Background Guidelines established by the National CholesterolEducation Program (NCEP) promote exercise and weight loss forthe treatment of abnormal lipoprotein levels. Little is known,however, about the effects of exercise or the NCEP diet, whichis moderately low in fat and cholesterol, in persons with lipoproteinlevels that place them at high risk for coronary heart disease.
Methods We studied plasma lipoprotein levels in 180 postmenopausalwomen, 45 through 64 years of age, and 197 men, 30 through 64years of age, who had low high-density lipoprotein (HDL) cholesterollevels (59 mg per deciliter in women and 44 mg per deciliterin men) and moderately elevated levels of low-density lipoprotein(LDL) cholesterol (>125 mg per deciliter but <210 mg perdeciliter in women and >125 mg per deciliter but <190mg per deciliter in men). The subjects were randomly assignedto aerobic exercise, the NCEP Step 2 diet, or diet plus exercise,or to a control group, which received no intervention.
Results Dietary intake of fat and cholesterol decreased duringthe one-year study (P<0.001), as did body weight, in womenand men in either the diet group or the diet-plus-exercise group,as compared with the controls (P<0.001) and the exercisegroup (P<0.05), in which dietary intake and body weight wereunchanged. Changes in HDL cholesterol and triglyceride levelsand the ratio of total to HDL cholesterol did not differ significantlyamong the treatment groups, for subjects of either sex. Theserum level of LDL cholesterol was significantly reduced amongwomen (a decrease of 14.5±22.2 mg per deciliter) andmen (a decrease of 20.0±17.3 mg per deciliter) in thediet-plus-exercise group, as compared with the control group(women had a decrease of 2.5±16.6 mg per deciliter, P<0.05;men had a decrease of 4.6±21.1 mg per deciliter, P<0.001).The reduction in LDL cholesterol in men in the diet-plus-exercisegroup was also significant as compared with that among the menin the exercise group (3.6±18.8 mg per deciliter, P<0.001).In contrast, changes in LDL cholesterol levels were not significantamong the women (a decrease of 7.3±18.9 mg per deciliter)or the men (10.8±18.8 mg per deciliter) in the diet group,as compared with the controls.
Conclusions The NCEP Step 2 diet failed to lower LDL cholesterollevels in men or women with high-risk lipoprotein levels whodid not engage in aerobic exercise. This finding highlightsthe importance of physical activity in the treatment of elevatedLDL cholesterol levels.
Elevated serum levels of low-density lipoprotein (LDL) cholesteroland reduced levels of high-density lipoprotein (HDL) cholesterolare important independent risk factors for coronary heart disease.1,2Reducing LDL cholesterol levels by means of drug therapy hasbeen shown to reduce the incidence of coronary heart diseaseamong men with hypercholesterolemia and dyslipidemia3,4 andalso to reduce the rate of death due to coronary heart diseasein patients with the disease.5 It is believed that reductionsin the serum LDL cholesterol level produced by dietary therapywill have similar benefits6; however, the diet recommended forreducing LDL cholesterol levels may reduce HDL cholesterol levelsto a similar degree.7,8
Earlier, we demonstrated that weight loss increased HDL cholesterollevels in moderately overweight men9 and that physical activityprevented the lowering of HDL cholesterol levels that usuallyresults from a low-fat diet in overweight men and women.10 Subsequently,the guidelines of the National Cholesterol Education Program(NCEP) Adult Treatment Panel, emphasizing the incorporationof weight loss and physical activity into dietary therapy forcholesterol management, were published.11
In the present one-year, randomized, controlled study of menand postmenopausal women with low HDL cholesterol levels andelevated LDL cholesterol levels (the Diet and Exercise for ElevatedRisk trial), we examined the effects of changes in diet andexercise, alone and together, on plasma lipoproteins. We hypothesizedthat HDL cholesterol levels would be raised by exercise butlowered by the NCEP Step 2 diet, that LDL cholesterol levelswould be reduced by the diet, and that the ratio of LDL to HDLcholesterol would be most improved by combining the diet withregular exercise.
