SciELO - Scientific Electronic Library Online

vol.34 issue2Evaluation of radioinduced damage and repair capacity in blood lymphocytes of breast cancer patientsImmunophenotype of normal and leukemic bone marrow B-precursors in a Brazilian population. A comparative analysis by quantitative fluorescence cytometry author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




Related links


Brazilian Journal of Medical and Biological Research

Print version ISSN 0100-879XOn-line version ISSN 1414-431X

Braz J Med Biol Res vol.34 no.2 Ribeirão Preto Feb. 2001 

Braz J Med Biol Res, February 2001, Volume 34(2) 177-182

Etofibrate but not controlled-release niacin decreases LDL cholesterol and lipoprotein (a) in type IIb dyslipidemic subjects

A.C. Sposito, A.P. Mansur, R.C. Maranhão, C.R.M. Rodrigues-Sobrinho, O.R. Coelho and J.A.F. Ramires

Divisão de Coronária, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil

Material and Methods
Correspondence and Footnotes


Etofibrate is a hybrid drug which combines niacin with clofibrate. After contact with plasma hydrolases, both constituents are gradually released in a controlled-release manner. In this study, we compared the effects of etofibrate and controlled-release niacin on lipid profile and plasma lipoprotein (a) (Lp(a)) levels of patients with triglyceride levels of 200 to 400 mg/dl, total cholesterol above 240 mg/dl and Lp(a) above 40 mg/dl. These patients were randomly assigned to a double-blind 16-week treatment period with etofibrate (500 mg twice daily, N = 14) or niacin (500 mg twice daily, N = 11). In both treatment groups total cholesterol, VLDL cholesterol and triglycerides were equally reduced and high-density lipoprotein cholesterol was increased. Etofibrate, but not niacin, reduced Lp(a) by 26% and low-density lipoprotein (LDL) cholesterol by 23%. The hybrid compound etofibrate produced a more effective reduction in plasma LDL cholesterol and Lp(a) levels than controlled-release niacin in type IIb dyslipidemic subjects.

Key words: etofibrate, niacin, lipoprotein (a), triglycerides, cholesterol


Fibrates and niacin have been successfully used to reduce triglyceride plasma concentration, with the additional benefit of increasing the levels of antiatherogenic high-density lipoprotein (HDL) cholesterol. The two drugs have synergistic effects on triglycerides and HDL with a considerable reducing action on low-density lipoprotein (LDL) cholesterol. Moreover, it has been observed that the combination of the two drugs leads to a substantial reduction in coronary artery disease (CAD) events (1-4). The advantages of this drug combination has led to the development of etofibrate in which clofibrate and niacin are covalently linked. In contact with plasma hydrolases, both constituents are gradually released, displaying a pharmacokinetic behavior similar to that of controlled-release formulations (5).

Some studies have shown that the traditional forms of niacin and fibrate could be of additional benefit by reducing plasma lipoprotein (a) (Lp(a)) levels (6-10). Lp(a) is an LDL-like lipoprotein, differentiated from LDL by the presence of an additional large protein molecule, the so-called apolipoprotein (a) (apo(a)) which is linked to apo B through disulfide bridges (11-14). Similarly to LDL, a high Lp(a) concentration in plasma has been associated with the prevalence and severity of CAD (15-18). This may be due to several causes, one of them related to apo(a) homology with plasminogen, the zymogen of plasmin, that presumptively results in competitive inhibition of fibrinolysis (19-23). Lp(a) may also accumulate in the subendothelium where it binds with high affinity to extracellular matrix components (24). The effect of controlled-release forms of fibrates and niacin on Lp(a) levels has not been explored in all its relevant aspects. In the present investigation, we sought to compare the effects of etofibrate with those of controlled-release niacin on Lp(a) and plasma lipid profile in patients with type IIb dyslipidemia.

