Lipid Regulating Drugs

Lipid regulating drugs are used to treat dyslipidaemias, primarily raised cholesterol. Hypercholesterolaemia is a major cause of atherosclerosis and contributes to the high levels of mortality we experience in the UK due to cardiovascular disease (CVD) and it is important as one of the three main modifiable risk factors for CVD (the others being smoking and hypertension).

Patients often ask what a 'normal' or 'healthy' serum cholesterol should be. Unfortunately, there is no clear dividing line between what a safe and unsafe level is, rather a continuous spectrum from low to higher risk, along which an individual's cholesterol should be interpreted in context with their other cardiovascular risk factors.¹

Practically, a total cholesterol level of 5.0 mmol/l or less in an untreated individual is considered desirable, yet a recent Department of Health survey suggests that the average in the UK was 5.9 mmol/l. In rural China and Japan, the average is 4 mmol/l.² Cholesterol levels tend to increase with age, so that 80% British men aged 45-64 years exceed the 5.0 mmol/l level. In other words, hyperlipidaemia is the 'norm' among the UK population.

See Hyperlipidaemia article.

We treat hyperlipidaemias in the expectation that lowering cholesterol will slow/halt atherosclerosis and thus help to reduce CVD. There is good accumulated evidence that reducing LDL and TChol levels with lipid regulating drugs is an effective way to prevent myocardial infarction (MI), coronary deaths, non-haemorrhagic strokes and reduce overall mortality rate from CVD:

• 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-analysis⁵ results has been criticised by some for over-estimating primary prevention benefit.⁶ 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)⁷ which showed that elderly patients, 65 to 80 years, had a significant reduction in risk of first major vascular event on simvastatin 40 mg daily.)
• A further CTTC meta-analysis showed that statins significantly reduce the risk of major vascular events in diabetics, regardless of baseline lipid characteristics or prior history of CVD. NNT over 5 years to prevent a major vascular event was 23.⁸
• The independence of the relationship between plasma triglycerides and CVD is controversial. Raised TGs are common in patients with CVD or at high risk of developing it. Whether this relationship is mediated by confounding factors such as total cholesterol, HDL, glucose levels and obesity is debatable. Similarly, clinical trial evidence is lacking indicating a robust relationship between lowering TG levels and CVD prevention.⁹

A recent study, the JUPITER trial,¹⁰ has shown evidence that even amongst apparently healthy individuals without hyperlipidaemia (LDL<3.4 mmol/l), treating those with elevated high-sensitivity CRP (>2 mg/l) with rosuvastatin 20 mg daily significantly reduced the rate of major cardiovascular events. The NNT over 1.9 years to prevent 1 major event was 120. Whether the statin's LDL reducing effect or its anti-inflammatory effect was primarily responsible remains unclear. Currently there is no UK guidance as regards CRP screening for CV risk and, to date, there have been no prospective trials randomising screening based on CRP alone.

CVD prevention requires lifestyle change and cannot be solely dependent on lipid modification drug therapy.
Personalised lifestyle advice should be given to all those found to be at a moderate or high CV risk, including the benefits of:¹¹

• A cardioprotective diet:
  • Reduce total fat intake to 30% or less of total energy intake.
  • Saturated fats should be less than 10% of total energy intake.
  • Intake of less than 300 mg cholesterol/day.
  • Substituting saturated fat with monounsaturated and polyunsaturated fat.
  • Eat fish at least twice a week, including a portion of oily fish.
  • Eating at least '5-a-day' of fruit and vegetables.
  • Omega-3 fatty acid supplements and plant sterols or stanols should not be routinely recommended for primary prevention.
• Physical activity and weight management:
  • A minimum of 30 minutes of moderate intensity (or more) exercise a day at least 5 days a week.
  • Incorporate exercise into everyday life e.g. stairs, brisk walking, cycling.
  • Offer support and advice to those who are overweight or obese towards achieving and maintaining a healthy weight.
• Alcohol consumption - drinking within safe limits (men<3-4 units/day, women<2-3 units/day) and avoid binge drinking.
• Smoking cessation - advise all smokers to stop, offer support, advice and referral to cessation services.

Hypercholesterolaemia 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 (secondary prevention only) and ezetimibe

Combined hyperlipidaemia & hypertriglyceridaemia^9,11

• Statins remain the treatment of choice where triglycerides are less than 5 mmol/l. Higher doses of statins may be required to achieve treatment goals in patients with FCH compared to isolated hypercholesterolaemia.
• 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.
• Ezetimibe may be added to a statin where a statin alone is insufficient.
• Combination treatment with a fibrate or nicotinic acid derivative may be used. There is only surrogate evidence of benefit for combination therapy and safety monitoring is required.

