Barbara M. Retzlaff

Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: Clues to mechanism of action of niacin

To minimize the cutaneous flushing symptoms associated with niacin use, a time-release capsule form of niacin has been formulated. Thus study compares the effects of time-release niacin with those of unmodified niacin on lipoprotein lipids, including HDL2 and HDL3, apoproteins A-I and A-II, clinical chemistries, symptomatic side effects, and adherence to the medication regimen. Seventy-one primarily hypercholesterolemic subjects were randomized to either unmodified niacin or time-release niacin ad took medication for a six-month period. The two groups were closely matched on anthropomorphic and lipid variables. Adherence to the therapeutic regimen at a dose of 1.5 g/d in the first month of treatment was similar in the two groups. Thereafter, at a dose of 3.0 g/d, adherence was in excess of 90% among subjects taking unmodified niacin but only 64% among those taking time-release niacin, chiefly because of aggravated gastrointestinal symptoms; cutaneous flushing side effects, however, were slightly less common with time-release niacin. At these levels of adherence, LDL cholesterol (C) was reduced 21% by unmodified niacin and 13% by the time release form. Plasma total triglyceride was reduced more with unmodified niacin (27%) than with time-release niacin (8% maximum), and HDL-C and HDL2-C were increased significantly with unmodified niacin (26% and 36%) and were not significantly changed by time-release niacin. Increased to a similar degree on both regimens were HDL3-C (approximately 35%) and apoA-I (approximately 12%). ApoA-II was not affected by either drug regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Insulin Resistance and Obesity on Lipoproteins and Sensitivity to Egg Feeding

Objective—This study was undertaken to determine if insulin resistance without and with obesity influences LDL response to dietary cholesterol and saturated fat. Methods and Results—We fed 0, 2, and 4 egg yolks per day to 197 healthy subjects in a 4-week, double-blind, randomized, crossover design. Subjects were dichotomized on body mass index (<27.5 and ≥27.5 kg/m2) and insulin sensitivity (insulin-sensitivity index ≥4.2×1.0−4 and <4.2×1.0−4 min−1 &mgr;U/mL), yielding insulin-sensitive (IS, n=65), insulin-resistant (IR, n=75), and obese insulin-resistant (OIR, n=58) subjects. Mean fasting baseline LDL cholesterol (LDL-C) levels were higher in IR and OIR subjects (3.44±0.67 and 3.32±0.80 mol/L) than in IS subjects (2.84±0.75 mmol/L) (P <0.001). Progressive triglyceride elevations and HDL-C decreases were seen across the 3 groups. Ingesting 4 eggs daily yielded significant LDL-C increases of 7.8±13.7% (IS) and 3.3±13.2% (IR) (both P <0.05) compared with 2.4±12.6% for OIR (NS). HDL-C increases were 8.8±10.4%, 5.2±10.4%, and 3.6±9.4% in IS, IR, and OIR, respectively (all P <0.01). Conclusions—Insulin resistance without and with obesity is associated with elevated LDL-C as well as elevated triglyceride and low HDL-C. The elevated LDL-C cannot be explained by dietary sensitivity, because the LDL-C rise with egg feeding is less in IR persons regardless of obesity status, probably attributable to diminished cholesterol absorption. The results suggest that dietary management of insulin resistance and obesity can focus more on restricting calories and less on restricting dietary fat.

Lipoprotein Lipid Response to the National Cholesterol Education Program Step II Diet by Hypercholesterolemic and Combined Hyperlipidemic Women and Men

The beFIT study tested whether teaching the NCEP step II diet (< 30% of calories from total fat and < 7% from saturated fat) is an effective therapy in hypercholesterolemic women and men with or without elevated triglycerides after 6 months. Hypercholesterolemic subjects had two LDL cholesterol measurements above the age- and sex-specific 75th percentile, and combined hyperlipidemic subjects additionally had similarly elevated triglyceride. Subjects were randomized to receive dietary intervention (eight weekly classes) immediately or 6 months later. Follow-up visits were quarterly, with lipid measurements and 4-day food records. Subjects randomized to delayed intervention did not report diet changes or experience lipid changes; the immediate intervention group significantly reduced fat and cholesterol intake, resulting in significant LDL cholesterol lowering. Six months after diet instruction, 178 women and 231 men reported total and saturated fat intakes of approximately 25% and 7.5% kcal LDL cholesterol was significantly reduced in women (7.6% and 8.1%) and men (8.8% and 8.1%) with hypercholesterolemia and combined hyperlipidemia, respectively, but was not different by sex or lipid disorder. Candidates for drug therapy were reduced from between 27% and 37% to 20%. HDL cholesterol was significantly decreased in women (-6.4% and -4.7%) but not in men (-1.3% and -2.7%). The 6.4% reduction in hypercholesterolemic women was significantly different from that of men. The significance of the HDL cholesterol reduction in women is unknown. LDL cholesterol response was similar between women and men and between hypercholesterolemic and combined hyperlipidemic subjects. LDL cholesterol lowering by diet can significantly reduce the number of hyperlipidemic persons requiring drug therapy.

