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Efectos de Dieta en Fibra Sobre El Colesterol

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  Long-Term Blood Cholesterol–Lowering Effects of a Dietary Fiber Supplement  Robert H. Knopp, MD, H. Robert Superko, MD, Michael Davidson, MD, William Insull, MD, Carlos A. Dujovne, MD,Peter O. Kwiterovich, MD, James H. Zavoral, MD, Kevin Graham, MD, Robert R. O’Connor, David A. Edelman, PhD Background:  The study evaluated the blood cholesterol–lowering effects of a dietary supplement of  water-soluble fibers (guar gum, pectin) and mostly non-water-soluble fibers (soy fiber, peafiber, corn bran) in subjects with mild to moderate hypercholesterolemia (LDL choles-terol, 3.37–4.92 mmol/L). Methods:  After stabilization for 9 weeks on a National Cholesterol Education Program Step 1 Diet,subjects were randomly assigned to receive 20 g/d of the fiber supplement ( n     87) ormatching placebo ( n     82) for 15 weeks and then receive the fiber supplement for 36 weeks. The efficacy analyses included the 125 subjects (58 fiber; 67 placebo) who weretreatment and diet compliant. One hundred two (52 fiber; 50 placebo) completed the15-week comparative phase. Of these subjects 85 (45 fiber; 40 placebo) elected to continuein the 36-week noncomparative extension phase. Results:  The mean decreases during the 15-week period for LDL cholesterol (LDL-C), totalcholesterol (TC), and LDL-C/HDL-C ratio were greater ( P   0.001) in the fiber group. Themean changes from pre-treatment values in LDL-C, TC, and LDL-C/HDL-C ratio forsubjects in the fiber group were  0.51 mmol/L (  12.1%),  0.53 mmol/L (  8.5%), and  0.30 (  9.4%), respectively. The corresponding changes in the placebo group were  0.05mmol/L (  1.3%),   0.05 mmol/L (  0.8%), and 0.05 (1.5%), respectively. The fibersupplement had no significant effects ( P   0.05) on HDL cholesterol (HDL-C), triglycer-ide, iron, ferritin, or vitamin A or E levels. Similar effects were seen over the subsequent 36-week noncomparative part of the study. Conclusions:  The fiber supplement provided significant and sustained reductions in LDL-C without reducing HDL-C or increasing triglycerides over the 51-week treatment period. Medical Subject Headings: (MeSH):  hypercholesterolemia, dietary fiber, long-term effects(Am J Prev Med 1999;17(1):18–23) © 1999 American Journal of Preventive Medicine Introduction M any studies have reported on the cholester-ol-lowering effects of water-soluble fibers, 1–4  with reductions in total cholesterol rang-ing from no change to over a 20% decrease. 3–6 Differences among studies may be attributed to thesmall numbers of subjects in some studies or failureto account for concurrent factors (e.g., diet) that alsomay affect cholesterol levels. In addition, any dietary intervention such as a fiber supplement may result in dietary modifications that in turn affect plasmalipids. 7 The present study evaluated the short- and long-term effects of a dietary fiber supplement (Choltrol  ,Novartis Consumer Health, Inc.) that contained amixture of water-soluble fibers (guar gum, pectin)and mostly non-water-soluble fibers (soy fiber, peafiber, corn bran). Although non-water-soluble fibershave minimal effects on plasma lipids, they wereincluded in the fiber supplement since they areconsidered important for good health because of their role in increasing stool bulk. 8 In addition, peafiber may lower postprandial and fasting triglyceridelevels. 