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Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1580-1587

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1580.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Differential Effect of National Cholesterol Education Program (NCEP) Step II Diet on HDL Cholesterol, Its Subfractions, and Apoprotein A-I Levels in Hypercholesterolemic Women and Men After 1 Year

The beFIT Study

Carolyn E. Walden; Barbara M. Retzlaff; Brenda L. Buck; Shari Wallick; Barbara S. McCann; Robert H. Knopp

From the Northwest Lipid Research Clinic, Department of Medicine (C.E.W., B.M.R., B.L.B., S.W., R.H.K.) and Department of Psychiatry and Behavioral Sciences (B.S.M.), School of Medicine, University of Washington, Seattle.

Correspondence to Robert H. Knopp, MD, University of Washington, Northwest Lipid Research Clinic, 326 Ninth Ave, Box 359720, Seattle WA 98104. E-mail rhknopp{at}u.washington.edu


*    Abstract
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Abstract—We previously reported that high density lipoprotein cholesterol (HDL-C) decreases more in hypercholesterolemic (HC) women than in HC men ingesting an National Cholesterol Education Program (NCEP) Step II diet for 6 months. We examined these subjects to determine whether the differential HDL-C reduction persists after 12 months and whether it is associated with decreased HDL2-C and apoprotein A-I. Subjects were screened from an industrial workforce and were defined as HC if 2 low density lipoprotein cholesterol measurements were >=75th percentile or defined as combined hyperlipidemic (CHL) if triglycerides were also >=75th percentile. The subjects were then taught the NCEP Step II diet in 8 weekly classes and counseled quarterly. Seventy-three HC and 92 CHL women (mean ages 43 and 44 years, respectively) and 112 HC and 106 CHL men (ages 45 and 41 years, respectively) were studied. All groups reported similar total fat (24% to 26% kcal) and saturated fat (7.1% to 7.9% kcal) intakes at 1 year. HDL-C decreased 7.6% in HC women (P<0.01), exceeding the nonsignificant 1.3% decrease in HC men (P=0.000). HDL2-C decreased 16.7% in HC women (P<0.01) compared with the nonsignificant 0.5% increase in HC men (P=0.000). In CHL women and men, HDL-C decreased 3.5% and 3.9% (both P<0.01); HDL2-C decreased more in women (7.1%, P<0.01) than in men (4.3%, a nonsignificant difference). Apoprotein A-I decreased significantly (5.3%, P<0.01) in HC women only. Plasma triglycerides were unchanged. Low density lipoprotein cholesterol and weight changes were not different among the 4 groups. HDL-C, HDL2-C, and apoprotein A-I levels decreased more in HC women than in HC men after following the NCEP Step II diet for 1 year, continuing a trend observed with HDL-C at 6 months. The total HDL-C and HDL2-C reductions narrow the baseline differences between men and women by 50%. Whether this reduction impacts women’s protection from cardiovascular disease deserves future study. Nonetheless, the results point to sex-based differences in intrahepatic glucose and fatty acid metabolism linked to alterations in HDL formation and removal.


Key Words: hypercholesterolemia • combined hyperlipidemia • HDL cholesterol • apoA-I • low fat diet


*    Introduction
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Heart disease is the most common cause of death in women and men in the United States.1 Hypercholesterolemia is a major modifiable cardiovascular disease (CVD) risk factor in both sexes.2 3 4 Dietary modification to lower LDL cholesterol (LDL-C) is the primary strategy for the population-based reduction in CVD risk.5 6 The National Cholesterol Education Program (NCEP) recommends reducing saturated fat intake in 2 steps, to <10% of calories (step I) and <7% of calories (step II), in the initial management of individuals with hypercholesterolemia, regardless of sex, before instituting pharmacological measures.6

Recently, we reported sex-equivalent reductions in LDL-C but significantly greater HDL cholesterol (HDL-C) reductions in hypercholesterolemic (HC) women compared with men 6 months after instruction in the NCEP Step II diet.7 The differential HDL-C decrease was most prominent in HC women (6.4%) versus HC men (1.3%) but was also observed in combined hyperlipidemic (CHL) women (4.7%) versus CHL men (2.7%). The differential HDL-C responses were not explained by differences in triglyceride response, saturated fat intake, or weight change.