Methods
Design of the Study
We used several strategies to recruit postmenopausal women 45through 64 years of age and men 30 through 64 years of age,who had both plasma HDL cholesterol levels below 60 mg per deciliter(1.55 mmol per liter) for women and 45 mg per deciliter (1.14mmol per liter) for men, the approximate mean for the U.S. population,12and plasma LDL cholesterol levels greater than 125 mg per deciliter(3.23 mmol per liter) but below 210 mg per deciliter (5.43 mmolper liter) for women and greater than 125 mg per deciliter butbelow 190 mg per deciliter (4.91 mmol per liter) for men. Potentialsubjects were excluded if they reported a history of heart disease,stroke, diabetes, recent cancer, other life-threatening illness,or any condition that limited their ability to engage in moderate-intensityexercise; if they were currently using insulin or medicationsfor heart problems, blood pressure, or high serum cholesterollevels; or if they smoked more than nine cigarettes per dayor consumed more than four alcoholic drinks daily. The womenwho enrolled in the study agreed not to change their hormonaltherapy, if any, for one year. After providing informed consent,participants had to meet criteria for fasting plasma HDL andLDL cholesterol levels, triglyceride levels (500 mg per deciliter[5.64 mmol per liter]), and resting blood pressure (<160/95mm Hg) at each of two morning clinic visits. Additional criteriaincluded plasma glucose levels that were less than 140 mg perdeciliter (7.77 mmol per liter) while the subjects were fastingand less than 200 mg per deciliter (11.10 mmol per liter) afteran oral glucose load; a body-mass index (the weight in kilogramsdivided by the square of the height in meters) of 32 or lessfor women and 34 or less for men; and normal results on a maximaltreadmill exercise test.
After the base-line assessments, 180 women and 197 men wererandomly assigned to one of four groups: that assigned to followthe NCEP Step 2 diet (47 women and 49 men); that assigned toaerobic exercise only (44 women and 50 men); that assigned toboth the NCEP Step 2 diet and exercise (43 women and 51 men);or a control group, which received neither intervention (46women and 47 men). Assignments were made by computer with useof a modified Efron procedure,13 which weighted the probabilityof assignment in order to balance groups in terms of samplesize and average HDL cholesterol levels and LDL cholesterollevels.
Dietary recommendations, based on the goals of the NCEP Step2 diet (less than 30 percent total fat, less than 7 percentsaturated fat, and less than 200 mg of cholesterol per day),11were presented to the subjects by registered dietitians. Participantsentered a 12-week adoption phase in which an individualizedcounseling session was followed by eight one-hour, mixed-sexgroup lessons on replacing dietary sources of saturated fatwith complex carbohydrates, low-fat dairy foods, and other alternatives,including lean meats. Weight loss was not emphasized in thegroup sessions, which were held separately for the diet-aloneand diet-plus-exercise groups and which averaged 15 personsper group. A six-to-eight-month maintenance phase consistedof monthly contacts with study dietitians, by mail or telephoneor in group or private meetings.
The aerobic-exercise program began with a private meeting withmembers of the exercise staff, followed by a six-week adoptionphase in which participants attended supervised, one-hour, mixed-sexexercise sessions, three times per week, that were held separatelyfor the exercise-alone and diet-plus-exercise groups. The subjectswere instructed not to discuss diet during these sessions. Throughouta seven-to-eight-month maintenance phase, participants couldattend supervised group sessions three times per week, supplementthe required monthly group sessions with home-based activities,or both, with the goal of engaging in aerobic activity equivalentto at least 16 km (10 mi) of brisk walking or jogging each week.The controls were asked to maintain their usual diet and exercisehabits until the tests at one year of follow-up were completed.