Material and Methods


Thirty consecutive patients submitted to clinical evaluation at the coronary outpatient clinic of the Heart Institute were enrolled in this study. The inclusion criteria were plasma concentration of Lp(a) above 40 mg/dl, total cholesterol above 240 mg/dl and triglyceride between 200 and 400 mg/dl in the last two measurements. The exclusion criteria were liver, renal, metabolic, inflammatory or neoplastic disease, alcoholism or known hypersensitivity to niacin or etofibrate. Patients with unstable angina or myocardial infarction during the last 6 months and diabetic patients with plasma glucose above 135 mg/dl or HbA1c above 7.5% were also excluded. The step-one diet of the National Cholesterol Education Program (NCEP) of the American Heart Association was recommended to all patients three months before randomization. At randomization, all patients were taking only nitrates, whose doses were not changed during the study. The patients were randomly selected for a double-blind treatment period with either 500 mg etofibrate (Tricerol®, Searle, São Paulo, SP, Brazil) or 500 mg polygel controlled-release niacin (Slo-Niacin®, Upsher-Smith Laboratories, Inc., Minneapolis, MN, USA) administered twice a day for a 16-week period. Etofibrate and niacin were placed in new vials labeled with the patient number and the vials were given directly to the patients by a research assistant. During the 4-week evaluation one patient in the etofibrate group and 4 in the niacin group did not return for study evaluation and were lost to follow-up. Thus, the final etofibrate group consisted of 14 subjects (12 males), mean age 56 ± 5 years, and the niacin group consisted of 11 subjects (8 males), mean age 57 ± 7 years. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the Heart Institute and all subjects gave informed consent to participate in the study.

Lipid and lipoprotein determinations

The first measurement after the diet period was considered to represent baseline values. Blood samples were obtained after a 12-h overnight fast, at baseline and after 4, 8, 12 and 16 weeks of treatment. Commercial enzymatic methods were used for the determination of total plasma cholesterol (CHOD-PAP, Boehringer-Mannheim Corp., Mannheim, Germany) and triglyceride concentration (Abbott Laboratories, North Chicago, IL, USA). HDL cholesterol was assayed by the same enzymatic method as for total cholesterol after precipitation of apo B lipoproteins with magnesium phosphotungstate. Very-low-density lipoprotein cholesterol and LDL cholesterol were calculated by the Friedewald formula (25). Plasma Lp(a) level was determined by radioimmunoassay using a kit supplied by Pharmacia (Uppsala, Sweden) (26). This assay is based on the determination of the apo(a) moiety of Lp(a).

Statistical analysis

All data are reported as means ± standard deviation. Plasma lipid variations were evaluated by analysis of variance (ANOVA). When the overall difference was statistically significant, differences within the evaluations were tested by the a posteriori Bonferroni test. Comparison between groups was performed by the Student t-test or Mann-Whitney test to analyze parametric and nonparametric data, respectively. Differences were considered significant when the probability value was <0.05.


There was no difference between the etofibrate and niacin groups regarding age, male/female ratio, frequency of smoking, hypertension, diabetes or body mass index values, and baseline plasma lipid and lipoprotein concentrations (Table 1). Table 2 shows the mean results and percent variation of plasma lipid and Lp(a) concentrations. There was no significant difference between the plasma lipid and lipoprotein concentrations determined before admission to the study and at baseline after the dietary orientation period (Table 2). Both drugs reduced total cholesterol, VLDL cholesterol and triglyceride levels to the same extent and were equally effective in enhancing HDL cholesterol. However, etofibrate markedly reduced plasma Lp(a) concentration by 26% and LDL cholesterol by 23%, an effect not obtained with niacin. LDL cholesterol tended to be reduced by 14% in the niacin group but its reduction was not statistically significant (P = 0.07).

None of the patients who completed the study reported any side effects after either drug. However, since 5 patients were lost to follow-up, we cannot assure the absence of side effects. For the 3 diabetic patients included there was no clinically significant alteration in plasma glucose concentration after niacin (114 and 124 mg/dl before treatment and 116 and 112 mg/dl after treatment, respectively) or etofibrate (106 mg/dl before treatment and 111 mg/dl after treatment). Regarding liver toxicity, there was no significant increase in alanine aminotransferase or aspartate aminotransferase after treatment with either drug (Table 3).


It is apparent from our results that etofibrate is more effective as an LDL cholesterol-lowering agent than niacin alone. Likewise, comparing our data with those obtained in the literature after treatment with fibrates, it seems that etofibrate produced a greater LDL cholesterol reduction (27-29). The main mechanism whereby fibrates reduce LDL cholesterol is probably by increasing LDL removal from plasma (29). This fibrate effect could be a result of the reduction of apo CIII, achieved by the activation of peroxisome proliferator-activated receptors (30). Recently, it was reported that niacin accelerates hepatic intracellular post-translational degradation of apo B, resulting in decreased apo B secretion by hepatocytes (31). A trend towards LDL cholesterol reduction (P = 0.07) was observed in the niacin group, suggesting that the niacin moiety of etofibrate somehow contributed to the reduction of LDL cholesterol in the etofibrate group. Thus, it is possible that a combination of decreased synthesis and increased catabolism may account for the higher LDL cholesterol reduction observed in the etofibrate-treated patients.