Wood et al8 reported that 1 year after following an NCEP Step I diet, a group of overweight premenopausal women had a nonsignificant decrease in HDL-C and a significant decrease in HDL2-C and that men had no significant change in either. Two studies implementing the more fat-restrictive Step II diet9 10 reported reductions in HDL-C, HDL2-C, and apoA-I in HC men and women combined. However, both studies were of short duration, and neither was designed to compare women and men or HC and CHL subjects.

Women are at lower CVD risk than are men, in part because of higher HDL-C and the antiatherogenic HDL2 subfraction.11 12 13 14 Low HDL-C is an independent risk factor for CVD,15 16 17 18 19 more so in women than in men.20 Therefore, it is important to know whether the most widely recommended diet for management of hypercholesterolemia can result in significant HDL-C lowering in women.

To further investigate the effect of the Step II diet on sex and hyperlipidemia-specific responses in HDL-C, we evaluated lipoprotein and apoprotein changes in HC and CHL women and men after 1 year of participation in the Boeing Employees Fat Intervention Trial (beFIT study), which provided a comprehensive program of dietary classes and follow-up counseling. The present study addresses the following questions: (1) Does the HDL-C decrease persist in women after 1 year? (2) Are HDL-C changes significantly different between women and men and between those with hypercholesterolemia and combined hyperlipidemia? (3) Does the HDL-C reduction involve the HDL2-C subfraction? (4) Is apoA-I decreased?


*    Methods
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Study Design
Details of the beFIT study design and protocol have been presented elsewhere.7 Briefly, subjects were recruited from an industrial workforce, were not taking lipid-altering medications, and had LDL-C only or LDL-C and triglyceride levels greater than the age- and sex-specific 75th percentile values.21 Subjects were taught the NCEP Step II diet during 8 weekly classes and were followed up quarterly for 1 year.7 At baseline and 1 year, a fasting blood sample was evaluated for lipoprotein lipids, apoA-I, and apoB, and a 4-day food record and a questionnaire about health habits and medical history were collected. The food records were reviewed by a dietitian during an interview and were analyzed by use of the University of Minnesota’s Nutrition Data System (NDS) software, consisting of food database versions 5A to 8A and nutrient database versions 20 to 23, which were updated as the information became available.22 Subjects in these analyses included 165 women and 218 men who had plasma and dietary data available obtained at baseline and at the 1-year follow-up. The present study was approved by the University of Washington Human Subjects Review Committee, and subjects gave informed consent.

Laboratory Methods
Blood samples were collected after a 10- to 12-hour fast into tubes containing dry EDTA to a final concentration of 1.5 mg/mL of blood. Total cholesterol and triglyceride levels were measured enzymatically. Cholesterol was measured by the Trinder-type method; triglycerides, by a UV method involving a free cholesterol blank.23 Cholesterol in HDL and in the HDL3 subfraction was measured enzymatically by the Abbott Spectrum Analyzer on plasma supernatant after precipitation of apoB-containing lipoproteins.24 HDL2-C was calculated as the difference between the HDL and HDL3 values. LDL-C was calculated as the infranatant cholesterol (density 1.006) minus HDL-C. ApoA-I and apoB were measured with a Behring Nephelometer.

Statistical Analysis
The analyses were based on an intent-to-treat approach; thus, no adjustments were made for dietary compliance, baseline factors, or changes in weight or lifestyle. The effect of age was specifically addressed by ANCOVA and had no effect on the lipoprotein or apoprotein comparisons. ANOVA was used to test for differences in baseline subject characteristics, nutrients, and lipids, in the 12-month nutrients, and in the percent change in lipids. The factors assessed were sex and lipid disorder and their interaction. A priori contrasts between women and men and between HC and CHL groups were tested by t test. Because the distribution of triglycerides is skewed, median values of triglycerides are presented, along with the mean, and the baseline value was logarithmically transformed to normalize and minimize the effects of outliers on hypothesis testing. Nonparametric tests confirmed the findings of parametric tests involving triglyceride percent change. A {chi}2 test was used to compare categorical data. Preintervention to postintervention changes were assessed via the paired t test. Because of the number of tests performed, significance levels <=0.01 were considered statistically significant, and 0.01<=P<=0.05 was considered marginally significant.


