Effect of gemfibrozil on levels of lipoprotein [ a ] in Type I 1 hyperlipoproteinemic subjects

Plasma lipoprotein[a] (Lp[a]) levels are highly correlated with angiographically demonstrable coronary heart disease, and elevated Lp[a] is an independent risk factor for atherosclerosis. Previous studies have provided evidence that the levels of Lp[a] and triglyceride are related, suggesting that Lp[a] might be altered by gemfibrozil, a drug well known for its efficacy in reducing plasma triglycerides. Accordingly, 18 type IIa and 16 type IIb hyperlipoproteinemic males aged 35-58 were treated for 3 months with 600 mg of gemfibrozil twice daily. The efficacy of the drug in altering lipid and lipoprotein levels was different in the two type groups. In type IIa and IIb subjects the respective changes in median levels were: total cholesterol, -7.5 and -8.5%; triglycerides, -35.6 and -54.4%; HDL-cholesterol, +9.0 and +11.0%; and Lp[a], -17.2 and +6.l%. Before and after gemfibrozil treatment, 7 type IIa and 10 type IIb subjects were given a 100 g/2 m* oral-fat load; triglycerides and Lp[a] were measured post-prandially at 0, 2, 4, 6, 8, and 10 h. The differences between beforeand aftergemfibrozil post-prandial curve integrated areas (PPCIA) were compared for triglycerides and Lp[a]. The changes in median PPCIA for triglycerides in types IIa and IIb were -54% and 53%, and for Lp[a] were -8% and +8%, respectively. I These results indicate i) that the levels of Lp[a] are about 2 times higher in type IIa than IIb subjects, and ii) that although gemfibrozil elicits a rather uniform decrease in fasting and post-prandial triglyceride levels in type IIa and IIb patients, the drug causes heterogeneous changes in Lp[a], suggesting that different metabolic mechanisms may be dominant in subjects showing opposing effects.-Jones, P. H., H. J. Pownall, W. Patsch, J. A. Herd, J. A. Farmer, C. PaytonRoss, K. T. Kimball, A. M. Cotto, and J. D. Morrisett. Effect of gemfibrozil on levels of lipoprotein[a] in Type I1 hyperlipoproteinemic subjects.J Lipid Res. 1996. 37: 1298-1308. Supplementary key words lipoproteins triglyceride postprandial lipemia apolipoproteins fibrates A number of different drugs developed for reducing plasma levels of cholesterol and triglyceride and/or the major lipoproteins transporting these lipids have also been tested for their capacity to reduce Lp[a] (1, 2). Atorvastatin, a new HMG-CoA reductase inhibitor, has recently been evaluated in patients with primary hypercholesterolemia. When the drug was administered at dosages of 5, 20, and 80 mg/day, LDL-cholesterol was markedly reduced by 29, 44, and 61%, but much less striking reductions of 4.0,7.9, and 14.2% were observed for Lp[a] (3). The earlier generation reductase inhibitors are not very effective in lowering Lp[a] levels, (4-8), and in some cases even elevate them (9). One notable exception to the above generalization is a study in which lovastatin decreased Lp[a] by 39% in hyperlipidemic kidney graft recipients (10). Nicotinic acid has long been used to treat hypercholesterolemic patients who are able to tolerate efficacious dosages. However, the effect of low dose niacin (1.5 g/day) on plasma Lp[a] levels appears to be minimal (0%) (11) . Nevertheless, a higher dose (1 g four times daily) lowers Lp[a] by 38% (12). Neomycin is effective alone, and even more so in combination with niacin (13). In type I1 hyperlipoproteinemic subjects given 2 g neomycin/day, a 24% reduction in Lp[a] was observed. When neomycin (2 g/day) was administered with niacin (3 g/day), Lp[a] was reduced by 45%. Significantly, those patients with the initially highest Lp[a] levels experienced the greatest reduction in Lp[a] with this combination therapy. In hypercholesterolemic patients with angiographically documented coronary artery disease, cholestyramine (3 g/day) and niacin (up to 6 g/day) for 1 year produced a 29% reduction in Lp[a] (14). In patients with primary hypercholesterolemia receiving niceritrol, a derivative of nicotinic acid, (1.5 g/day) for 12 weeks, the drug was not effective in lowering Lp[a] if those subjects had an initial mean level of 10.6 mg/dl, but the drug produced a 34% decrease in a subgroup Abbreviations: total-C, total cholesterol; TG, triglyceride; VLDLL, very low density lipoprotein cholesterol calculated by dividing the triglyceride value by 5; HDLC, high density lipoprotein cholesterol; Lp[a], lipoprotein[a]; Lp[a]-P, Lp[a] protein (includes apo[a]) and apoB-100); Lp[a]-T, Lp[a] total mass estimated by dividing Lp[a]-P by 0.33; Lp[a]-C, Lp[a] cholesterol estimated by multiplying Lp[a]-I' by 1.05; LDL-C, low density lipoprotein calculated from the equation LDL-C = (Total-C)-(VLDLC)-(HDL-C)-(Lp[a]-C); PPCIA, post-prandial curve integrated area. 