Very severe isolated hypertriglyceridaemia⁹

• Where TG >10mmol/l, prescribe a fibrate and refer for specialist assessment.
• Fish oils in high dose, often combined with a fibrate, are effective in treating severe isolated hypertrigylceridaemia.

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 MI¹³ or in preventing coronary events after percutaneous coronary angiography. Early initiation of statin therapy in acute coronary syndrome (ACS) has long term survival benefits, with a relatively small NNT (NNT=84 over 2 years to prevent 1 death).¹⁴

Who should be on a statin?

Evidence of the beneficial effects of statin therapy in those even at low cardiovascular risk¹ has huge resource implications. New NICE guidelines suggest that statins should be prescribed:¹¹

• To all adults with:
  • A history of CHD, angina, stroke, TIA, peripheral vascular disease
  • Monogenic lipid disorder e.g. familial hypercholesterolaemia
• For primary prevention:
  • Those aged 40-74 years with a 10 year CVD risk estimated as 20% or more. Note, Framingham risk equations may overestimate risk in UK populations. Where risk is near the threshold, consider also ethnicity, family history of premature CHD, low SES, severe obesity, comorbidities such as chronic kidney disease, SLE, rheumatoid arthritis which will all increase risk level.
  • Those aged over 75 years and likely to benefit, particularly true if smoker and hypertensive. Consider comorbidities, risks/benefit ratio and patient preference.
  In some situations, statin treatment should be initiated without recourse to formal estimation of cardiovascular risk. These include:^1,2,3
  • All diabetics over 40.
  • Diabetics at any age with additional risk factors e.g. hypertension, metabolic syndrome, total cholesterol >6 or a strong family history.¹⁵
  • Those with renal dysfunction including diabetic neuropathy.
  • Where the ratio of total cholesterol:HDL is 6 or more.

NICE suggests that 'a systematic strategy should be used to identify people aged 40–74 who are likely to be at high risk', effectively advocating screening in this age group to identify those likely to benefit from statin therapy and other interventions.

Side-effects^{16,17,18,19,20}

Statins are usually well-tolerated. About 1-3% complain of side effects including fatigue, headache, nausea, indigestion or change in bowel habit.² Important but rarer side-effects include:

• Muscle effects²¹
  • The most important adverse effect of these drugs is a myopathy characterised by muscle and tendon pain, stiffness, muscle weakness and cramping. This occurs with an incidence of about 1.2 per 10,000 treatment years in the UK.
  • Statin induced myopathy includes a spectrum from asymptomatic increase in serum creatine kinase to myalgia, myositis and, most seriously, rhabdomyolysis. Rhabdomyolysis is rare (0.1 per 10,000 treatment years) but potentially life-threatening.
  • Mean duration of treatment prior to onset of symptoms is 6 months. Muscle symptoms that develop in a patient who has been on statins over several years are unlikely to be due to the drugs.
    

    Risk of myopathy is increased where: Underlying muscle disorders Multisystem diseases (e.g. diabetes) Renal or liver impairment Untreated hypothyroidism Vigorous exercise Intercurrent illness Major surgery or trauma 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 (e.g. fibrates, nicotinic acid, calcium channel blockers, ciclosporin, amiodarone, macrolide antibiotics, azole antifungals, protease inhibitors, warfarin) Diet - excess intake of grapefruit or cranberry juice

  • Genetic factors, such as polymorphisms in cytochrome P450 isoenzymes, that increase the risk of statin induced myopathy are increasingly being identified. In the future, this may offer a way to identify those most at risk.²²
• Hepatotoxicity - rare and dose-dependent and usually reversible. Liver failure due to statin use occurs in 1/1,000,000 person years of treatment.²³

Other concerns include:

• Newly identified class effects include: depression, sleep disturbance, sexual disturbance and memory loss.²⁴ Erectile dysfunction associated with statin use has been suggested from a small study that the quality of erections diminishes after starting a statin, with 22 % having new onset erectile dysfunction. This is reversed on stopping the drug.²⁵ However there have been very few yellow card reports of this problem despite very large numbers of men receiving statins.
• Interstitial lung disease - rare but patients should be aware to seek help if they develop dyspnoea, non-productive cough and worsening in general health.²⁴
• Peripheral neuropathy - rare, attributable risk 12/100,000 person years of treatment.²³
• 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 Scandinavian Simvastatin Survival Study (4S) follow-up at 10 years,^26,27 and meta-analyses have not revealed any effect on cancer incidence or cancer deaths.^28,29

