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 (TChol) 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% of British men aged 45-64 years exceed the 5.0 mmol/L level. In other words, hyperlipidaemia is the 'norm' among the UK population.

Causes of dyslipidaemia

See separate article Hyperlipidaemia.

Primary and secondary cardiovascular disease prevention

See separate articles Primary Prevention of Cardiovascular Disease and Secondary Prevention of Cardiovascular Disease.

Statins

(or 3-hydroxy-3-methylglutaryl co-enzyme 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 upregulated and increased LDL uptake from plasma takes place, lowering plasma LDL-C. 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 cardioprotective effects of early statin use following acute myocardial infarction (MI)⁶ or in preventing coronary events after percutaneous coronary angiography. Institution of statins in the early stages of an MI may reduce the risk of developing atrial fibrillation.⁷ Early initiation of statin therapy in acute coronary syndrome (ACS) has long-term survival benefits, with a relatively small number needed to treat (NNT): NNT = 84 over 2 years to prevent 1 death).⁸

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 National Institute for Health and Clinical Excellence (NICE) guidelines suggest that statins should be prescribed:⁹

• To all adults with:
  • A history of CHD, angina, stroke, transient ischaemic attack (TIA), and peripheral vascular disease.
  • Monogenic lipid disorder, e.g. familial hypercholesterolaemia (FH).
• 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 socio-economic status, severe obesity, comorbidities such as chronic kidney disease, systemic lupus erythematosus and rheumatoid arthritis, which will all increase risk level.
  • Those aged over 75 years and likely to benefit, particularly true if a 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 aged over 40 years.
  • Diabetics at any age with additional risk factors, e.g. hypertension, metabolic syndrome, TChol >6 mmol/L or a strong family history.¹⁰
  • Those with renal dysfunction, including diabetic neuropathy.
  • Where the ratio of TChol:HDL is 6 or more.

NICE suggests that "a systematic strategy should be used to identify people aged 40-74 years 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.

Lipid dysfunction is an early feature of type 2 diabetes and one review of the literature suggested that all diabetics should be on a statin.¹¹

Side-effects^{12,13,14,15,16}

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 effects:¹⁷
  • 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 (CK) 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 with: 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 years. 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.¹⁸
• Hepatotoxicity: rare and dose-dependent and usually reversible. Liver failure due to statin use occurs in 1/1,000,000 person years of treatment.¹⁹ Statins should not be withheld in patients with high cardiovascular risk who have raised transaminases of no clinical relevance or who have stable hepatic disease. Risk assessment needs to be done in individual patients.²⁰

Other concerns include:

• Newly identified class effects include: depression, sleep disturbance, sexual disturbance and memory loss.²¹ A small study suggested that erectile dysfunction is associated with statin use, with the quality of erections diminishing after starting a statin, and with 22% having new-onset erectile dysfunction. This is reversed on stopping the drug.²² 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 that they should seek help if they develop dyspnoea, nonproductive cough and worsening in general health.²¹
• Peripheral neuropathy - rare, attributable risk 12/100,000 person years of treatment.¹⁹
• Carcinogenicity - statins are carcinogenic in animal studies. However, the evidence base concerning their use in humans has been reassuring.²³

Targets

Initiating and monitoring treatment

Choosing a statin:

• NICE currently recommends generic simvastatin 40 mg daily as the first-choice drug for primary and secondary prevention.⁹
• Where this is not tolerated, suggested alternatives are:⁹
  • Dose reduction of simvastatin.
  • Switching 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)²⁵ failed to demonstrate a difference in all-cause mortality or nonfatal MI/fatal CHD rates between patients receiving pravastatin 40 mg daily and those receiving usual care.
• Primary care trusts 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.²⁶ However, one individual practice-based study refuted this.²⁷

• 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 ACS should be commenced on high-intensity statins (simvastatin 80 mg or equivalent).

• Check lipids (fasting specimens required to quantify LDL fraction and triglycerides (TGs) 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 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.⁹

  Where CK is:17 Normal: this is myalgia. Continue a statin where symptoms are tolerable and not progressive. If intolerable, stop and consider an alternative statin challenge or alternative lipid-lowering therapy. <10 x 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 to persist, refer for electromyography and/or muscle biopsy. >10 x 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.⁹
  

  A rise in aspartate transaminase (AST) and alanine aminotransferase (ALT) <3 x 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 >3 x ULN - stop the statin temporarily before rechallenging or reduce the dose reduction with closer monitoring.