Clinical Procedures
At base line and after one year, subjects came to the clinicseveral times to provide data on physical measures, aerobicfitness, and plasma lipoprotein and glucose levels. The body-massindex was determined by measuring the weight on a standard beambalance, during two visits, and the height with a Harpendenstadiometer. The means of three measures of the following wererecorded with participants standing: waist (narrowest circumferenceviewed from the front); abdominal girth (at the umbilicus);and hip (largest horizontal circumference around the buttocks).Resting heart rate and systolic and diastolic blood pressurewere determined in duplicate on two morning visits, as previouslydescribed.14 Oxygen uptake during a graded treadmill exercisetest was determined every 30 seconds, with use of a previouslydescribed semiautomated metabolic-analysis system.15 For aerobiccapacity (maximal oxygen uptake in milliliters of oxygen consumedper minute and per kilogram of body weight per minute), we usedthe average of the two highest values in 30-second samples recordedduring the final minutes of exercise. Venous blood was collectedat two morning visits, after subjects had abstained from allfood and drink, except water, for 12 to 16 hours and from vigorousactivity for at least 12 hours, and was mixed with 1.5 mg ofEDTA per milliliter. Aliquots of plasma were stored at –80°Cfor later assay of apolipoproteins. During one clinic visit,subjects consumed 75 g of glucose after the collection of fastingblood samples; venous blood was collected two hours later forthe assessment of glucose tolerance.
Laboratory Procedures
Lipoprotein values at base line and at one year are reportedas the means of two fasting values. Plasma levels of total cholesteroland triglycerides were measured by enzymatic procedures.16,17HDL cholesterol was measured by dextran sulfate–magnesiumprecipitation,18 followed by enzymatic measurement of the non-precipitatedcholesterol.16 Very-low-density lipoprotein (VLDL) cholesterollevels were calculated as the triglyceride level divided by5,19 unless triglyceride levels exceeded 400 mg per deciliter(4.52 mmol per liter), in which case VLDL cholesterol was measuredby enzymatic methods,16 after ultracentrifugation of serum for18 hours.20 LDL cholesterol was calculated as total cholesterolminus the sum of HDL cholesterol plus VLDL cholesterol.19 Valueswere consistently within specified limits as monitored by theLipid Standardization Program of the Centers for Disease Controland Prevention and the National Heart, Lung, and Blood Institute.Apolipoproteins A-I and B were measured by rate immunonephelometry(Array, Beckman, Brea, Calif.).21 Plasma glucose was measuredby National Health Laboratories, San Diego, California.
Assessment of Diet
At base line and at one year, the subjects completed five unannounced24-hour dietary-recall questionnaires, in the form of computer-assistedtelephone interviews, with use of two-dimensional food posters.22Nutrient intake was calculated with use of Food Database software,versions 5A and 6A, and Nutrient Database software, version2.4 (Minnesota Nutrition Data System, Nutrition CoordinatingCenter, University of Minnesota, Minneapolis).23 Data for eachperiod represent the mean of the data from four weekday andone weekend 24-hour dietary-recall records.
Statistical Analysis
Analysis of variance was used as a global test for differencesin the degree of change from base-line values among groups,calculated separately for each sex. When the analysis of varianceindicated significant differences between groups (P<0.05),post hoc comparisons were made, with the Bonferroni adjustmentof significance levels for six possible pairwise comparisons,at the 5 percent level of significance, in two-tailed tests(i.e., a P value <0.0083 for a given pair is reported asP<0.05 in this report). The log of the triglyceride levelwas used in the analyses, but the values are presented in commonclinical units (milligrams per deciliter [millimoles per liter]).
Results
The screening procedures excluded 421 of 789 women and 341 of767 men because they had HDL cholesterol levels at or above60 mg per deciliter or 45 mg per deciliter, respectively. Anadditional 111 women and 172 men did not meet the criteria forthe LDL cholesterol or triglyceride level, 20 women and 11 mendid not meet the criteria for blood pressure or glucose, and35 women and 30 men chose not to continue with the screening.Of the remaining 202 women and 213 men who were eligible, 22women and 16 men were excluded because they had positive orequivocal treadmill tests, and 180 women and 197 men thereforeunderwent randomization. Of these, 177 women (98 percent) and190 men (96 percent) returned for lipid measurements at oneyear. Missing data for variables presented here were distributedevenly among the treatment groups; no more than three personswithin a group had missing data for any given variable.
