Statins

The statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in cholesterol synthesis, especially in the liver.

Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration.

Statins should be considered for all patients, including the elderly, with symptomatic cardiovascular disease such as those with coronary heart disease (including history of angina or acute myocardial infarction), occlusive arterial disease (including peripheral vascular disease, non-haemorrhagic stroke, or transient ischaemic attacks).

In patients with diabetes mellitus, the risk of developing cardiovascular disease depends on the duration and complications of diabetes, age, and concomitant risk factors. Statin therapy should be considered for all patients over 40 years with diabetes mellitus (type 1 and 2).

In younger patients with diabetes, treatment with a statin should be considered if there is target-organ damage, poor glycaemic control (HbA1c greater than 9%), low HDL-cholesterol and raised triglyceride concentration, hypertension, or a family history of premature cardiovascular disease.

Statins are also used for the prevention of cardiovascular disease events in asymptomatic individuals who are at increased risk ). Statin treatment should also be considered if the total cholesterol concentration to HDL-cholesterol ratio exceeds 6.

Cautions

Hypothyroidism should be managed adequately before starting treatment with a statin . Statins should be used with caution in those with a history of liver disease or with a high alcohol intake—see also Hepatic impairment,.
There is little information available on a rational approach to liver-function monitoring; however, a NICE guideline suggests that liver enzymes should be measured before treatment, and repeated within 3 months and at 12 months of starting treatment, unless indicated at other times by signs or symptoms suggestive of hepatotoxicity.
Those with serum transaminases that are raised, but less than 3 times the upper limit of the reference range, should not be routinely excluded from statin therapy. Those with serum transaminases of more than 3 times the upper limit of the reference range should discontinue statin therapy.
Statins should be used with caution in those with risk factors for myopathy or rhabdomyolysis ; patients should be advised to report unexplained muscle pain.

Hepatic impairment

Statins should be used with caution in those with a history of liver disease and avoided in active liver disease or when there are unexplained persistent elevations in serum transaminases.

Pregnancy

Statins should be avoided in pregnancy as congenital anomalies have been reported and the decreased synthesis of cholesterol possibly affects fetal development. Adequate contraception is required during treatment and for 1 month afterwards.

Breast-feeding

The manufacturers of atorvastatin, fluvastatin, rosuvastatin, and simvastatin advise avoiding use in mothers who are breast-feeding as there is no information available. The manufacturers of pravastatin advise against use in breast-feeding mothers as a small amount of drug is present in breast milk.

Side-effects

The statins have been associated with myalgia, myopathy, myositis, and rhabdomyolysis .
Statins can alter liver function tests, and rarely cause hepatitis and jaundice; pancreatitis and hepatic failure have been reported very rarely.

Other side-effects include gastro-intestinal disturbances, sleep disturbance, headache, dizziness, depression, paraesthesia, asthenia, peripheral neuropathy, amnesia, fatigue, sexual dysfunction, thrombocytopenia, arthralgia, visual disturbance, alopecia, and hypersensitivity reactions (including rash, pruritus, urticaria, and very rarely lupus erythematosus-like reactions).

In very rare cases, statins can cause interstitial lung disease; if patients develop symptoms such as dyspnoea, cough, and weight loss, they should seek medical attention.

Statins can cause hyperglycaemia and may be associated with the development of diabetes mellitus, particularly in those already at risk of the condition.

Muscle effects

The risk of myopathy, myositis, and rhabdomyolysis associated with statin use is rare.

Although myalgia has been reported commonly in patients receiving statins, muscle toxicity truly attributable to statin use is rare. Muscle toxicity can occur with all statins, however the likelihood increases with higher doses and in certain patients.

Statins should be used with caution in patients at increased risk of muscle toxicity, including those with a personal or family history of muscular disorders, previous history of muscular toxicity, a high alcohol intake, renal impairment, hypothyroidism, and in the elderly.

There is an increased incidence of myopathy if a statin is given at a high dose, or if it is given with a fibrate (the combination of a statin and gemfibrozil should preferably be avoided), with lipid-lowering doses of nicotinic acid, with fusidic acid (risk of rhabdomyolysis—the combination of a statin and fusidic acid should be avoided;

temporarily discontinue statin and restart 7 days after last fusidic acid dose), or with drugs that increase the plasma-statin concentration, such as macrolide antibiotics, imidazole and triazole antifungals, and ciclosporin—(statins);

close monitoring of liver function and, if muscular symptoms occur, of creatine kinase is necessary.

In patients at increased risk of muscle effects, a statin should not usually be started if the baseline creatine kinase concentration is more than 5 times the upper limit of normal (some patients may present with an extremely elevated baseline creatine kinase concentration, due to e.g. a physical occupation, or rigorous exercise—specialist advice should be sought regarding consideration of statin therapy in these patients).

If muscular symptoms or raised creatine kinase occur during treatment, other possible causes (e.g. rigorous physical activity, hypothyroidism, infection, recent trauma, and drug or alcohol addiction) should be excluded before statin therapy is implicated.
When a statin is suspected to be the cause of myopathy, and creatine kinase concentration is markedly elevated (more than 5 times upper limit of normal), or if muscular symptoms are severe, treatment should be discontinued.
If symptoms resolve and creatine kinase concentrations return to normal, the statin should be reintroduced at a lower dose and the patient monitored closely; an alternative statin should be prescribed if unacceptable side-effects are experienced with a particular statin.

Statins should not be discontinued in the event of small, asymptomatic elevations of creatine kinase. Routine monitoring of creatine kinase is unnecessary in asymptomatic patients.

G MOHAN.