Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary. The recommendations that follow are based on the previous version of the guideline.
The levels of evidence [A-D] supporting the recommendations are defined at the end of the "Major Recommendations" field.
Basic Rules
- 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 as if the patient 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; The Database of Abstracts of Reviews of Effectiveness (DARE)-993524, 2000; Ross et al., 1999; DARE-999402, 2002) [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, pravastatin, simvastatin, lovastatin, cholestyramine, and gemfibrozil have been tested in randomized double-blind trials lasting at least 5 years ("Randomised trial of cholesterol lowering," 1994) [A]. There are long lasting trials on atorvastatin and fluvastatin, as well.
- A statin is the drug of choice (Bucher, Griffith, & Guyatt, 1999; DARE-993524, 2000; Ross et al., 1999; DARE-999402, 2002) [A] unless the main abnormality is hypertriglyceridaemia in combination with a low HDL cholesterol concentration.
- 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 (phenotype) |
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 triglyceride <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.
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 resins results in additive effects (Schectman & Hiatt, 1996; DARE-978010, 1999) [C].
Adverse Effects
- Statins are usually well tolerated, even by elderly patients.
- Serum aminotransferase concentrations rise in about 2% of the patients.
- 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
Dosage recommendations can be found in the original guideline document.
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
Dosage recommendations can be found in the original guideline document.
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 to15%. 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
Dosage recommendations can be found in the original guideline document.
Adverse Effects
- Almost 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
Dosage recommendations can be found in the original guideline document.
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
Dosage recommendations can be found in the original guideline document.
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 after 1 to 2 months. A slight increase (ad 2 x) in serum ALT concentration is an indication for follow-up, not necessarily for discontinuation of the drug. If unexplained myalgia occurs, determine serum creatine kinase.
- Fibrates: ALT or aspartate aminotransferase (AST) and alkaline phosphatase are 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. 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 Evidence
- There is little reduction in risk of ischaemic heart disease in the first two years after lowering cholesterol. Lowering serum cholesterol by 10% decreased the risk of coronary heart disease (CHD) by 54% at the age of 40, by 39% at the age of 50, 27% at the age of 60, 20% at the age of 70, and 19% at the age of 80 (Law, Wald, & Thompson, 1994; DARE-948027, 1999) [A].
- Lipid lowering by drugs, especially beta-hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA) inhibitors, is effective in patients with renal disease (Massy et al., 1995; DARE-951884, 1999) [C].
- According to one systematic review, fluvastatin, micronized fenofibrate, and simvastatin were the most cost-effective drugs in reducing the total cholesterol/HDL ratio (Lacour, Derderian, & Lelolier, 1998; DARE-980618, 2000) [C]. However, the analysis is sensitive to changes in the cost of the drugs.
- Fenofibrate reduces serum triglycerides, total cholesterol, and LDL cholesterol (Guay, 1999; DARE-992121, 2002) [A].
- Garlic appears to have small short-term benefits on lipid-lowering and antiplatelet factors (Ackermann et al, 2001; DARE-20018130, 2002; Agency for Healthcare Research & Quality (AHRQ), 2000; Health Technology Assessment Database: HTA-20010948, 2004) [B].
Definitions:
Levels of Evidence
- Strong research-based evidence. Multiple relevant, high-quality scientific studies with homogenic results.
- Moderate research-based evidence. At least one relevant, high-quality study or multiple adequate studies.
- Limited research-based evidence. At least one adequate scientific study.
- No research-based evidence. Expert panel evaluation of other information.
