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Reduction of Lp(a) plasma levels by bezafibrate
Atherosclerosis, 100 (1993) 127- 128 0 1993 Elsevier Scientific Publishers Printed and Published in Ireland
ATHERO
Ireland,
Ltd. All rights reserved.
0021-9150/93/$06.00
05035
Letter to the Editors
Reduction of Lp(a) plasma levels by bezafibrate F.M. Maggia,b, G.M. Biasi” and A.L. Catapanoa,b Yeniro
per lo studio, la Prevenzione e la Terapia delle Vasculopatie Aterosclerotiche and blnstitute of Pharmacological Sciences. University of Milan, Milan (Italy) (Received (Accepted
9 February, 15 February,
1992) 1992)
Key words: Hypolipidemic drug; LDL; Apo B; Hypertriglyceridemia
Dear Editors,
Lp(a) is a plasma lipoprotein particle consisting of a plasminogen-like protein, ape(a), linked via a disulphide bridge to the apo B moiety of a low density lipoprotein (LDL) particle [l]. High plasma levels of Lp(a) are an independent risk factor for atherosclerotic disease [ 11. Current hypolipidaemic regimens do not satisfactorily lower plasma Lp(a). Low fat diets, or diets enriched with monounsaturated 06 fatty acids have no effects [2], diets rich in fish oil cause only a modest reduction of Lp(a) [3]. Furthermore, some powerful hypolipidaemic drugs are ineffective [4], with the exception of nicotinic acid [5,6]. In an open, non-controlled study, bezafibrate lowered plasma levels of Lp(a) in patients with high levels of Lp(a) [7]. To date no controlled studies have been reported. We report here the reCorrespondence to: Alberico L. Catapano, Pharmacological Sciences, Via Balzaretti, Italy. Tel.: 2-20488302; Fax: 2-29404961.
Ph.D., Institute of 9, 20133 Milano,
sults of a double blind study on the effects of a 6month treatment with bezatibrate on the plasma levels of Lp(a) in subjects with hyperlipidaemia Type IIa or b. All patients gave informed consent to the study and the study was approved by the Scientific Committee of the University Center. Fifty subjects with plasma levels of Lp(a) 2 12 U/d1 were admitted to the study and were randomly allocated to one of the two groups after a wash out period of 2 months: (A) bezafibrate retard 400 mg/day; (B) placebo; drug and placebo were given once a day in the evening. Seven patients dropped out from the study (3 bezafibrate, 4 placebo) for reasons, to the best of our knowledge, unrelated to the treatment. One patient died of myocardial infarction in the bezalibrate group. Plasma lipids and lipoproteins were evaluated by standard procedures, Lp(a) levels by a radioimmunoassay from Pharmacia (Uppsala, Sweden); inter and intra assay C.V. were 3.7% and 5% respectively. Bezatibrate significantly reduced (P < 0.01)
128 TABLE I PLASMA Lp(a) LEVELS BEFORE AND AFTER TREATMENT WITH BEZAFIBRATE Treatment
n
Lp(a) U/d1 f S.E.M. Time 0
Bezafibrate R 400 mg/day Placebo
??7.9
21
41.5
20
60.9 * 13.5
1 month
3 months
6 months
43.0 f 7.2;
40.3 f 7.1;’
41.3 f 8.2**
60.1 f 12.0
58.0 f 12.7
59.7 f 12.8
*P < 0.05 and **P < 0.01 vs. time 0, Student’s t-test for paired data.
total cholesterol from 260 f 33 to 220 f 19 mg/dl and LDL cholesterol from 185 f 30 to 147 ?? 22 mg/dl. bezafibrate Furthermore, significantly increased HDL cholesterol (+ 12%) and reduced plasma triglycerides (-31%) (both P < 0.01). All these parameters were not affected in the placebo group (not shown). The effect of bezafibrate on Lp(a) plasma levels reached statistical significance after 1 month of therapy (Table 1) and was sustained up to 6 months; placebo did not affect Lp(a) concentrations. Whether this effect is peculiar to bezafibrate or can be extended to the tibrate class remains to be addressed. Preliminary data indicate that this is not the case for gemfibrozil [8]. In recent years much attention has been focused on the interaction of risk factors in dyslipidaemic patients. The lowering of Lp(a) as well as the reduction of plasma levels of fibrinogen, a known risk factor for coronary artery disease, by bezafibrate [9] suggests that this drug may act on several metabolic derangements present in dyslipidaemic patients and can be of value when aiming at reducing the overall cardiovascular risk. Furthermore, the availability of a well tolerated drug that lowers Lp(a) levels sets the stage for evaluating the effect of Lp(a) reduction on coronary or peripheral artery disease.
