Expert Commentary

W. Virgil Brown, MD, Emory University School of Medicine, Charles Howard Candler Professor of Internal Medicine, Director, Division of Arteriosclerosis and Lipid Metabolism, Chief, Medicine and Primary Care Service Line, Atlanta VA Medical Center, Atlanta, Georgia

Elevated levels of low-density lipoprotein (LDL) cholesterol are generally considered a risk factor for adverse cardiovascular outcomes and are, therefore, commonly treated in the clinical setting. A large body of evidence now supports relationships between low levels of high-density lipoprotein (HDL) cholesterol and elevated levels of triglycerides and increased cardiovascular risk. Furthermore, trials of therapies that reduce triglycerides and raise HDL cholesterol (eg, fibrates and niacin) have demonstrated that correcting these abnormalities can slow stenotic progression and reduce adverse cardiovascular event rates, with modest or no effect on LDL cholesterol levels.^1-3 These findings support aggressive therapy of triglyceride levels in patients with low HDL cholesterol and elevated cardiovascular risk, regardless of their LDL cholesterol levels. Specifically, patients with elevated cardiovascular risk and HDL cholesterol levels <40 mg/dL and triglyceride levels >200 mg/dL, these elevated triglyceride levels should be treated with therapies that specifically alter these abnormalities.

Pharmacologic therapies that effectively reduce triglycerides and raise HDL cholesterol include the fibrates and niacin. In the clinical setting, statins remain the mainstay of lipid-lowering therapy. Whereas statins may have modest effects on HDL cholesterol and triglyceride levels, their primary target is LDL cholesterol. In contrast, fibrates specifically raise HDL cholesterol levels and lower triglyceride levels and should be considered for first-line therapy in patients with HDL cholesterol and/or triglyceride abnormalities in which LDL cholesterol is within an acceptable range. Gemfibrozil, fenofibrate, and bezafibrate have all demonstrated cardiovascular benefits in such patients. In clinical studies, fibrates have been associated with significant reductions (up to 36%) in adverse cardiovascular event rates.^4-7 Niacin may also be beneficial in these patient populations, however, niacin as single-drug therapy has much less supporting data to document the long-term reduction of cardiovascular events. As with fibrates, niacin products have been shown to reduce the progression of stenosis compared to placebo; however, data supporting the use of niacin alone for primary prevention of cardiovascular events in these patients is lacking. Results of the Coronary Drug Project demonstrated benefit in reducing a recurrent myocardial infarction. LDL cholesterol-lowering drugs (resins or statins) can be added to fibrate or niacin therapy if LDL cholesterol levels progress outside the normal range. Niacin therapy has been most clearly beneficial when in combination with these drugs. The benefit of combining niacin with the newly released cholesterol absorption inhibitor, ezetimibe, has not been explored.

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)⁸ discusses treatment of low HDL cholesterol levels and elevated triglyceride levels as second-tier strategy. The proposal that "non-HDL cholesterol" (total cholesterol minus HDL cholesterol) be targeted in persons with triglyceride over 200 mg/dL is a viable approach to manage those with LDL cholesterol in the target range. This places less emphasis on HDL cholesterol and uses all risk factors to set this triglyceride-related target. The data described in this Cardiology Express Report support stronger recommendations for the identification and treatment of patients with abnormal HDL cholesterol and/or triglyceride levels, regardless of their LDL cholesterol status.

Introduction

The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) emphasizes the importance of identifying and treating patients with elevated levels of LDL cholesterol to prevent adverse cardiovascular outcomes.⁸ However, results of several recent trials suggest that low levels of HDL cholesterol and elevated levels of triglycerides are also associated with increased cardiovascular risk. Furthermore, several studies have demonstrated that treatment of these abnormalities is associated with significant cardiovascular benefits. These data, which were recently reviewed in an editorial by Sprecher and colleagues and published in the American Journal of Cardiology in March 2003,⁹ indicate a need for more aggressive control of HDL cholesterol and triglyceride levels.

