Authors

• Nenad Lakušić — Special Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice, Croatia — ORCID: 0000-0002-2329-2582

Abstract

In spite of ample evidence supporting the direct effectiveness of statins in the reduction of total and low-density lipoprotein (LDL) cholesterol and long-term effects in primary and secondary prevention of cardiovascular diseases, in everyday practice we are still faced with various prejudices against the undesired effects of treatment and the possible adverse effects of statins, not only among patients, but among some physicians as well. The basic mechanism of action of statins is inhibiting 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase (HMG-CoA), a key enzyme in cholesterol synthesis. Their other potential mechanisms are stabilization of atherosclerotic plaque and reduction of endothelial dysfunction, as well as inflammatory and post-thrombotic intravascular processes. The side effects of treatment with statins are generally mild, with a frequency comparable to placebo, and usually do not require the termination of treatment. It is necessary to emphasize that patients must always be encouraged to adopt an active, non-sedentary lifestyle that includes regular physical activity, due to its clear positive effects in the prevention and treatment of dyslipidemia and cardiovascular diseases.

Keywords

statins, dyslipidemia, cardiovascular prevention

DOI

Full Text

## Introduction Medication for cholesterol reduction, also known as statins, are the foundation of the prevention and treatment of cardiovascular diseases and are frequently prescribed in clinical practice (1, 2). In spite of ample evidence supporting the direct effectiveness of statins in the reduction of total and low-density lipoprotein (LDL) cholesterol and long-term effects in primary and secondary prevention of cardiovascular diseases (3-6), in everyday practice we are still faced with various prejudices against the undesired effects of treatment and the possible adverse effects of statins, not only among patients, but some physicians as well. ## Mechanism of action The basic mechanism of action of statins is inhibiting 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase (HMG-CoA), a key enzyme in cholesterol synthesis in all bodily cells, especially hepatocytes. This leads to a reduction in the endogenous synthesis of total cholesterol and LDL cholesterol, and to the reduction of their concentration in the blood (1). The main representatives of the group that are most frequently used in Croatia are atorvastatin (10-80 mg), simvastatin (20-80 mg), rosuvastatin (5-40 mg), and fluvastatin (40-80 mg). Generally, rosuvastatin is the strongest for the reduction of LDL cholesterol when the maximum doses for individual representatives of the group are taken into account. In other words, rosuvastatin and atorvastatin are more effective than simvastatin and especially fluvastatin when it comes to the reduction of LDL cholesterol (7-9). All in all, statins have a minimal effect on the increase of the concentration of HDL cholesterol, up to 5% on average. Simvastatin and rosuvastatin are more effective in increasing the concentration of high-density lipoprotein (HDL) cholesterol than atorvastatin (8, 10, 11). Atorvastatin and rosuvastatin are the most effective in the reduction of the concentration of triglycerides, and their effect is dependent on the dose and initial concentration of triglycerides (8, 12, 13). Since cholesterol synthesizes in the body takes place mostly in the early hours of the morning, one should prescribe that statins with a short half-life (simvastatin 1 to 5%); 2** should be used. After several months, the dose is adjusted to the measured values of LDL cholesterol. The recommended values of LDL cholesterol in secondary prevention of cardiovascular diseases, or for patients with a confirmed coronary, carotid, or significant atherosclerotic disease of the peripheral arteries, aneurysm of the abdominal aorta, chronic kidney disease, diabetes type 2, or very high risk for developing a cardiovascular disease (total SCORE >10%) are: LDL cholesterol < 1.8 mmol/L, or reduced by at least 50% of measured values before treatment. It should be noted that current guidelines for dyslipidemia treatment state that practically all patients with diabetes should include statins in their medication treatment irrespective of LDL cholesterol levels, due to the risk profile described above. Regardless of the phase of prevention the patient may be in the progression of a cardiovascular disease, apart from the treatment with statin, the patient should always be encouraged to adopt an active, non-sedentary lifestyle, i.e. regular physical activity, due to its clear positive effects on the lipid profile (23, 24) and, therefore, the long-term outcomes of the treatment. ## Side effects of statin treatment The side effects of statin treatment are relatively rare and mild, frequently on the level of placebo, and do not require the termination of treatment. ## Gastrointestinal side effects Mild gastrointestinal difficulties are rare, but come in the form of nausea, abdominal cramps, diarrhea, or constipation. ## Liver damage Among numerous patients, but