When to Treat Hypertriglyceridemias
The guidelines for use of drugs to treat familial hyper-triglyceridemia type IV are less well defined than those for hypercholesterolemia. One should account for plasma HDL in deciding to treat hypertriglyceridemias with the intent of decreasing the risk for CHD. Moderate hypertriglyceridemia (200–500 mg/dL) with-out low HDL may not be an independent risk factor for CHD. However, the results of a recent clinical trial indi-cate that hypertriglyceridemia is an independent risk factor for ischemic stroke. Results of the Helsinki Heart Study showed that the reduced risk of CHD with use of gemfibrozil (discussed later) was correlated with eleva-tion of HDL plus reduction of VLDL triglyceride rather than reduction of LDL cholesterol. Gemfibrozil has lit-tle effect on plasma LDL.
Low HDL cholesterol ( 35 mg/dL) is an independ-ent risk factor for CHD. HDL appears to antagonize atherogenesis by at least two mechanisms. HDL can mobilize cholesterol from extrahepatic cells (such as ar-terial wall foam cells) and transport it to the liver for disposal (reverse cholesterol transport); HDL also has antioxidant properties. HDL contains the potent an-tioxidant enzyme paraoxonase, which may protect LDL lipids from oxidation. Thus, hypertriglyceridemia with concurrent low HDL cholesterol should be treated to reduce the risk of CHD. Treatment of hypertriglyc-eridemia independent of HDL levels may also be worthwhile to decrease the risk of ischemic cerebrovas-cular disease. Very high plasma triglycerides ( 1000 mg/dL) are clearly a risk factor for pancreatitis and must be treated for this reason.
As with drugs that lower LDL cholesterol, dietary plus other lifestyle changes should accompany drug therapy of hypertriglyceridemia. Reduction of body weight to ideal is probably the single most important di-etary goal. Because patients with familial hypertriglyc-eridemia may have increased liver capacity to synthe-size fat from carbohydrate, attention should be given to restricting excessive carbohydrate and alcohol.
The three structurally related fibrates available in the United States are gemfibrozil (Lopid), fenofibrate (Tricor) and clofibrate (Atromid-S). They share common uses and toxicities. The fibrates typically lower VLDL triglyceride by 40% or more and elevate plasma HDL cholesterol by 10 to 15%. The reduction of plasma triglycerides in humans appears due to increased lipopro-tein lipase (LPL) activity. The fibrates activate a nuclear receptor (transcription factor) termed peroxisomal pro-liferation activated receptor (PPAR) that is a member of the steroid hormone receptor superfamily. PPAR in-creases transcription of the LPL gene and decreases tran-scription of the apolipoprotein CIII gene (apo CIII). Since LPL is responsible for catabolism of VLDL triglyc-eride and apo CIII is an inhibitor of LPL activity, the combined consequences of these changes are increased LPL activity and enhanced removal of triglyceride from the circulation (mechanism II in Fig. 23.2).
The elevation of HDL levels by fibrates may be due to two drug actions: induced synthesis of apo-A1, the principal apoprotein of HDL, and increased assembly of new HDL particles in the circulation. Surface com-ponents of VLDL contribute to formation of HDL, as the VLDL particles are reduced in size through the ac-tion of LPL. The increased rate of catabolism of VLDL caused by the fibrates would provide more components for assembly of HDL particles.
The fibrates are mainly used to treat two hyperlipi-demias, familial hypertriglyceridemia (type IV) and dysbetalipoproteinemia (type III). They are also useful in the treatment of hypertriglyceridemia associated with type II diabetes (secondary hyperlipidemia). The fibrates are the drugs of choice in treating hypertriglyc-eridemias, particularly those associated with low levels of HDL cholesterol. The fibrates additionally appear to shift LDL particles to larger, hence less atherogenic, species.
Type III or dysbetalipoproteinemia is a rare condi-tion in which cholesterol-enriched VLDL remnants, called -VLDL, accumulate in the plasma. They are atherogenic particles. Dysbetalipoproteinemia is a ge-netic condition associated with expression of an unusual form of apolipoprotein E (apo E2 versus the normal E3) that leads to reduced plasma clearance of these lipoproteins by the liver. Through stimulation of LPL and perhaps other lipases, the fibrates accelerate clear-ance of these -lipoproteins. Both plasma cholesterol and triglyceride levels are elevated in dysbetalipopro-teinemia and in combined hyperlipidemia, type IIb. However, the drug treatments are different for the two conditions. Type IIb hyperlipoproteinemia requires use of agents that lower both LDL and VLDL particles; for example, a statin plus niacin, niacin alone, or niacin in combination with a fibrate. Care should be taken in dis-tinguishing between types IIb and III as the cause of the elevated cholesterol plus triglyceride. This can be achieved by examining the profile of the elevated plasma lipoproteins separated by electrophoresis. A broad -band is seen in type III but distinct - and pre--bands are seen in type IIb.
The fibrates are generally well tolerated, with GI distress being the most likely complaint. Other adverse effects include myositis and erectile dysfunction, partic-ularly with clofibrate. There is ongoing concern about the fibrates increasing the risk of gallstones, although the extent of risk is unclear. Because clofibrate was as-sociated with increased mortality in early clinical trials, it should be considered as a second-line drug.
The fibrates potentiate the actions of the coumarin anticoagulants, such as warfarin, so care should be taken to reduce the dose of simultaneously administered anti-coagulants, and plasma prothrombin should be fre-quently measured until the level stabilizes. As men-tioned earlier, great care should be given to combining a statin with a fibrate, since this combination may in-crease the risk of myositis and perhaps rhabdomyolysis. Table 23.4 summarizes major interactions of drugs that lower cholesterol.