Lipid Regulating Drugs

• There is good accumulated evidence that lipid regulating drugs are effective in preventing myocardial infarction (MI), coronary deaths, non-haemorrhagic strokes and overall mortality rate from CVD. The Cholesterol Treatment Trialists' Collaboration (CTTC) meta-analysis of CVD prevention trials¹ showed:
  • For secondary prevention, the number-needed-to-treat (NNT) with a statin over five years to prevent a major vascular event (including death) is 21.
  • For primary prevention, over the same duration of treatment, the NNT is 40.
• Statins give the greatest benefits to those with the highest absolute baseline risk and where taken over longer durations.
• The benefits of statin treatment are independent of age, sex and cholesterol baseline. This has been taken to suggest that statins should be considered for everyone with an increased vascular risk irrespective of cholesterol level, moving away from the treatment of hyperlipidaemia per se.
• The CTTC meta-analysis¹ results has been critisized by some for over-estimating primary prevention benefit.² If analysis is limited to primary prevention trials where patients had no pre-existing vascular disease, they argue that there is no evidence of:
  • Reduction in total mortality
  • Benefit to women
  • Benefit to anyone aged over 69. (This run contrary to the findings of the Heart Protection Study (HPS)³ which showed that elderly patients (65 to 80 years) had a reduction in risk of first major vascular event on Simvastatin 40 mg daily equivalent to that of the whole cohort.)
• Lipid-regulating drugs should be combined, as appropriate,⁴ with:
  • Lifestyle measures
  • Antihypertensives
  • Aspirin

• Personalised lifestyle advice⁵ - all those found to be at a moderate or high CV risk should receive diet and lifestyle advice to include :
  • Mediterranean diet⁶
  • Substituting saturated fat with unsaturated fat
  • Increasing fish consumption⁷
  • Reducing salt
  • Eating at least '5-a-day' of fruit and vegetables
  • Promoting exercise and weight loss
  • Smoking cessation
  • Moderating alcohol intake^8,4
• Dietary management can reduce baseline lipid levels by a small amount and tends to be useful as an adjunct to drug treatment. However, the benefit of this intervention is to encourage people to adopt a healthier overall lifestyle, addressing risk factors for CVD beyond cholesterol.
• Plant sterol containing foods (eg Benecol margarine) are an option as part of a cholesterol lowering diet (reducing total cholesterol by about 10 % when substituted for part of the daily fat intake), but note cost, lack of RCTs with clinical outcome and limited safety data.⁹

Hypercholestrolaemia and CVD prevention

• Statins are the treatment of choice and dominate treatment in primary care and elsewhere.
• Second-line options include fibrates, anion-exchange resins, nicotinic acid and fish oils.

Combined hyperlipidaemia & hypertriglyceridaemia

• Statins remain the treatment of choice where triglycerides are less than 5 mmol/l.
• Above this level, opinion varies as to whether to use a fibrate or statin as first-line therapy.
• High-dose statins almost match fibrates in triglyceride reduction and have stronger evidence for CHD prevention but fibrates achieve greater reductions in triglyceride (TG) combined with increases in HDL.

Very severe isolated hypertriglyceridaemia

• Where TG > 10mmol/l, prescribe a fibrate and refer for specialist assessment.

or 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) Reductase inhibitors

Mode of action

• Competitive inhibitors of the rate-limiting step of hepatic cholesterol synthesis. With a reduced cholesterol pool in the liver, LDL receptor expression is up-regulated and increased LDL uptake from plasma takes place, lowering plasma LDL cholesterol. This protects against the development of atheroma.
• Statins are also thought to have non-cholesterol related effects such as restoring/improving endothelial function and anti-inflammatory properties. These are implicated in possible cardio-protective effects of early statin use following acute MI¹⁰ or in preventing coronary events after percutaneous coronary angiography.

Who should be on a statin?