Despite the structural similarity of Lp(a) to LDL particles and the presence of the LDL receptor ligand, i.e., apo B, only 25% of the plasma Lp(a) pool is removed by means of the LDL receptor (32). The presence of apo(a) is assumed to be the factor diminishing the affinity of Lp(a) for the receptor, since dissociation of the protein by cleavage of the disulfide linkages results in binding affinity similar to that of LDL (33). The apo(a) interference in the apo B binding domain of LDL receptor is probably the mechanism whereby lipid-lowering drugs that increase the expression of LDL receptors, such as statins, are ineffective in reducing plasma Lp(a) concentrations (6,34,35).

By an unknown mechanism of action, fibrate treatment and the use of estrogen as a contraceptive or for hormone replacement therapy consistently reduce plasma Lp(a) concentrations (6-8,36-39). Other drug therapies that have produced a significant reduction in Lp(a) concentration include niacin alone or in combination with a bile acid sequestrant or neomycin (9,10,40). Niacin reduces Lp(a) levels without affecting the fractional catabolic rate of the lipoprotein, suggesting that treatment with this drug decreases the rate of Lp(a) synthesis and not its removal from plasma (41). In the traditional form, niacin at 4 g/day decreased the plasma Lp(a) concentrations by 38% in hypercholesterolemic patients (9). However, it is very difficult to maintain patient compliance with this dosage due to the side effects of niacin and lower doses of sustained-release niacin are more tolerable. Because of the pharmacokinetic behavior of the drug, lower doses of sustained-release niacin have also been suggested to have comparable effects on plasma lipid and lipoproteins in comparison with the regular doses of traditional niacin. Recently, some sustained-release forms of niacin have been shown to reduce Lp(a) (42,43). Nonetheless, this was not observed in the present study using treatment with a polygel controlled-release niacin. These contradictory results may be due to different study populations or to pharmacokinetic differences in these sustained-release forms. A comparative study of these sustained-release forms is necessary to unravel possible pharmacokinetic differences.

After contact with plasma hydrolases both constituents of etofibrate (clofibrate and niacin) are gradually released with a pharmacokinetic behavior similar to that of sustained-release forms. Therefore, the action of etofibrate on Lp(a) may either be caused by the fibrate moiety of the compound or by the niacin moiety, since treatment with either drug administered alone causes this effect. Klör et al. (44) reported a 16.6% reduction of plasma Lp(a) levels after a short (one month) treatment period with 1 g/day etofibrate in patients with Lp(a) above 50 mg/dl. In our study, with the same dose we showed that a prolonged (4 months) treatment period may result in a greater (26%) Lp(a) reduction. Nevertheless, it should be pointed out that our patients had somewhat lower pretreatment Lp(a) values that might eventually have influenced the outcome of treatment.

Since the present study was not designed to determine the lipid-lowering effect of the NCEP step-one diet, we included patients that were already following the routine dietary orientation for CAD patients of the Heart Institute. Therefore, it is not unexpected that there was no difference in the plasma lipid concentrations determined before admission to the study and at baseline.

In conclusion, we observed that etofibrate was more efficient than polygel controlled-release niacin in reducing plasma LDL cholesterol and Lp(a) levels in patients with type IIb dyslipidemia and Lp(a) above 40 mg/dl.


1. Cayen MN, Robinson WT, Dubuc J & Dvornik D (1979). Pharmacokinetics and hypolipidemic activity of clofibrate-nicotinic acid combinations in rats. Biochemical Pharmacology, 28: 1163-1167.        [ Links ]

2. Rosenhamer G & Carlson LA (1980). Effect of combined clofibrate-nicotinic acid treatment in ischemic heart disease. Atherosclerosis, 37: 129-142.        [ Links ]

3. Carlson LA, Danielson M, Ekberg I, Klintemar B & Rosenhamer G (1977). Reduction of myocardial reinfarction by the combined treatment with clofibrate and nicotinic acid. Atherosclerosis, 28: 81-86.        [ Links ]

4. Carlson LA & Rosenhamer G (1988). Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Medica Scandinavica, 223: 405-418.        [ Links ]

5. Series JJ, Caslake MJ, Kilday C, Cruickshank A, Demant T, Packard CJ & Shepherd J (1988). Influence of etofibrate on low density lipoprotein metabolism. Atherosclerosis, 69: 233-239.        [ Links ]

6. Ramires JAF, Mansur AP, Solimene MC, Maranhão R, Chamone D, da Luz P & Pileggi F (1995). Effects of gemfibrozil versus lovastatin on increased serum lipoprotein (a) levels of patients with hypercholesterolemia. International Journal of Cardiology, 48: 115-120.        [ Links ]