9 From the N.W. Lipid Research Clinic (Knopp), Harborview MedicalCenter, Seattle, Washington; Berkeley HeartLab, Inc. (Superko), SanMateo, California; Chicago Center for Clinical Research (Davidson),Chicago, Illinois; Lipid Research Clinic (Insull), Methodist Hospitaland Baylor College of Medicine, Houston, Texas; Lipid and Arterio-sclerosis Prevention Clinic (Dujovne), Kansas University Hospital,Kansas City, Kansas; Lipid Research Clinic (Kwiterovich), JohnsHopkins University, Baltimore, Maryland; Preventive Cardiology In-stitute (Zavoral), Fairview Southdale Hospital, Edina, Minnesota;Preventive Cardiology Department (Graham), Minneapolis Heart Institute, Minneapolis, Minnesota; Novartis Pharmaceuticals Corpo-ration (O’Connor), East Hanover, New Jersey; Medical ResearchConsultants (Edelman), San Diego, California. Address correspondence to: David A. Edelman, PhD, MedicalResearch Consultants, 4317 Alder Drive, San Diego, CA 92116.E-mail: David_Edelman@scirex.com. Address reprint requests to: Robert R. O’Connor, Novartis Phar-maceuticals Corporation, 59 Route 10, East Hanover, NJ 07936. 18  Am J Prev Med 1999;17(1) 0749-3797/99/$–see front matter© 1999 American Journal of Preventive Medicine PII S0749-3797(99)00039-2  Methods and Materials Selection of Subjects Men and women attending each study clinic were askedto participate in the study if based on a review of theirmedical records they had mild to moderate hypercho-lesterolemia, but otherwise were in good health. Sub- jects were included in the study if they were 18–70 yearsof age, had not used any hypolipidemic drugs for at least 2 months, were not using foods or food supple-ments to lower plasma lipid levels, were within 30% of their ideal body weight, and gave their written in-formed consent to participate. The study was approvedby an Institutional Review Board at each study center. Study Design Eligible subjects were monitored on a National Choles-terol Education Program (NCEP) Step 1 Diet  10 for at least 9 weeks before being randomly assigned to treat-ment with the fiber supplement or placebo. Subjects were to continue on their Step 1 Diet throughout theirparticipation in the study. Before the start of treatment and after completing 8, 14, 32, and 50 weeks of treatment, subjects completed 3-day food diaries from which a dietician derived food record rating (FRR)scores. 11  A computer-assisted analysis of the diaries wasperformed to confirm adherence to the Step 1 Diet.Subjects with low-density lipoprotein cholesterol(LDL-C) of 3.37–4.92 mmol/L and triglycerides  3.43mmol/L at 6 and 3 weeks before the start of treatment  were randomly assigned to treatment with either thefiber supplement or placebo. Each clinic was to enrollat least 20 subjects who were to be randomly assigned inequal numbers to each treatment group. After the start of treatment, subjects were to return every 3 weeks for15 weeks for measurement of plasma levels of totalcholesterol (TC), high-density lipoprotein (HDL-C)and triglycerides, and then every 6 weeks for the next 36 weeks. Plasma apolipoproteins (apo) A-1 and Bconcentrations, and serum iron, ferritin, and vitamins A and E concentrations were measured before the start of treatment, after 6 and 15 weeks of treatment andthen every 6 weeks for the next 36 weeks.Subjects were randomized to receive 20 g/d of thefiber supplement (15 g/d of a mixture of guar gum andpectin and 5 g/d of a mixture of soy fiber, pea fiber,and corn bran) or placebo. The placebo and fibersupplement were identical in appearance and taste,and were supplied in identical packets. Subjects were touse one packet before dinner throughout treatment,one packet before breakfast every other day during thesecond week of treatment, and one packet beforebreakfast every day during the remainder of treatment.The contents of each packet were to be mixed with 296mL of skim milk, juice, or water and consumed within5 minutes. Each packet contained 10 g of the fiber mixor 5.2 g of placebo (non-water-soluble fiber derivedfrom cellulose which was expected to have no signifi-cant effect on plasma lipids). After 15 weeks of placebotreatment, subjects were assigned to use 2 packets/day of the fiber supplement (one before