Evidence of the beneficial effects of statin therapy in those even at low cardiovascular risk⁴ has huge resource implications. However the question of who should be on a statin is slightly less contentious since a weight of new guidance was issued over the last couple of years: NICE guidelines published in 2006,¹¹ Joint British Society guidelines (JBS-2) in December 2005⁴ and SIGN CVD prevention guidelines in 2007.¹² Broadly these guidelines concur that statins should be prescribed:

• To all adults with clinical evidence of CVD, including peripheral vascular disease.
• For primary prevention, for those with a 10 year risk of greater than 20 % of developing CVD. This represents a significantly lower threshold than the previous 30% level.
• All diabetics over 40 and those over 18 with complications, hypertension, metabolic syndrome, total cholesterol >6 or a strong family history.¹³
• In individuals with certain hyperlipidaemias regardless of CVD risk:⁵
  • Where Total Cholesterol to High Density Lipoprotein ratio (TChol:HDL) is 6 or more
  • Those with familial hyperlipidaemias

Contraindications^{14,15,16,17,18}

Include:

• Active liver disease (or persistently abnormal LFTs)
• In pregnancy and breast-feeding as may affect embryonic development (from animal studies) - ensure adequate contraception during treatment and for 1 month afterwards
• Porphyria

Cautions^{14,15,16,17,18}

Include:

• History of liver disease or high alcohol intake
• Hypothyroidism should be adequately treated before commencing a statin

Interactions^{14,15,16,17,18}

Include:

• Warfarin and simvastatin, fluvastatin and rosuvastatin. Monitor INR closely until stable as INR will occasionally increase with these statins.
• Cytochrome P450 : There are important differences in how the different drugs are metabolised by cytochrome P450 isoenzymes and therefore risks of interactions.
  • Substrates for CYP3A4 : atorvastatin, simvastatin
  • Substrates for CYP2C9 : fluvastatin
  • Not metabolised by P450 enzymes : pravastatin, rosuvastatin

Drugs that inhibit CYP3A4 as these will increase plasma levels of atorvastatin and simvastatin and risk of dose-related side-effects.¹⁹

Side-effects^{14,15,16,17,18}

Statins are usually well-tolerated with the most common adverse side-effects being headache, nausea and abdominal pain. Important but rarer side-effects include:

• Muscle effects
  • The most important adverse effect of these drugs is a myopathy characterised by muscle pain and stiffness.
  • This can progress to rhabdomyolysis - a rare (1/100 000 treatment years) but life-threatening complication.
  • Measure creatine kinase (CK) urgently if a patient reports muscle pain and stop the drug whilst this is investigated.
  • CSM advises that the risk of myopathy is increased where:
    • Underlying muscle disorders
    • Renal impairment
    • Untreated hypothyroidism
    • Alcohol abuse
    • Age over 70
    • Co-prescription with other lipid lowering drugs
    • Past history of myopathy with any lipid-lowering drug
    • Co-prescription of drugs that inhibit cytochrome P450 CYP3AE (see above)
• Hepatotoxicity - rare and dose-dependent. Usually reversible.

Other concerns include:

• Erectile dysfunction - suggestion from small study that the quality of erections diminishes after starting a statin, with 22 % having new onset erectile dysfunction which is reversed on stopping the drug²⁰ but there have been very few yellow card reports of this problem despite very large numbers of men receiving statins.
• Carcinogenicity - statins are carcinogenic in animal studies and we are now using them beyond the duration of the existing safety data. However, reassuringly there was no excess of cancer cases in CTTC data and the Scandanavian Simvastatin Survival Study (4S) follow-up at 10 years.^21,22

Targets ²³

Confusion exists between National Service Framework (NSF) targets (current Department of Health recommendation²⁴) and JBS-2 targets which are much more stringent. Whilst there is evidence of benefit of attaining lower targets, it remains contentious whether this outweighs the associated risks and costs. Further NICE guidance is due later this year (2007) to help clarify the situation.
NSF targets:

• LDL<3.0 mmol/l or 30 % reduction from baseline
• TChol <5.0 mmol/l or 30 % reduction from baseline

• LDL<2.0 mmol/l or 30% reduction from baseline
• TChol < 4.0 mmol/l or 25 % reduction from baseline

(with both NSF and JBS-2 targets, aim for the absolute or relative reduction that gives the lower cholesterol)

Quality and Outcomes framework (QOF) for nGMS: the standard remains 5 mmol/l TChol.

