0.00001)

REVASCULARISATIONS

0.4 0.6 0.8 1.0 1.2 1.4


SIMVASTATIN: MAJOR VASCULAR EVENTSSIMVASTATIN: MAJOR VASCULAR EVENTS

(10269) (10267)

SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO better

Vascularevent

898 1212Major coronary

444 585Any stroke

939 1205Revascularisation

(19.8%) (25.2%)24% SE 3reduction

2033 2585

(2P<0.00001)

ANY OF ABOVE

0.4 0.6 0.8 1.0 1.2 1.4


SIMVASTATIN:SIMVASTATIN:MAJOR VASCULAR EVENT by YEARMAJOR VASCULAR EVENT by YEAR

0 1 2 3 4 5 60

5

10

15

20

25

30

Years of follow-up

5(3) 20(4) 35(5)

SIMVASTATIN

PLACEBO

46(5) 54(7) 60(18)Benefit/1000 (SE):

Pe

op

le s

uff

eri

ng

eve

nts

(%

)


SIMVASTATIN: MAJOR VASCULAR EVENTSIMVASTATIN: MAJOR VASCULAR EVENTby LDL & TOTAL CHOLESTEROLby LDL & TOTAL CHOLESTEROL

(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO betterLipid levelsat entry

LDL cholesterol (mmol/l)

598 756(17.6%) (22.2%)< 3.0 (116 mg/dl)

484 646(19.0%) (25.7%) 3.0 < 3.5

951 1183(22.0%) (27.2%) 3.5 (135 mg/dl)

Total cholesterol (mmol/l)

360 472(17.7%) (23.1%)< 5.0 (193 mg/dl)

744 964(18.9%) (24.5%) 5.0 < 6.0

929 1149(21.6%) (26.8%)> 6.0 (323 mg/dl)

24% SE 3reduction(2P<0.00001)

2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4


SIMVASTATIN: Main conclusionsSIMVASTATIN: Main conclusions

After allowance for non-compliance, 40mg daily simvastatin safely reduces the risk of heart attack, of stroke, and of revascularisation by about one-third

5 years of statin treatment typically prevents these “major vascular events” in about:

100 of every 1000 people with previous MI 80 " " " other CHD 70 " " " cerebrovascular disease 70 " " " other arterial disease 70 " " " diabetes (age 40+)

irrespective of cholesterol level (or age, or sex, or other treatments)


05

10152025303540

Cor o

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Even

t R

ate

(%

)

Sacks FM et al. Sacks FM et al. CirculationCirculation 2002;105:1424-1428. 2002;105:1424-1428.

Prospective Pravastatin Pooling Project: Prospective Pravastatin Pooling Project: Coronary Event Rates in CARE and LIPID Coronary Event Rates in CARE and LIPID Patients with Baseline LDL-C <3.3mmol/LPatients with Baseline LDL-C <3.3mmol/L

<60 F M + — + — + — >27

<27

<40

>40

>150

<150

Age Sex HTN Smoking DM BMI HDL-C TG

*****PravastatinPravastatin

PlaceboPlacebo

*p=.004*p=.004**p (interaction) =.005**p (interaction) =.005

>60

Cumulative Coronary Event Rates in Cumulative Coronary Event Rates in Diabetic and Nondiabetic Patients with Diabetic and Nondiabetic Patients with

Baseline LDL-C <3.3mmol/LBaseline LDL-C <3.3mmol/L

0

5

10

15

20

25

30

35

40

Cu

mu

lati

ve R

isk

of

Coro

nary

E

ven

t or

Pro

ced

ure

(%

)

Years Follow-up

Sacks FM et al. Sacks FM et al. CirculationCirculation 2002;105:1424-1428. 2002;105:1424-1428.

0 1 2 3 4 6 75

Placebo DiabeticPravastatin NondiabeticPravastatin DiabeticPlacebo Nondiabetic

Are the effects of Statins solely Are the effects of Statins solely explained by reduction in explained by reduction in

cholesterol ?cholesterol ?