breakfast and onebefore dinner). At each clinic visit subjects were pro- vided with a supply of their assigned treatment and were to return all unused packets from their previoussupply. Treatment compliance was determined fromthe number of unused packets. To reduce potentialbias, subjects were not provided with information ontheir cholesterol levels throughout their participationin the study. Laboratory Determinations Laboratory determinations were performed at a centrallaboratory (Medical Research Laboratories, Cincinnati,OH, USA). TC, HDL-C, and triglyceride levels weremeasured on a Hitachi 737 analyzer (BoehringerMannheim Diagnostics, Indianapolis, IN, USA) withmicroenzymatic procedures in accordance with theNational Heart, Lung, and Blood Institute/Centers forDisease Control Lipid Standardization Program.HDL-C was isolated using the modified heparin-Mn 2  procedure to precipitate very low-density lipoproteinand LDL-C. 12 LDL-C was estimated from TC, HDL-Cand triglycerides. 13 During the study, the coefficients of  variation were 1.1% to 1.3% for TC, 1.6% to 2.0% forHDL-C, and 0.9% to 2.0% for triglycerides. Apo A-1 andB assays were performed with competitive enzyme-linked immunoassay procedures using well-character-ized and specific monoclonal antibodies. Vitamin A and E levels were measured by high-pressure liquidchromatography following solvent extraction. Serumiron levels were measured with an Abbott TDx Analyzerusing fluorescence polarization, and serum ferritinlevels were measured with an Abbott IMx Analyzerusing a microparticle enzyme immunoassay (Abbott Diagnostics). Statistical Methods The planned sample size was 40 efficacy-evaluablesubjects in each treatment group at the end of the15-week treatment period. This was sufficient to pro- vide 80% power to detect a significantly difference (   0.05, two-tail) of 8% in LDL-C between the fiber andplacebo groups.Changes from pre-treatment values in cholesterol,triglycerides, iron, ferritin, and vitamin A and E levelsduring the 15-week comparative phase were analyzedusing repeated measures analyses of covariance. Thestatistical model for these analyses included an overallmean and the effects of treatment, treatment week,treatment by treatment week interaction, and sex, andpre-treatment age, weight, body mass index, and FRR score as covariates. Since large within subject coeffi-  Am J Prev Med 1999;17(1)  19  cients of variation for LDL-C and TC have been re-ported  14 , the mean of the last two pre-treatment valuesof LDL-C, TC, HDL-C and triglycerides were used asbaseline values. Proportions were compared using Fish-er’s exact test.Changes from pre-treatment values in cholesterol,triglycerides, iron, ferritin, vitamin A and E levels, body  weight, and FRR score during the 36-week extensionphase were analyzed separately for subjects initially assigned to use the fiber supplement and for subjects who changed to the fiber supplement after 15 weeks of treatment with placebo. These changes were analyzedusing repeated measures analyses of covariance modelsthat included an overall mean, effects of treatment  week and sex, and pre-treatment age, weight, body massindex, and FRR score as covariates.Effects were considered to be statistically significant if the associated  P  -value was   0.05. Statistical analyses were performed using the SAS statistical software. Exclusion from Efficacy Analysis Table 1 gives the numbers of subjects enrolled in thestudy, randomized to treatment, and who completedthe 15-week comparative phase and entered and com-pleted the 36-week extension phase. Of the 282 subjectsenrolled, 169 (60%) completed the 9-week diet stabili-zation phase and were randomized to treatment (87fiber; 82 placebo). In each treatment group, 81 subjectsreturned for at least one follow up evaluation. Sevensubjects (6 fiber; 1 placebo) did