These drugs are collectively known as statins. Subsequent studies by many investigators led to the identification of a number of natural and synthetic compounds that also inhibit the enzymatic activity of HMG-CoA reductase. It was originally discovered in 1976 by Akira Endo in Japan and shown to be a potent competitive inhibitor of HMG-CoA reductase it binds to the enzyme with a K i ~ 10 –9 M, compared to a K m ~ 10 –6 M for the natural substrate HMG-CoA ( Endo et al., 1976). Mevinolin is a fungal metabolite that is structurally related to HMG-CoA. One class of drugs, referred to collectively as statins, has proved to be extremely effective in lowering plasma LDL levels and in reducing the progression of atherosclerosis and clinically associated problems. Hypercholesterolemia is associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, and increased mortality. Espenshade, in Encyclopedia of Biological Chemistry (Third Edition), 2021 StatinsĮlevated LDL cholesterol levels (hypercholesterolemia) are relatively common in populations consuming a western diet.
The goals for lowering LDL cholesterol levels as established by the National Cholesterol Education Program are shown in Table 5. The primary nonpharmacological approach to reducing LDL cholesterol levels is to limit saturated fat, trans fatty acids, and cholesterol, increased physical activity, and maintain a healthy body weight. Efforts in this area have been hampered by the lack of a safe, noninvasive, inexpensive, and accurate measure of atherosclerotic plaque. More recent interest has centered on the potential for regression of atherosclerotic lesions by nonpharmacological means. Primary prevention trials resulting in decreased LDL cholesterol levels have led to reduced rates of atherosclerosis. Migration studies which have resulted in elevations in LDL cholesterol levels, presumably due to environmental factors (diet and lifestyle), have supported these observations. Similar observations have been made within populations. Cross-cultural comparisons have clearly identified a positive relationship between LDL cholesterol levels and the incidence of atherosclerosis. The higher the estimated risk for CHD the lower the LDL cholesterol goals. Ten-year risk for CHD can be estimated using the criteria presented in Table 5. Risk category is determined on the basis on the presence of existing coronary heart disease (CHD) and CHD risk equivalents (other clinical forms of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease diabetes or multiple risk factors that confer a 10-year risk for CHD > 20%) or the number risk factors ( Table 2). There are three categories of risk that determine LDL cholesterol lowing goals ( Table 4). LDL levels below 2.57 mmol l −1 are classified as desirable, 2.58–3.34 mmol l −1 are classified in the near or above optimal, 2.35–4.41 mmol l −1 are classified in the borderline high, 4.12–4.89 mmol l −1 are classified in the high and above 4.91 mmol l −1 are classified as very high ( Table 3).
Elevated LDL cholesterol levels are currently considered to be the primary risk factor for the development of atherosclerosis.
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