Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC).

OBJECTIVE: Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. METHODS: Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' follow-up. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. RESULTS: Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (.13 mmol/L), 3.3 mg/dL (.09 mmol/L), and 2.0 mg/dL (.05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. CONCLUSION: Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence.

Long-term effects of cis and trans monounsaturated (18:1) and saturated (16:0) fatty acids on the synthesis and secretion of apolipoprotein A-I- and apolipoprotein B-containing lipoproteins in HepG2 cells.

The objective of this study was to compare the long-term effects of oleic (cis 18:1), elaidic (trans 18:1), and palmitic (16:0) acids on hepatic lipoprotein production, using HepG2 cells as an experimental model. The net accumulation in the medium of apolipoprotein A-I (apoA-I) was not significantly altered by fatty acids, whereas that of apoB was increased with oleic and elaidic acids. Oleic acid, and to a lesser extent elaidic and palmitic acids, increased the mass of triglycerides in the medium and the incorporation of [(3)H]glycerol into secreted triglycerides. The incorporation of [(14)C]acetate into cellular and secreted total cholesterol was stimulated by 96% and 83%, respectively, with elaidic acid but was not significantly modified by oleic or palmitic acid. Relative to oleic acid, the secretion of (14)C-labeled phospholipids and triglycerides was decreased 28% to 31% with elaidic and palmitic acids whereas that of free cholesterol and cholesteryl esters was enhanced 93% and 73%, respectively, with elaidic acid but remained unchanged with palmitic acid. Compared with oleic acid, elaidic acid stimulated the secretion of very low density lipoprotein cholesterol (VLDL-Chol), low density lipoprotein cholesterol (LDL-Chol), and high density lipoprotein cholesterol (HDL-Chol) by 43%, 70%, and 34%, respectively, whereas palmitic acid decreased VLDL-Chol but had no significant effect on LDL-Chol and HDL-Chol. The ratios of total cholesterol to HDL-Chol were 3.17, 3.60, and 3.25 with oleic, elaidic, and palmitic acids, respectively; the corresponding ratios of LDL-Chol to HDL-Chol were 0.87, 1.10, and 0.93, respectively. Compared with oleic and palmitic acids, the LDL and HDL particles secreted in the presence of elaidic acid contained higher levels of free cholesterol and cholesteryl esters and a lower content of phospholipids. The phospholipid-to-total cholesterol ratios of HDL were 1.05, 0.40, and 0.76 with oleic, elaidic, and palmitic acids, respectively. Our results indicate that in comparison with cis monounsaturated and saturated fatty acids, trans fatty acids have more adverse effects on the concentration and composition of lipoproteins secreted by HepG2 cells.

Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children.

BACKGROUND: Few studies have shown the efficacy and safety of lower-fat diets in children. OBJECTIVE: Our objective was to assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease LDL-cholesterol concentrations in children. DESIGN: A 6-center, randomized controlled clinical trial was carried out in 663 children aged 8-10 y with LDL-cholesterol concentrations greater than the 80th and less than the 98th percentiles for age and sex. The children were randomly assigned to either an intervention group or a usual care group. Behavioral intervention promoted adherence to a diet providing 28% of energy from total fat, <8% from saturated fat,

Methods, results, and lessons learned from process evaluation of the high 5 school-based nutrition intervention.

This article describes the process evaluation of High 5, a school-based intervention targeting fruit and vegetable consumption among fourth graders and their families. The outcome evaluation involved 28 schools randomized to intervention or control conditions. The intervention included classroom, family, and cafeteria components. Process evaluation was completed on each of these components by using observations, self-report checklists, surveys, and other measures. Results indicated high implementation rates on the classroom activities. Moderate family involvement was attained, perhaps diminishing intervention effects on parent consumption. Cafeterias provided environmental cues, and fruit and vegetable offerings as directed by the program. A lower dose of the intervention was delivered to schools with larger African American enrollments and lower-income families. This article provides insights into the effective elements of a school-based dietary intervention and provides suggestions for process evaluation in similar studies.