not return for any follow-up evaluations. To evaluate the effects of thefiber supplement on cholesterol levels without theconfounding effects of treatment compliance and di-etary changes, the efficacy analyses were restricted tothe 125 subjects (58 fiber; 67 placebo) who at eachevaluation were at least 80% compliant with theirtreatment regimen, were compliant with their Step 1Diet, i.e., had a FRR score of    15, 12 and were treatedfor at least 6 weeks. Approximately equal numbers of subjects at each study site were excluded form theanalyses. Of the 102 subjects who completed the 15- week comparative phase, 85 (83%) entered the 36-weeknoncomparative phase and returned for at least onefollow-up evaluation. Results There were no significant differences between thepre-treatment characteristics of subjects assigned to usethe fiber supplement or placebo, except for the FRR score (Table 2). The mean FRR score for the fibergroup was slightly higher (9.9 versus 8.3;  P     0.05),indicating a slightly higher level of fat intake. Subjects were 26–69 years of age (mean age: fiber, 51.1 years;placebo, 53.7 years;  P     0.052), 65% were male, and95% were white. All subjects were within 30% of theirideal body weight. There were no significant differ-ences between the two treatment groups in their pre-treatment plasma cholesterol or triglyceride values(Table 3). 15-Week Comparative Phase Treatment with the fiber supplement significantly de-creased ( P     0.001) LDL-C, TC, LDL-C/HDL-C, andapo B compared to placebo (Table 3). No significant changes from baseline were observed in any of theother lipoprotein variables. There was no significant decrease over the treatment period in LDL-C, TC, orLDL-C/HDL-C ratio. There were no significant differ-ences between males and females in their changes inlipoprotein values and no covariate was statistically significant. Over the 15-week treatment period, the Table 1.  Study enrollment  Fibersupplement Placebo a  Enrolled, started Step 1diet 282Completed 9-week diet stabilization169 (60%)Randomized to treatment 87 82Evaluated afterrandomization b 81 81Included in efficacy analyses c 58 67Completed 15-weekcomparative phase52 (90%) 50 (75%)Entered 36-weekextension phase45 40Completed 36-weekextension phase40 (89%) 30 (75%) a Subjects were switched from placebo to fiber supplement in exten-sion phase. b Seven subjects (6 fiber; 1 placebo) did not return for follow-upevaluation after they were randomized to treatment. c Excluded from the efficacy analyses: less than 80% diet compliant (3fiber; 4 placebo); not compliant with Step 1 Diet (19 fiber; 10placebo), did not complete at least 6 weeks of treatment (1 fiber). Table 2.  Baseline subject characteristics Placebo( n   81)Fibersupplement ( n   81)  p   Value a   Age (years) 51.1  10.0 b 53.7  10.3 0.052Range 29–67 26–69Male (%) 64.2 64.2 1.000 White (%) 91.4 97.5 0.17 Weight (kg) 75.4  12.4 75.7  14.1 0.41Range 51.4–110.0 41.8–111.4Body mass index(kg/m 2 )25.7  3.3 25.7  3.6 0.51Food record ratingscore8.3  4.4 9.9  5.2 0.022 a  p   Values from Fisher’s exact test for discrete variables and from t-test for continuous variables. b Mean  standard deviation. 20  American Journal of Preventive Medicine, Volume 17, Number 1  mean change from baseline in LDL-C, TC, and LDL-C/HDL-C ratio for subjects using the fiber supplement  were   0.51 mmol/L (  12.1%),   0.53 mmol/L(  8.5%), and  0.30 (  9.4%), respectively. The corre-sponding changes in the placebo group were   0.05mmol/L (  1.3%),   0.05 mmol/L (  0.8%), and 0.05(1.5%), respectively.During the 15-week treatment period there were nosignificant changes in the mean daily cholesterol andfiber consumption based on analyses of the 3-day fooddiaries. Also, there were no significant differencesbetween the fiber supplement and placebo groups inthe mean changes from baseline in weight, FRR score,or iron, ferritin, or vitamin A and E concentrations. Nocovariate was statistically significant. 