'To whom correspondence should be addressed. 1298 Journal of Lipid Research Volume 37, 1996 by gest, on N ovem er 6, 2017 w w w .j.org D ow nladed fom whose mean initial level was 19.2 mudl ( l5) . Niceritrol has also been found to be effective in lowering Lp[a] in patients with end-stage renal disease, a condition in which levels are typically elevated. Acipimox, another analog of niacin, is better tolerated but less efficacious than the parent drug (16). Fibric acid derivatives have also been studied for their potential to lower Lp[a]. In type IIa, IIb, and IV subjects treated with sustained-release bezafibrate for 42 weeks, there were reductions of 30,23, and 24% in Lp[a] levels (17), respectively. A somewhat smaller reduction was observed in a group of patients with type IIa or IIb hyperlipoproteinemia where bezafibrate with retarded release of the active drug (400 mg/day) caused a 15% decrease in Lp[a] levels within 3 months (18). Conflicting results have been reported about the effects of gemfibrozil on Lp[a] levels. When used to treat type I1 or type IV patients with elevated cholesterol (y7.7 mmol/l) and/or triglyceride (y2.5 mmol/l), the drug caused no significant changes in Lp[a] (19). In the Helsinki Heart study, a group of subjects receiving gemfibrozil experienced a 27% reduction in serum apoB, but virtually no change in Lp[a] (20). When gemfibrozil was administered to cynomolgus monkeys in weekly escalating doses of 50, 125, and 200 mg/kg per day, the drug caused dose-dependent reductions in plasma Lp[a] of 16.3,39.5, and 63.8% (21), respectively, an effect reversible within 3 weeks. In a recent multi-drug study, the effects of three different fibrates on Lp[a] levels were compared in type IV hyperlipoproteinemics (22). Bezafibrate, gemfibrozil, and fenofibrate raised Lp[a] levels by 53, 28, and 44%, respectively. In a small study of 12 subjects with mean age 70 years, with hypercholesterolemia, and with Lp[a] levels y30 mg/dl, gemfibrozil treatment combined with a Mediterranean diet lowered the median Lp[a] level from 36.5 to 8.4 m u d l (23). Finally, in a group of 27 nondiabetic patients aged 37-68 with hypercholesterolemia and hypertriglyceridemia, the mean Lp[a] level was decreased from -24 to 18 m u d l (25%) by a 12-week treatment with gemfibrozil(24). In the present study, the effect of gemfibrozil on Lp[a] levels has been examined in type IIa and type IIb patients not only in the fasted state, but post-prandially as well. A primary objective of the study was to determine hyperlipidemic conditions under which the drug might be effective, and also to identify patient subpopulations in which the drug might be more efficacious than others. METHODS bolism and Atherosclerosis Clinic of The Methodist Hospital. A single exception was subject 4 whose cholesterol level decreased to 194 mg/dl after screening but before the study was begun. Criteria for exclusion from the study included active liver disease, biliary cirrhosis, or biliary dysfunction causing elevation of serum transaminase more than 20% above normal levels; preexisting gall bladder disease such as cholelithiasis or cholecystitis; treated hyperthyroidism, nephrotic syndrome, or dislipoproteinemias; secondary hypercholesterolemia due to obstructive liver disease; chemical substance abuse including alcoholic beverages (more than 4 oz of alcohol/day); treatment with a lipid-lowering drug and/or procedure (e.g., apheresis) without a full month cessation for metabolic re-equilibration; treatment with other drugs that might affect lipid levels or interact with gemfibrozil such as immunosuppressive or anticoagulant agents or neomycin; severe obesity (>30% over ideal body weight); unstable angiopectoris; myocardial infarction within the previous 4 months. Subjects qualifying for the study were thoroughly instructed in the details of the protocol which had been approved by the human research review boards of Baylor College of Medicine and The Methodist Hospital. Upon signing a statement of informed consent, 40 prospective subjects were entered into the study; 6 of these did not complete the study. Type IIa and IIb patients were distinguished by fasting triglyceride levels below and above 250 mg/dl, respectively.