Increasing the fruit and vegetable consumption of fourth-graders: results from the high 5 project.

BACKGROUND: This study evaluated the effects of a school-based dietary intervention program to increase fruit and vegetable consumption among fourth-graders. METHODS: Twenty-eight elementary schools were randomized to an immediate intervention condition or to a delayed intervention control condition. Measures of diet and psychosocial variables were collected at base line and 1 and 2 years post-baseline. The intervention included classroom, parent, and cafeteria components. RESULTS: Mean daily consumption of fruit and vegetables was higher for the intervention children compared with controls at Follow-up 1 (X(t) = 3.96, X(c) = 2.28) and at Follow-up 2 (X(t) = 3.20, X(c) = 2.21). Macro- and micronutrient changes favoring the intervention children were also observed at both Follow-up 1 and Follow-up 2. Mean daily consumption of fruit and vegetables was higher for intervention parents compared with controls at Follow-up 1 (X(t) = 4.23,X(c) = 3.94) but not at Follow-up 2. CONCLUSIONS: Strong effects were found for the High 5 intervention on fruit and vegetable consumption, on macro- and micro-nutrients, and on psychosocial variables. Future work is needed to enhance the intervention effects on parents' consumption and to test the effectiveness of the intervention when delivered by classroom teachers.

Evaluation and management of dyslipoproteinemia in children.

The major goal of the evaluation and management of DLP in children is to provide safe and effective therapy with lifestyle modification. There is a strong rationale for the initiation of DLP treatment in childhood to limit the earliest stages of atherosclerosis, to establish lifelong lifestyle changes in diet and activity, and to limit the acquisition of additional CVD risk factors such as smoking and obesity. The NCEP has recommended screening for children with a parent with total cholesterol of 240 mg/dL or greater or a parent or grandparent with onset of CVD before age 55 years. Clinical evaluation and management are based on an LDL-C level of 130 mg/dL or greater. This approach to screening has a low sensitivity to identify children with DLP. Initial therapy is with a step 1 diet followed by the step 2 diet if necessary. Medications are reserved for older children with LDL-C of 190 mg/dL or greater after diet therapy or 160 mg/dL or greater with other CVD risk factors.

Design of "High 5": a school-based study to promote fruit and vegetable consumption for reduction of cancer risk.

BACKGROUND: This paper describes the methods used in "High 5," a school-based study to increase fruit and vegetable consumption for cancer risk reduction. METHODS: Twenty-eight elementary schools were matched and randomized to intervention or control conditions. All students were assessed based on diet and psychosocial variables at baseline and one and two years post-baseline. The intervention included classroom, parent, and environmental components. RESULTS: The study recruited 1,698 families and retained 85%. The two conditions were equivalent at baseline; 50% female students, 81% to 84% European-American students, and 2.9 servings of fruit and vegetables per day. Good completion was achieved across the intervention components (e.g., 90% of lessons taught, 72% of parent materials read, 3.6 servings of fruit and vegetables offered in cafeterias). CONCLUSIONS: The use of school-based programs, with strong evaluation designs, will enhance knowledge about the modification of nutrition behavior and cancer risk in children. Lessons learned from the study are reported.

Prevalence of obesity with increased blood pressure in elementary school-aged children.

The objectives of this study were to estimate the prevalence of obesity in school-aged children in Jefferson County, Alabama; to learn when school-aged children become obese; to determine the susceptible groups; and to study the association between obesity and blood pressure. During the school year, 5,953 children, ranging in age from 5 years to 11 years, were screened for weight, height, and blood pressure, using standardized techniques. We found that obesity, defined as > or = 120% of ideal body weight for height, is prevalent in 5-year-old to 11-year-old children. The prevalence of obesity in girls at age 5 was 23% in blacks and 10% in whites, rising to 47% in blacks and 27% in whites by age 11. In boys, the prevalence of obesity at age 5 was 13% in blacks and 6% in whites, rising to 29% in blacks and 22% in whites by age 11. The prevalence of obesity is significantly greater in black than in white children and is also significantly greater in girls than boys. The systolic and diastolic blood pressures were significantly higher in obese than in non-obese children. We conclude that the significant prevalence of childhood obesity and an associated complication, increased blood pressure, emerge in school-aged children. Thus, we recommend investigations of prevention and intervention programs to be used in the school setting.