References Utermann, G., The mysteries of lipoprotein(a), Sciences, 246 (1989) 904. Gavish, D., Azrolan, N., Cundey, K. et al., Fish oil reduces plasma Lp(a) levels and affects post prandial association of ape(a) with triglyceride rich lipoproteins, Clin. Res., A250 (1990) (Abstr.). Beil, F.U., Terres, W., Orgass, M. et al., Dietary fish oil lowers lipoprotein(a) in primary hypertriglyceridemia, Atherosclerosis, 90 (199 1) 95. Kostner, G.M., Gavish, D., Leopold, B. et al., HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels, Circulation, 80 (1989) 1313. Gurakar, A., Hoeg, J.M., Kostner, G. et al., Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment, Atherosclerosis, 57 (1985) 293. Carbon, L.A., Hamsten, A., and Asplund, A., Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid, J. Int. Med., 226 (1989) 271. Bimmermann, A., Boerschmann, C., Schwartzkopff, W., Von Baeyer, H. and Schleicher, J., Effective therapeutic measures for reducing lipoprotein(a) in patients with dyslipidemia: lipoprotein(a) reduction with sustainedrelease bezatibrate, Curr. Ther. Res. Clin. Exp., 49 (1991) 635. Jones, P.H., Gotto, A.M., Jr., Pownall, H.J., Patsch, W., Farmer, J.A., Payton-Ross, C., Cocanougher, B., Kimball, K., Ghazzaly, K.K. and Morrisett, J.D., Effect of gemfibrozil on plasma lipoprotein(a) levels in type Ha and IIb hyperlipoproteinemia, In: The Second International Conference on Lipoprotein(a), New Orleans, 1992, p. 130 (Abstr.). Niort, G., Bulgarelli, A., Cassader, M. and Pagano, G., Effect of short term treatment with bezatibrate on plasma fibrinogen, fibrinopeptide A, platelet activation and blood filterability in atherosclerotic hypertibrinogenemic patients, Atherosclerosis, 71 (1988) 113.
ATHERO
Ireland,
Ltd. All rights reserved.
0021-9150/93/$06.00
05035
Letter to the Editors
Reduction of Lp(a) plasma levels by bezafibrate F.M. Maggia,b, G.M. Biasi” and A.L. Catapanoa,b Yeniro
per lo studio, la Prevenzione e la Terapia delle Vasculopatie Aterosclerotiche and blnstitute of Pharmacological Sciences. University of Milan, Milan (Italy) (Received (Accepted
9 February, 15 February,
1992) 1992)
Key words: Hypolipidemic drug; LDL; Apo B; Hypertriglyceridemia
Dear Editors,
Lp(a) is a plasma lipoprotein particle consisting of a plasminogen-like protein, ape(a), linked via a disulphide bridge to the apo B moiety of a low density lipoprotein (LDL) particle [l]. High plasma levels of Lp(a) are an independent risk factor for atherosclerotic disease [ 11. Current hypolipidaemic regimens do not satisfactorily lower plasma Lp(a). Low fat diets, or diets enriched with monounsaturated 06 fatty acids have no effects [2], diets rich in fish oil cause only a modest reduction of Lp(a) [3]. Furthermore, some powerful hypolipidaemic drugs are ineffective [4], with the exception of nicotinic acid [5,6]. In an open, non-controlled study, bezafibrate lowered plasma levels of Lp(a) in patients with high levels of Lp(a) [7]. To date no controlled studies have been reported. We report here the reCorrespondence to: Alberico L. Catapano, Pharmacological Sciences, Via Balzaretti, Italy. Tel.: 2-20488302; Fax: 2-29404961.
