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 and morbidity in the UK due to cardiovascular disease (CVD). 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 constitutes a safe level and what constitutes an unsafe level; 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.
Causes of dyslipidaemia
See the separate article on Hyperlipidaemia.
Prevention of cardiovascular disease
(or 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors)
The statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) competitively inhibit HMG-CoA reductase. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration but are less effective than fibrates in reducing triglyceride concentration.
Mode of action and indications
- 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 and there is a firm evidence base for their use in both primary and secondary prevention of CVD.
- Statins are also thought to have non-cholesterol-related effects such as restoring/improving endothelial function and anti-inflammatory properties. These are implicated in benefits seen when statins use is initiated early following an acute myocardial infarction, after percutaneous coronary angiography and in acute coronary syndrome (ACS)[4, 5].
- Statins may also have a role to play in the regression of atheroma.
- Statins may also reduce the risk of developing atrial fibrillation.
Who should be on a statin?
National Institute for Health and Care Excellence (NICE) guidelines suggest that statins should be prescribed:
- To all adults with:
- For primary prevention:
- All those aged up to 84 years who have a 10-year risk of cardiovascular disease of 10% or more as measured by the QRISK2 risk assessment tool, if lifestyle measures have been ineffective.
- All adults with type 1 diabetes who are aged over 40 years or have had diabetes for more than 10 years, or have established nephropathy or have other cardiovascular risk factors.
- Atorvastatin should be used for primary or secondary prevention of CVD for people with chronic kidney disease (CKD).
- In the past there has been much debate as to the long-term benefits versus risk of statins in primary prevention. A recent systematic review has confirmed a reduction in all-cause mortality, vascular events and revascularisations. Furthermore, these benefits far outweigh the adverse effects of statins.
- Those with diabetes at any age with additional risk factors - eg, hypertension, metabolic syndrome, TChol >6 mmol/L or a strong family history.
- 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 those with diabetes should be on a statin.
Statins are usually well tolerated. Side-effects may including fatigue, headache, nausea, indigestion or change in bowel habit. Important but rarer side-effects include:
- The most important adverse effect of these drugs is myalgia characterised by muscle and tendon pain, stiffness, muscle weakness and cramping. This affects 5-10% of patients taking statins.
- 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 six 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 (eg, 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 (eg, fibrates, nicotinic acid, calcium-channel blockers, ciclosporin, amiodarone, macrolide antibiotics, azole antifungals, protease inhibitors, warfarin).
- Diet - intake of grapefruit (simvastatin, atorvastatin and lovastatin) or cranberry juice (fluvastatin).
- Genetic factors, such as polymorphisms in cytochrome P450 isoenzymes, that increase the risk of statin-induced myopathy are increasingly being identified and may become more important in the future.
Rare and dose-dependent and usually reversible. 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 - decisions should be made on an individual basis.
Nov 2017 - Dr Hayley Willacy recently read a BMJ paper looking at long-term use of statins. They followed 3,234 participants in the US Diabetes Prevention Program Outcomes Study for a period of 10 years. The most commonly prescribed statins were simvastatin (40%) and atorvastatin (37%). Taking a statin was associated with a 36% heightened risk of subsequently being diagnosed with type 2 diabetes, compared to those who had not been prescribed these medicines. This risk fell to 30% after taking account of the clinical criteria used to determine the need for statin treatment. Although those who were prescribed statins had slightly higher levels of blood glucose to start with, this still didn't explain their higher rates of diabetes. They found no link between the potency of the statin used and diabetes risk, nor between the reduction in low-density lipoprotein. This suggests monitoring HbA1c may also be useful in this group.
Other medical societies have suggested similarly lower targets of LDL-C - eg, the European Society of Cardiology recommends an LDL-C <2.5 mmol/L in primary prevention and an even lower target of <1.81 mmol/L in patients with diabetes or those at high CVD risk[3, 4, 5].
Initiating and monitoring treatment
Choosing a statin
Before starting lipid modification therapy for primary prevention of CVD, a blood test for full lipid profile should be taken (total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides.
- NICE currently recommends atorvastatin 20 mg daily as the first-choice drug for primary prevention and atorvastatin 80 mg daily for secondary prevention.
- Where this is not tolerated, suggested alternatives are:
- Dose reduction of statin.
- Switching to an alternative statin preparation.
- Check lipids (fasting specimens required to quantify LDL fraction and triglycerides (TGs) accurately) and LFTs prior to starting treatment.
- Exclude any secondary causes of hypercholesterolaemia (eg, 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:Where CK is:
- 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.
- If the CK level is less than 10 x the upper limit then a low dose of the same or different statin can be tried. If myalgia returns then ezetimibe monotherapy can be tried. Ezetimibe can also be combined with a low-dose statin to help achieve target cholesterol levels.
- Repeat LFTs after three months of treatment, after any further dose increases and at a year. Do not repeat again unless clinically indicated:
- 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 with closer monitoring.
- A full lipid profile should be measured after three months of treatment and the target should be a greater than 40% reduction in non-HDL cholesterol.
- Do not forget concordance. Many patients stop taking statins altogether within a year or take them at less than the prescribed dose. Statins need to be taken in the long term (over years) to derive the fullest benefit. 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.
