Dietary regulations and lifestyle changes are the primary approach in the treatment of hyperlipidemia. However, this approach often fails to provide desired blood lipid levels. In many cases, drug therapy comes to the fore. Before starting treatment; The lipid profile and risk factors should be evaluated, the desired target lipid levels should be determined by considering the risk factors, and adaptation to diet and lifestyle changes should be ensured.
Although the effectiveness of lipid-lowering treatments has been demonstrated with strong evidence, the rate of use of cholesterol drugs is still low and target values can be reached only in 50% of patients using drugs (1). The reasons for this may be insufficient dose, non-compliance with the guidelines, side effects and patient non-compliance. The clinician has 3 options to achieve the goal. These ; high doses with the old statin, the use of combined drugs (such as ezetimibe) or the use of new, potent statins. It is recommended to start with a low-dose statin and gradually increase it. A 6% reduction in LDL-Cholesterol can be achieved by increasing the statin dose by 2 times, so this method may be an option for 10% of target patients. Combination therapy may be an option for those with mixed dyslipidemia. Combination of fibrates and statins is successful, but this combination is not desirable due to the risk of myopathy. Fibrates have been shown to reduce TG levels and increase HDL cholesterol. Therefore, there is evidence that fibrates reduce cardiovascular disease rates in cases with low HDL and high TG levels, but the evidence is not so positive in cases with high LDL (2,3). In combination, the risk is higher with Gemfibrozil than with fenofibrates (4). Niacin + statin seems to be the appropriate combination in cases with high LDL-Cholesterol and low HDL-Cholesterol. In addition to statin, the use of the cholesterol absorption inhibitor ezetimibe resulted in a 12-14% reduction in LDL-Cholesterol levels.
In 1994, the results of the 4S study (Scandinavian Simvastatin Survival Study), which can be considered as a landmark regarding statins, were published. In this study, 4444 coronary artery disease patients were examined and it was shown that statin therapy not only reduced the frequency of cardiovascular events but also increased survival (5).
There are currently six different active substances in this group: simvastatin, lovastatin, fluvastatin, pravastatin, atorvastatin and rosuvastatin. Cerivastatin has been withdrawn from the market due to the high risk of myopathy. The efficacy and safety profiles of these drugs are very close to each other. The clinical doses used for each result in a similar reduction in LDL cholesterol. At conventional doses, statins cause a 15-30% decrease in total cholesterol, a 20-60% decrease in LDL cholesterol, a 10-20% decrease in triglyceride, and a 5-10% increase in HDL cholesterol.
In fact, recommendations on drug therapy vary from country to country. In England, it is used in secondary prevention to reduce ischemic events in atherosclerotic patients, and it is also recommended in primary prevention in asymptomatic patients with a total cholesterol of 194 mg/dl or with a risk of developing coronary heart disease over 30% in 10 years. In the USA, statin therapy is recommended for anyone with a 10% or greater risk of coronary heart disease in 10 years and an LDL cholesterol > 100 mg/dl. In the WHO report, statins, antihypertensives, and low-dose aspirin are recommended for secondary prevention of cardiovascular diseases, thus suggesting a 50% reduction in mortality and disability rates.
Studies have shown that a 1% decrease in LDL cholesterol is associated with a 1% decrease in CVD, but a 1% increase in HDL cholesterol is associated with a 3% decrease in CVD (6).
The positive effects of statins led the US National Survival Institute to implement a guiding program called the National Cholesterol Education Program (NCEP ATP) in 1985. While ATP-I included recommendations on primary prevention, ATP-II, which was renewed in the light of the scientific data obtained, recommended more intensive treatment in high-risk group patients, and ATP-III targeted aggressive cholesterol-lowering treatment and lower LDL cholesterol values in certain patient groups.