*    Results
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Subject Characteristics
After 1 year, 266 of the 692 subjects enrolled to begin dietary classes had dropped or were excluded from the study. Ninety-two subjects were excluded for protocol violations: 55 did not complete the baseline visit or at least 5 classes, 15 started taking exclusionary or lipid-altering medications, 13 women were pregnant, and 9 had high thyroid-stimulating hormone. Additionally, 174 were self-excluded: 119 for time or logistic constraints, 13 because of problems with the diet, and 26 for other reasons, such as loss of or relocation of job and serious health problems that precluded continuation in the study. The excluded subjects were 2.5 years older than those in the analysis (P=0.01) but were not different with respect to weight, lipoproteins, apoproteins, or reported dietary intake. Of the remaining 426 subjects, 32 completely or partially missed the 1-year visit, and 11 did not have adequate blood samples for HDL subfraction or apoA-I analysis. The characteristics of the remaining 383 subjects included in these analyses are shown in Table 1Down. The CHL women were significantly heavier and had a higher body mass index than did HC women. The CHL men were younger than the HC men, and both groups of men had more formal education than did the women.


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  		Table 1. Preintervention Demographics of Women and Men With Hypercholesterolemia or Combined Hyperlipidemia Who Completed 1 y of Follow-Up

Dietary Intakes
Table 2Down shows the effect of the intervention on nutrient intake and body weight after 1 year. Each group reported lower caloric intakes and higher percents of calories from protein and carbohydrates. Total fat intake decreased from baseline levels of {approx}34% kcal to {approx}24% kcal in HC men and 26% kcal in HC and CHL women and CHL men. Intakes of saturated, monounsaturated, and polyunsaturated fatty acids were significantly decreased in each group, with the exception of polyunsaturated fats in HC women. Dietary fiber intake increased in all groups but was significantly higher only in CHL women and HC men. Dietary cholesterol intake was significantly reduced in all groups. The differences in the intakes of dietary fiber and cholesterol between women and men were not significant when adjusted for caloric intake. The only differences in dietary intakes at 1 year by sex and lipid disorder were lower caloric intakes in HC and CHL women and higher protein caloric intake in CHL women. Compared with the baseline value, weight loss was significant for CHL women (-1.7 kg), HC men (-2.4 kg), and CHL men (-1.8 kg) but not for HC women (-0.8 kg). The mean weight loss was not statistically different among the 4 groups, even after adjusting for the baseline weight differences.


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  		Table 2. Nutrient Intakes From 4-d Food Records and Body Weight for Women and Men With Hypercholesterolemia or Combined Hyperlipidemia Before and 1 y After Starting NCEP Step II Diet

Effects on Lipoproteins and Apoproteins
Baseline and 1-year plasma values are shown in Table 3Down. Triglyceride concentrations did not change significantly within any group or among the groups; the median changes were 2.1% and 6.8% in HC and CHL women, respectively, and 8.2% and 0.3% in HC and CHL men, respectively. Total and LDL-C levels were significantly lower after 1 year in each group, and the decreases were not different among the 4 groups (see Figure 1Down for LDL-C). ApoB levels declined slightly in each group and were statistically significant only in HC women (-5.1%, P=0.000) and marginally significant in CHL women (-2.5%, P=0.023) and CHL men (-1.9%, P=0.019).


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  		Table 3. Lipoprotein Lipids, ApoA-I, and ApoB in Women and Men With Hypercholesterolemia or Combined Hyperlipidemia Before and 1 y After Starting NCEP Step II Diet



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  		Figure 1. Percent changes in LDL-C in HC and CHL women and men 1 year after instruction in the NCEP Step II diet.