also among some physicians, there is an unjustified fear of and resistance to statins because they “damage” the liver. Unfavorable effects on liver function and an increase in the concentration of liver enzymes during statin treatment are on the level of placebo, which means that the rate is around 1% (25-27). Even a mild increase in the number of transaminase enzymes is generally not a sign of hepatotoxicity, but of enzyme induction in hepatocytes. Today, it is believed necessary to determine the concentration of transaminase enzymes in the blood before beginning statin treatment, and that routine check-ups of transaminase enzymes are not required after beginning treatment and should be determined only by clinical indication. An increase in the concentration of transaminase enzymes (alanine aminotransferase – ALT) in blood higher than triple the upper limit of normal values is an indication that treatment should be stopped, the dosage lowered, or the statin changed (28). ## Myopathy, myonecrosis, rhabdomyolysis Development of myopathy connected to statin treatment is a rare and potentially very serious side effect. The incidence of clinically significant myonecrosis during statin treatment is 0.1% of treated patients (29). The pathogenetic mechanism has yet to be fully explained. There is mention of the effect of statin on the synthesis of the coenzyme Q10 or ubiquinone, which has an important role in the production of energy required for normal muscle function (30, 31). Clinically, it manifests through pain and weakness of various muscle groups, and is often similar to myalgia caused by influenza. Apart from clinical symptoms, the diagnosis of significant myonecrosis requires laboratory proof of at least a ten-time increase in the activity of creatine kinase (CK) enzyme. The most severe form of the disease is rhabdomyolysis connected to statin use, defined as myonecrosis with myoglobinuria, or the development of acute kidney failure (32). Such severe manifestations of the disease most commonly occur when there is a concomitant therapy of medicines such as cyclosporin, gemfibrozil, macrolide antibiotics, niacin, digoxin, warfarin, etc (33). Genetic predisposition is also said to be a risk factor in the development of statin myopathy, as well as some neuromuscular diseases, hypothyroidism, kidney insufficiency, etc (32, 33). It is believed that fluvastatin and pravastatin are associated with the smallest incidence of myopathy (34). In everyday practice, it is reasonable to measure CK activity when introducing a statin into treatment, whereas later during treatment it is not necessary to routinely measure it except when there are clinical symptoms such as weakness or muscle pain. ## Increase of blood glucose and development of diabetes type 2 It is possible that statins may cause a small increase in the risk of developing diabetes type 2 or have an adverse effect on glycemia regulation in patients who already have diabetes. That risk is more pronounced in patients treated with doses of statin that were high when compared with moderate doses (35). Taking into consideration the results of large studies that confirmed that statin treatment in patients with diabetes reduces risk of undesired cardiovascular effects and mortal outcomes, such favorable effects outweigh the mild increase in the risk of unfavorable effects on glucose metabolism (36, 37). ## Erectile dysfunction and statins In everyday work we sometimes receive patients treated with a statin who complain about erectile dysfunction and associate it with their treatment, resist taking the medicine, or cancel the treatment of their own volition. Existing literature does not support such a view. On the contrary, there are studies that claim that a reduction in erectile dysfunction is one of possible “non-cardiovascular” benefits of statin treatment (38, 39). ## Red yeast rice and dyslipidemia Remedies made of red yeast rice are nowadays very popular among laymen and used to reduce cholesterol in the blood, and patients are often more likely to take them instead of statins for dyslipidemia regulation. Such remedies contain various active substances, and the favorable effect of the rice comes from monacolins, which block cholesterol synthesis in the liver. Monacolin K, found in red yeast rice, is chemically identical to lovastatin, but its dosage in remedies is smaller than the one usually used in medication (40)! ## Conclusion Several decades of experience with the application of statins, as well as firm and well-documented evidence from a large number of patients treated worldwide, show that statins are an unavoidable medication in the treatment of dyslipidemia and the prevention and treatment of cardiovascular diseases. The side effects of statin treatment are usually mild, with incidence on the level of placebo, and commonly do not require the termination of treatment. In conclusion, it should certainly be noted that patients must always be encouraged to adopt an active, non-sedentary lifestyle, i.e. regular physical activity, due to its clear positive effects in the prevention and treatment of dyslipidemia and cardiovascular diseases.

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