Lescol Review Article
Lipids or fats in the body are classified into three groups: cholesterol, triglycerides, and phospoholipids. Upon entering the body via the digestive system, dietary lipids from the foods we eat are absorbed and transported throughout the body in the form of protein-lipid complexes known as lipoproteins. The three classes of lipoproteins are low-density lipoproteins (LDL), high-density lipoproteins (HDL), and very low-density lipoproteins (VLDL). Intermediate-density lipoproteins (IDL) are lipoproteins with densities between VLDL and LDL.
In predisposed people such as the obese, abnormalities in the levels of lipoproteins can occur, resulting in a condition called hypercholesterolemia. This condition is defined as a state of elevated cholesterol levels, the primary indicator being LDL and total cholesterol.
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A low level of HDL is also often observed. The table below summarizes the classification of cholesterol levels according to the 2001 National Cholesterol Education Program guidelines.
Classification of different cholesterol levels
Total Cholesterol: <200 -Desirable; 200239 - Borderline high; >240 - High
LDL Cholesterol: <100 - Optimal; 100129 - Near or above optimal; 130159 - Borderline high; 160189 - High; >190 - Very high
HDL Cholesterol: <40 - Low; >60 - High Triglycerides; <150 - Normal; 150199 Borderline high; 200499 High; >500 Very high
Such abnormalities in plasma lipid levels increase a persons risk for potentially fatal chronic diseases such as coronary heart disease, myocardial infarction or heart attack, and stroke. This is because the excess cholesterol deposits in the lining of the arteries, where they accumulate and create an obstruction, resulting in a condition called atherosclerosis.
Worldwide, hypercholesterolemia is estimated to affect 1 out of every 500, and in the United States alone, slightly more than 50% of citizens older than 20 years old have abnormal cholesterol levels. This highly alarming statistic is magnified by the fact that more than 50% of borderline to high-risk individuals remain unaware of their condition, and fewer than 50% of those with the highest risk are actually receiving medications. Thus, lipid profiling every five years is recommended in those 20 years old and above, and more frequently in those with risk factors such as diabetes, hypertension, cigarette-smoking, and family history. Men older than 45 years and women older than 55 years are also subject to increased monitoring.
Initial therapy for hypercholesterolemia involves lifestyle changes such as diet restrictions, regular exercise, and weight reduction if necessary. Patients should stay away from foods high in total and saturated fat and cholesterol. If these measures are insufficient to produce normal cholesterol levels, pharmacologic therapy with lipid-lowering agents is recommended. Of these agents, HMG-CoA reductase inhibitors, or statins, are the gold standard and first line drugs because of their high potency and proven efficacy and tolerability. Advantages of the statins include a greater effectiveness in lowering LDL cholesterol, ease of administration, good side-effect profile, and a proven mortality benefit in both those with hypercholesterolemia and those at risk (NCEP, 2001).
Statins exert their action by interrupting the rate-limiting step in cholesterol biosynthesis, the conversion of hydroxy-3-methylglutaryl coenzyme A, or HMG-CoA to mevalonate. This occurs through the inhibition of the enzyme HMG-CoA reductase. Because they deplete cholesterol, the body stimulates an increase in LDL receptors on liver cells, thereby increasing the clearance of LDL from the circulation. They have also been proven to reduce triglycerides and increase HDL cholesterol. Throughout the years, many statins have been released in the market, such as lovastatin, pravastatin, simvastatin, atorvastatin, and others. One such drug is Lescol (fluvastatin).
Lescol is a cholesterol-lowering agent belonging to the HMG-CoA reductase inhibitor class. It has an empirical formula of C24H25FNO4Na. Lescol is the first entirely synthetic drug of the statins, and is structurally different from the naturally-derived members of this class. Its approved use is to provide reductions in total cholesterol, LDL cholesterol, triglycerides and Apo B levels, and to elevate HDL cholesterol levels in patients with primary hypercholesterolemia and mixed dyslipidemia, who display inadequate response to dietary restrictions. It is also indicated to reduce cholesterol levels in adolescents 10-16 years old who are at least one year post menarche with heterozygous familial hypercholesterolemia who presents inadequate response to dietary restrictions as well as:
LDL-C remains > 190 mg/dL or
LDL-C remains > 160 mg/dL and the patient has a family history of premature cardiovascular disease, or two or more other cardiovascular risk factors are present.
