Statins

What are they

Statins are a group of molecules belonging to the category of so-called lipid-lowering agents, synthesized on the model of a fungal metabolite (mevastatin) whose pharmacological activity was discovered in 1975.

Characteristic property of statins is the ability to lower blood cholesterol levels. For this they can be used in cardiology in the treatment of the so-called “high cholesterol” (called hypercholesteroloma) in medicine).

Their most significant effect is the reduction of LDL cholesterol (also known as “bad” cholesterol). They also help reduce triglyceride levels and increase HDL cholesterol levels (also known as “good” cholesterol).

Their action can slow down the formation of atherosclerotic plaques, thickening of the artery wall associated with serious events such as heart attack and stroke.

Cardiovascular risk

High levels of total cholesterol and LDL cholesterol are risk factors for developing cardiovascular disease. The latter kill more than 4 million people every year in Europe alone and are the leading cause of death in Italy.

Their main victims are women (55%), but before the age of 65 they cause more deaths among men. Those who survive have to live with a chronic disease that can profoundly alter the quality of life.

Cardiovascular prevention passes first of all from the commitment to maintain one’s weight in the norm and from a healthy lifestyle that includes a healthy and balanced diet and regular physical activity and that excludes, instead, smoking and excessive alcohol consumption. This protects not only cardiovascular disease, but also other chronic diseases and the risk of cancer.

For heart and artery health, it is especially important that levels of “bad” cholesterol do not rise excessively. From this point of view, a diet low in saturated fats is of great help, but rich in the monounsaturated fats of olive oil and polyunsaturated fats of fish and nuts.

Acting on nutrition is essential even when a diagnosis of high LDL cholesterol has already been received. However, if changes in eating behaviors are not sufficient to achieve the expected results, it may be necessary to combine the diet with a treatment based on drugs. Among the most prescribed to deal with this problem stand out statins.

Many large-scale clinical trials have shown that these drugs significantly reduce both the incidence of cardiovascular disease and mortality due to these diseases. In addition, their intake has been associated with a slowing of the progression of atherosclerosis of the coronary arteries (the arteries that supply the heart) or, in some cases, its regression.

Mechanism of action

Statins increase the removal of circulating LDL (Low Density Lipoprotein) lipoproteins – those that carry “bad” cholesterol – thereby reducing plasma levels.

The mechanism by which they produce this effect takes place in the liver.

Statins, in fact, block the activity of HMGCoA-reductase (hydroxymethylglutaryl-coenzyme A-reductase), the enzyme that catalyzes the first chemical reaction of the process that leads to the synthesis of cholesterol by liver cells.

In particular, HMGCoA-reductase is involved in the synthesis of mevalonate, a precursor of sterols – including cholesterol. By inhibiting it, statins lead to a reduction in cholesterol and LDL production.

The consequent reduced availability of “endogenous” cholesterol (so called to distinguish it from the “exogenous” cholesterol of food origin) pushes hepatocytes to recover cholesterol from the blood, increasing the uptake of circulating LDL.

This is because statins increase the number of LDL receptors on liver cells. As a result, both the uptake and disposal of LDL cholesterol increase, and plasma concentrations of other lipoproteins (such as those rich in triglycerides) also tend to decrease.

The effect on LDL cholesterol levels depends on the doses taken and varies depending on the drug used, but generally all statins are able to reduce them.

However, the response to treatment may differ from patient to patient, and in some cases it may be necessary to switch to taking a more potent statin than initially prescribed.

The results of therapies may depend on genetic factors that control cholesterol metabolism or hepatic absorption and metabolism of statins. In addition, poor adherence to therapy has been observed in some clinical trials, which may impair the effectiveness of the drug.

The other effects of statins

Reducing LDL cholesterol is the main effect of statins, but these drugs also exert other actions.

Some may bring additional benefits to the cardiovascular system. These are the anti-inflammatory effect, the antioxidant effect, the possible increase in “good” cholesterol and the possible reduction of triglyceride levels.