The Northwest Lipid Research Clinic Fat Intake Scale: validation and utility.

OBJECTIVES This paper describes the Northwest Lipid Research Clinic Fat Intake Scale, a brief dietary questionnaire to screen and monitor dietary intake related to plasma cholesterol levels. METHODS The 12-item instrument assesses intake of foods high in fat, saturated fat, and cholesterol. Test-retest reliability was assessed on 194 men and 116 women with high cholesterol prior to a dietary intervention study. To measure validity and responsiveness to dietary change, scores were compared with 4-day food records before and after diet education classes. RESULTS Test-retest correlation coefficients were .88 for men and .90 for women (2 weeks between scores). Scores for men and women were correlated with nutrients shown by food records at baseline (.47 and .54, total fat; .50 and .51, saturated fat) and 18 months postintervention (.52 and .58, total fat; .56 and .64, saturated fat; all Ps < .001). Mean scores decreased from about 30 to 23 (P < .001, paired t test). CONCLUSIONS The Fat Intake Scale, a qualitative instrument, has acceptable reliability and validity for estimating the level of cholesterol-related diet components and reflects dietary modification. The format of the instrument also lends itself to patient education and goal setting.

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

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 HDL(2)-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). HDL(2)-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); HDL(2)-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, HDL(2)-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 HDL(2)-C reductions narrow the baseline differences between men and women by 50%. Whether this reduction impacts womens 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.

Relationship of self-effecacy to cholesterol lowering and dietary change in hyperlipidemia.

This study examined whether self-efficacy was associated with lipid lowering and dietary change among men undergoing dietary counseling to lower cholesterol levels. Twenty-five hyperlipidemic men (total cholesterol ≧220 mg/dL) participated in four weeks of dietary instruction. Plasma lipids were measured prior to treatment, at posttreatment, and at three- and twelvemonth follow-up. Dietary intake and self-efficacy as measured by the revised Eating Self-Efficacy Scale (ESES-R) were assessed at pretreatment, posttreatment, and three-month follow-up. Pre-treatment to posttreatment increases in self-efficacy in situations characterized by negative affect were related to extent of lipid lowering and dietary change. Although subjects showed significant reductions in cholesterol levels following treatment, by one year, lipid levels had returned to pretreatment values. Factors related to long-term maintenance of dietary change and lipid lowering among hyperlipidemics merit further research.

Association of plasma phospholipid transfer protein activity with IDL and buoyant LDL: impact of gender and adiposity

Current data suggest that phospholipid transfer protein (PLTP) has multiple metabolic functions, however, its physiological significance in humans remains to be clarified. To provide further insight into the role of PLTP in lipoprotein metabolism, plasma PLTP activity was measured, and lipoproteins were analyzed in 134 non-diabetic individuals on a controlled diet. Insulin sensitivity index (Si) and body fat composition were also determined. Plasma PLTP activity was comparable between men (n=56) and women (n=78). However, in women but not in men, plasma PLTP activity was positively correlated with cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, and apolipoprotein (apo) B (r=0.38-0.45, P< or =0.001), and with body mass index (BMI), subcutaneous and intra-abdominal fat (SCF, IAF) (r=0.27-0.29, P<0.02). Among the different apo B-containing lipoproteins (LpB) in women, PLTP was most highly correlated with intermediate density lipoproteins (IDL) and buoyant LDL (r=0.45-0.46, P<0.001). The correlation with IDL was significant only in women with BMI < or =27.5 kg/m(2) (n=56). In men with BMI < or =27.5 kg/m(2) (n=35), PLTP activity was significantly correlated with buoyant LDL (r=0.40, P<0.02) and high density lipoprotein (HDL) (r=0.43, P<0.01). These data provide evidence for a role of PLTP in LpB metabolism, particularly IDL and buoyant LDL. They also suggest that gender and obesity-related factors can modulate the impact of PLTP on LpB.