Table 1 and Table 2 present means (±SD) for base-linevalues and changes in those values at one year in women andmen, respectively, according to group, for dietary and fitness-relatedvariables. Analysis of variance revealed no significant differencesamong the groups at base line in any variable listed in Table 1or 2. The mean age was 56.9±5.1 years for women and47.8±8.9 for men. For both sexes, caloric intake decreasedsignificantly in the groups assigned to diet and diet plus exercise,as compared with the exercise group, but not as compared withthe controls, and the degree of change in weight at one yeardid not differ significantly between the diet group and thediet-plus-exercise group.
Table 2. Base-Line Values for Variables Related to Diet and Fitness in Men and Changes at One Year, According to Study Group.
Among the women, the composition of the diet was similar tothat of the NCEP Step 1 diet11 at base line in all groups andwas not significantly changed at one year in the controls orthe subjects assigned to exercise alone; both groups followingthe Step 2 diet significantly reduced the percentage of caloriesfrom total, saturated, and monounsaturated fat and cholesteroland achieved NCEP Step 2 goals. Among the men, the mean base-linefat intake slightly exceeded Step 1 goals in all groups, butthe two groups following the diet reduced fat and cholesterolintake significantly, as compared with the controls and theexercise group, and achieved Step 2 goals, whereas the compositionof the diet was unchanged in the other groups. The mean base-linebody-mass index was 26.3±3.2 for the women and 27.0±2.8for the men. For women and men, significant weight loss occurredin both diet groups, as compared with the control and exercisegroups, and changes in weight did not differ significantly betweenthe diet and diet-plus-exercise groups or between patients assignedto exercise only and controls. Mean reductions in the waist-to-hipratio were significant among the men assigned to diet plus exercise,as compared with the controls and those assigned to exerciseonly, but they did not differ significantly among the othergroups. Women and men in both the exercise and the diet-plus-exercisegroups had significantly increased maximal oxygen consumptionas compared with the control and diet groups.
Table 3 and Table 4 present base-line values and changes atone year, according to study group, for lipoprotein levels andother risk factors for coronary heart disease in women and men,respectively. Analysis of variance revealed no significant differencesamong the groups for any variable at base line (Table 3 andTable 4) or for the ratio of LDL to HDL cholesterol (3.5±0.7for women; 4.4±0.7 for men). Significant changes in theHDL cholesterol level were not observed for either sex, norwere changes in triglyceride levels. Total and LDL cholesterollevels were significantly reduced among both women and men inthe diet-plus-exercise group, as compared with the controls,and among men in the diet-plus-exercise group, as compared withthe group assigned to exercise only. There were no significantreductions in total and LDL cholesterol levels for either sexin the diet group. Changes in the ratio of total to HDL cholesteroldid not differ significantly among the groups for either sex,nor did changes in the ratio of LDL to HDL cholesterol amongwomen (P=0.39 by analysis of variance). However, the LDL:HDLcholesterol ratio was significantly reduced among the men assignedto diet plus exercise (–0.6±0.7), as compared withthe controls (–0.1±1.0, P<0.05), but was notsignificantly changed in the exercise group (–0.2±0.7)or among men in the diet group (–0.2±0.6), as comparedwith the other groups (P=0.01 by analysis of variance).
Table 4. Base-Line Values for Risk Factors for Coronary Heart Disease in Men and Changes at One Year, According to Study Group.