“Good” cholesterol can increase by 5-10%, while triglycerides can decrease by between 30 and 50%. Some of the most effective statins (atrovastatin and rosuvastatin) significantly reduce triglyceride levels especially when taken at high doses and in patients who have high triglycerides.

In addition, statins have also been tested against conditions such as dementia, fatty liver disease, cancer, venous thromboembolism and polycystic ovary syndrome. However, the data collected to date do not seem to be sufficient to certify the effectiveness of these drugs in the treatment of these diseases.

What are they?

The molecules belonging to the group of statins currently in use in Italy are:

– atorvastatin

– fluvastatin

– lovastatin

– pravastatin

– rosuvastatin

– simvastatin.

Directions

Statins are indicated to reduce plasma cholesterol levels above normal values, in order to prevent cardiovascular and cerebrovascular damage caused by atherosclerosis in subjects at risk (with arterial hypertension, hypercholesterolemia, hypertriglyceridemia, hyperglycemia or diabetes , overweight, smoking) or in patients who have already suffered a heart attack or stroke or are suffering from coronary artery disease or peripheral arterial disease.

With reference to therapeutic objectives, statins have been divided into two groups:

If the therapeutic objective is not achieved, statins may be associated with other lipid-lowering drugs (ezetimibe, fibrates, ion exchange resins, nicotinic acid).

Side effects and contraindications

Statins are generally well tolerated. Any side effects, often transient, may consist of symptoms such as gastrointestinal disorders, skin rashes, headache.

In a small percentage of cases (0.5-2%) they can provoke an asymptomatic increase in liver transaminase levels, which usually regresses by reducing the dosage of the drug.

The use of statins is associated, albeit with a low incidence, with the risk of forms of muscle toxicity: myalgia (1-5% of cases), myositis (0.1-0.2%) and rhabdomyolysis (0.01-0.02%).

Most of the possible side effects associated with statin administration are mild and tend to disappear. Muscle problems and liver abnormalities are rare events, but it cannot be excluded that the doctor deems it necessary to perform regular analyzes to evaluate possible liver dysfunction.

The appearance of muscle toxicity seems to be linked to some predisposing factors, among which the main one is the concomitant intake of other drugs that are metabolized in a similar way to statins (for example fibrates, cyclosporine, macrolides, warfarin, digoxin and azole antifungals).

Interactions with other medicinal products are the key critical aspect of statin treatment. In fact, often those who take them suffer from diseases that also require the administration of other drugs that, in combination with statins, can in some cases reduce their effectiveness or increase the risk of side effects, such as the development of myopathy.

In general, the possibility of interaction with warfarin and coumarins, fibrates and ezetimibe should be considered before taking any statin.

More specifically, simvastatin and atorvastatin may interact with active substances that inhibit or stimulate metabolism through the cytochrome P450 enzyme (CYP3A4) and with those that influence the activity of transport proteins, e.g. itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, cyclosporine, danazol, verapamil and amiodarone, diltiazem, warfarin and coumarins, ezetimibe and fibrates. They should also not be taken together with grapefruit juice.

St. John’s wort and drugs such as efavirenz and rifampicin can reduce both blood simvastatin and atorvastatin concentrations. The latter can also be reduced by colestipol, but the combination of the two medicines may increase the effects on blood lipid levels.

Fluvastatin should instead be taken with caution together with ciclosporin, fluconazole, phenytoin and glibencamise, while in the case of prevastatin care should be taken with the combination with ciclosporin, erythromycin and clarithromycin. In addition, its plasma levels decrease when cholestyramine and colestipol are taken.

Finally, rosuvastatin is contraindicated with cyclosporine. Its combination with HIV protease inhibitors is not recommended and antacids reduce its plasma levels.

Taking statins is contraindicated in the presence of biliary diseases and liver dysfunction (acute or chronic), as well as in pregnancy and children.