Safety of a fat-reduced diet: the Dietary Intervention Study in Children (DISC).

OBJECTIVE: To assess the relationship between energy intake from fat and anthropometric, biochemical, and dietary measures of nutritional adequacy and safety. DESIGN: Three-year longitudinal study of children participating in a randomized controlled trial; intervention and usual care group data pooled to assess effects of self-reported fat intake; longitudinal regression analyses of measurements at baseline, year 1, and year 3. PARTICIPANTS: Six hundred sixty-three children (362 boys and 301 girls), 8 to 10 years of age at baseline, with elevated low-density lipoprotein cholesterol, who are participants of the Dietary Intervention Study in Children. MEASURES: Energy intake from fat assessed from three 24-hour recalls at each time point was the independent variable. Outcomes were anthropometric measures (height, weight, body mass index, and sum of skinfolds), nutritional biochemical determinations (serum ferritin, zinc, retinol, albumin, beta-carotene, and vitamin E, red blood cell folate, and hemoglobin), and dietary micronutrients (vitamins A, C, E, thiamin, riboflavin, niacin, vitamins B-6, B-12, folate, calcium, iron, zinc, magnesium, and phosphorus). RESULTS: Lower fat intake was not related to anthropometric measures or serum zinc, retinol, albumin, beta-carotene, or vitamin E. Lower fat intake was related to: 1) higher levels of red blood cell folate and hemoglobin, with a trend toward higher serum ferritin; 2) higher intakes of folate, vitamin C, and vitamin A, with a trend toward higher iron intake; 3) lower intakes of calcium, zinc, magnesium, phosphorus, vitamin B-12, thiamin, niacin, and riboflavin; 4) increased risk of consuming less than two-thirds of the Recommended Dietary Allowances for calcium in girls at baseline, and zinc and vitamin E in boys and girls at all visits. CONCLUSIONS: Lower fat intakes during puberty are nutritionally adequate for growth and for maintenance of normal levels of nutritional biochemical measures, and are associated with beneficial effects on blood folate and hemoglobin. Although lower fat diets were related to lower self-reported intakes of several nutrients, no adverse effects were observed on blood biochemical measures of nutritional status. Current public health recommendations for moderately lower fat intakes in children during puberty may be followed safely.

Reproducibility of measurement of resting energy expenditure in prepubertal girls.

We determined the reproducibility of measuring resting energy expenditure (REE) and the effect on REE of spending the night before testing at home compared with in a clinical research center. We studied 19 prepubertal girls aged 6.0-10.1 y with a mean weight-for-height of 108% of ideal. REE was measured for 30 min with a metabolic monitor after 12 h of fasting on three consecutive mornings during two different hospitalizations 6 wk apart. The initial REE measurement of each hospitalization was obtained on admission and the second and third measurements were performed during the 3-d hospitalization. Energy intake was ad libitum and was recorded while the children were in the research center. Body composition was determined twice with dual-energy X-ray absorptiometry. No significant effect on REE of day within visit was found across visits. There was no significant difference between the initial REE measurement and the second and third measurements. The mean REEs for the two hospitalizations were highly correlated. The mean CV in intraindividual REE (ie, all six measurements) was 5.8% and was unchanged when adjusted for fat-free body mass (FFM) or body weight. The mean CV in interindividual REE decreased when adjusted for FFM or body weight. Because REE was highly reproducible, a single measurement can suffice for energy expenditure studies in girls aged 6-10 y. Admission to a clinical research setting is not necessary for a reliable determination of REE.

Feasibility of a clinic-based hypocaloric dietary intervention implemented in a school setting for obese children.

