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Circulation. 1997;96:2113-2114

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(Circulation. 1997;96:2113-2114.)
© 1997 American Heart Association, Inc.

Articles

Benefits of Fibrate Drugs in Coronary Heart Disease Patients With Normal Cholesterol Levels

Richard J. Havel, MD

From the Cardiovascular Research Institute, University of California, San Francisco.

Correspondence to Richard J. Havel, MD, Professor of Medicine, Cardiovascular Research Institute, University of California, San Francisco, 505 Parnassus Avenue, L-1337, San Francisco, CA 94143-0130. E-mail havelr{at}itsa.ucsf.edu


Key Words: Editorials • coronary disease • cholesterol • fibrates


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
Most young and middle-aged persons who develop coronary heart disease (CHD) have some form of dyslipidemia with mild to moderate increases in plasma cholesterol or triglyceride concentrations (or both), often accompanied by reduced concentrations of HDL cholesterol. In such patients, treatment with diet or drugs directed mainly at lowering the concentration of atherogenic lipoproteins reduces the progression of coronary artery atherosclerotic disease and associated clinical events and prolongs life.1 Although many patients with CHD have abnormalities affecting all of the major lipoprotein classes (VLDL, LDL, and HDL), in some only a single class is affected. Low HDL cholesterol is a powerful risk factor for CHD, even when total cholesterol concentrations are normal.2 Although low HDL cholesterol is usually accompanied by increased VLDL cholesterol and triglyceride concentrations in populations (but not by high concentrations of LDL cholesterol),3 isolated low HDL cholesterol is frequent in CHD patients.4

How to manage patients with isolated low HDL cholesterol, particularly those with manifest atherosclerotic vascular disease, is unclear. Increased physical activity and judicious use of alcoholic beverages can increase HDL cholesterol, usually modestly. Drugs that increase HDL cholesterol generally lower atherogenic lipoprotein concentrations as well, and the benefit of such drug use is generally ascribed primarily to reduced concentrations of these lipoproteins, especially LDL. However, recent observational studies and some clinical trials have placed increased emphasis on changes in components of VLDL as determinants of the progression of coronary artery atherosclerosis, assessed angiographically. For example, in the Montreal Heart Study,5 the concentration of cholesterol associated with remnants of triglyceride-rich lipoproteins but not LDL cholesterol predicted both progression of coronary artery atherosclerosis and associated clinical events, and in the Monitored Atherosclerosis Progression Study,6 components associated with high VLDL concentrations predicted progression of mild and moderate but not severe coronary artery atherosclerosis in patients randomized to placebo or lovastatin therapy.

Drugs of the fibrate class are usually prescribed to lower triglyceride concentrations in patients with normal or only slightly elevated concentrations of LDL. In the Helsinki Heart Study,7 a primary prevention trial, treatment with gemfibrozil reduced the incidence of CHD manifestations in individuals with high plasma triglyceride concentrations (>200 mg/dL [2.3 mmol/L]) and a ratio of LDL cholesterol to HDL cholesterol >5, but not in those lacking one or both of these abnormalities. Recently, in another fibrate trial conducted in Sweden, the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT),8 drug treatment slowed progression of coronary artery stenoses in young myocardial infarction survivors and dramatically reduced coronary events (from 11 to 3). Drug treatment reduced VLDL cholesterol and triglycerides by {approx}36% and increased HDL cholesterol by 9%. Notably, LDL cholesterol concentrations were unaffected.

In this issue of Circulation, Frick et al9 report a much larger Finnish angiographic trial of the effect of gemfibrozil on progression of coronary artery atherosclerosis in patients after coronary artery bypass surgery who had isolated low HDL cholesterol. The Lipid Coronary Angiography Trial (LOCAT) involved 372 patients who were randomized to gemfibrozil or placebo and had two angiograms separated by an average of 32 months. Patients with LDL cholesterol >174 mg/dL (4.5 mmol/L) or serum triglycerides >354 mg/dL (4.0 mmol/L) were excluded, as were patients with HDL cholesterol >42.5 mg/dL (1.1 mmol/L). Mean concentrations of these analytes were 140 mg/dL (3.63 mmol/L), 143 mg/dL (1.64 mmol/L), and 31.2 mg/dL (0.82 mmol/L), respectively. Although some patients may have had hypertriglyceridemia, average HDL cholesterol concentrations were much lower than would be expected from the concentration of serum triglycerides,3 consistent with the designation of isolated low HDL cholesterol. Treatment with bezafibrate reduced coronary artery disease progression by several criteria in native vessels and reduced the development of graft lesions but did not affect lesions distal to graft insertions. As in the other fibrate trials, drug treatment mainly reduced VLDL triglyceride concentrations by {approx}40% and increased HDL cholesterol concentrations by {approx}15% compared with the placebo group. LDL cholesterol concentrations were reduced by {approx}10% compared with the placebo group, as expected for patients with relatively normal plasma triglyceride concentrations.