HDL-C, HDL2-C, and HDL3-C levels were higher at baseline in HC compared with CHL subjects and in women compared with men. HDL-C concentrations decreased significantly in HC and CHL women and in CHL men but not in HC men (Figure 2Down). The decrease was greater in HC women than in CHL women (P=0.030) but was not different between HC and CHL men. HC women had a greater HDL-C reduction than did HC men, but no difference was seen between CHL women and men. HDL2-C levels decreased significantly in HC and CHL women but not in either group of men (Figure 2Down). The 16.7% decrease in HC women was greater than the 7.1% decrease in CHL women (P=0.024) and the 0.5% increase in HC men (P=0.000). The HDL2-C decrease was not statistically different between CHL women and men, although it was somewhat greater in women. HDL3-C decreased significantly in HC women (-2.4%) and CHL men (-3.7%) but not in CHL women (-1.3%) or HC men (-0.7%); however, there were no differences among groups. The only significant change in apoA-I was a 5.3% decrease in HC women, which was different from apoA-I in CHL women (P=0.006) and HC men (P=0.001, Figure 2Down).



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  		Figure 2. Percent changes in HDL-C, HDL2-C, and apoA-I in HC and CHL women and men 1 year after instruction in the NCEP Step II diet.

The percent changes in HDL2-C can be large relative to concentration changes because of the low plasma levels of this lipoprotein fraction. Therefore, the absolute changes in HDL2-C and HDL3-C concentrations were examined as well. HDL2-C levels decreased more in women than in men: for HC women, 0.08 mmol/L (-3.1 mg/dL); for CHL women, 0.04 mmol/L (-1.4 mg/dL); for HC men, 0.00 mmol/L (-0.3 mg/dL); and for CHL men, 0.01 mmol/L (-0.4 mg/dL). The absolute changes in HDL3-C compared with those of HDL2-C were less in women and greater in men, and none approached the HDL2-C decrease in HC women.

To determine whether different numbers of subjects for each sex and lipid disorder group had adverse responses to dietary changes, subjects were classified as having a decrease in HDL-C, HDL2-C, or apoA-I versus no change or an increase in each parameter. As shown in Figure 3Down, there was a significant difference in the number of subjects with decreases in HDL-C ({chi}2 12.28, P=0.006) and HDL2-C ({chi}2 12.60, P=0.006) and a marginal difference for apoA-I ({chi}2 7.80, P=0.050). A greater percentage of HC women, 70% to 78%, had reductions in the 3 parameters (P<0.005 for HDL-C and HDL2-C and P<0.025 for apoA-I) compared with {approx}50% to 60% of subjects in the other groups. The proportion of subjects with decreases in these 3 parameters was not different among CHL women, HC men, and CHL men.



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  		Figure 3. Percentage of HC and CHL women and men who had decreases in HDL-C, HDL2-C, or apoA-I 1 year after instruction in the NCEP Step II diet. Significant differences in the percent of HC women with decreased values compared with CHL women, HC men, and CHL men combined are as follows: *P<0.005 and {dagger}P<0.025.


*    Discussion
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 *Discussion
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The beFIT study is the largest long-term study yet conducted to compare the lipoprotein responses to a low fat diet between HC women and men. Study participants were not highly selected; they were excluded only if they were already on an NCEP Step II diet, were taking lipid-altering medications, had a high thyroid-stimulating hormone (a potential cause of hypercholesterolemia), or were women who were or had recently been pregnant. The purpose of the study was to determine whether teaching the NCEP Step II diet to moderately HC and CHL women and men resulted in similar lipoprotein lipid responses over the short and long term. After 6 months, which is the interval typically recommended for dietary effort before drug therapy,25 the LDL-C reduction was similar in women and men, but women had greater HDL-C reductions than did men.7

The present analysis of 1-year follow-up data confirms those findings and extends them to include HDL subfractions and apoproteins. The results answer the 4 questions posed. First, the HDL-C decrease in women previously observed at 6 months persists at 1 year. Second, in HC but not CHL subjects, HDL-C decreases more in women than in men. Third, the HDL-C reduction occurs primarily in the HDL2 subfraction, which decreased 16.7% and 7.1% in HC and CHL women, respectively, but did not change in men. Fourth, apoA-I decreased significantly only in HC women, in keeping with the HDL-C and HDL2-C decreases in this group. The differences in these responses do not appear to be due to differential dietary adherence, LDL-C or triglyceride response, or weight change.

