Diabetes & the Heart

Management of Dyslipidaemia in Diabetics

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 cholesterol, and calculate serum low-density lipoprotein 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 family history) in order to screen family members.
If an increased serum low-density lipoprotein cholesterol concentration is the most important lipid abnormality a statin is the drug of choice [A].
If an increased triglyceride concentration (>3 - 5 mmol/L) and a low high-density lipoprotein cholesterol are the most important abnormalities a fibrate may be drug of choice.

General principles on the choice of drug

In postmenopausal women the favorable effect of estrogens on blood lipids and possibly on risk of ischaemic heart disease (as well as a favorable effect on the endothelium) should be considered although statin therapy is preferred.
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.
A statin is the drug of choice unless the main abnormality is hypertriglyceridaemia in combination with a low high-density lipoprotein 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

Dyslipidaemic (phenotype)	Drug of choice
Hypercholesterolaemia alone (Familial hypercholesterolaemia)	Statin 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 <3.0-5.0 mmol/L Fibrate if hypertriglyceridaemia is the main problem (despite diet), and serum cholesterol does not exceed 6.5 mmol/L Fibrate plus statin (be careful about adverse effects on muscle during combination treatment)
Pure hypertriglyceridaemia	Reducing weight and limiting alcohol consumption is essential before drug treatment is considered. Control of diabetes should be improved. Fibrate
Hypothyroidism	Thyroxin substitution normalizes the lipid abnormality if it is caused by hypothyroidism [B]
Postmenopausal hypercholesterolaemia	Consider oestrogren substitution

Statins

The most important group of antihyperlipidaemic agents.

Mechanism of action

Based on the inhibition of the HMG-CoA reductase resulting in the inhibition of cholesterol synthesis in hepatocytes. The number of low-density lipoprotein receptors on hepatocytes is increased, and the elimination of low-density lipoprotein from the blood is enhanced. Part of the action may be through very low-density lipoprotein or even other mechanisms.

Effectiveness

Low-density ipoprotein is decreased by 30 to 40%.
High-density lipoprotein is increased by 5 to 15%.
Triglycerides are decreased by 10 to 30%.
Combining statins with resins results in additive effects [C].

Adverse effects

Statins are usually well tolerated, even by elderly patients.
Serum aminotransferase concentrations rise in about 5% 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 ten times above the upper limit of the reference value are significant. The incidence of myopathy is about 0.5%.
The risk of myopathy is increased by simultaneous treatment with cyclosporine, fibrate, macrolide or conazole medication.

Dosage

Note: dosage recommendations can be found in the complete EBM Guidelines CD-ROM.

Resins (cholestyramin, cholestipol)

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 low-density lipoprotein receptors and intake of cholesterol into hepatocytes.

Effectiveness

Serum total and low-density lipoprotein cholesterol concentration decrease by 15-30%.
Serum triglyceride concentration may increase slightly.

Dose

Note: dosage recommendations can be found in the EBM Guidelines CD-ROM.

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
Thyroxin
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 low-density lipoprotein cholesterol are decreased by 10-15%. High-density lipoprotein and triglyceride concentration remain unchanged.
Guar gum is a suitable alternative in hypercholesterolaemia associated with diabetes as supplement to diet or in severe hypercholesterolaemia combination with statins or fibrates.

Dose

Note: dosage recommendations can be found on the EBM Guidelines CD-ROM.

Adverse effects

Almost 50% of the patients have adverse effects.
Abdominal distention, flatulence, diarrhoea.

Fibrates (gemfibrozil, bezafibrate, fenofibrate, clofibrate)

Mechanism of action

Fibrates act through the nuclear PPAR system which regulates lipid metabolism.

Effectiveness

Triglyceride concentration is decreased by 20-70%.
High-density lipoprotein cholesterol is increased by 10-25%.
Low-density lipoprotein 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.
Eventual 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, disease of gallbladder.

Dosage

Note: dosage recommendations can be found in the EBM Guidelines CD-ROM.

Follow-up of a patient on cholesterol-lowering drugs

Lipid concentrations should be controlled after 1-2 months, then after 3-6 months and thereafter annually.
Before changing the drug wait for the effect for 3-6 months.
Make sure that the target lipid levels are achieved.

Laboratory tests

Statins: serum alanine aminotransaminase should be determined after 1-2 months. A slight increase (ad 2 x) in serum alanine aminotransaminase concentration is an indication for follow-up, not necessary for discontinuation of the drug. If unexplained myalgia occurs determine serum creatine kinase.
Fibrates: Alanine aminotransaminase or aspartate aminotransferase and alkaline phosphatase are determined after 1 to 2 months, and thereafter at 6 to 12 month intervals. If used in combination with statins, alanine aminotransaminase 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. Five or more years after the reduction of cholesterol concentration by 0.6 mmol/l the reduction of incidence of ischaemic heart disease is 25% according to controlled trials and 27% according to cohort studies [A].
Lipid lowering by drugs, especially HMG-CoA inhibitors, is effective in patients with renal disease [C].