Good patient information and education improve 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.
- 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 remedies (eg, St John's wort) and non-drugs (eg, grapefruit juice). Always seek advice.
- Take statins at night when they have a slightly greater effect.
Statins in children
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. 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.
NICE recommends that ezetimibe be used as a treatment of adults with primary heterozygous-familial or non-familial hypercholesterolaemia in the following circumstances:
- 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.
NB: NICE does not recommend routinely using a fibrate for primary or secondary prevention of CVD, or for people with CKD, type 1 diabetes or type 2 diabetes.
The fibrates (bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil) act mainly by decreasing serum triglycerides. Fibrates are first-line therapy only in those whose serum-triglyceride concentration is greater than 10 mmol/L or in those who cannot tolerate a statin. In type 2 diabetes, fenofibrate can be added to a statin for those with a serum-triglyceride concentration exceeding 2.3 mmol/L, despite six months of treatment with a statin and optimal glycaemic control.
- 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 (ie in mixed hyperlipidaemia), LDL reduction remains the priority and thus statins tend to remain first-line.
- They are uncommonly used in primary CVD prevention and for most other dyslipidaemias, fibrates have been superseded by statins.
- 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.
- 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.
Hypoalbuminaemia, gallbladder disease, nephrotic syndrome, and photosensitivity to fibrates.
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.
- Myopathy and rhabdomyolyis - risk is increased if impaired renal function.
- Gastrointestinal side-effects - more common.
- Hypersensitivity reaction (urticaria, pruritus, photosensitive rash).
Starting a fibrate
NICE does not recommend any particular fibrate for use in CVD prevention in those intolerant of a statin. NICE 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). However, there is inadequate evidence to choose between them based on efficacy.
Such treatment (statin + fibrate) may be used when statin therapy alone has not reduced 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.
- 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.
- 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.
- Discontinue the fibrate if serum aminotransferases are three or more times the upper limit of 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.
NB: NICE does not recommend using any of these medications for primary or secondary prevention of CVD, or for people with CKD, type 1 diabetes or type 2 diabetes.
Further reading and references
Cardiovascular risk assessment and lipid modification; NICE Quality Standard, September 2015
Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia; NICE Technology Appraisal Guidance, February 2016
Guidelines for the Management of Dyslipidaemias; European Society of Cardiology (2011)
Management of Acute Myocardial Infarction in patients presenting with ST-segment elevation; European Society of Cardiology (2012)
Management of Acute Coronary Syndromes (ACS) in patients presenting without persistent ST-segment elevation; European Society of Cardiology (2011)
Nozue T, Yamamoto S, Tohyama S, et al; Comparison of arterial remodeling and changes in plaque composition between patients with progression versus regression of coronary atherosclerosis during statin therapy (from the TRUTH study). Am J Cardiol. 2012 May 1109(9):1247-53. doi: 10.1016/j.amjcard.2011.12.016. Epub 2012 Feb 9.
Hung CY, Lin CH, Loh el-W, et al; CHADS(2) score, statin therapy, and risks of atrial fibrillation. Am J Med. 2013 Feb126(2):133-40. doi: 10.1016/j.amjmed.2012.06.027.
Taylor F, Huffman MD, Macedo AF, et al; Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013 Jan 311:CD004816. doi: 10.1002/14651858.CD004816.pub5.
Lipid modification - primary and secondary CVD prevention; NICE CKS, December 2008 (UK access only)
Kamari Y, Bitzur R, Cohen H, et al; Should all diabetic patients be treated with a statin? Diabetes Care. 2009 Nov32 Suppl 2:S378-83.
Sathasivam S, Lecky B; Statin induced myopathy. BMJ. 2008 Nov 6337:a2286. doi: 10.1136/bmj.a2286.
Lasker SS, Chowdhury TA; Myalgia while taking statins. BMJ. 2012 Aug 14345:e5348. doi: 10.1136/bmj.e5348.
Crandall JP, Mather K, Rajpathak SN, et al; Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. BMJ Open Diabetes Res Care. 2017 Oct 105(1):e000438. doi: 10.1136/bmjdrc-2017-000438. eCollection 2017.
Schedlbauer A, Davies P, Fahey T; Interventions to improve adherence to lipid lowering medication. Cochrane Database Syst Rev. 2010 Mar 17(3):CD004371. doi: 10.1002/14651858.CD004371.pub3.
Psaty BM, Rivara FP; Universal screening and drug treatment of dyslipidemia in children and adolescents. JAMA. 2012 Jan 18307(3):257-8. doi: 10.1001/jama.2011.1916. Epub 2011 Dec 15.
Franssen R, Vergeer M, Stroes ES, et al; Combination statin-fibrate therapy: safety aspects. Diabetes Obes Metab. 2009 Feb11(2):89-94. Epub 2008 Jun 1.
Fazio S; Management of mixed dyslipidemia in patients with or at risk for cardiovascular disease: A role for combination fibrate therapy. Clin Ther. 2008 Feb30(2):294-306.
Davidson MH, Armani A, McKenney JM, et al; Safety considerations with fibrate therapy. Am J Cardiol. 2007 Mar 1999(6A):3C-18C. Epub 2006 Dec 8.