The data reported thus far from LOCAT provide some support for using drugs of the fibrate series to treat CHD patients with normal concentrations of atherogenic lipoproteins and low HDL cholesterol. Indeed, the favorable angiographic outcome was comparable to that achieved by treating CHD patients who had higher cholesterol concentrations with other drugs, particularly those of the statin class. Statins, however, may reduce coronary events in patients with normal as well as high plasma cholesterol concentrations.10 Yet to be reported from LOCAT are detailed lipoprotein and other biochemical studies and information on the relationship between the metabolic effects of gemfibrozil treatment and outcome. Although the mean concentration of plasma triglycerides was normal in this study, the concentration in some patients may have exceeded 200 mg/dL (2.3 mmol/L), corresponding to those who benefited clinically from treatment with gemfibrozil in the Helsinki Heart Study.7 Fibrates also have well-defined effects on hemostatic functions, including reducing the concentration of fibrinogen, as observed in BECAIT,8 which could also influence disease progression.

Information relating angiographic outcome to other patient characteristics in LOCAT will also be of interest. More than 80% of patients were taking ß-blockers, which reduce HDL cholesterol concentrations, leaving only a small number of patients for separate assessment. The exclusion criterion for fasting serum glucose concentration was 140 mg/dL (7.8 mmol/L), so that some patients clearly had some impairment of glucose tolerance, if not frank diabetes. Analyses in this regard could be applied to the placebo group as well as the gemfibrozil group, as could information about other behaviors influencing HDL concentrations, such as physical activity and alcohol use.

The results of LOCAT also provide support for the thesis that the beneficial effects of lipid-modifying drugs apply to multiple classes with distinct modes of action. The statins reduce hepatic cholesterol synthesis, thereby increasing the number of LDL receptors in the liver,11 whereas fibrates activate certain nuclear transcription factors (peroxisome proliferator–activated receptors) that alter the synthesis of several plasma apolipoproteins as well as lipoprotein lipase.12 Thus, although such drugs may have other actions as well, their effects are likely to be mediated in large part through their effects on plasma lipoproteins. Drugs of the fibrate class, as well as statins and other drugs, do not have discrete effects within the spectrum of plasma lipoproteins, however. Although fibrates have been used mainly to reduce VLDL concentrations and statins to reduce LDL concentrations, the latter effectively reduce VLDL cholesterol (and IDL cholesterol, generally included with LDL cholesterol in clinical studies), and both classes of drug increase HDL cholesterol concentrations. Thus, it is appropriate to be cautious about assigning a treatment benefit to the change in a single lipoprotein class. In LOCAT, the treatment benefit could be related to reduced concentration of components of VLDL (including remnant lipoproteins), alterations in the size and properties of LDL (such as reduced concentrations of small, dense LDL), increased concentration or altered properties of HDL (affecting reverse cholesterol transport or oxidative modification of atherogenic lipoproteins), or alterations of hemostatic functions, such as reduced concentration of fibrinogen. More detailed analyses expected from LOCAT may provide some insights into the mechanism by which gemfibrozil reduced the progression of coronary lesions, but such analyses are unlikely to be definitive.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Havel RJ, Rapaport E. Management of primary hyperlipidemia. N Engl J Med. 1995;332:1491-1498.[Free Full Text]
  2. Adult Treatment Panel II. National Cholesterol Education Program: second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Circulation. 1994;89:1333-1445.[Medline] [Order article via Infotrieve]
  3. Myers LH, Phillips NR, Havel RJ. Mathematical evaluation of methods for estimation of the concentration of the major lipid components of human serum lipoproteins. J Lab Clin Med. 1976;88:491-505.[Medline] [Order article via Infotrieve]
  4. Lamarch B, Després J-P, Moorjani S, Cantin B, Dagenais GR, Lupien P-J. Triglycerides and HDL cholesterol as risk factors for ischemic heart disease: results from the Québec cardiovascular study. Atherosclerosis. 1996;119:235-245.[Medline] [Order article via Infotrieve]
  5. Phillips NR, Waters D, Havel RJ. Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation. 1993;88:2762-2770.[Abstract/Free Full Text]
  6. Hodis HN, Mack WJ, Azen SP, Alaupovic P, Pogoda JM, LaBree L, Hemphill LC, Kramsch DM, Blankenhorn DH. Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Circulation. 1994;90:42-49.[Abstract/Free Full Text]
  7. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Mänttäri M, Heinonen OP, Frick MH. Joint effects of serum triglycerides and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation. 1992;85:37-45.[Abstract/Free Full Text]
  8. Ericsson C-G, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996;347:849-853.[Medline] [Order article via Infotrieve]
  9. Frick MH, Syvänne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesäniemi A, Pasternack A, Taskinen M-R, for the Lopid Coronary Angiography Trial (LOCAT) Study Group. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation. 1997;96:2137-2143.[Abstract/Free Full Text]
  10. Byrne C. Lipids and secondary prevention of ischaemic heart disease: lipid lowering treatment is now indicated for patients with "normal' cholesterol concentrations. BMJ. 1996;313:1273-1274.[Free Full Text]
  11. Tobert JA. New developments in lipid lowering therapy: the role of inhibitors of hydroxy methylglutaryl-coenzyme A reductase. Circulation. 1987;76:534-538.[Abstract/Free Full Text]
  12. Auwerx J, Schoonjans K, Fruchart J-C, Staels B. Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR. Atherosclerosis. 1996;124(suppl):S29-S37.



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