• 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.
• The Medicines and Healthcare products Regulatory Agency (MHRA) advised that simvastatin 80 mg should only be considered in patients with severe hypercholesterolaemia and high risk of cardiovascular complications, who have not achieved their treatment goals on lower doses, when benefits are expected to outweigh the potential risks. This is in contradiction to the previous NICE advice that this dose should be offered to all secondary care prevention patients where TChol of 4 mmol/L or less (or LDL-C of 2 mmol/L or less) has not been achieved.³
• 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.²⁹ 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 regimens.³⁰

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.³¹
• 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, over-the-counter (OTC) remedies (e.g. St John's wort) and nondrugs (e.g. grapefruit juice). Always seek advice.
• Take statins at night when they have a slightly greater effect.³²

Over-the-counter simvastatin³³

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, including:

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

Concerns include:

• Evidence which is not strong for this strategy and has been extrapolated from clinical trials using higher doses.
• Absolute risk reductions being likely to be small.
• Patients possibly not volunteering that they are taking the drug, raising worries about risks of interactions, etc.
• A likelihood of patient being undermonitored and undertreated.
• There being no cholesterol-lowering targets for this population.
• Compliance being likely to be poorer than with medically prescribed statins because of cost implications.
• That this policy may lead to less agressive statin prescribing by GPs themselves.³⁴
• One Scottish study found that the majority of GPs responding to a postal questionnaire did not support the idea of pharmacists selling simvastatin. The concerns were that proper checks on blood pressure and cholesterol levels were not being properly assessed prior to sale.³⁵

Statins in children³⁶

The American Academy of Pediatricians has advocated the use of targeted screening and pharmacological treatment of hypercholesterolaemia in children for some time. Until recently, it only recommended anion exchange resins, which are physiologically inert, but it has now recommended the first-line use of statins in the over-8s. Statins appear effective and safe in the short-term (data from FH studies), but long-term safety data for their use in children are lacking.³⁷ 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.³⁸

Ezetimibe³

NICE recommends that ezetimibe be used as a treatment of adults with primary heterozygous-familial or non-familial hypercholesterolaemia only in the following circumstances:⁹

• Where statins are contra-indicated or not tolerated
• In conjunction with a statin where serum TChol or LDL-C is not appropriately controlled by initial statin therapy (after appropriate dose titration or because dose titration is limited by intolerance) and when consideration is being given to changing the initial statin therapy to an alternative statin.

However, the evidence base to support use of ezetimibe for primary and secondary prevention is very small.³⁹

The 'Ezetimibe and Simvastatin in Hypercholesterolaemia Enhances Atherosclerosis Regression' (ENHANCE) study⁴⁰ failed to show any difference in carotid intima-medial thickening between 'simvastatin only' and 'simvastatin + ezetimibe' treatment groups over 2 years, despite decreased LDL-C in the combination group. Furthermore, there was a higher incidence of cancers in the combination group.

Fibrates^3,41

(Bezafibrate,⁴² ciprofibrate,⁴³ fenofibrate,⁴⁴ and gemfibrozil.⁴⁵)

• Current clinical guidelines recommend fibrates as the treatment of choice for severe isolated hypertriglyceridaemia (triglycerides (TGs) >10 mmol/L), but where this co-exists with hypercholesterolaemia (i.e. in mixed hyperlipidaemia), LDL-reduction remains the priority and thus statins tend to remain first-line.⁴¹
• They are uncommonly used in primary and, for most other dyslipidaemias, fibrates have been superseded by statins.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, consequently lowering plasma TGs (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%) by increasing apoA-I and apoA-II gene transcription.³
• Evidence of efficacy in treating cardiovascular risk and of safety is less substantial than for statins: trials showed significant lipid-lowering but this did not necessarily translate into significant clinical gains.
• One study, however, suggested that fenofibrate may have a role to play in reducing the microvascular complications of diabetes.⁴⁶
• 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 TGs (or raised HDL) to target levels. This is usually initiated by a specialist. 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 >10 x ULN occur in about 1 in 1,000 individuals on combination therapy).
• Concomitant treatment with ciclosporin.
• Renal insufficiency (check U&Es prior to commencing treatment).
• Older age.
• Female sex.³

Side-effects

These include:

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

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

Starting a fibrate

Drug choice: NICE does not recommend any particular fibrate for use in CVD prevention in those intolerant of a statin.⁹ Clinical Knowledge Summaries (CKS) suggest the use of bezafibrate and fenofibrate, in preference to gemfibrozil (based on risk of drug interactions and expense) and ciprofibrate (based on difficulty of titration) but there is inadequate evidence to choose between them based on efficacy.³

Combination treatment:⁴¹ such treatment (statin + fibrate) may be used when statin therapy alone has not reduced triglycerides (TGs) or raised HDL to target levels.

