Brazilian Journal of Medical and Biological Research (2001) 34: 177-182 Etofibrate versus controlled-release niacin 177 ISSN 0100-879X Etofibrate but not controlled-release niacin decreases LDL cholesterol and lipoprotein (a) in type IIb dyslipidemic subjects A.C. Sposito, A.P. Mansur, Divisão de Coronária, Instituto do Coração, Faculdade de Medicina, R.C. Maranhão, Universidade de São Paulo, São Paulo, SP, Brasil C.R.M. Rodrigues-Sobrinho, O.R. Coelho and J.A.F. Ramires Abstract Correspondence Etofibrate is a hybrid drug which combines niacin with clofibrate. Key words J.A.F. Ramires After contact with plasma hydrolases, both constituents are gradually · Etofibrate Grupo de Coronariopatias released in a controlled-release manner. In this study, we compared the · Niacin Divisão Clínica · effects of etofibrate and controlled-release niacin on lipid profile and Lipoprotein (a) Instituto do Coração, HC, FM, USP · Triglycerides plasma lipoprotein (a) (Lp(a)) levels of patients with triglyceride Av. Dr. Eneas C. Aguiar, 44 · Cholesterol 05403-000 São Paulo, SP levels of 200 to 400 mg/dl, total cholesterol above 240 mg/dl and Brasil Lp(a) above 40 mg/dl. These patients were randomly assigned to a Fax: +55-11-3069-5310 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 Publication supported by FAPESP. groups total cholesterol, VLDL cholesterol and triglycerides were equally reduced and high-density lipoprotein cholesterol was in- creased. Etofibrate, but not niacin, reduced Lp(a) by 26% and low- Received February 2, 2000 density lipoprotein (LDL) cholesterol by 23%. The hybrid compound Accepted November 17, 2000 etofibrate produced a more effective reduction in plasma LDL choles- terol and Lp(a) levels than controlled-release niacin in type IIb dyslipidemic subjects. Introduction of this drug combination has led to the devel- opment of etofibrate in which clofibrate and Fibrates and niacin have been success- niacin are covalently linked. In contact with fully used to reduce triglyceride plasma con- plasma hydrolases, both constituents are centration, with the additional benefit of in- gradually released, displaying a pharmacoki- creasing the levels of antiatherogenic high- netic behavior similar to that of controlled- density lipoprotein (HDL) cholesterol. The release formulations (5). two drugs have synergistic effects on triglyc- Some studies have shown that the tradi- erides and HDL with a considerable reduc- tional forms of niacin and fibrate could be of ing action on low-density lipoprotein (LDL) additional benefit by reducing plasma lipo- cholesterol. Moreover, it has been observed protein (a) (Lp(a)) levels (6-10). Lp(a) is an that the combination of the two drugs leads LDL-like lipoprotein, differentiated from to a substantial reduction in coronary artery LDL by the presence of an additional large disease (CAD) events (1-4). The advantages protein molecule, the so-called apolipopro- Braz J Med Biol Res 34(2) 2001 178 A.C. Sposito et al. tein (a) (apo(a)) which is linked to apo B were randomly selected for a double-blind through disulfide bridges (11-14). Similarly treatment period with either 500 mg etofibrate to LDL, a high Lp(a) concentration in plasma (Tricerol®, Searle, São Paulo, SP, Brazil) or has been associated with the prevalence and 500 mg polygel controlled-release niacin severity of CAD (15-18). This may be due to (Slo-Niacin®, Upsher-Smith Laboratories, several causes, one of them related to apo(a) Inc., Minneapolis, MN, USA) administered homology with plasminogen, the zymogen twice a day for a 16-week period. Etofibrate of plasmin, that presumptively results in com- and niacin were placed in new vials labeled petitive inhibition of fibrinolysis (19-23). with the patient number and the vials were Lp(a) may also accumulate in the subendo- given directly to the patients by a research thelium where it binds with high affinity to assistant. During the 4-week evaluation one extracellular matrix components (24). The patient in the etofibrate group and 4 in the effect of controlled-release forms of fibrates niacin group did not return for study evalua- and niacin on Lp(a) levels has not been tion and were lost to follow-up. Thus, the explored in all its relevant aspects. In the final etofibrate group consisted of 14 sub- present investigation, we sought to compare jects (12 males), mean age 56 ± 5 years, and the effects of etofibrate with those of con- the niacin group consisted of 11 subjects (8 trolled-release niacin on Lp(a) and plasma males), mean age 57 ± 7 years. The study lipid profile in patients with type IIb dyslipi- protocol conformed to the ethical guidelines demia. of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the Material and Methods Heart Institute and all subjects gave informed consent to participate in the study. Population Lipid and lipoprotein