Atherosclerosis can be viewed as an inflammatory process

Statins could affect inflammatory process by 2ary effect on LDL uptake by macrophages (as

source of CRP) 1ary effect on the acute phase-response

Both scenarios suggest an exclusive focus on cholesterol reduction may be misplaced

Cardiovascular Risk Prediction:Cardiovascular Risk Prediction: the role of hs-CRP (1) the role of hs-CRP (1)

Women’s Health Survey – Women’s Health Survey – long term effects of ASA & long term effects of ASA & vit Evit E

Baseline samples from Baseline samples from 27,939 patients27,939 patients

Mean age 55. 25% had HT, Mean age 55. 25% had HT, 12% smoked, 45% on HRT & 12% smoked, 45% on HRT & 2.5% had DM2.5% had DM

Followed for mean of 8 yearsFollowed for mean of 8 years

Endpoint of MI, stroke, Endpoint of MI, stroke, revascularization of CV revascularization of CV deathdeath

Ridker et al, NEJM 2002;347:1557

Cardiovascular Risk Cardiovascular Risk Prediction:Prediction:

the role of hs-CRP (2) the role of hs-CRP (2)

CRP provides additional risk prediction to that provided CRP provides additional risk prediction to that provided by Framingham risk assessor across all LDL-C groups.by Framingham risk assessor across all LDL-C groups.

Statins have an Effect on Statins have an Effect on Inflammatory Markers such as CRPInflammatory Markers such as CRP

CHEST study (Heart 2003;5:2-7) – in 80 dyslipidaemic patients statins (atorva, simva and pravastatin) reduced CRP at 1 week with further falls up to 12 weeks. Fall in CRP correlated closely with the fall in LDL-cholesterol

PRINCE study (JAMA 2001;286:9) – primary prevention study of 1702 subjects randomised to placebo or 40mg prava and CRP followed to 24 weeks. Prava reduced CRP by 17%

Atheroscleosis 2003;166:129 – 186 Type2 DM patients randomised to placebo or 10/80mg atorvastatin. Atorva reduced CRP by 15 & 47% without significant effect on plasma IL-6

Platelet Receptor Inhibition in Platelet Receptor Inhibition in Ischemic Syndrome Management Ischemic Syndrome Management (PRISM): Statin Therapy Reduced (PRISM): Statin Therapy Reduced

Event RateEvent Rate

02468

1012141618

Event

Rate

s [M

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y, M

I] (

%)

30-day Follow-up Period0 1 2 3 4 75

Heeschen C et al. Heeschen C et al. CirculationCirculation 2002;105:1446-1452. 2002;105:1446-1452.

Statins discontinuedStatins discontinued

No statinsNo statins

Statin continuedStatin continued

Current Unresolved Issues on the Current Unresolved Issues on the Use of StatinsUse of Statins

For For secondary preventionsecondary prevention we should treat all patients with we should treat all patients with established IHD but …established IHD but …

How soon after an event should they be started?How soon after an event should they be started?

Is dose-titration versus LDL-chol still appropriate?Is dose-titration versus LDL-chol still appropriate?

Should we simply put all patients on a high dose of a statin Should we simply put all patients on a high dose of a statin without titration in keeping with HPS?without titration in keeping with HPS?

For For primary preventionprimary prevention is the current threshold of 30% risk is the current threshold of 30% risk over 10 years too stringent? over 10 years too stringent?

