The levels of evidence [A-D] supporting the recommendations are defined at the end of the "Major Recommendations" field.
Basic Principles
- Make sure that an effective diet has been implemented, and start drug therapy without delay, if clearly indicated.
- People with atherosclerotic disease or diabetes are the most important target groups.
- Determine serum cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, and calculate serum low-density lipoprotein (LDL) cholesterol according to the Friedewald equation before commencing drug treatment.
- Rule out secondary hypercholesterolaemia. If the cause of secondary hypercholesterolaemia cannot be managed, treat the patient as if he had primary hypercholesterolaemia.
- Identify patients with familial hypercholesterolaemia (serum cholesterol usually above 8 mmol/L, xanthomas, family history) in order to screen family members.
- If an increased serum LDL cholesterol concentration is the most important lipid abnormality, a statin is the drug of choice (Bucher, Griffith, & Guyatt, 1999; Ross et al., 1999) [A].
- If an increased triglyceride concentration (>4.5 mmol/L) and a low HDL cholesterol concentration are the most important abnormalities a fibrate may be the drug of choice.
General Principles on the Choice of Drug
- Of the drugs in common use, cholestyramine, gemfibrozil, simvastatin, pravastatin, lovastatin, atorvastatin, fluvastatin and fenofibrate have been tested in randomized double-blind trials lasting at least 3 years (Scandinavian Simvastatin Survival Study Group, 1994) [A].
- A statin is the drug of choice [A] unless the main abnormality is hypertriglyceridaemia or a low HDL cholesterol concentration. In these cases, even a fibrate may be considered.
- Resins and guar gum are safe during pregnancy and in children because they are not absorbed from the intestine. Their adverse effects may cause problems.
Choice of Drug According to the Type of Hyperlipidaemia
Table. Selection of Lipid Lowering Drug According to the Type of Hyperlipidaemia
| Dyslipidaemic (pheno)type |
Drug of Choice |
| Hypercholesterolaemia alone (familial hypercholesterolaemia) |
Statin or a combination of a statin and ezetimibe or a combination of a statin and a resin (the dose of resin <20 g to avoid adverse effects). |
| Both cholesterol and triglycerides increased |
Statin if serum triglycerides <4.5 mmol/L.
Fibrate plus statin if increasing the dose of statin is not sufficient (the need for combination treatment should be evaluated by a specialist).
|
| Pure hypertriglyceridaemia |
Reducing weight and limiting alcohol consumption is essential before drug treatment is considered. Control of diabetes should be improved.
Fibrate.
|
| Hypothyroidism |
Thyroxine substitution normalizes the lipid abnormality if it is caused by hypothyroidism. |
|
Statins
The most important group of antihyperlipidaemic agents (Bucher, Griffith, & Guyatt, 1999; Ross et al., 1999) [A]
Mechanism of Action
Based on the inhibition of the hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase resulting in the inhibition of cholesterol synthesis in hepatocytes. The number of LDL receptors on hepatocytes is increased, and the elimination of LDL from the blood is enhanced. Part of the action may be through very low-density lipoprotein (VLDL) or even other mechanisms.
Effectiveness
- LDL is decreased by 30% to 40%.
- HDL is increased by 5% to 15%.
- Triglycerides are decreased by 10% to 30%.
- Combining statins with ezetimibe or resins (Schectman & Hiatt, 1996) [C] results in additive effects.
Adverse Effects
- Statins are usually well tolerated, even by elderly patients.
- Serum aminotransferase concentrations rise in about 2% of the patients. The clinical significance of this is unclear because the patients often have other factors that may increase the transaminase concentrations. There is no conclusive evidence that statin therapy would cause significant liver damage.
- Serum creatine kinase need not be determined routinely. The test is indicated if the patient has unexplained myalgias or muscular symptoms. Concentrations 10 times above the upper limit of the reference value are significant. The incidence of myopathy is about 0.5%.
- The incidence of notable muscular side effects is <0.1%.
- The risk of myopathy is increased by:
- Simultaneous cyclosporine, fibrate, macrolide, or conazole medication
- Very high age
- Multiple diseases
- Operations
- Hypothyroidism
- Individual cases of polyneuropathy have been described in connection with statin treatment.
Dosage
- Adjust the dose (Illingworth & Tobert, 1994; Hsu, Spinler, & Johnson, 1995) [A] according to response. Doubling the dose provides a further decrease of serum cholesterol by 7%.
- Atorvastatin:10 to 80 mg/day
- Fluvastatin: (20) to 40 to 80 mg/day
- Lovastatin: 20 to 80 mg
- Pravastatin: 20 to 40 mg/day
- Simvastatin: 10 to 80 mg
- Rosuvastatin: 10 to 40 mg/day
Resins (Cholestyramine, Colestipol)
Mechanism of Action
- The resins absorb bile acids in the intestine, prevent their reabsorption, and increase their excretion in the faeces.
- They do not increase the excretion of neutral steroids or cause fat malabsorption.
- The enhanced excretion of bile acids results in increased metabolism of cholesterol into bile acids and further in an increase in the number of LDL receptors and intake of cholesterol into hepatocytes.