The objective of this study was to examine whether a protein-sparing modified fast diet and a hypocaloric balanced diet are effective in a clinic-based dietary intervention implemented in a school setting high-risk weight loss program for superobese (> or = 140% of their ideal body weight for height [IBW] children. A group of children from two suburban public schools in New Orleans, Louisiana were randomized to either dietary-intervention group and control group. Children were followed for 6 months. In the dietary-intervention-group, 12 of 44 superobese children [ages 8.8 to 13.4 years, weight 144% to 212% of IBW] volunteered to participate. In the control group, 7 of 19 superobese children [ages 9.4 to 12.9 years, weight 140% to 195% of IBW] volunteered to participate. During the first 9 weeks, 12 superobese children were placed on a 2520 to 3360 J (600 to 800 Cal) protein-sparing modified fast diet. Subsequently, the diets of all children were increased in a 3-month period 420 J (100 Cal) every 2 weeks until a 5040 J (1200 Cal) per day balanced diet was attained. In both groups, height and weight were obtained at baseline, 10 weeks, and 6 months; and biochemical measurements were performed at baseline and 6 months. At 6 months the 12 superobese children on protein-sparing modified fast diet had a significant weight loss from baseline (-5.6 +/- 7.1 kg, ANOVA p < 0.02); a significant decrease in percentage IBW (-24.3 +/- 20%, ANOVA p < 0.002); and had positive growth velocity Z-score (1.3 +/- 1.6, ANOVA p < 0.05). Six children were not superobese at 6 months. At 6 months eight of 12 children were active participants and 11 of 12 children were followed. Decrease in blood pressure, as well as, downward trends in serum lipids were observed at 6 months. No clinical complications were observed. At 6 months, the 7 control superobese children, when compared with baseline had gained weight (2.8 +/- 3.1 kg, ANOVA p < 0.008); but had no significant change in percentage IBW (-0.3 +/- 5.9%, ANOVA p = 0.61); and had no changes in growth velocity Z-score (0.1 +/- 1.3, ANOVA p = 0.83). These children did not have any change in blood pressure and an upward trend in serum lipids were observed at 6 months. Protein-sparing modified fast diet and a hypocaloric balanced diet appear to be effective in a group of superobese-school-age children in a medically supervised clinic-based program implemented in a school setting over a 6-month period. The efforts of committed clinic staffs, school officials, peers, and family involvement were crucial to the success of this intervention program in promoting and maintaining weight loss over a 6-month period. Further research with a specific comparison of the hypocaloric diets with longer follow-up periods in the school setting is necessary. In the meantime, these diets should be used only with close medical supervision.

Impact of intestinal lengthening on the nutritional outcome for children with short bowel syndrome.

Survival among children with short bowel syndrome has increased with the use of supportive nutritional techniques including parenteral and enteral nutrition. Further improvement in outcome has been sought by using intestinal lengthening procedures to lengthen the bowel, improve intestinal motility, initiate a progressive increase in intestinal mucosal mass, and thereby improve tolerance to enteral nutrition. The authors examine the growth parameters and the tolerance to enteral nutrition in children with refractory short bowel syndrome before and after intestinal lengthening procedures. For seven children, the percentage of calories from enteral nutrition, the medical and surgical complications, and the number of days in the hospital (1 year before and 2 years after the lengthening procedure) were evaluated. The mean birth weight was 1,991 g (range, 1,198 to 3,096 g). The initial diagnoses requiring bowel resection included necrotizing enterocolitis, multiple small bowel atresias, gastroschisis with midgut volvulus, cloacal exstrophy, and long-segment Hirschsprung's disease. The mean length of the residual small bowel was 49 cm (range, 6 to 92 cm). All but one child had surgical resection of the ileocecal valve. The percentage of enteral nutrition calories significantly increased by 9 months after the procedure (P < .008, analysis of variance). Only one child has been completely weaned from parenteral nutrition. All children's growth parameters have been maintained or improved (weight/age, height/age, and weight/height). Few major medical and surgical complications have been observed. Central venous catheter infection has been the most common medical complication. The mean number of hospitalization days decreased during the second year after the lengthening procedure. The authors conclude that the intestinal lengthening procedure enhances the tolerance for enteral nutrition, improves the nutritional status, and decreases the need for hospitalization. The procedure should be considered for children with refractory short bowel syndrome who require prolonged parenteral nutrition.