Low HDL Cholesterol and Elevated Triglycerides are Predictors of Increased Cardiovascular Risk

A large body of evidence now indicates that abnormal levels of HDL cholesterol and triglycerides are associated with increased cardiovascular risk. The relationship between HDL cholesterol and cardiovascular risk is an inverse one and is independent of other known cardiovascular risks. Evidence from the Framingham Heart Study indicates that for each 10 mg/dL increase in HDL cholesterol, cardiovascular risk decreases 50%.¹⁰

Elevated triglycerides are also associated with increased cardiovascular risk. Levels >100 mg/dL are associated with 50% greater risk than levels <100 mg/dL and levels >150 mg/dL are associated with a two-fold increase in risk.¹¹ Whereas some studies have demonstrated that elevated triglyceride is an independent risk factor for cardiovascular events,¹² others have been unable to separate the risk associated with elevated triglyceride from that associated with low HDL cholesterol. In fact, lower HDL cholesterol appears to increase cardiovascular risk as triglyceride levels progressively increase. Triglyceride metabolism and HDL metabolism in the blood plasma are intricately linked. This is demonstrated most clearly in the metabolic syndrome where obesity and insulin resistance have profound impact on this system. Additional studies are needed to further the understanding of the relationship between these abnormalities. Weight loss remains first-line therapy of this complex and integrated group of risk factors.

Regardless of whether the risks associated with low HDL cholesterol and elevated triglycerides are independent or interrelated, they clearly affect cardiovascular health. For this reason, pharmacologic therapies are needed that safely and effectively normalize levels of HDL cholesterol and triglycerides.

Fibrates: Targeted HDL Cholesterol/Triglyceride Therapies

Three classes of drugs have triglyceride reducing and HDL cholesterol-raising effects: fibrates, niacin, and statins. Fibrates safely and effectively reduce triglycerides in patients with dyslipidemia.^4-7 Triglyceride-lowering effects likely result from reduced synthesis of the lipoprotein lipase inhibitor apoC-III,¹³ and subsequent increased clearance of very-low density lipoprotein (VLDL) and chylomicron remnants;¹⁴ decreased hepatic triglyceride synthesis;¹⁵ and increased lipoprotein lipase in peripheral tissues. Increased HDL cholesterol levels are probably the result of the reduced transfer of cholesterol ester from HDL to VLDL and a prolongation of HDL residence time in the plasma. Some LDL reduction may result from the enhanced excretion of cholesterol in the bile which has the unfortunate (but rarely evident) consequence of increasing the lithogenicity of bile.

Niacin also targets HDL cholesterol and triglycerides. Effects on HDL cholesterol likely result from inhibition of HDL apolipoprotein A-I uptake by liver cells,¹⁶ whereas effects on triglycerides likely result from decreased hepatic VLDL production; and increased triglyceride clearance. Initial observations regarding decreased adipose lipolysis¹⁷ and subsequent reduction in transfer of free fatty acids to the liver¹⁸ are probably not the major mechanism of action. However, niacin is associated with annoying adverse cutaneous effects of flushing and pruritus. Niacin is contraindicated in patients with hyperuricemia, history of cardiac arrhythmias, and various inflammatory conditions. In some patients, it can worsen insulin resistance but this is less common than once thought.^19,20 The less well-regulated over-the-counter niacin preparations may be associated with a much higher incidence of adverse reactions.

Lastly, statins produce meaningful reductions in triglyceride levels and increase HDL cholesterol levels 5% to 10%. Triglyceride-lowering effects probably result from changes in LDL receptors, direct effects on intrahepatic packaging of VLDL and LDL,²¹ enhanced lipoprotein lipase activity, and/or decreased apoC-III. Changes in HDL cholesterol levels appear to be related to reductions VLDL remnants. The benefit of the statin-induced HDL cholesterol elevations have not been clearly demonstrated in the large clinical trials. The dramatic benefits of statins are on LDL cholesterol and the consistent benefit in clinical trials appears to be the product of its LDL cholesterol-reducing effect.

Angiographic Benefits of Fibrates

The results from 3 angiographic trials (Lopid Coronary Angiography Trial [LOCAT],² Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT],¹ and Diabetes Atherosclerosis Intervention Study [DAIS]³) demonstrated the benefits of fibrates (gemfibrozil, bezafibrate, and fenofibrate), alone or as combination therapy in patients with low HDL cholesterol and elevated triglyceride levels. In these studies, improvements in HDL cholesterol and triglycerides were associated with significantly less progression of stenosis than placebo, despite a lack of effect on LDL cholesterol levels (Figure 1).