Dietary compliance in the present study was determined by food records. By use of the doubly labeled water technique, energy expenditure has been precisely measured and compared with food records.26 27 Underreporting by 10% to 20% of calories is typical, with obese and formerly obese individuals, especially women, underreporting to a greater extent. There is not yet a way to know whether some types of foods are more or less underreported than others. In the present study, reported baseline intakes provide 25 and 23 kcal/kg for HC and CHL women, respectively, and 28 kcal/kg for HC and CHL men. The caloric reduction at 1 year is greater than can be attributed to weight loss (which was only 1% to 3% of baseline weight) and probably represents record-keeping "fatigue," because 6 records had been kept by this visit. However, nutrients such as total and saturated fat (as percentage of calories) were not different between men and women at baseline or after intervention. These data suggest that compliance was similar between the sexes.

Some studies,8 9 10 11 28 29 30 31 32 33 34 35 but not all,36 37 38 have reported reductions in HDL-C in response to low fat diets. However, most were short term, and only a few presented sex-specific results. The diet studies that have provided sex-specific data disagree, reporting similar HDL-C responses between women and men,10 28 32 35 greater reductions in women,7 8 31 and greater reductions in men.38 The discrepancies in these reported results may reflect the differences in study protocols, including subject characteristics, provided versus self-selected foods, nutrient composition, and usually short study duration. Wood et al8 have performed the only other long-term study in which men and women were compared. In that study, which included overweight and not necessarily hyperlipidemic subjects, HDL-C increased in men and decreased in premenopausal women after 1 year on the NCEP Step I diet. These results are in general agreement with our own.

Regarding HDL2-C, our finding that beFIT women, but not men, had significant reductions in HDL2-C is consistent with the few studies that have reported the effects of low fat diets on HDL subfractions in women and men or in women only. Wood et al8 found that women, but not men, had reduced HDL2-C in response to an NCEP Step I diet. In a study reported by Cole et al,29 premenopausal moderately HC women fed a 21% fat American Heart Association Phase 3 Diet experienced a 35% reduction in HDL2-C. However, men were not studied. Conversely, Clifton, Nestel, and colleagues39 40 reported a greater increase in HDL-C and especially HDL2-C by women than by men ingesting a saturated fat–supplemented diet in 2 separate investigations. In summary, previous and present evidence indicates that women, but not men, experience significant reductions in HDL2-C levels in response to low fat diets over the short and long term.

ApoA-I is the major structural and regulatory protein of HDL and, like HDL, is higher in women than in men,41 and is lower in patients with myocardial infarction42 and coronary artery disease.43 . However, it is not as strong a predictor of future disease as is HDL-C.43 44 Only HC women in the present study had a significant reduction in apoA-I, which was {approx}5 times more than that of the other groups. Two other NCEP Step II diet trials, lasting 6 to 9 weeks,9 10 reported significant reductions in apoA-I in women and men together. ApoA-I did not change in premenopausal moderately HC women on an American Heart Association Phase 3 Diet.29 However, in the Wood et al8 Step I diet study, premenopausal women, but not men, had significantly decreased apoA-I, again concurrent with our results.

Another important finding of the present study is that only HC women had significant reductions in all 3 plasma levels inversely related to CVD risk, ie, HDL, HDL2-C, and apoA-I. It is noteworthy that these decreases occurred in 70% (apoA-I) to 78% (HDL-C) of the women and were not an artifact due to a small number of study subjects experiencing large decreases.