Ph.D., Institute of 9, 20133 Milano,
sults of a double blind study on the effects of a 6month treatment with bezatibrate on the plasma levels of Lp(a) in subjects with hyperlipidaemia Type IIa or b. All patients gave informed consent to the study and the study was approved by the Scientific Committee of the University Center. Fifty subjects with plasma levels of Lp(a) 2 12 U/d1 were admitted to the study and were randomly allocated to one of the two groups after a wash out period of 2 months: (A) bezafibrate retard 400 mg/day; (B) placebo; drug and placebo were given once a day in the evening. Seven patients dropped out from the study (3 bezafibrate, 4 placebo) for reasons, to the best of our knowledge, unrelated to the treatment. One patient died of myocardial infarction in the bezalibrate group. Plasma lipids and lipoproteins were evaluated by standard procedures, Lp(a) levels by a radioimmunoassay from Pharmacia (Uppsala, Sweden); inter and intra assay C.V. were 3.7% and 5% respectively. Bezatibrate significantly reduced (P < 0.01)
128 TABLE I PLASMA Lp(a) LEVELS BEFORE AND AFTER TREATMENT WITH BEZAFIBRATE Treatment
n
Lp(a) U/d1 f S.E.M. Time 0
Bezafibrate R 400 mg/day Placebo
??7.9
21
41.5
20
60.9 * 13.5
1 month
3 months
6 months
43.0 f 7.2;
40.3 f 7.1;’
41.3 f 8.2**
60.1 f 12.0
58.0 f 12.7
59.7 f 12.8
*P < 0.05 and **P < 0.01 vs. time 0, Student’s t-test for paired data.
total cholesterol from 260 f 33 to 220 f 19 mg/dl and LDL cholesterol from 185 f 30 to 147 ?? 22 mg/dl. bezafibrate Furthermore, significantly increased HDL cholesterol (+ 12%) and reduced plasma triglycerides (-31%) (both P < 0.01). All these parameters were not affected in the placebo group (not shown). The effect of bezafibrate on Lp(a) plasma levels reached statistical significance after 1 month of therapy (Table 1) and was sustained up to 6 months; placebo did not affect Lp(a) concentrations. Whether this effect is peculiar to bezafibrate or can be extended to the tibrate class remains to be addressed. Preliminary data indicate that this is not the case for gemfibrozil [8]. In recent years much attention has been focused on the interaction of risk factors in dyslipidaemic patients. The lowering of Lp(a) as well as the reduction of plasma levels of fibrinogen, a known risk factor for coronary artery disease, by bezafibrate [9] suggests that this drug may act on several metabolic derangements present in dyslipidaemic patients and can be of value when aiming at reducing the overall cardiovascular risk. Furthermore, the availability of a well tolerated drug that lowers Lp(a) levels sets the stage for evaluating the effect of Lp(a) reduction on coronary or peripheral artery disease.
References Utermann, G., The mysteries of lipoprotein(a), Sciences, 246 (1989) 904. Gavish, D., Azrolan, N., Cundey, K. et al., Fish oil reduces plasma Lp(a) levels and affects post prandial association of ape(a) with triglyceride rich lipoproteins, Clin. Res., A250 (1990) (Abstr.). Beil, F.U., Terres, W., Orgass, M. et al., Dietary fish oil lowers lipoprotein(a) in primary hypertriglyceridemia, Atherosclerosis, 90 (199 1) 95. Kostner, G.M., Gavish, D., Leopold, B. et al., HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels, Circulation, 80 (1989) 1313. Gurakar, A., Hoeg, J.M., Kostner, G. et al., Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment, Atherosclerosis, 57 (1985) 293. Carbon, L.A., Hamsten, A., and Asplund, A., Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid, J. Int. Med., 226 (1989) 271. Bimmermann, A., Boerschmann, C., Schwartzkopff, W., Von Baeyer, H. and Schleicher, J., Effective therapeutic measures for reducing lipoprotein(a) in patients with dyslipidemia: lipoprotein(a) reduction with sustainedrelease bezatibrate, Curr. Ther. Res. Clin. Exp., 49 (1991) 635. Jones, P.H., Gotto, A.M., Jr., Pownall, H.J., Patsch, W., Farmer, J.A., Payton-Ross, C., Cocanougher, B., Kimball, K., Ghazzaly, K.K. and Morrisett, J.D., Effect of gemfibrozil on plasma lipoprotein(a) levels in type Ha and IIb hyperlipoproteinemia, In: The Second International Conference on Lipoprotein(a), New Orleans, 1992, p. 130 (Abstr.). Niort, G., Bulgarelli, A., Cassader, M. and Pagano, G., Effect of short term treatment with bezatibrate on plasma fibrinogen, fibrinopeptide A, platelet activation and blood filterability in atherosclerotic hypertibrinogenemic patients, Atherosclerosis, 71 (1988) 113.