determinations Thirty consecutive patients submitted to clinical evaluation at the coronary outpatient The first measurement after the diet pe- clinic of the Heart Institute were enrolled in riod was considered to represent baseline this study. The inclusion criteria were plasma values. Blood samples were obtained after a concentration of Lp(a) above 40 mg/dl, total 12-h overnight fast, at baseline and after 4, 8, cholesterol above 240 mg/dl and triglyceride 12 and 16 weeks of treatment. Commercial between 200 and 400 mg/dl in the last two enzymatic methods were used for the deter- measurements. The exclusion criteria were mination of total plasma cholesterol (CHOD- liver, renal, metabolic, inflammatory or neo- PAP, Boehringer-Mannheim Corp., Mann- plastic disease, alcoholism or known hyper- heim, Germany) and triglyceride concentra- sensitivity to niacin or etofibrate. Patients tion (Abbott Laboratories, North Chicago, with unstable angina or myocardial infarc- IL, USA). HDL cholesterol was assayed by tion during the last 6 months and diabetic the same enzymatic method as for total cho- patients with plasma glucose above 135 mg/ lesterol after precipitation of apo B lipopro- dl or HbA1c above 7.5% were also excluded. teins with magnesium phosphotungstate. The step-one diet of the National Choles- Very-low-density lipoprotein cholesterol and terol Education Program (NCEP) of the A- LDL cholesterol were calculated by the merican Heart Association was recom- Friedewald formula (25). Plasma Lp(a) level mended to all patients three months before was determined by radioimmunoassay using randomization. At randomization, all patients a kit supplied by Pharmacia (Uppsala, Swe- were taking only nitrates, whose doses were den) (26). This assay is based on the determi- not changed during the study. The patients nation of the apo(a) moiety of Lp(a). Braz J Med Biol Res 34(2) 2001 Etofibrate versus controlled-release niacin 179 Statistical analysis mean results and percent variation of plasma lipid and Lp(a) concentrations. There was no All data are reported as means ± standard significant difference between the plasma li- deviation. Plasma lipid variations were evalu- pid and lipoprotein concentrations determined ated by analysis of variance (ANOVA). When before admission to the study and at baseline the overall difference was statistically sig- after the dietary orientation period (Table 2). nificant, differences within the evaluations Both drugs reduced total cholesterol, VLDL were tested by the a posteriori Bonferroni cholesterol and triglyceride levels to the same test. Comparison between groups was per- extent and were equally effective in enhancing formed by the Student t-test or Mann-Whitney HDL cholesterol. However, etofibrate mark- test to analyze parametric and nonparamet- Table 1 - Baseline clinical characteristics. ric data, respectively. Differences were con- sidered significant when the probability value The groups did not differ significantly. was <0.05. Groups Results Etofibrate Niacin (N = 14) (N = 11) There was no difference between the Age (years) 56 ± 5 57 ± 7 etofibrate and niacin groups regarding age, Male (N) 12 8 male/female ratio, frequency of smoking, hy- Body mass index (kg/m2) 26.7 ± 4 27.1 ± 3 Cigarette smoking (N) 3 2 pertension, diabetes or body mass index val- Hypertension (N) 4 3 ues, and baseline plasma lipid and lipoprotein Diabetes mellitus (N) 1 2 concentrations (Table 1). Table 2 shows the Table 2 - Plasma lipid and lipoprotein (a) concentrations at admission to the study, baseline concentrations and concentrations after treatment with etofibrate (E) or niacin (N). *P<0.05 compared to group N. Data are reported as means ± SD (mg/dl) and were analyzed by ANOVA. D%, Percent variation; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipopro- tein. Admission Baseline Weeks of treatment D%P 4 8 12 16 Total cholesterol E group 292 ± 38 295 ± 30 242 ± 43 223 ± 36 225 ± 32 220 ± 37 -26 ± 7 <0.0001 N group 297 ± 40 302 ± 41 268 ± 47 251 ± 38 256 ± 35 249 ± 37 -18 ± 5 <0.01 LDL cholesterol E group 201 ± 21 196 ± 17 168 ± 31 153 ± 23 153 ± 21 152 ± 25 -23 ± 4* <0.0001 N group 203 ± 19 210 ± 22 198 ± 36 183 ± 26 185 ± 22 181 ± 26 -14 ± 7 0.07 HDL cholesterol E group 32 ± 5 33 ± 6 38 ± 5 47 ± 7 43 ± 5 44 ± 5 +33 ± 8 <0.0001 N group 32 ± 6 32 ± 7 37 ± 4 40 ± 5 43 ± 6 41 ± 3 +28 ± 8 <0.0001 VLDL cholesterol E group 60 ± 6 62 ± 7 35 ± 5 28 ± 4 29 ± 5 28 ± 5 -53 ± 4 <0.0001 N group 62 ± 5 62 ± 5 33 ± 4 28 ± 5 28 ± 5 28 ± 5 -54 ± 5 <0.0001 Triglycerides E group 294 ± 35 317 ± 39 170 ± 32 143 ± 29 145 ± 32 142 ± 36 -56 ± 9 <0.0001 N group 309 ± 49 304 ± 55 167 ± 37 141 ± 38 140 ± 37 139 ± 35 -55 ± 10 <0.0001 Lipoprotein (a) E group 51 ± 5 51 ± 4 47 ± 5 --38 ± 6 -26 ± 5* <0.0001 N group 49 ± 6 48 ± 5 49 ± 6 --44 ± 5 -8 ± 3 0.08 Braz J Med Biol Res 34(2) 2001 180 A.C.