Targets³⁰

Initiating and monitoring treatment

Choosing a statin^30,32

• NICE currently recommends generic simvastatin 40 mg daily as the first choice drug for primary and secondary prevention.¹¹
• Where this is not tolerated, suggested alternatives are:¹¹
  • Dose reduction of simvastatin.
  • Switch to to an alternative preparation such as generic pravastatin 40 mg daily. The evidence for the use of pravastatin is generally weaker. The antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT)³³ 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.
• PCTs using high levels of generic statins have been as successful in achieving QOF targets as those with higher use of atorvastatin, rosuvastatin or fluvastatin, supporting the use of the less expensive, generic statins.³⁴

Starting dose

Arguments regarding the best strategy for selecting an appropriate starting dose have been won out by the evidence-based, 'fire and forget' approach ahead of the 'titrate to target' strategy in the latest NICE guidance.¹¹

• A universal starting dose of simvastatin 40 mg is recommended.
• It is still worth considering lower starting doses in patients considered to be at increased risk of myopathy.
• Only patients with acute coronary syndrome (ACS) should be commenced on high-intensity statins (simvastatin 80 mg or equivalent).

Biochemistry³⁵

• Check lipids (fasting specimens required to quantify LDL fraction and TG accurately) and LFTs prior to starting.
• Exclude any secondary causes of hypercholesterolaemia (e.g. hypothyroidism) or if present ensure maximally treated before commencing specific lipid-lowering therapy.
• There is no consistent recommendation regarding the necessity of measuring CK prior to the outset of statin therapy (for example, not recommended by NICE but recommended by the American Heart Association). Slightly raised CK is common in the untreated, general population.
• Measure creatine kinase (CK) and TFTs urgently if a patient reports muscle pain and stop the drug whilst this is investigated.
• Do not routinely monitor CK unless clinically indicated.¹¹

  Where CK is:21 Normal: this is myalgia. Continue statin where symptoms are tolerable and not progressive. If intolerable, stop and consider alternative statin challenge or alternative lipid lowering therapy. <10x upper limit of normal (ULN): this is myositis. Again continue if symptoms are tolerable or stop and consider alternatives if not. Where muscular symptoms or raised CK continue persist, refer for electromyography and/or muscle biopsy. >10x ULN: this is rhabdomyolysis. Statin therapy should be discontinued. Be suspicious clinically of this situation, where the patient has brown urine. Check renal function and urine myoglobin. An alternative lipid lowering drug should be considered, and re-exposure to statins only after a careful risk/benefit analysis.

• Repeat LFTs after 3 months of treatment, after any further dose increases and at a year. Do not repeat again unless clinically indicated.¹¹
  

  A rise in transaminases(AST, ALT) <3x ULN - relatively common, reported in 1-2 % of patients and usually occurs in the first three months. Do not routinely stop statin treatment at this level. A rise in transaminases >3x ULN - stop the statin temporarily before rechallenging or reduce the dose reduction with closer monitoring.

Reaching lipid targets³

• Following NICE guidance, no recheck of lipid levels is necessary for primary prevention. For secondary prevention or for audit purposes, lipid levels are repeated after about 12 weeks' treatment with a statin.
• In secondary prevention, where a total cholesterol of 4 mmol/l or less (or LDL-cholesterol of 2 mmol/l or less) is not achieved, NICE recommends:
  • Considering increasing to simvastatin 80 mg daily. Patient preference, comorbidities, issues of multiple drug regimens and absolute benefits/risks involved should be considered carefully. High-dose statins in stable CVD in trials such as Treating to New Targets (TNT) trial³⁶ and IDEAL³⁷ have shown only limited benefits with increased risk of side-effects.
  • "A drug of similar efficacy and acquisition cost to simvastatin 80 mag" may be considered - but only higher dose atorvastatin has clinical outcome data with substantially greater costs at present.
  • No further titration beyond this step is recommended. Note, even on simvastatin 80 mag daily, more than 50% of patients will not achieve the JBS targets.
• For patients with ACS, there are no specific lipid targets in the guidance, nor a stated duration of treatment.
• Do not forget concordance. 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.⁷ 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 regimens³⁸