7. Ramires JAF, Sposito AC, Mansur AP, Solimene MC, Chamone D, da Luz PL & Pileggi F (1997). Gemfibrozil reduces elevated lipoprotein (a) levels in hypercholesterolemic patients. Arquivos Brasileiros de Cardiologia, 68: 257-260.        [ Links ]

8. Bimmerman A, Boerschmann C, Schwartzkoff W, von Bayer H & Schleicher J (1991). Effective therapeutic measures for reducing lipoprotein (a) in patients with dyslipidemia. Lipoprotein (a) reduction with sustained-release bezafibrate. Current Therapeutic Research, Clinical and Experimental, 49: 635-643.        [ Links ]

9. Carlson LA, Hamsten A & Asplund A (1989). Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. Journal of Internal Medicine, 226: 271-276.        [ Links ]

10. Gurakar A, Hoeg JM, Kostner G, Papadopoulos NM & Brewer Jr HB (1985). Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis, 57: 293-301.        [ Links ]

11. Gaubatz JW, Heideman C, Gotto Jr AM, Morrisett JD & Dahien GH (1983). Human plasma lipoprotein (a) - structural properties. Journal of Biological Chemistry, 254: 4582-4589.        [ Links ]

12. Simons K, Ehnholm C, Renkonen O & Bloth B (1970). Characterization of the lipoprotein (a) lipoprotein in human plasma. Acta Pathologica et Microbiologica Scandinavica, 78: 459-466.        [ Links ]

13. Gaubatz JW, Chari MV, Nava ML & Guyton JR (1987). Isolation and characterization of the two major apoproteins in human lipoprotein (a). Journal of Lipid Research, 28: 69-79.        [ Links ]

14. Fless GM, Rolih CA & Scanu AM (1984). Heterogeneity of human plasma lipoprotein (a). Isolation and characterization of the lipoprotein subspecies and their apoproteins. Journal of Biological Chemistry, 259: 11470-11478.        [ Links ]

15. Scanu AM & Fless GM (1990). Lipoprotein (a) heterogeneity and biological relevance. Journal of Clinical Investigation, 85: 1709-1715.        [ Links ]

16. Cambillau M, Simon A, Amar J, Giral P, Atger P, Segond P, Levenson J, Merli I & PCVMETRA Group (1992). Serum Lp(a) as a discriminant marker of early atherosclerotic plaque at three extracoronary sites in hypercholesterolemic men. Arteriosclerosis and Thrombosis, 12: 1346-1352.        [ Links ]

17. Loscalzo J (1990). Lipoprotein(a): a unique risk factor for atherothrombotic disease. Arteriosclerosis, 10: 672-679.        [ Links ]

18. Armstrong VW, Cremer P, Eberle E, Manke A, Schulze F, Wieland H, Kreuzer H & Seidel D (1986). The association between serum Lp(a) concentrations and angiographically assessed coronary atherosclerosis. Dependence on serum LDL levels. Atherosclerosis, 62: 249-257.        [ Links ]

19. Loscalzo J, Weinfeld M, Fless GM & Scanu AM (1990). Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis, 10: 240-245.        [ Links ]

20. Harpel PC, Gordon BR & Parker JS (1989). Plasminogen catalyzes binding of lipoprotein (a) to immobilized fibrinogen and fibrin. Proceedings of the National Academy of Sciences, USA, 86: 3847-3851.        [ Links ]

21. Rouy D, Grailhe P, Nigon F, Chapman J & Angles-Cano E (1991). Lipoprotein (a) impairs the generation of plasmin by fibrin bound t-PA. In vitro studies in a plasma milieu. Arteriosclerosis and Thrombosis, 11: 629-638.        [ Links ]

22. Miles LA, Fless GM, Levin EG, Scanu AM & Plow EF (1989). A potential basis for the thrombotic risks associated with Lp(a). Nature, 339: 301-303.        [ Links ]

23. Hajjar KA, Gavish D, Breslow JL & Nachman RL (1989). Lipoprotein (a) modification of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature, 339: 303-305.        [ Links ]

24. Beisiegel U (1991). Lipoprotein (a) in the arterial wall. Current Opinion in Lipidology, 2: 317-321.        [ Links ]

25. Friedewald WT, Levy RI & Fredrickson DS (1972). Estimation of low-density lipoprotein cholesterol in plasma without use of preparative ultracentrifuge. Clinical Chemistry, 18: 499-502.        [ Links ]

26. Albers JJ, Adolphson JL & Hazzard WR (1977). Radioimmunoassay of human plasma lipoprotein (a) lipoprotein. Journal of Lipid Research, 18: 331-338.        [ Links ]