Effect of ethanol on the synthesis and secretion of apoA-I- and apoB-containing lipoproteins in HepG2 cells.

The short- and long-term effects of ethanol on the production of lipids and apolipoproteins (apo) in HepG2 cells were studied. Short-term incubation with 1% ethanol caused a significant 32% increase in the cellular content of both triglycerides and cholesteryl esters. Under these conditions, the net accumulation in the medium of triglycerides, unesterified cholesterol, cholesteryl esters, apoA-I, and apoE was stimulated by 75%, 41%, 43%, 19%, and 39%, respectively. ApoA-I and apoE mRNA levels increased by 15%. The major short-term effect of ethanol was on the net accumulation of apoB in the medium which was stimulated by 56-100% in the presence of 0.1-1.0% ethanol. Under these conditions, apoB mRNA abundance was elevated by 17-26% and LDL receptor activity was unchanged. The increase in apoB accumulation in the medium was predominantly due to augmented secretion of newly synthesized apoB-100 which was evident at 0.05% ethanol. The secretion of newly synthesized apoA-I was not altered by short-term incubation with < or = 0.5% ethanol. The rate of apoB production was positively correlated with the cellular and secreted cholesteryl esters and secreted triglycerides. Addition of Pfizer CP-113,818, an inhibitor of acyl-CoA:cholesterol acyltransferase, caused a 69% reduction in the secretion of cholesteryl esters and a 24% decrease in that of apoB-100. In contrast to the short-term effect of ethanol, long-term incubation with ethanol resulted in a dose-dependent increase in the secretion of newly synthesized apoA-I without significantly affecting that of apoB-100. The increase in apoA-I secretion was evident at 0.05% ethanol and reached a maximum of 77% at 0.5% ethanol. These observations indicate that in HepG2 cells the effect of ethanol on the production of apoA-I- and apoB- containing lipoproteins is both time- and dose-dependent and is different in these two apolipoproteins.

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Comparison of two hypocaloric diets in obese children.

OBJECTIVE: To examine whether a protein-sparing modified fast diet and a hypocaloric balanced diet are safe and effective for children in an outpatient weight reduction program. DESIGN: Randomization of two groups to either diet, with follow-up at 14.5 months. SETTING: Physician or parent referral to outpatient program at Children's Hospital of New Orleans, La. PARTICIPANTS: Nineteen children, ranging in age from 7.5 to 16.9 years, weighing 45% to 131% more than the mean weight for age, sex, and height. INTERVENTION: During the first 10 weeks, 10 children were placed on a protein-sparing modified fast diet (2520 to 3360 J), and nine children and adolescents were placed on a hypocaloric balanced diet (3360 to 4200 J). Subsequently, all participants were placed on a hypocaloric diet; calories were increased from 4200 to 5040 J in a 3-month period and maintained for 1 year. SELECTION PROCEDURES: Children were assigned to one of two diets for the first 10 weeks according to their time of enrollment. MEASUREMENTS/MAIN RESULTS: Both diets produced significant weight loss during the first 6 months. However, the protein-sparing modified fast diet produced significantly greater changes in the percentage of overweight at 10 weeks (-30% vs -14%) and at 6 months (-32% vs -18%). At 10 weeks, a significant loss of adipose tissue with preservation of lean body mass occurred in the protein-sparing modified fast group. A transient slowing of growth velocity was noted at 6 months in both dietary groups compared with values at 14.5 months. Growth velocity approached normal levels at 14.5 months compared with standards for North American children. When dietary groups were combined, the initial mean blood pressure decreased significantly at all points in the study. The initial mean serum cholesterol value also decreased significantly at 10 weeks. No biochemical or clinical complications were observed. CONCLUSIONS: These hypocaloric diets appear to be safe and effective in the short-term management of pediatric obesity. However, these diets should not be used without close medical supervision.