Means of individual percentage changes in plasma HDL and LDLcholesterol levels are presented with 95 percent confidenceintervals, for both sexes, in Figure 1. The percentage increasesin HDL cholesterol levels among both women and men in the exercisegroup did not reach statistical significance as compared withthe changes in the other groups. There was a significant reductionin the LDL cholesterol level among women in the diet-plus-exercisegroup, as compared with the controls, and among men in the diet-plus-exercisegroup, as compared with those in the control group and the exercisegroup, but the change was not significant among either men orwomen in the diet group as compared with the other groups.
Figure 1. Mean Changes in Plasma HDL Cholesterol and LDL Cholesterol Levels in the Study Groups at One Year.
The vertical lines represent 95 percent confidence intervals. Significance levels, after Bonferroni's adjustment for the six pairwise comparisons, are indicated as follows: the asterisk denotes P<0.05 for the comparison with the control group, the dagger P<0.001 for the comparison with the control group, and the double dagger P<0.001 for the comparison with the exercise group.
As Table 3 shows, the level of apolipoprotein A-I was significantlyreduced among women in the diet-plus-exercise group, as comparedwith those in the exercise group, whereas changes in apolipoproteinB levels did not differ significantly among the women in thevarious groups. In contrast, the level of apolipoprotein B wassignificantly reduced among men in the diet-plus-exercise group,as compared with those in the exercise and control groups, whereaschanges in apolipoprotein A-I levels in men did not differ significantlyamong the groups (Table 4). The degree of change in fastingand two-hour (post-challenge) glucose levels did not differsignificantly among the groups for either sex. The resting heartrate was significantly lower among both sexes in the diet-plus-exercisegroup than in the control group. Resting diastolic blood pressurewas also lower among the men in the diet-plus-exercise groupthan among the men in the control group.
Discussion
This study extends our previous investigations of the effectsof diet, exercise, and weight loss on plasma lipoprotein levelsin overweight men9,10 and premenopausal women10 to men and postmenopausalwomen who are at high risk for coronary heart disease becausethey have low HDL cholesterol levels and moderately elevatedLDL cholesterol levels. We restricted the study to persons withLDL cholesterol levels at which drug therapy is not recommendedbefore an attempt is made to lower LDL cholesterol levels throughlong-term reduction of dietary fat, particularly saturated fat.6,11We wanted to determine whether changes in the diet would furtherreduce HDL cholesterol levels, thereby potentially increasing,rather than decreasing, the risk of coronary heart disease,and whether the addition of aerobic exercise to the Step 2 dietwould offset this adverse effect, as we previously demonstratedin a study of overweight men and premenopausal women.10 In thecurrent study, the NCEP Step 2 diet failed to reduce LDL cholesterollevels significantly in either men or women as compared withcontrols; when the diet was combined with aerobic exercise,however, the resulting reductions in LDL cholesterol levelswere significant, with no adverse effects on HDL cholesterol.
On average, both the women and men who were eligible for thisstudy had initial dietary fat intakes that approximated thosein the NCEP Step 1 diet, a fact that may have contributed totheir low HDL cholesterol levels. Nonetheless, their base-lineLDL cholesterol levels would prompt a physician following theNCEP guidelines to recommend dietary therapy to achieve a Step2 diet.11 Our results suggest that the stepped dietary approachof the NCEP is unlikely by itself to result in substantial reductionsin LDL cholesterol levels, particularly since many patientswill not be provided with a dietary program as comprehensiveas that used here. It is worth recognizing, however, that theNCEP guidelines stress the importance of further reductionsin the dietary intake of fat and cholesterol. It may be thatgreater emphasis on increased consumption of certain foods,such as grains, fruits, and vegetables, would yield a differentresult.