36-Week Extension Phase The analyses of covariance showed that for subjects whocontinued to use the fiber supplement and for subjects who changed from placebo to the fiber supplement,there was a significant decreases from baseline inLDL-C, TC, and LDL-C/HDL-C ratio, but not forHDL-C or triglycerides. There were no significant dif-ferences between males and females in their changes inlipoprotein values and no covariate was statistically significant.The mean changes from baseline in LDL-C, TC, andLDL-C/HDL-C during the extension phase are shownin Table 4. The mean percentage decrease from base-line for subjects who used the fiber supplement throughout the extension phase was 11.6% for LDL-C,7.5% for TC, and 7.3% for LDL-C/HDL-C. The meanpercentage decrease over the extension phase for sub- jects who changed from placebo to the fiber supple-ment after week 15 was 8.8% for LDL-C, 5.2% for TC,and 7.8% for LDL-C/HDL-C.For similar duration of use of the fiber supplement,the mean reductions from baseline in LDL-C, TC andLDL-C/HDL-C ratio were smaller for subjects whochanged from placebo to the fiber supplement com-pared to those for subjects who used the fiber supple-ment throughout the study (Tables 3 and 4). For eachtreatment group, there were no significant changes inbody weight or FRR score, or iron, ferritin or vitamin A or E levels during the 36-week extension period. Side Effects During the 15-week comparative phase, 5 (6%) subjectsin the fiber group and 3 (4%) in the placebo group withdrew from the study because of treatment-relatedgastrointestinal side effects. Among subjects who con-tinued in the study after week 15, 2 (3%) in the fibergroup and 5 (7%) who changed from placebo to fiber withdrew from the study because of treatment-relatedgastrointestinal side effects.During the initial 15 weeks of the study, treatment- Table 3.  LDL cholesterol, total cholesterol (TC), HDL cholesterol, LDL-C/HDL-C ratio, triglycerides (TG), andapolipoprotein (Apo) A-1 and B at baseline and changes from baseline after 6, 12, and 15 weeks of treatment with fiber orplacebo Fiber supplement Baseline( n   58) Week 6( n   56) Week 12( n   54) Week 15( n   52) LDL-C (mmol/L) 4.22  0.44   0.47  0.49 (  11.1%) a  0.56  0.49 (  13.3%) a  0.41  0.36 (  9.7%) a TC (mmol/L) 6.29  0.57   0.47  0.59 (  7.5%) a  0.55  0.53 (  8.7%) a  0.44  0.45 (  7.0%) a HDL-C (mmol/L) 1.40  0.32   0.03  0.11 (  2.1%)   0.04  0.12 (  2.9%)   0.02  0.14 (  1.4%)LDL-C/HDL-C ratio 3.17  0.82   0.29  0.41 (  9.1%) a  0.34  0.39 (  10.7%) a  0.25  0.37 (  7.9%) a TG (mmol/L) 1.47  0.57 0.07  0.43 (4.8%) 0.10  0.51 (6.8%) 0.01  0.43 (0.7%) Apo A-1 (g/L) 1.50  0.26   3.2  11.0 (  2.1%) *   2.6  14.5 (  1.7%) Apo B (g/L) 1.42  0.26   13.7  20.8 (  9.6%) a *   14.3  21.1 (  10.0%) a PlaceboBaseline( n   67) Week 6( n   63) Week 12( n   58) Week 15( n   50) LDL-C (mmol/L) 4.13  0.44 0.01  0.42 (0.2%)   0.15  0.37 (  3.6%) 0.00  0.41 (0.0%)TC (mmol/L) 6.17  0.50 0.07  0.50 (1.1%)   0.16  0.41 (  2.6%)   0.03  0.47 (  0.5%)HDL-C (mmol/L) 1.35  0.34   0.01  0.16 (  0.7%)   0.06  0.14 (  4.4%)   0.02  0.16 (  1.5%)LDL-C/HDL-C ratio 3.23  0.83 0.04  0.42 (1.2%) 0.02  0.48 (0.6%) 0.06  0.42 (1.9%)TG (mmol/L) 1.51  0.64 0.17  0.65 (11.2%) 0.09  0.51 (6.0%)   0.03  0.50 (  2.0%) Apo A-1 (g/L) 1.47  0.23 1.7  16.5 (1.2%) *   3.8  18.1 (  2.6%) Apo B (g/L) 1.36  0.24 1.6  19.0 (1.2%) * 3.6  20.5 (2.6%) *  Test not performed. Values given in table are mean  standard deviation. Values in parentheses are the percentage change from the baseline. Baseline  mean of last two pre-treatment values. a Statistically significant reduction vs. placebo (  p   0.001).  Am J Prev Med 1999;17(1)  21

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