ATP-II targeted more aggressive cholesterol-lowering therapy and lower LDL cholesterol values in high-risk patients. The highest risk group is individuals with coronary artery disease or equivalent diseases. Non-coronary atherosclerotic diseases (peripheral arterial disease, symptomatic or more than 50% stenosis of the carotid arteries, etc.) and diabetes mellitus, which are considered to be equivalent to coronary artery disease, are also included in the high risk group. Target cholesterol values recommended by ATP-III according to risk groups are given in Table 1.
Studies after the publication of ATP-II have led to the preparation of ATP-III, which recommends more aggressive cholesterol-lowering approaches. Especially recent studies suggest that ATP-III targets are also insufficient in some patient groups. Although cholesterol targets of ATP-III are generally adopted, it is thought that more aggressive treatment should be applied, especially in high-risk patients with low HDL cholesterol levels. It was first shown in the Heart Protection Study (HPS) that better clinical results can be obtained by lowering LDL cholesterol more than NCEP ATP III recommendations in high-risk patients (7). Later, with the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis s Myocardial Infarction 22 (PROVE IT-TIMI 22) study, it was recommended to reduce the LDL cholesterol target below the 70 mg/dl limit in high-risk patients.[6] In both studies, it was observed that LDL cholesterol and the risk of cardiovascular events were in a linear relationship, and the risk of cardiovascular events decreased as LDL cholesterol decreased. According to these studies, there is no cutoff point where further lowering of LDL cholesterol would not provide additional benefit. The TNT study, the results of which were announced recently, also confirmed the results of these two studies.[9] . ATP III treatment targets interpreted according to recent clinical data are shown in Table 2. Compared to the original recommendations of ATP-III, the target LDL cholesterol values in this table and the threshold for starting pharmacological treatment appear to be lower. The recommended LDL cholesterol level in high-risk patients is below 100 mg/dl. However, recent data suggest that 70 mg/dl is a better target, especially in the very high-risk patient group. If the LDL cholesterol value is below 100 mg/dl in a high-risk patient, using statins to bring it below 70 mg/dl is an appropriate treatment option. If a high-risk patient has a high triglyceride level or a low HDL cholesterol level, adding fibrate or nicotinic acid to statin therapy is appropriate. In patients in the intermediate risk group, the recommended LDL cholesterol target is below 130 mg/dl, while the data show that values below 100 mg/dl can be considered as the target in these patients. In this group, administering statin therapy to those with LDL cholesterol levels between 100-130 mg/dl in order to reach LDL cholesterol values below 100 mg/dl is an approach supported by recent studies. If statin therapy is initiated in a high- or intermediate-risk patient, the dose of therapy should be such that it can provide a 30-40% reduction from baseline LDL cholesterol levels. In low-risk patients, LDL cholesterol targets are the same as ATP III.
Doubts about the safety of statins have increased recently, when aggressive lipid therapy recommendations have come to the fore. Statin side effects concentrate more on the liver and muscle. However, this side effect is dose dependent and reversible. There is no evidence that they increase existing hepatic disease, but their use is still contraindicated in cholestasis and active liver disease. Myalgia and fatigue can be seen in 2-7% of patients, and myopathy associated with muscle tenderness, weakness, and creatinine kinase increase more than 10 times is seen at a rate of 0.01-0.5% (10). In very rare cases (0.15 fatal cases in 1 million uses), excessive CPK elevation may result in muscle necrosis, renal failure due to myoglobinuria, and rhabdomyolysis characterized by rhabdomyolysis. Atorvastatin, lovastatin and simvastatin are primarily metabolized via the Cytocrome P 450 3A4 pathway. When used together with drugs such as fibrate, cyclosporine, macrolide antibiotics, digoxin, warfarin, which are metabolized through this route, the risk of side effects increases and important drug reactions can occur(4). Since rosuvastatin does not use this pathway, it has less side effects.
Epidemiological studies have suggested that statins increase the incidence of stroke, but the HPS study revealed the opposite. There was a 25% decrease in the incidence of first stroke in patients using simvastatin (7). Mild transient proteinuria was detected during statin therapy. This was thought to be related to the pharmacological effect of statins on proximal renal tubular function(11). Its incidence is less than 5% and it has not been associated with renal failure.