The efficacy of Lescol has been investigated in over 20,000 patients in a large number of clinical trials. It was established in these studies that a dose of 20 and 40 mg daily of Lescol produced serum LDL reductions of 22 to 24% and 29.5%, respectively, and 80 mg of Lescol daily reduced LDL cholesterol by as much as 36%, with little or no difference in tolerability. Total cholesterol can also be reduced by 15 to 21%, and triglycerides by 1 to 12%. In addition to this, a small increase in HDL cholesterol was also observed. Concomitant use of Lescol with other lipid-lowering agents produced a further decrease of 5 to 10% in LDL (Plosker and Wagstaff, 1996).
The long term efficacy of Lescol was assessed in the Fluvastatin Long-Term Extension Trial (FLUENT), using a clinical scenario which was closer to office-based chronic therapy of hypercholesterolemia patients. 918 patients with severe primary hypercholesterolemia were enrolled in the FLUENT study and at the end of the 2-year study period, it was observed that Lescol provided an LDL reduction of 25 to 34%, comparable to most HMG-CoA reductase inhibitors.
In another efficacy study by Van dam and Kastelein (2001), 61.8% of 1501 patients with primary hypercholesterolemia achieved their desired LDL cholesterol level with dosage titration using Lescol. Patients without coronary heart disease (CHD) reached their LDL goals earlier than those with CHD. Meanwhile, adverse events related to Lescol were described as mild to moderate in nature.
The primary disadvantage of HMG-CoA reductase inhibitors is their high cost. In this regard, many health care organizations have regarded Lescol as an important agent among the statins, primarily because of its low cost. In a randomized crossover comparative cost-effectiveness study between Lescol and another HMG-CoA reductase inhibitor, lovastatin, it was found that although lovastatin provided greater reductions in LDL and total cholesterol, cost per percent reduction in LDL cholesterol was less for Lescol, and that the cost per patient was more favorable for Lescol in low and moderate risk patients (Hilleman, Woodruff, Holmberg, et al., 2000). Another study by Kong, Gandhi, Crawford, et al. (1996), also states that Lescol, which lowers LDL levels by approximately 25%, is the most cost-effective agent in patients who require such a reduction for treatment. This conclusion was supported by another cost-effectiveness study, wherein 299 patients were treated with one of four statins, including Lescol. After calculating cost-effectiveness ratios using data from medical costs, pharmacy costs, and LDL reduction, Lescol was found to be the most cost-effective agent (Spearman, Summers, Moore, et al., 1997)
Use in Children
Lescol is also highly effective in children and adolescents 10 to 16 years old with heterozygous familial hypercholesterolemia. In a single-arm two center study of 80 children, a decrease of 33.9% in LDL cholesterol, 27.1% in total cholesterol, 5.3% in triglycerides, and 24.2% in apolipoprotein B was observed. HDL levels of the children were also increased by 5.3% (van der Graaf, Nierman, Firth, et al., 2006).
The most common adverse effects related to Lescol, as with other statins, are gastrointestinal disturbances. Other adverse effects may include headache or dizziness, rashes, and insomnia. Aside from these, liver enzymes such as aminotransferase may be reversibly elevated, which is why liver function must always be monitored throughout therapy. Myopathy and increase creatine phosphokinase serum levels may also occur, resulting to muscle pain and weakness. Patients who are taking Lescol with drugs such as cyclosporine, fibrates, or niacin possess a greater risk of developing this side effect. In rare cases, hepatitis, pancreatitis, rhabdomyolysis and acute renal failure may occur (Sweetman, 2009).
Hilleman, D. E., Woodruff, M. P., Holmberg, M. J., et al., 2000, Comparative cost-effectiveness of fluvastatin and lovastatin in patients with hypercholesterolemia
Kong, S. X., Gandhi, S. K., Crawford, S. Y., et al., 1996, Pharmacoeconomic evaluation of HMG-CoA reductase inhibitors in the treatment of hypercholesterolemia
NCEP, 2001, Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
Plosker, G. L., and Wagstaff, A. J., 1996, Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolemia
Spearman, M. E., Summers, K., Moore, V., et al., 1997, Cost-effectiveness of initial therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to treat hypercholesterolemia in a primary care setting of a managed care organization
Sweetman, S. C. ed., 2009, Martindale, The complete drug reference 36th ed, London: Pharmaceutical Press, 1433
Van Dam, M., and Kastelein, J., 2001, Efficacy and tolerability of fluvastatin in a titration dosage regimen in hyperlipidaemic patients: Results of a multicentre phase IV study
Van der Graaf, A., Nierman, M. C., Firth, J. C., et al., 2006, Efficacy and safety of fluvastatin in children and adolescents with heterozygous familial hypercholesterolemia
Lescol Review Article