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins.

BACKGROUND: Lovastatin produces consistent dose-related reductions in plasma levels of low density lipoprotein (LDL) cholesterol along with variable decreases in triglycerides and increases in high density lipoprotein (HDL) cholesterol. Patient characteristics from the Expanded Clinical Evaluation of Lovastatin (EXCEL) study were examined to determine their association with the magnitude of lovastatin-induced changes in these lipids and lipoproteins. METHODS AND RESULTS: After a baseline period consisting of dietary therapy, 8,245 patients with moderate hypercholesterolemia were randomized to five groups that received 48 weeks of treatment with either placebo or daily doses of lovastatin ranging from 20 to 80 mg. By use of linear statistical models, 20 different patient characteristics were examined for modification of the dose-dependent responses observed. For LDL cholesterol, the following were associated with enhanced lowering (p less than 0.05; percent changes are placebo-corrected, adjusted mean changes from baseline for the 80-mg/day lovastatin group): full drug compliance (-41.9%) versus 80% compliance (-20.3%); an age of 65 (-43.4%) versus 45 years (-38.1%) for women; white race (-40.9%) versus black race (-38.0%); and 4.5-kg weight gain (-42.6%) versus 4.5-kg weight loss (-37.9%). Similar relations for enhanced triglyceride lowering were found with older age and weight gain. Patients with initially low HDL cholesterol (less than 0.91 mmol/l) and high triglycerides (greater than 2.26 mmol/l) had enhanced responses for these parameters: placebo-corrected percent changes at 80 mg/day were -27.4% for triglycerides and +12.3% for HDL cholesterol. CONCLUSIONS: Overall, patient characteristics had very little impact of clinical importance on the dose-dependent LDL cholesterol lowering found with lovastatin. In patients with initially high levels of triglycerides and low levels of HDL cholesterol, the elevation of HDL cholesterol produced by lovastatin appears to be enhanced.

Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin.

This randomized, double-blind, multicenter, diet-and-placebo-controlled study was designed to clarify the dose-response relationship of lovastatin therapy to lipid-modifying efficacy and drug-related adverse events. Exclusion criteria were minimized so that study patients were representative of the majority of patients with moderate hypercholesterolemia seen in medical practice. After 6 weeks on the American Heart Association Step 1 Diet, a total of 8,245 patients were randomly assigned to 48 weeks of treatment with diet and placebo or lovastatin at dosages of 20 or 40 mg once a day or 20 or 40 mg twice a day. All adverse events were monitored, with particular attention to evaluation of liver and muscle. Liver transaminase elevations suggestive of possible hepatotoxicity, defined as successive elevations in either aspartate transaminase or alanine aminotransferase greater than 3 times the upper limit of normal, occurred in equal numbers of placebo and lovastatin 20 mg/day treated patients (0.1%). The frequencies were higher in lovastatin 40 mg/day and 80 mg/day patient groups (0.9 and 1.5%, respectively). No patient was diagnosed as having clinically symptomatic hepatic dysfunction. Creatinine kinase (CK) elevations above the upper limit of normal occurred frequently in placebo- (29%), as well as lovastatin-treated patients (29-35%), and muscle symptoms were reported with similar frequency in all groups (7-9%). The combination of muscle symptoms with marked CK elevations (greater than 10 times the upper limit of normal) was seen in only five patients: one in a 40 mg/day dose group and four in the 80 mg/day dose group. No patient developed rhabdomyolysis. The incidence of clinical and laboratory adverse events requiring discontinuation was 6% for the placebo group and from 7% (20 mg/day) to 9% (80 mg/day) for lovastatin treatment groups. No new types of adverse experiences related to lovastatin treatment were reported. Lovastatin, as an adjunct to diet for the reduction of elevated LDL cholesterol, was generally very well tolerated.