Approaches to the management of statin intolerant patients

ByAshraf Reda, MD,FESC

Prof and head of Card. Dep., Menofiya UniversityPresident of WGLVRChairman of EGYBAC

The problem

• 5% -10% side effects with statin• More patients become statin eligible• The use of high dosage• Combination therapy• Special situations: Pregnancy-Elderly-Children• Run in phases may underestimate the

problem

Non CV mortality with the high doses need further evaluation

Elevated liver enzymes:1.2% vs 0.2% p<0.001

Rhabdomyolysis 2 cases(80mg) vs 3 cases(10mg)

5461 pts. were excluded in the run in phase

Higher doses= More adverse effects“TNT”

IDEAL Trial: Serious Adverse Events

Presented at AHA 2005Presented at AHA 2005

Liver Enzyme Elevation Myalgia0%

1%

2%

0.97%

2.2%

0.11%

1.1%

Atorvastatin Simvastatin

%

p<0.001

ALT >3x upper limit of normal

p<0.001

Liver enzyme elevation and myalgia (%)

Elevated Liver Enzymes: What to do?

• Less than 1%• Usually asymptomatic• Rarely cause Liver failure• Reversible• Usually improve with continuing statin or

reducing the dose• Change to another statin is an option

Muscle Symptoms

• Myalgia is the most common (1.5-3.5%)

• Myopathy: Less common (0.05%)

• Rhabdomyolysis: Serious ( 1/10000)

Co-Q 10

• May reduce statin induced muscle symptoms

• No large well controlled studies

• Minimal side effects

8

-

Populations at risk

• Elderly > 75-80• Small body mass index• Hepatic or renal dysfunction• Concomitant medications• Large amount of Grapefruit• Combination lipid lowering therapy

Steps to Minimize the Risk of Muscle Toxicity with Fibrate–Statin Combination Therapy

Use statin alone for non-HDL-C goals

Use fish oils or niacin rather than fibrates

Keep the doses of the statin and fibrate low

Dose the fibrate in the AM and the statin in the PM

Avoid in renal impairment

Discontinue therapy if muscle symptoms are present and CK is >10 times the upper limit of normal

CYP2C9 CYP3A4

Alprenolol

FluvastatinHexobarbital

N-desmethyldiazepan

Tolbutamide

Warfarin

Clarithromycin

Cyclosporine A

ErythromycinKetoconazole

Itraconazole

Mibefradil

Midazolam

NefazodoneNifedipine

Protease inhibitors

Terbinafine

Verapamil

Adapted form Corsini A et al. Atherosclerosis, 2002; 35–40.

Drug–Drug Interactions with Statins

AtorvastatinCerivastatin Lovastatin

Simvastatin

Amlodipine

Diltiazem

Quinidine

SildefanilWarfarinClopidogril

AtorvastatinCerivastatin Lovastatin

Simvastatin

Erythtromycine

If not tolerated what to do?

• DC Statin temporarily to be sure that the Side effects are statin related

• Re-challenge with a lower dose or change to other statin

• If multiple statins are not tolerated we can use less effective drugs(Resin, Ezetimibe, Niacin, Fibrate)

• More intense Life style change program

SOMETIMES STATIN COULDN’T BE AN APTION

Referred because of abnormal lipid profile

• 32 yrs female• 30 weeks twin pregnancy• IUF• +ve FH (CABG for the Father @ 45yrs)• Father T Cholesterol known to be more than

300 mg/dl• Border line Bl. G.• No Ho DM or hypertension

Lipid profile

• 1st set : T.Ch: 320mg/dl, TGs: 580onmg/dl

• The day of exam: T ch: 310mg/dl ,TGs: 640 mg/dl

Plan

• No statin during pregnancy and lactation• Fibrates are tumerogenic for the fetous

WHAT TO DO?• Omega III : safe but no LDL lowering effect• Glucose-Insulin infusion• Immunoadsorpton session??

New Statin Intolerance Clinic:Work up

• Validated questionnaire including FH of statin intolerance

• Level of CK and Vit. D• Renal and thyroid function tests• Genetic testing for statin efficacy and potential

toxicity• Proximal muscle strength evaluation• Percutaneous muscle biopsy

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Conclusions

• Statin intolerance is not common however the numbers are increasing as Millions are receiving statin

• Side effects with a statin do not mean that other statin couldn’t be used

• Elderly, Low BMI, hepatic or renal dysfunction, high dosage and combinations are important predictors

Immunoadsorption- LDL aphaeresis (to take away [Greek])Indications: *failure medical (>LDL>200 mg/dl with CAD)and > 300 mg/dl without CAD

*Coast s 3000 / tt every 2 weeks for life

Statin in childhood for familial dyslipidemia

• The earlier to start the better (CIMT)

• As early as 8 years is effective and probably safe

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Apo A-1 Milano• Five weekly infusions of an ApoA-I Milano/ phospholipid

complex produced significant regression of coronary atheroma burden by IVUS.

• Adverse events were similar to placebo.

• Coronary disease is more dynamic than previously realized and can be rapidly affected by agents that augment reverse cholesterol transport.

APO-A1Another non statin way to do it

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Limone sul Garda

•Rare R173C mutation in apoA-I

•Circulates as dimers and monomers

•HDL/apoA-I deficiency

•Mild hypertriglyceridemia

•Paradoxical resistance to heart disease“Gain of Function”

Mutation

Characteristics of humanApoA-IMilano Carriers

Discovered in 1979

With LDL 300, TG 520mg/dl start with

1. Fenofibrate2. statin3. Statin + Fibrate4. Statin+ Ezetemib

When liver enzymes increase to 1.5 times base line

1. Continue with the same dose2. Change to another statin3. Reduce the dose4. Replace with fibrate

All are contraindications to statin therapy except

1. Pregnancy2. Lactation3. Liver cirhosis4. Active hepatitis

All are RF for statin muscle toxicity except

• Age below 40 yrs• Renal impairment• Liver dysfunction• Combination therapy

All can improve statin intolerance except

• Adding Co Q10• Giving fibrate @AM and Statin @PM• Using 2c9 metabolized statin• Using Cyp3A4 metabolized statin

CardioEgypt 2011

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