• 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. Whether or not this increased risk of myotoxicity in combination with statins is a class effect is debatable.⁴⁷
• Do not exceed 10 mg simvastatin and 20 mg rosuvastatin when combined with a fibrate.
• Gemfibrozil should not be used with a statin as the risk of myotoxicity is 15 times that with fenofibrate.⁴⁸

• Check U&Es prior to treatment, particularly if using in combination with a statin, as renal insufficiency increases the risk of myotoxicity. Adjust the dose if there is evidence of renal insufficiency. Routine ongoing monitoring of creatinine levels, etc. is not required.⁴⁹
• Discontinue the fibrate if serum aminotransferases are three or more times the upper limit of the normal.
• Check CK level only if myopathy or rhabdomyolysis is suspected: stop treatment if the CK level is five times the upper limit of normal or more.

Additional lipid-regulating drugs

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.

Document references

1. No authors listed, JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005 Dec;91 Suppl 5:v1-52.
2. Bhatnagar D, Soran H, Durrington PN; Hypercholesterolaemia and its management. BMJ. 2008 Aug 21;337:a993. doi: 10.1136/bmj.a993.
3. Lipid modification - primary and secondary CVD prevention, Clinical Knowledge Summaries (December 2008)
4. Implementation uptake report: statins for the prevention of cardiovascular events, NICE, September 2008
5. Coronary Heart Disease Statistics; British Heart Disease Foundation Statistics website, 2010
6. Fonarow GC, Wright RS, Spencer FA, et al; Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality.; Am J Cardiol. 2005 Sep 1;96(5):611-6. [abstract]
7. Danchin N, Fauchier L, Marijon E, et al; Impact of early statin therapy on development of atrial fibrillation at the acute Heart. 2010 Nov;96(22):1809-1814. [abstract]
8. Bavry AA, Mood GR, Kumbhani DJ, et al; Long-term benefit of statin therapy initiated during hospitalization for an acute coronary syndrome: a systematic review of randomized trials. Am J Cardiovasc Drugs. 2007;7(2):135-41. [abstract]
9. Lipid modification, NICE Clinical Guideline (May 2008); (Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease.)
10. Reckless JP; Diabetes and lipid lowering: where are we? BMJ. 2006 May 13;332(7550):1103-4.
11. Kamari Y, Bitzur R, Cohen H, et al; Should all diabetic patients be treated with a statin? Diabetes Care. 2009 Nov;32 Suppl 2:S378-83.
12. Summary of Product Characteristics - Zocor® film-coated tablets; Merck Sharp and Dohme Limited, updated March 2010; electronic Medicines Compendium
13. Summary of Product Characteristics - Lipitor® tablets; (atorvastatin), Pfizer Limited, Updated April 2010, electronic Medicines Compendium
14. Summary of Product Characteristics - Crestor® tablets (rosuvastatin), Astra Zeneca UK Ltd, August 2008
15. Summary of Product Characteristics - Lipostat® tablets, (pravastatin) Bristol-Myers Squibb Pharmaceuticals Ltd, January 2007
16. Summary of Product Characteristics - Lescol® capsules (fluvastatin), Novartis Pharmaceuticals UK Limited, updated August 2010; electronic Medicines Compendium
17. Sathasivam S, Lecky B; Statin induced myopathy. BMJ. 2008 Nov 6;337:a2286. doi: 10.1136/bmj.a2286.
18. Link E, Parish S, Armitage J, et al; SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med. 2008 Aug 21;359(8):789-99. Epub 2008 Jul 23. [abstract]
19. Law M, Rudnicka AR; Statin safety: a systematic review. Am J Cardiol. 2006 Apr 17;97(8A):52C-60C. Epub 2006 Feb 3. [abstract]
20. Calderon RM, Cubeddu LX, Goldberg RB, et al; Statins in the treatment of dyslipidemia in the presence of elevated liver Mayo Clin Proc. 2010 Apr;85(4):349-56. [abstract]
21. Statins: class effects identified; Drug Safety Update Volume 1, Issue 7, Medicines and Healthcare products Regulatory Agency, Feb 2008
22. Statins and erectile dysfunction, 148-52; Bandolier, June 2006
23. Boudreau DM, Yu O, Johnson J; Statin use and cancer risk: a comprehensive review. Expert Opin Drug Saf. 2010 Jul;9(4):603-21. [abstract]
24. Hayward RA, Hofer TP, Vijan S; Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006 Oct 3;145(7):520-30. [abstract]
25. No authors listed; Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002 Dec 18;288(23):2998-3007. [abstract]