Initiating and monitoring treatment

Choosing a statin^23,25,26,27

• NICE currently recommends initiating statin therapy with an effective drug of low acquisition cost.¹¹
• Based on current evidence and cost, it can be argued that generic simvastatin 40 mg daily is the statin of choice for primary and secondary prevention of CVD.
• Where this is not tolerated, alternatives are:
  • Dose reduction of simvastatin to 20 mg.
  • Switch to generic pravastatin 40 mg daily. The evidence for its use is generally weaker - the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT)²⁸ failed to demonstrate a difference in all cause mortality or non-fatal MI/fatal CHD rates between patients receiving pravastatin 40 mg daily and those receiving usual care.
  • Use atorvostatin. The lipid-lowering arm of the Anglo-Scandinavian cardiac outcome trial (ASCOT-LLA),²⁹ in contrast to ALLHAT, did demonstrate a significant reduction in absolute risk of death and cardiovascular events between hypertensives who received 10 mg (low dose) atorvastatin and those receiving placebo. A small mean serum cholesterol reduction (1.3 mmol for compared to 0.3 mmol for those on placebo) translated into a reduction in incidence of fatal MIs and non fatal coronary events of 3.4/1000 per year and a reduction in stroke of 2/1000 per year.³⁰
• There is as yet no definitive long-term clinical outcome or safety data available for rosuvastatin and the National Prescribing Centre advise atorvastatin or pravastatin second-line with rosuvastatin reserved for more resistant cases.³¹

Regardless of which statin is chosen, it needs to be at a dose sufficient to achieve the cholesterol lowering targets and taken long-term as prescribed.

Starting dose

Different strategies for selecting an appropriate starting dose:

• 'Evidence -based dose' strategy's rationale it that the starting dose should be that with the best evidence of efficacy (ie atorvastatin 10-20 mg, fluvastatin 80 mg, pravastatin 40 mg and simvastatin 20-40 mg nocte).
• The 'titrate to target' strategy uses lower starting doses to minimize the risk of toxicity and avoid using an unnecessarily high dose in many individuals to reach treatment targets.
• Lower starting doses should be considered for people at increased risk of myopathy

Biochemistry³²

• Check lipids (fasting specimens required to quantify LDL fraction and TG accurately) and LFTs and CK prior to starting.
• Exclude any secondary causes of hypercholestrolaemia (eg hypothyroidism) or if present ensure maximally treated before commencing specific lipid-lowering therapy.
• Repeat LFTs after 8 weeks of treatment, after any further dose increases and annually thereafter.
  An increase in transaminases is relative common, reported in 1-2 % of patients and usually occurs in the first three months.
• Repeat CK if normal at pre-treatment test only if muscular symptoms cause concern.

  Monitoring statins - biochemical abnormalities
  	Significantly abnormal result when:	Frequency	Action
  CK	x5 ULN (upper limit of normal)	Rare	Stop statin and seek specialist advice.
  Transaminases (AST, ALT)	x3 ULN	Common	Temporary 'drug holiday' or dose reduction with closer monitoring.

Reaching lipid targets⁵

How relevant is rechecking lipid levels after commencing treatment?

• Many of the major studies, such as HPS, have not titrated doses of statins to reach specific cholesterol targets leading many to arguel that a pragmatic and evidence-based approach is to prescribe 40 mg simvastatin empirically without subsequent checks or chasing target levels.³³
• However, QOF ensures that most GPs will check post-treatment levels and actively work towards target lipid levels with their patients:
  • Repeat lipids after 8 weeks' treatment with a statin (or adjusting dose).
  • Once the target range has been met annual checks should suffice.

• Increasing the dose of the current statin.
• Consider the use of atorvastatin.
• Consider the use of rosuvastatin. All patients should start on an initial 10 mg dose for at least 4 weeks prior to considering increasing its dose. The 40 mg dose is contraindicated in those with predisposing risk factors for muscle toxicity and requires specialist supervision. Patients of Asian origin should have a maximum dose of 20 mg daily.
• Consider concordance if targets are not met, even with maximum recommended doses. Many patients stop taking statins altogether within a year or take them at less than the prescribed dose. The evidence shows that patients need to take their medication in the long-term (over years) to derive the fullest risk reduction.³ A Cochrane Review looking at improving concordance with lipid-lowering medication found the most effective interventions were:
  • Improved patient information and education
  • Telephone reminders
  • Simplifying drug regimens³⁴
• Consider referral - specialist lipid clinics can assist with cases of particularly stubborn hypercholestrolaemia or mixed hyperlipidaemias where combination therapy may be required.

Intensive statin therapy

This is a fresh area of controversy. On the assumption that statins are relatively harmless drugs with almost universal benefit, should we be treating cardiovascular risk more aggressively ie higher doses of statins to achieve lower lipid targets?
High dose atorvostatin (80 mg) has recently been compared with low dose atorvostatin (10 mg) in the Treating to New Targets (TNT) trial³⁵ and with simvastatin (20 mg) in the IDEAL study.³⁶ Neither showed significant reduction in overall mortality and TNT showed a higher incidence of adverse events in the high dose group, as might be expected.
On the basis of this, many argue that we should stick to standard doses²² although the SIGN 2007 guideline¹² does make a case for those with symptomatic CVD to be considered for intensive statin therapy.