Whether the Step II diet–induced HDL-C and HDL2-C reductions in women are related to coronary artery disease is unknown. Several facts suggest that the reduction is potentially important. Low HDL-C and HDL2-C are independent risk factors for CVD in cross-sectional prospective studies.15 16 17 18 19 42 44 45 HDL-C and HDL2-C levels are higher in women compared with men, which is an inverse of the lower age-adjusted rates for coronary disease in women compared with men.11 12 13 14 41 The observed HDL-C and HDL2-C reductions with the Step II diet are not small when viewed from the standpoint of the baseline differences between women and men. The 0.13 mmol/L (5 mg/dL) HDL-C drop in HC women equals half of the 10 mg/dL baseline difference between HC women and HC men. Likewise, the 0.08 mmol/L (3 mg/dL) drop in HDL2-C is half of the 6 mg/dL difference observed between women and men in the present study. HDL-C is a stronger risk predictor in women than in men. In an analysis of several studies, Gordon et al20 calculated that a 1-mg/dL decrease in HDL-C was associated with increased CVD risk of 3% to 5% in women and 2% to 3% in men. If that algorithm applies to HDL decreases reported in the present study, CVD risk increases 15% and 6% in HC and CHL women, respectively, and 2% and 4% in men. The HDL-C reduction might be related to an unfavorable mechanism. Synthesis of saturated fat and triglycerides or other hepatic metabolic realignments from increased dietary carbohydrate might be increased despite the absence of a statistically significant increase in plasma triglycerides usually associated with this effect.46 47 More studies are required to address mechanistic and CVD end-point issues.

Alternatively, the reduction in HDL-C levels in women following the Step II diet may not have an unfavorable effect on CVD. For instance, high fat feeding is associated with an increase in HDL-C, yet no one recommends a high fat diet for this purpose. It is conceivable that women may adapt HDL metabolism to shifts in dietary fat and carbohydrate more readily than men (eg, see Reference 40 ). The HDL rise and fall may represent a protective adaptation to fat feeding that is stronger in women than in men over the long term (as suggested by Vélez-Carrasco et al48 ). Finally, Brinton et al49 have speculated that the low fat diet–induced reduction in HDL-C is benign because it is associated with a reduction in apoA-I entry, whereas individuals with primary reductions in HDL-C have enhanced apoA-I removal. Vélez-Carrasco et al have recently confirmed the diet-induced reduction in apoA-I secretion with low fat diet. However, these studies were either short term and/or not specific to sex or the presence of hyperlipidemia. That apoA-I and HDL-C are both reduced indicates that the effect involves more than a putative increase in hepatic scavenger receptor B-1 activity.50 51

Although the novel findings in the present study pertain to a sex-specific reduction in HDL-C with the Step II diet, the study also demonstrates a continued reduction in LDL at 12 months in women that is equivalent to that in men. Thus, the potential benefit from the Step II diet continues to be the reduction in LDL as well as the cumulative nonlipid benefits of reductions in body weight, blood pressure, plasma insulin and glucose, insulin sensitivity, and oxidative stress47 52 The question posed by the present study is whether the HDL reduction in women materially subtracts from this benefit.

In summary, no studies are available that specifically address the hypotheses that a diet-induced reduction in HDL-C is or is not significant for CVD risk. Although the significance of the Step II diet–induced HDL-C decrease in women requires further study, the present study clearly establishes that a sex-specific difference in the HDL-C response to the Step II diet exists. Its mechanism is an extremely interesting physiological problem, suggesting sex-based differences in intrahepatic glucose and fatty acid metabolism linked to alterations in HDL formation and removal.

In conclusion, the present results confirm those previously reported for HDL-C after 6 months of follow-up and extend the observations to HDL2-C and apoA-I. Women with elevated cholesterol and normal triglyceride levels at baseline had the most adverse HDL responses, which could not be attributed to statistically significant differences in dietary adherence, weight change, or cholesterol and triglyceride responses among the sex and lipid-disorder groups. The mechanisms of these sex-differential responses are unknown, but further investigation is warranted. The significance of the HDL-C, HDL2-C, and apoA-I reductions for CVD risk in women is also unknown but requires further study because the effect could be adverse. We conclude that the NCEP Step II diet can provide long-term benefit to cardiovascular health by lowering LDL-C. However, alternative diets that lower LDL-C but do not reduce HDL-C should be evaluated and may prove preferable for HC women.


*    Acknowledgments
 
This work was supported by National Institutes of Health grants HL-44878 from the National Heart, Lung, and Blood Institute and DK-35816 from the Clinical Nutrition Research Unit and by a generous gift from the Robert B. McMillen Family Trust. The authors thank George Gey, MD, and the staff of the Boeing Medical Department for their dedicated support of this project.

Received October 4, 1999; accepted February 16, 2000.


*    References
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 *References
 

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