Concern that substantial reductions in dietary fat content (to20 to 22 percent of calories), with a reciprocal increase incarbohydrate intake, will raise triglyceride levels24 or impairglucose tolerance25 was not supported in this trial, possiblybecause of weight loss in the groups that followed the Step2 diet. Therefore, adoption of the NCEP Step 2 diet does notappear to be associated with these risk factors in euglycemicwomen or men with low HDL cholesterol levels and elevated LDLcholesterol levels. Nonetheless, the recommendation of a low-fat,high-carbohydrate diet remains controversial.26,27
Most data supporting the widespread belief that lowering dietaryfat and cholesterol will reduce LDL cholesterol levels are derivedfrom observational and cross-sectional population studies andstudies conducted in institutional settings or metabolic wards,6,8,11,28rather than under conditions of clinical practice (i.e., amongpeople living in the community who choose their own foods).Under such conditions, Hunninghake et al. observed no changein the LDL:HDL cholesterol ratio in men and women who initiallyhad high LDL cholesterol levels while consuming the NCEP Step2 diet, as compared with their levels while consuming a high-fat,high-cholesterol diet, during which levels of both LDL cholesteroland HDL cholesterol were reduced.7 In addition, HDL cholesterollevels were lowered, along with the levels of LDL cholesteroland apolipoprotein B, in men with hypercholesterolemia whendietary fat was reduced from a base-line level of 34 to 36 percentof total calories from fat to 22 to 25 percent.24
In our previous controlled study of moderately overweight menand premenopausal women with a high-fat base-line diet, a weight-reducingNCEP Step 1 diet failed to reduce LDL cholesterol levels significantlyin men, with or without exercise, as compared with a controlgroup, but it did significantly reduce LDL cholesterol levelsin women. HDL cholesterol levels were significantly reducedin the women who made only dietary changes, however, as comparedwith those who also exercised, despite the fact that there wasno greater weight loss with the addition of exercise.10 Amongmen, the addition of aerobic exercise produced greater weightloss and significant elevation of the HDL cholesterol level;this effect was not seen with diet alone. The LDL:HDL cholesterolratio was significantly lowered, as compared with that in thecontrol group, among the men assigned to dietary changes alone,but not among the women, whereas this ratio was lowered in bothmen and women assigned to diet plus exercise.
In the current study of men and postmenopausal women with elevatedLDL cholesterol levels and low HDL cholesterol levels at baseline, a reduction of about 8 percent in dietary fat intake wasachieved, as in our previous study,10 but the reductions inLDL cholesterol levels were not significant for either sex withoutthe addition of exercise. Although even small reductions inLDL cholesterol levels may yield epidemiologically importantreductions in the risk of coronary heart disease, these findingsdemonstrate the importance of an exercise program when dietalone has not adequately reduced LDL cholesterol levels. Furthermore,the benefits of exercise in terms of the reduction in the riskof cardiovascular disease extend far beyond improvements inthe lipoprotein profile,29 and increased physical activity isnow recommended for patients at all cholesterol levels.11
An interesting question is how the addition of exercise enhancedthe effects of diet on LDL cholesterol. The diet-plus-exercisegroup may have adhered more closely to the diet than the groupassigned to the diet alone; however, analyses of nutrients listedin multiple 24-hour dietary-recall records showed no significantdifferences in mean values between the two groups that followedthe diet, for either sex. Furthermore, the amount of weightloss did not differ significantly between the groups assignedto the diet, and the slightly greater weight loss among menand women in the diet-plus-exercise group could have been dueto increased energy expenditure. The combination of reduceddietary fat and increased use of energy from fat through exercisemay create a physiologic state that is particularly beneficialto lipid metabolism even in the absence of weight loss.30,31
The fact that weight loss did not differ significantly betweenthe diet group and diet-plus-exercise group suggests that theamount of exercise achieved in the diet-plus-exercise groupwas not great enough to increase weight loss. The absence ofweight loss in the exercise group may explain why the HDL cholesterollevels were not significantly improved in these groups, sinceweight loss may be a crucial factor in the increases in HDLcholesterol levels observed with exercise,30,31,32,33 whetherweight loss is achieved solely by caloric restriction or byincreased physical activity, with no dietary change.9 Greaterweight loss might also have produced a greater reduction inLDL cholesterol levels. Although LDL cholesterol levels werenot reduced even among men with substantial weight loss in eitherof our previous randomized, controlled trials,9,10 reductionsin LDL cholesterol levels have been associated with weight lossin other studies.34
In conclusion, these data strongly support recommendations11to add exercise to diet for the management of lipoprotein levelsassociated with a high risk of coronary heart disease. Togetherwith our previous findings,9,10 they suggest that weight lossshould be further emphasized, when appropriate, particularlyin counseling men and women who have both low HDL cholesterollevels and elevated LDL cholesterol levels.