Patient advice⁵

Good patient information and education improves compliance. Important messages to get across include:

• These drugs reduce cardiovascular risk. In the case of primary prevention, we are not treating established disease and an individual's perception of their risk will alter the likelihood of their taking the drug therapy as prescribed.
• These drugs need to be taken as ongoing medications. Stopping taking them will result in the loss of benefit.
• Serious side-effects are unlikely but if muscle pain or weakness is experienced, this should be reported immediately to the doctor.
• Take statins at night when they have a slightly greater effect.³⁷

Over-the-counter (OTC) simvastatin^38,39

Simvastatin is now licensed OTC for primary prevention of CHD. Britain was the first country to endorse this approach in 2004..
Simvastatin 10 mg nocte (sold as Zocor Heart-Pro ®) can be bought by those with a 10-15% 10 year CHD risk (this would include:

• All men aged 55 years and over
• Men aged 45-55 and women over 55 who:
  • Have a family history of CHD
  • Are smokers
  • Are obese
  • Are of South Asian descent)

Concerns include:

• Evidence is not strong for this strategy and has been extrapolated from clinical trials using higher doses.
• Absolute risk reductions are likely to be small.
• Patients may not volunteer they are taking the drug, raising worries about risks of interactions etc.
• Patients are likely to be undermonitored and undertreated.
• There are no cholesterol-lowering targets for this population.
• Compliance is likely to be poorer than with medically prescribed statins because of cost implications.
• This policy may be leading to less agressive statin prescribing by GPs themselves.⁴⁰

• A new lipid-regulating drug, ezetimibe is a selective inhibitor of intestinal cholesterol absorption.
• It is licensed as an adjunct to dietary manipulation and statin therapy in patients with hypercholestrolaemia for primary prevention only.
• In combination with simvastatin, it appears to lower LDL cholesterol significantly more than atorvostatin at matched doseage (VYVA trial).⁴³
• It is not currently licensed in Europe for combination therapy with fibrates.
• Currently there is no evidence that it is a safer or more effective clinical strategy than using a maximal statin dose. Its effects alone or as an adjunct on cardiovascular mortality and morbidity remain unknown.

(Bezafibrate,⁴⁴ Ciprofibrate,⁴⁵ Fenofibrate,⁴⁶ and Gemfibrozil⁴⁷).

• These are much less commonly used in primary care and tend to be prescribed under advice of a specialist, particularly if used in combination with a statin.⁴
• They act in the liver to reduce cholesterol synthesis, reduce secretion of very low density lipoproteins (VLDLs) and increase the removal of VLDLs from the blood and consequently lower plasma triglycerides and to a lesser extent plasma cholesterol. They increase the plasma HDL.
• Evidence of efficacy in treating CV risk and safety is less substantial than for statins.
• When used in combination with a statin, fenofibrate and bezafibrate are the usual candidates. Gemfibrozil should not be used with a statin.

Indications

For monotherapy:

• Treatment of hyperlipoproteinaemias (especially types IIa&b, III, IV and V)
• Primary prevention of coronary heart disease which has not responded to other measures (gemfibrozil-licensed for middle-aged men only)

For combination with a statin:

• Treatment of mixed dyslipidaemias
• Treatment of resistant hypercholestrolaemia

Contra-indications

See specific drug monographs.

Cautions

As with statins, myotoxicity is the most important adverse effect of this class of drugs. Risk is increased by:

• concomitant treatment with statins (CK levels > 10x ULN occur in about 1 in 1000 individuals on combination therapy)
• Concomitant treatment with ciclosporin
• Renal insufficiency (check U&Es prior to commencing treatment)
• Older age
• Female sex⁵

Side-effects

Include:

• Myopathy and rhabdomyolyis - rare but serious
• Gastrointestinal side-effects - more common
• Hypersensitivity reaction (urticaria, pruritis, photosensitive rash)

For individual drug's side-effect profiles see specific drug monographs.

Other lipid-regulating drugs are unlikely to be initiated in primary care but may be used on occasion by secondary care lipid clinics. They include:

• Colesytramine and colestipol
• Nicotinic Acid and acipomox
• Omega-3-Fish Oils