27. Ruotolo G, Ericsson CG, Tettamanti C, Karpe F, Grip L, Svane B, Nilsson J, de Faire U & Hamsten A (1998). Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). Journal of the American College of Cardiology, 32: 1648-1656.        [ Links ]

28. Durrington PN, Mackness MI, Bhatnagar D, Julier K, Prais H, Arrol S, Morgan J & Wood GN (1998). Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Atherosclerosis, 138: 217-225.        [ Links ]

29. Grundy SM & Vega GL (1987). Fibric acids: effects on lipids and lipoprotein metabolism. American Journal of Medicine, 83: 9-20.        [ Links ]

30. Haubenwallner S, Essenburg AD, Barnett BC, Pape ME, DeMattos RB, Krause BR, Minton LL, Auerbach BJ, Newton RS & Leff T (1995). Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. Journal of Lipid Research, 36: 2541-2551.        [ Links ]

31. Jin FY, Kamanna VS & Kashyap ML (1999). Niacin accelerates intracellular apo B degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (HepG2) cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 19: 1051-1059.        [ Links ]

32. Snyder ML, Polacek D, Scanu AM & Fless GM (1992). Comparative binding and degradation of lipoprotein (a) and low density lipoprotein by human monocyte-derived macrophages. Journal of Biological Chemistry, 267: 339-346.        [ Links ]

33. Armstrong VW, Walli AK & Seidel D (1985). Isolation, characterization, and uptake in human fibroblasts of an apo(a)-free lipoprotein obtained on reduction of lipoprotein(a). Journal of Lipid Research, 26: 1314-1323.        [ Links ]

34. Jacob BG, Richter WO & Schwandt P (1990). Lovastatin, pravastatin and serum lipoprotein (a). Annals of Internal Medicine, 112: 713-714 (Letter).        [ Links ]

35. Kostner GM, Gavish D, Leopold B, Bolzano K, Weitraub MS & Breslow JL (1989). HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation, 80: 1313-1319.        [ Links ]

36. Schram JH, Boerrigter PJ & The TY (1995). Influence of two hormone replacement therapy regimens, oral oestradiol valerate and cyproterone acetate versus transdermal oestradiol and oral dydrogesterone, on lipid metabolism. Maturitas, 22: 121-130.        [ Links ]

37. Porkka KV, Erkkola R, Taimela S, Raitakari OT, Dahlen GH & Viikari JS (1995). Influence of oral contraceptive use on lipoprotein (a) and other coronary heart disease risk factors. Annals of Medicine, 27: 193-198.        [ Links ]

38. Gilabert J, Estelles A, Cano A, Espana F, Barrachina R, Grancha S, Aznar J & Tortajada M (1995). The effect of estrogen replacement therapy with or without progestogen on the fibrinolytic system and coagulation inhibitors in postmenopausal status. American Journal of Obstetrics and Gynecology, 173: 1849-1854.        [ Links ]

39. Kim CJ, Min YK, Ryu WS, Kwak JW & Ryoo UH (1996). Effect of hormone replacement therapy on lipoprotein (a) and lipid levels in postmenopausal women. Influence of various progestogens and duration of therapy. Archives of Internal Medicine, 156: 1693-1700.        [ Links ]

40. Spinler SA & Cziraky MJ (1994). Lipoprotein(A): physiologic function, association with atherosclerosis, and effects of lipid-lowering drug therapy. Annals of Pharmacotherapy, 28: 343-351.        [ Links ]

41. Seed M, O'Connor B, Perombelon N, O'Donnell M, Reaveley D & Knight BL (1993). The effect of nicotinic acid and acipimox on lipoprotein (a) concentration and turnover. Atherosclerosis, 101: 61-68.        [ Links ]

42. Lepre F, Campbell B, Crane S & Hickman P (1992). Low-dose sustained release nicotinic acid (Tri-B3) and lipoprotein (a). American Journal of Cardiology, 70: 133.        [ Links ]

43. Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA, Brusco OA & Brody J (1998). Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. American Journal of Cardiology, 82: 74U-81U.        [ Links ]

44. Klör E, Loy S & Huth K (1994). Effects of etofibrate therapy on high lipoprotein (a) levels in patients with hypercholesterolemia. Current Therapeutic Research, Clinical and Experimental, 55: 988-996.        [ Links ]

Correspondence and Footnotes

Address for correspondence: J.A.F. Ramires, Grupo de Coronariopatias, Divisão Clínica, Instituto do Coração, HC, FM, USP, Av. Dr. Eneas C. Aguiar, 44, 05403-000 São Paulo, SP, Brasil. Fax: +55-11-3069-5310.

Publication supported by FAPESP. Received February 2, 2000. Accepted November 17, 2000.

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License