Plasma sterol evidence for decreased absorption and increased synthesis of cholesterol in insulin resistance and obesity

BACKGROUND The rise in LDL with egg feeding in lean insulin-sensitive (LIS) participants is 2- and 3-fold greater than in lean insulin-resistant (LIR) and obese insulin-resistant (OIR) participants, respectively. OBJECTIVE We determined whether differences in cholesterol absorption, synthesis, or both could be responsible for these differences by measuring plasma sterols as indexes of cholesterol absorption and endogenous synthesis. DESIGN Plasma sterols were measured by gas chromatography-mass spectrometry in a random subset of 34 LIS, 37 LIR, and 37 OIR participants defined by the insulin sensitivity index (S(I)) and by BMI criteria selected from a parent group of 197 participants. Cholestanol and plant sterols provide a measure of cholesterol absorption, and lathosterol provides a measure of cholesterol synthesis. RESULTS The mean (±SD) ratio of plasma total absorption biomarker sterols to cholesterol was 4.48 ± 1.74 in LIS, 3.25 ± 1.06 in LIR, and 2.82 ± 1.08 in OIR participants. After adjustment for age and sex, the relations of the absorption sterol-cholesterol ratios were as follows: LIS > OIR (P < 0.001), LIS > LIR (P < 0.001), and LIR > OIR (P = 0.11). Lathosterol-cholesterol ratios were 0.71 ± 0.32 in the LIS participants, 0.95 ± 0.47 in the LIR participants, and 1.29 ± 0.55 in the OIR participants. After adjustment for age and sex, the relations of lathosterol-cholesterol ratios were as follows: LIS < OIR (P < 0.001), LIS < LIR (P = 0.03), and LIR < OIR (P = 0.002). Total sterol concentrations were positively associated with S(I) and negatively associated with obesity, whereas lathosterol correlations were the opposite. CONCLUSIONS Cholesterol absorption was highest in the LIS participants, whereas cholesterol synthesis was highest in the LIR and OIR participants. Therapeutic diets for hyperlipidemia should emphasize low-cholesterol diets in LIS persons and weight loss to improve S(I) and to decrease cholesterol overproduction in LIR and OIR persons.

Plasma lipid concentrations during episodic occupational stress

The possibility that stress affects plasma lipid concentrations has been the subject of recent investigation, but the findings are equivocal in nonlaboratory settings. To determine whether psychological stress contributes to variability in plasma lipid concentrations and concomitant changes in health behaviors, the effect of increased work load on plasma lipids and apolipoproteins was examined in 173 lawyers. Plasma cholesterol, triglyceride, and apolipoprotein concentrations were studied during periods of high work load (corresponding to impending tax deadlines) and during periods of usual work load. Self-reports of stress, work load, and time pressure, and cortisol, blood pressure, and heart rate were measured to verify that impending deadlines were associated with increased stress levels. Health behaviors which may affect plasma lipoprotein concentrations, including dietary intake and exercise, were also examined. High work load was accompanied by increases in self-reported work load among lawyers most directly affected by the impending deadlines. Plasma apolipoprotein B and triglycerides increased during periods of high work load (M=1.9 mg/dL,SD=10.1 andM=5.3,SD=34.4, respectively). No changes in dietary intake and exercise were observed. Psychological stress (high work load) is associated with potentially atherogenic changes in plasma lipid concentrations. While the lipoprotein effect of this short-term work stress is small, the effects of longer-term stress on multiple risk factors including triglycerides and apolipoprotein B could have significance for the development of coronary artery disease.

Nutritional intake of women and men on the NCEP Step I and Step II diets

OBJECTIVE Restriction of dietary fat and cholesterol are recommended for treating hyperlipidemia, but may alter vitamin or mineral intakes. We evaluated changes in nutrients of individuals taught the National Cholesterol Education Program (NCEP) Step II diet. METHODS Subjects participated in a randomized controlled trial of the cholesterol-lowering effect of the NCEP Step II diet. Eligibility criteria included elevated fasting plasma LDL-cholesterol, no lipid-altering medications, and diet not already fat-modified. Subjects attended eight weekly dietitian-led classes. Four-day food records collected 6 months post-intervention were compared to baseline records. RESULTS Of 409 subjects with complete data, 123 met Step I and 166 met Step II diet criteria. Intakes of micronutrients associated with fruits and vegetables (beta-carotene and vitamin A, vitamin C, folic acid, magnesium, and potassium) increased on both diets. Patterns of decreased mean intake and/or fewer subjects consuming 2/3 Recommended Dietary Allowance were seen for calcium, vitamin E, and zinc. CONCLUSIONS NCEP Step I and II diets generally match or exceed unmodified diet for vitamin and mineral content. Premenopausal women do not appear to be at increased risk of low iron intake. Vitamin E intake decreases, although the significance is unknown in the context of lower fat intake and increased intake of other antioxidants. Diet counseling and materials should encourage sources of calcium for women, and zinc for both women and men.