Clinical Benefits of Fibrates

The cardiovascular benefits of fibrates have also been demonstrated clinically. The incidence of adverse cardiovascular events was reduced 34% in the Helsinki Heart Study,⁴ 22% in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT),⁵ and 36% in the Stockholm Ischaemic Heart Disease Secondary Prevention Study⁷ (Figure 2).

In the Helsinki Heart Study,⁴ the greatest cardiovascular benefit associated with gemfibrozil therapy was observed in patients who had low HDL cholesterol levels and high triglyceride levels at baseline. In VA-HIT,⁵ moderate increases in HDL cholesterol (5 mg/dL) were associated with significant risk reduction (11%) in patients with low HDL cholesterol and normal LDL cholesterol levels over 5 years. (Patients with characteristics of type 2 diabetes and the metabolic syndrome demonstrated the greatest benefit.) In the Stockholm Secondary Prevention Study,⁷ the ischemic heart disease death rate was reduced 60% in patients who experienced reductions in triglycerides >30%. Lastly, patients with baseline triglyceride levels >200 mg/dL who participated in the Bezafibrate Infarction Prevention (BIP) study,⁶ experienced a 39.5% decrease in adverse cardiovascular events (P = .02) Although we do not have results from a study directly and prospectively addressing the issue, there is strong evidence that the population with insulin resistance, high triglycerides and low HDL cholesterol are particularly benefited by treatment with fibrates.

Niacin Alone and in Combination with Other Lipid-lowering Drugs

Results of trials using niacin, resins, and statins further support the beneficial effects of treating low HDL cholesterol and high triglycerides to prevent adverse cardiovascular outcomes. Niacin was associated with a 27% decrease in nonfatal myocardial infarction over 5 years and an 11% decrease in mortality over 15 years in a secondary prevention trial (the Coronary Drug Project).²² Niacin and simvastatin therapy were associated with a >60% reduction in cardiovascular events and decreased angiographic progression compared to "usual care" in patients with normal to low HDL cholesterol levels who participated in a community-based study.²³ However, the addition of antioxidant vitamins to the regimen appeared to blunt the HDL cholesterol benefit thus reducing the benefit for a decrease in cardiovascular events and angiographic improvement. Lastly, combination niacin plus resin or lovastatin plus resin therapies were associated with reduced progression of stenosis.^24-26 The beneficial effects observed in this latter trial were attributed to both reductions in LDL cholesterol and increases in HDL cholesterol levels.

Clinical Implications

Low levels of HDL cholesterol and elevated levels of triglycerides are clearly associated with increased cardiovascular risk. Evidence from several large, well-designed clinical trials supports aggressive treatment of abnormal triglyceride levels when associated with low HDL cholesterol, even in patients with LDL cholesterol levels that are near or within target levels (Table 1). Specifically, fibrate therapy should be initiated in patients with low HDL cholesterol (<40 mg/dL) and low LDL cholesterol (<130 mg/dL) who have increased cardiovascular risk (>20% global risk and/or type 2 diabetes, with or without clinically significant atherosclerotic disease). Fibrate therapy is recommended for these patients in patients who have triglycerides >150 mg/dL. Niacin is recommended as second-line therapy, as there is less evidence to support its cardiovascular benefits and some concern regarding its safety. LDL cholesterol-lowering drugs (resins or statins) can be added if LDL cholesterol levels progress outside the normal range. In consideration of the recent data from the Heart Protection Study²⁷ and the ASCOT trial,²⁸ one must consider statins as the preferred drug in very high-risk patients whose LDL cholesterol is in the vicinity of 100 mg/dL and whose triglycerides are not elevated.

Conclusion

Substantial evidence exists to support the relationships between low HDL cholesterol levels and elevated triglyceride levels and increased cardiovascular risk. This is particularly true in type 2 diabetes and the metabolic syndrome. LDL cholesterol control remains the first order for management of risk, but aggressive treatment of elevated triglyceride with HDL cholesterol elevation can significantly reduce stenotic progression and reduce the risk for adverse cardiovascular outcomes, even when there is no added effect on LDL cholesterol. Fibrates, and secondarily niacin, should be considered for patients who have these lipid abnormalities.

References

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