Supported by a grant (HL-45733) from the National Heart, Lung,and Blood Institute.
We are indebted to the participants in the trial; to Lisa Cooper,M.S., R.D., and Charlene Kirchner, R.D., for assistance withthe dietary intervention; to Cathy Norbutas and Dan Williams,Ph.D., for assistance with the exercise intervention; to AnnetteKeochekian, M.S., R.D., for assistance with recruitment; toSue Swope, R.N., for managing the clinic; to Beth Williams,M.D., and M. Rebecca Duran-Guarino, M.D., for medical supervision;to Adriana Krauss and Darius Jatulis, M.S., for data management;to Ann N. Varady, M.S., and Helena C. Kraemer for statisticalconsultation and analyses; to Marlene Hunter and the staff ofthe Stanford Center for Research in Disease Prevention BiochemistryLaboratory for lipoprotein analyses; and to the members of ourscientific advisory board: Steven N. Blair, P.E.D. (chair),Gail E. Butterfield, Ph.D., R.D., Stephen P. Fortmann, M.D.,Richard J. Brand, Ph.D., and Eva Obarzanek, Ph.D., R.D.
Source Information
From the Stanford Center for Research in Disease Prevention, Stanford University School of Medicine, Stanford, Calif.
Address reprint requests to Dr. Stefanick at 730 Welch Rd., Suite B, Palo Alto, CA 94304-1583.
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Fontana, L., Villareal, D. T., Weiss, E. P., Racette, S. B., Steger-May, K., Klein, S., Holloszy, J. O., and the Washington University School of Medicine C,
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Lau, D. C.W., Douketis, J. D., Morrison, K. M., Hramiak, I. M., Sharma, A. M., Ur, E., for members of the Obesity Canada Clinical Practic,
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Lau, D. C.W., Douketis, J. D., Morrison, K. M., Hramiak, I. M., Sharma, A. M., Ur, E., pour les membres du Groupe d'experts d'Obesite Can,
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Redman, L. M., Heilbronn, L. K., Martin, C. K., Alfonso, A., Smith, S. R., Ravussin, E., for the Pennington CALERIE Team,
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Hsia, J., Margolis, K. L., Eaton, C. B., Wenger, N. K., Allison, M., Wu, L., LaCroix, A. Z., Black, H. R., for the Women's Health Initiative Investigators,
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Hansen, K. C, Zhang, Z., Gomez, T., Adams, A. K, Schoeller, D. A
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Bruckert, E.
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Fletcher, B., Berra, K., Ades, P., Braun, L. T., Burke, L. E., Durstine, J. L., Fair, J. M., Fletcher, G. F., Goff, D., Hayman, L. L., Hiatt, W. R., Miller, N. H., Krauss, R., Kris-Etherton, P., Stone, N., Wilterdink, J., Winston, M.
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Sturman, M. T., Morris, M. C., Mendes de Leon, C. F., Bienias, J. L., Wilson, R. S., Evans, D. A.
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Li, Z., Otvos, J. D., Lamon-Fava, S., Carrasco, W. V., Lichtenstein, A. H., McNamara, J. R., Ordovas, J. M., Schaefer, E. J.
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Thompson, P. D., Buchner, D., Pina, I. L., Balady, G. J., Williams, M. A., Marcus, B. H., Berra, K., Blair, S. N., Costa, F., Franklin, B., Fletcher, G. F., Gordon, N. F., Pate, R. R., Rodriguez, B. L., Yancey, A. K., Wenger, N. K.