Patient advice³

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.
• Offer clear information regarding an individual's absolute risk of CVD and about the absolute benefits and harms of an intervention over a 10-year period. Decision making aids are available.³⁹
• 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.
• These drugs may have multiple interactions, both with prescribed medication, OTC remedies (e.g. St Johns Wort) and non-drugs (e.g. grapefruit juice). Always seek advice.
• Take statins at night when they have a slightly greater effect.⁴⁰

Over-the-counter (OTC) simvastatin⁴¹

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

• 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.⁴²

Statins in children⁴³

The American Academy of Pediatricians have advocated the use of targeted screening and pharmacological treatment of hypercholestrolaemia in children for some time. Until recently, they only recommended anion exchange resins, which are physiologically inert, but have now recommended the first-line use of statins in the over 8s. Long-term safety data for their use in children is lacking. Controversy reigns over whether it is appropriate to use pharmacological treatment to treat children with modifiable lifestyle factors (in particular, obesity) rather than developing broader public health preventative strategies.⁴⁴

• 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 Hypercholesterolaemia for primary prevention only.
• In combination with simvastatin, it appears to lower LDL cholesterol significantly more than atorvastatin at matched dosage (VYVA trial).⁴⁸ Ezetimibe appears to reduce LDL cholesterol by 15–20% when used alone and by about 20–25% when combined with a statin.³
• However, the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolaemia Enhances Atherosclerosis Regression) study⁴⁹ failed to show any difference in carotid intima-medial thickening between simvastatin only and a simvastatin+ezetimibe treatment groups over 2 years, despite a decreased LDL cholesterol in the combination group. Trials looking at clinically significant end-points, such as major adverse cardiovascular events, are awaited.⁴⁹
• Current NICE guidance for its use is as a treatment for adults with primary (heterozygous familial and non-familial) hypercholesterolaemia where:¹²
  • A statin would normally be used but it is contra-indicated or not tolerated or is likely to cause interactions or side-effects.
  • In combination with a statin, where higher doses of statin are not tolerated or as an alternative to switching to a different statin. Where used like this, the least expensive form of ezetimibe should be prescribed. Inegy®, a combination product, is currently more expensive than separate prescriptions.
• 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.
• Some concerns about a possible increased risk of cancer associated with the use of ezetimibe have emerged, largely based on the SEAS trial where an increased frequency of cancer was seen in the simvastatin-ezetimibe group compared to placebo.⁵⁰ However, further analysis of this trial and two other large scale trials did not reveal evidence of a significant effect of ezetimibe on rates of cancer but longer-term data is required.⁵¹

(Bezafibrate,⁵³ Ciprofibrate,⁵⁴ Fenofibrate,⁵⁵ and Gemfibrozil⁵⁶).

• These are one of the oldest groups of drugs used to treat dyslipidaemias but have largely been superseded by statins. They are uncommonly used in primary care and tend to be prescribed under advice of a specialist, particularly if used in combination with a statin.¹
• 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 (by 30-50%) and to a lesser extent plasma cholesterol (TChol and LDL reduction of 0-30%). They increase the plasma HDL (by 2-20%).
• Evidence of efficacy in treating CV risk and safety is less substantial than for statins: trials showed significant lipid-lowering but this did not necessarily translate into significant clinical gains.
• Current clinical guidelines tend to recommend them as the treatment of choice for severe isolated hypertriglyceridaemia but where this co-exists with hypercholesterolaemia, LDL-reduction remains the priority and thus statins tend to remain first line.
• Gemfibrozil may be used for primary prevention where a statin or other effective treatment is not tolerated. It is licensed for men only.
• Combination treatment (statin+fibrate) may be used when statin therapy alone has not reduced triglycerides (or raised HDL) to target levels. When used in combination with a statin, fenofibrate and bezafibrate are the usual candidates. Gemfibrozil should not be used with a statin. Robust evidence for the benefit of a combination approach is lacking and there is an increased risk of myopathy and rhabdomyolysis so the likely risk/benefit ratio needs careful consideration.

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 sex³

Side-effects

Include:

• Myopathy and rhabdomyolyis - rare but serious
• Gastrointestinal side-effects - more common
• Hypersensitivity reaction (urticaria, pruritus, 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:

• Colestyramine and colestipol
• Nicotinic Acid and acipimox
• Omega-3-Fish Oils