26. Petty D, Lloyd D; Can cheap generic statins achieve national cholesterol lowering targets? J Health Serv Res Policy. 2008 Apr;13(2):99-102. [abstract]
27. Hickman J; Does higher usage of low-cost statins correlate with a poorer achievement in Br J Gen Pract. 2010 Jan;60(570):50-2. [abstract]
28. Smellie WS, Wilson D, McNulty CA, et al; Best practice in primary care pathology: review 1. J Clin Pathol. 2005 Oct;58(10):1016-24. [abstract]
29. Collins R, Armitage J, Parish S, et al; MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.; Lancet. 2003 Jun 14;361(9374):2005-16. [abstract]
30. Schedlbauer A, Schroeder K, Peters TJ, et al; Interventions to improve adherence to lipid lowering medication. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004371. [abstract]
31. Patient decision aid for statin prescribing, National Prescribing Centre interactive (NPCi); As recommended in NICE guidelines
32. Wallace A, Chinn D, Rubin G; Taking simvastatin in the morning compared with in the evening: randomised controlled trial. BMJ 2003 Oct 4;327(7418):788.
33. No authors listed; Simvastatin over the counter. Drug Ther Bull. 2005 Apr;43(4):25-8. [abstract]
34. Filion KB, Chris Delaney JA, Brophy JM, et al; The impact of over-the-counter simvastatin on the number of statin prescriptions in the United Kingdom: a view from the General Practice Research Database. Pharmacoepidemiol Drug Saf. 2007 Jan;16(1):1-4. [abstract]
35. Stewart D, Cunningham IT, Hansford D, et al; General practitioners' views and experiences of over-the-counter simvastatin in Br J Clin Pharmacol. 2010 Sep;70(3):356-9. [abstract]
36. No authors listed; Statins for children? Lancet. 2008 Jul 19;372(9634):178.
37. Vuorio A, Kuoppala J, Kovanen PT, et al; Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD006401. [abstract]
38. de Ferranti S, Ludwig DS; Storm over statins--the controversy surrounding pharmacologic treatment of children. N Engl J Med. 2008 Sep 25;359(13):1309-12.
39. Ezetimibe: room for review?; National Prescribing Centre, 2010
40. Kastelein JJ, Akdim F, Stroes ES, et al; Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3;358(14):1431-43. Epub 2008 Mar 30. [abstract]
41. Drug safety advice - fibrates; Drug safety update vol 1, issue 4, Medicines and Healthcare products Regulatory Agency, Nov 2007
42. Summary of Product Characteristics - Bezalip® Mono; (bezafibrate) Roche Products Limited, electronic Medicines Compendium, updated December 2009
43. Summary of Product Characteristics - Modalim® tablets; (ciprofibrate), Sanofi Aventis, electronic Medicines Compendium, updated October 2006
44. Summary of Product Characteristics - Lipantil® Micro 200 capsules; Summary of Product Characteristics - Lipantil Micro® 200 capsules, Fournier Pharmaceuticals Ltd, electronic Medicines Compendium, updated September 2009
45. Summary of Product Characteristics - Lopid® capsules and tablets, Pfizer Ltd, electronic Medicines Compendium, updated August 2008
46. Ansquer JC, Foucher C, Aubonnet P, et al; Fibrates and microvascular complications in diabetes--insight from the FIELD Curr Pharm Des. 2009;15(5):537-52. [abstract]
47. Franssen R, Vergeer M, Stroes ES, et al; Combination statin-fibrate therapy: safety aspects. Diabetes Obes Metab. 2009 Feb;11(2):89-94. Epub 2008 Jun 1. [abstract]
48. Fazio S; Management of mixed dyslipidemia in patients with or at risk for cardiovascular disease: A role for combination fibrate therapy. Clin Ther. 2008 Feb;30(2):294-306. [abstract]
49. Davidson MH, Armani A, McKenney JM, et al; Safety considerations with fibrate therapy. Am J Cardiol. 2007 Mar 19;99(6A):3C-18C. Epub 2006 Dec 8. [abstract]

Internet and further reading

• Tenenbaum A, Fisman EZ; "If it ain't broke, don't fix it": a commentary on the positive-negative results Cardiovasc Diabetol. 2010 Jun 15;9:24. [abstract]
• Hippisley-Cox J, Coupland C; Unintended effects of statins in men and women in England and Wales: population BMJ. 2010 May 20;340:c2197. doi: 10.1136/bmj.c2197. [abstract]
• Brugts JJ, Yetgin T, Hoeks SE, et al; The benefits of statins in people without established cardiovascular disease but BMJ. 2009 Jun 30;338:b2376. doi: 10.1136/bmj.b2376. [abstract]

Acknowledgements