Effectiveness
- Serum total and LDL cholesterol concentration decrease by 15% to 30%.
- Serum triglyceride concentration may increase slightly.
Dosage
- Cholestyramine 16 to 32 g/day
- Cholestipol 20 to 40 g/day
Adverse Effects
- Bowel symptoms: constipation, flatulence, nausea, epigastric pain
- Deficiency of fat-soluble vitamins and folic acid
Interactions
- The absorption of the following drugs may be affected. These drugs should be taken at least 1 hour before or 4 hours after the resin.
- Digoxin
- Thyroxine
- Warfarin
- Thiazide diuretics
Guar Gum
Mechanism of Action
Guar gum is an unabsorbable dietary fibre, galactomannan. The mechanism of action is similar to that of resins. Guar gum also increases the excretion of neutral steroids in the faeces.
Effectiveness
- Serum total cholesterol and LDL cholesterol are decreased by 10% to 15%. HDL and triglyceride concentration remain unchanged.
- Guar gum is a suitable alternative in hypercholesterolaemia associated with diabetes as a supplement to diet or in severe hypercholesterolaemia in combination with statins or fibrates.
Dosage
Adverse Effects
- About 30% of the patients have adverse effects
- Abdominal distention, flatulence, diarrhoea
Fibrates (Gemfibrozil, Bezafibrate, and Fenofibrate)
Mechanism of Action
Fibrates act through the nuclear peroxisome proliferator-activated receptor (PPAR) system that regulates lipid metabolism.
Effectiveness
- Triglyceride concentration is decreased by 20% to 70%.
- HDL cholesterol is increased by 10% to 25%.
- LDL cholesterol is decreased if the initial concentration is high.
Adverse Effects
- Mild abdominal and bowel irritation
- Myalgia and an increase in serum creatine kinase concentration
- Possible formation of gallstones
- Increase in serum transaminase levels
- Retention of water, growth of mammary tissue, and impotence are rare.
Interactions
Protein-bound drugs are released and their concentrations are increased (warfarin, sulphonylureas).
Contraindications
Severe renal or hepatic dysfunction, diseases of the gallbladder
Dosage
- Gemfibrozil: 600 to 1200 mg/day divided into 2 to 3 doses
- Bezafibrate: 400 mg x 1 at lunch
- Fenofibrate: 200 mg x 1 with meal
Ezetimibe
For patients whose hypercholesterolemia cannot be treated with statin or when the effect is insufficient, ezetimibe is a good choice.
Mechanism of Action
- Prevents cholesterol from being absorbed in the small intestine.
- Effect is additive to statins which prevent cholesterol synthesis.
Effectiveness
- Alone diminishes the concentration of LDL cholesterol 18% to 19 %, triglycerides 4% to 11% and increases the concentration of HDL cholesterol 2% to 3%
- Combining ezetimibe with statin is additive and equals a large dose of statin in reducing cholesterol level.
Dosage
Side Effects
The studies conducted so far show little side effects.
Follow-up of a Patient on Cholesterol-lowering Drugs
- Lipid concentrations should be controlled after 1 to 2 months, then after 3 to 6 months, and thereafter annually, if necessary.
- Before changing the drug, wait for the effect for 3 to 6 months.
- Make sure that the target lipid levels are achieved (see the Finnish Medical Society Duodecim guideline "Treatment of Hyperlipidaemia: Aims and Selection").
Laboratory Tests
Statins
- Serum alanine aminotransferase (ALT) should be determined 1 to 2 months after the onset of therapy and thereafter usually once a year.
- Concentrations greater than twice the upper limit of the reference range are clinically significant. A slight increase in serum ALT concentration is an indication for follow-up, not necessarily for discontinuation of the drug.
- If unexplained myalgia occurs, serum creatine kinase should be determined if necessary.
Fibrates
- Serum ALT is determined after 1 to 2 months, and thereafter at 6- to 12-month intervals. If used in combination with statins, ALT should be determined at 3- to 4-month intervals (when combined with a fibrate, the statin dosage should be only half of the normal).
- If myalgia occurs, serum creatine kinase should always be examined.
Indications for Specialist Consultation
- Need for a drug combination
- A lipid disorder associated with another complicated disease
- Serum triglyceride concentration is primarily above 10 mmol/L or remains above 5 mmol/L despite treatments.
- Very high serum cholesterol concentration (above 15 mmol/L)
- Ischaemic heart disease or xanthomas occur in childhood or in adolescents or young adults.
Related Resources
Refer to the original guideline document for related evidence, including Cochrane reviews and other evidence summaries.
Definitions:
Classification of the Quality of Evidence
| Code |
Quality of Evidence |
Definition |
| A |
High |
Further research is very unlikely to change our confidence in the estimate of effect.
- Several high-quality studies with consistent results
- In special cases: one large, high-quality multi-centre trial
|
| B |
Moderate |
Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate.
- One high-quality study
- Several studies with some limitations
|
| C |
Low |
Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate.
- One or more studies with severe limitations
|
| D |
Very Low |
Any estimate of effect is very uncertain.
- Expert opinion
- No direct research evidence
- One or more studies with very severe limitations
|
GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group 2007 (modified by the EBM Guidelines Editorial Team).
