Agent Against Atherosclerosis

Extended release fluvastatin appears effective in reversing low HDL problem-Prof. Tomlinson

Dyslipidemia refers to an abnormality in the plasma levels of high-density lipoproteins (HDL), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and triglycerides. Abnormal plasma levels of such lipids stimulate the production and increased plasma levels of cholesterol, which eventually results in the formation of atheromatous plaques, the progenitor of atherosclerosis.

    According to Prof. Brian Tomlinson, professor of clinical pharmacology at the Chinese University of Hong Kong, deterring atheroma formation requires not only decreasing LDL plasma levels but also increasing HDL serum levels. Prof. Tomlinson spoke before a recent medical symposium organized by the Philippine Heart Association and Novartis Healthcare Philippines, Inc.

New Concepts

    The National Cholesterol Education Program II (NCEP-2) study showed LDL, total cholesterol, HDL, and triglycerides represent one set of risk factors for coronary heart disease (CHD). These are in addition to such other factors as familial (genetic) influence, smoking, diabetes, obesity, and blood pressure. Lately however, there is a growing awareness that other risk factors also change the target lipid levels. Thus NCEP guidelines do not recommend placing all patients with CHD on lipid-lowering drugs regardless of their LDL levels.

    Prof. Tomlinson said there is an inverse relationship between HDL and coronary heart disease, citing among other investigations, the Framingham Heart Study. "Calculations from this study show that by increasing plasma HDL levels by 1mg/dL, the risk of coronary event can be lowered by two percent among men and three percent among women," he noted. On the other hand, he said low HDL levels increase CHD risk even when total cholesterol is normal (Figure 1). "HDL, LDL, and triglyceride levels interact such that a combination of high triglycerides and LDL plus low HDL presents the greatest risk," he added.

    Studies also show that HDL levels below 40 mg/dL occur in 40 to 60 percent of patients with coronary disease, which is often associated with higher CHD risk even if total cholesterol is below 200 mg/dl. The risk rises if LDL and triglyceride levels are higher and the patient smokes or has hypertension and diabetes mellitus.

    Prof. Tomlinson said that in cases where triglyceride levels are high and HDL particles are enriched with triglycerides, hepatic lipase enzyme rapidly converts HDL 2 to HDL 3, which is smaller, more dense, and rapidly catabolized. This is the main reason why during hypertriglyceridemia, HDL levels are reduced. In the same manner, LDL enriched with triglycerides also undergo catabolism through hepatic lipase, producing smaller and denser particles that are more easily taken up by the endothelial lining of blood vessels and produce foam cells more readily. Overall, hypertriglyceridemia presents an atherogenic lipid profile that arises from a whole pattern of abnormal lipids, which are particularly atherogenic.

Improving HDL Levels

    Lifestyle modifications like weight reduction, smoking cessation, and exercise can do much to increase HDL considerably. Alcohol can increase HDL, but for patients with high triglyceride levels, alcohol tends to worsen the problem. Prof. Tomlinson cautioned against full diet restriction, noting that very limited fat and calorie intake could lower HDL levels. He noted that people, particularly Asians, who have diets very low in fat but high in carbohydrates, also have low HDL levels.

    In terms of medication for increasing HDL cholesterol levels, Prof. Tomlinson said fibrates have been shown to increase HDL as far back as 20 years ago beginning with the Helsinki Heart Study, a placebo-controlled primary prevention trial that showed gemfibrozil increased HDL while decreasing triglyceride and LDL levels. The more recent Bizafibrate Infarction Prevention study involving 3,122 patients with prior myocardial infarction and evidence of ischemia also showed 10 percent rise in HDL and 24 percent drop in triglycerides. The Veterans Administration-HDL Intervention Trial (VA-HIT) used gemfibrozil in patients with coronary heart disease and low HDL plasma levels. The results: 7.5 percent increase in HDL and 24.5 percent reduction in triglycerides.

Statin Role

    Statins appear to do better and more consistently, observed Prof. Tomlinson, citing angiographic and clinical event trials on the drug. One of them, the Lipoprotein and Coronary Atherosclerosis Study (LCAS), showed greater change in minimum luminal diameter of blood vessels among patients treated with fluvastatin vis-à-vis placebo. The outcome was more pronounced and statistically significant among patients that had HDL less than 35mg/dL at the start of the program. Prof. Tomlinson said it meant that coronary disease patients with low HDL stand to benefit more from fluvastatin than those with high HDL.

    On the other hand, the Airforce/Texas Coronary Atherosclerosis Prevention Study (AFCAPS-TEXCAPS) showed that aside from lowering LDL by 25 percent, lovastatin increased HDL by six percent and reduced TG by 15 percent. It yielded a 37 percent reduction in incidence of coronary events over five years, again more significantly among those with low HDL at the start. Prof. Tomlinson said this pattern was observed in several other studies.

NCEP-2 Guidelines

    The NCEP guidelines revised in May 2001 advocate aggressive therapy for patients at high risk of developing coronary disease. Recognizing that having diabetes mellitus is equivalent to already having coronary artery disease, the guidelines emphasize estimating the absolute risk of coronary events using multiple risk factors-age, smoking, total cholesterol, HDL, systolic blood pressure, and treatment of hypertension-and an equation based on the Framingham Risk Prediction Score. A 20 percent 10-year risk for developing coronary artery disease warrants aggressive therapy, according to Prof. Tomlinson. Among others, aggressive therapy means initiating drug therapy if the plasma LDL level is more than 130 mg/dL, and bringing down plasma LDL level to less than 100 mg/dL.

    The new guidelines also recognize the importance of controlling multiple metabolic risk factors such as low HDL, high triglycerides, obesity, glucose intolerance, and hypertension. It is also recommended that the total lipoprotein profile be measured. The guidelines now consider HDL level of <40mgdL-no longer <35 mg/dL-as low. On the other hand, triglyceride level of 150 mg/dL is deemed "borderline high."

Superior Features

    Studies show that statins have similar effects on triglycerides, as most of them have clear trophic effects beneficial in preventing coronary events. But studies show they differ in their potency for LDL lowering, route of metabolism, lipid solubility, and effects on HDL. Prof. Tomlinson pointed out that although lovastatin, simvastatin and fluvastatin may have similarities in chemical structure, fluvastatin has different pharmacokinetic properties, notably its extreme water solubility, lipid solubility, and long half-life.

    The newer extended-released formulation (Lescol XL) has very low plasma levels that are steady for a long period. Prof. Tomlinson said new data are accumulating showing fluvastatin's effectiveness in increasing HDL, irrespective of the LDL, triglyceride, or risk factor levels (Figure 2). "This new extended release preparation of fluvastatin appears to be very effective in reversing the problem of low HDL in the subgroup of subjects who are most at risk," observed Prof. Tomlinson.

    Another factor to consider when giving statins is their susceptibility to drug interactions. Prof.Tomlinson said fluvastatin exhibits lesser problems on interaction. A study showed fluvastatin combined with gemfibrozil is safe and effective in lowering LDL and increasing HDL plasma levels. "In patients with very high triglyceride levels, if control using statins is inadequate, then it would be safe to add a fibrate such as gemfibrozil to get a very significant improvement in the lipid profile," he said.

    With focus now placed on also increasing HDL instead of just lowering LDL, Prof. Tomlinson said the extended release formulation of fluvastatin-alone or in combination therapy-confers very favorable effects on HDL. Moreover, it has low potential for drug interaction, offering a very useful form of therapy in the prevention of atherosclerosis.