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Kurl, S., Laukkanen, J. A., Rauramaa, R., Lakka, T. A., Sivenius, J., Salonen, J. T.
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Thompson, P. D., Buchner, D., Pina, I. L., Balady, G. J., Williams, M. A., Marcus, B. H., Berra, K., Blair, S. N., Costa, F., Franklin, B., Fletcher, G. F., Gordon, N. F., Pate, R. R., Rodriguez, B. L., Yancey, A. K., Wenger, N. K.
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Furukawa, F., Kazuma, K., Kawa, M., Miyashita, M., Niiro, K., Kusukawa, R., Kojima, M.
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King, A. C., Friedman, R., Marcus, B., Castro, C., Forsyth, L., Napolitano, M., Pinto, B.
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Nieman, D. C., Brock, D. W., Butterworth, D., Utter, A. C., Nieman, C. C.
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Ravnskov, U.
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Rodriguez, C. J., Sacco, R. L., Sciacca, R. R., Boden-Albala, B., Homma, S., Di Tullio, M. R.
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Janssen, I., Fortier, A., Hudson, R., Ross, R.
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Lichtenstein, A. H., Ausman, L. M., Jalbert, S. M., Vilella-Bach, M., Jauhiainen, M., McGladdery, S., Erkkila, A. T., Ehnholm, C., Frohlich, J., Schaefer, E. J.
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Fletcher, G. F., Balady, G. J., Amsterdam, E. A., Chaitman, B., Eckel, R., Fleg, J., Froelicher, V. F., Leon, A. S., Pina, I. L., Rodney, R., Simons-Morton, D. A., Williams, M. A., Bazzarre, T.
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Lee, I-M., Blair, S. N., Allison, D. B., Folsom, A. R., Harris, T. B., Manson, J. E., Wing, R. R.
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Krauss, R. M., Eckel, R. H., Howard, B., Appel, L. J., Daniels, S. R., Deckelbaum, R. J., Erdman, J. W. Jr, Kris-Etherton, P., Goldberg, I. J., Kotchen, T. A., Lichtenstein, A. H., Mitch, W. E., Mullis, R., Robinson, K., Wylie-Rosett, J., St. Jeor, S., Suttie, J., Tribble, D. L., Bazzarre, T. L.
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Krauss, R. M., Eckel, R. H., Howard, B., Appel, L. J., Daniels, S. R., Deckelbaum, R. J., Erdman, J. W. Jr, Kris-Etherton, P., Goldberg, I. J., Kotchen, T. A., Lichtenstein, A. H., Mitch, W. E., Mullis, R., Robinson, K., Wylie-Rosett, J., St. Jeor, S., Suttie, J., Tribble, D. L., Bazzarre, T. L.
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Krauss, R. M., Eckel, R. H., Howard, B., Appel, L. J., Daniels, S. R., Deckelbaum, R. J., Erdman, J. W. Jr, Kris-Etherton, P., Goldberg, I. J., Kotchen, T. A., Lichtenstein, A. H., Mitch, W. E., Mullis, R., Robinson, K., Wylie-Rosett, J., St. Jeor, S., Suttie, J., Tribble, D. L., Bazzarre, T. L.
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Lee, I-M., Sesso, H. D., Paffenbarger, R. S. Jr
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Walden, C. E., Retzlaff, B. M., Buck, B. L., Wallick, S., McCann, B. S., Knopp, R. H.
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Hill, J. O., Melanson, E. L., Wyatt, H. T.
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Barnard, R. J., Baschetti, R., Ornish, D., Lichtenstein, A. H., Van Horn, L.
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Purnell, J. Q, Knopp, R. H, Brunzell, J. D
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James, K.
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Ornish, D., Scherwitz, L. W., Billings, J. H., Gould, K. L., Merritt, T. A., Sparler, S., Armstrong, W. T., Ports, T. A., Kirkeeide, R. L., Hogeboom, C., Brand, R. J.
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59 mg per deciliter in women and 
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