FibratesFibrates FA oxidation in muscle and

liver and lipogenesis in the liver

Most effective at reducing VLDL (TG); smaller in LDL-chol but useful in HDL-chol

Act as PPAR ligands (cf glitazones) - reduced expression of Apo C11 is key to VLDL catabolism

Main side effects

GI intolerance

1-2% increase in the incidence of gallstones

Important interactions

increased risk of myositis on a statin

reduction in dose requirements (~30%) for patients on warfarin

Nicotinic AcidNicotinic Acid 1ary effect is reduced FA mobilization from the periphery

hepatic VLDL synthesis

Is the agent with largest impact on HDL, and the only agent that lowers Lp(a) (by ~ 30%)

Usually employed in combination with fibrate, resin or statin – this avoids side effects of higher doses

Major side effectsFlushing – prostaglandin mediatedSkin drying & GI intolerance

Anion-Exchange ResinsAnion-Exchange Resins Sequester bile acids (BA) in the

gut hence blocking enterohepatic cycling of BA e.g. cholestyramine and colestipol

2ary effect on cholesterol synthesis actually VLDL and hyperTG may limit use

Usually used in combination with a statin

Major side effect – not palatable and constipate

Important interactions – bind polar drugs such as warfarin, digoxin, thyroxine and statins give 1 hr before resin

‘‘Super’ StatinsSuper’ Statins New ‘Superstatins’

Rosuvastatin launched 2003, Pitavastatin expected 2005

‘Super’ is an exaggeration

Do we really need them?

No doubt that reduction in ischaemic end-points is a class-effect

Proven safety should probably be the major concern following cerivastatin withdrawal

Older statins going generic i.e. costs likely to fall

Does the intensity of Lipid reduction Does the intensity of Lipid reduction matter?matter?

PROVE IT-TIMI 22 Trial (NEJM 2004; 350:1495)

designed as a non-inferiority study of the two agents

4162 patients within 10 days of an ACS were randomized to pravastatin 40mg/d or atorvastatin 80mg/d

followed up for mean of 24 months

Atorvastatin limb produced a 16% reduction in primary end point events

LDL-cholesterol was 1.6 mmol/l vs 2.46 in pravastatin limb

Note early separation of event curves vs. 12-18 m delay in 2ary prevention trials – does this still reflect differences in the pleiotropic actions of the 2 statins?

The Z phase of the A to Z Trial: intense The Z phase of the A to Z Trial: intense vs leisurely simvastatin, SS vs leisurely simvastatin, SS

• Patients with ACS randomised to either SS 40mg/d for 1/12 then 80mg/d OR placebo for 4/12 then SS 20mg/d

• No difference in 1ary end point (composite CV death, non-fatal MI, ACS or need for revasc) in first 4/12

• Differences only obvious after 6-8/12

• Only 10 episodes of myopathy (9 in intense limb)

0

0.5

1

1.5

2

2.5

3

3.5

0m 1m 4m 8m 24m

LDL-C levels

Intense

Leisurely

Newer Therapies - EzetimibeNewer Therapies - Ezetimibe Novel inhibitor of intestinal cholesterol

transporter (? SR-B1)

Rapidly metabolised to glucuronide (EZEG) – which has 400x the potency of EZE and prolongs action by enterohepatic cycling

No important adverse effects OR significant drug interactions

Effective in mild/moderate HC as monotherapy or in combination with statins for moderate/severe HC where it acts synergistically

Unlike resins does not raise TG - actually falls and again synergism with a statin


Emerging Therapy - TorcetrapibEmerging Therapy - Torcetrapib

Novel inhibitor of cholesteryl ester transfer protein, (CETP), that is normally responsible for transfer of these esters from HDL to Apo-B1 => fall in HDL-cholesterol content and particle size.

NEJM 2004;350:1505NEJM 2004;350:1505

• small rise in HDL with atorvastatin 20mg/d• much larger and dose-dependent rise with Torcetrapib


Important pointsImportant points Hyperlipidemia is common and a major risk factor for

IHD and stroke

Intervention with a statin is highly effective and can reduce risk by ~ 1/3rd

Statins are safe but still under prescribed even to high risk groups (e.g. diabetics)

HPS has still to impact on guidelines and clarification needed on the dogma of dose-titration

Prescription of statins is likely to expand substantially driven by appearance of generics and OTC sales?


Documents

Treatment of hyperlipidaemia