Margot J. Mellies

Lovastatin (Mevinolin) in the Treatment of Heterozygous Familial Hypercholesterolemia: A Multicenter Study

STUDY OBJECTIVE To evaluate the efficacy and tolerability of lovastatin under controlled conditions in heterozygous familial hypercholesterolemia. DESIGN Randomized, double-blind, placebo-controlled, multicenter trial. SETTING Five lipid clinics with a central laboratory and coordinating center. PATIENTS 101 adult patients with heterozygous familial hypercholesterolemia. INTERVENTIONS Patients were on a lipid-lowering diet throughout the study. After a 4-week placebo baseline period, patients were randomized to five equal treatment groups. Each group received a different sequence of placebo or lovastatin 5 to 40 mg twice daily or 20 to 40 mg once daily in the evening, during three consecutive 6-week periods. MEASUREMENTS AND MAIN RESULTS The mean reductions in total plasma cholesterol and low-density lipoprotein cholesterol across the dosage ranges were 14% to 34% and 17% to 39%, respectively (p compared with zero and placebo less than 0.01). High-density lipoprotein cholesterol and apolipoproteins AI and AII rose slightly. Apolipoprotein B fell substantially at the higher dosage levels (-23% at 40 mg twice daily, p less than 0.01), indicating a reduction in the concentration of circulating low-density lipoprotein particles. Maximum response was achieved in 4 to 6 weeks. Twice-daily dosing was slightly more efficient than once-daily dosing. Of those patients receiving 40 mg twice a day, 89% had a fall in low-density lipoprotein cholesterol of at least 20%, and 61% had a fall of at least 40%. Adverse effects attributable to lovastatin were minimal, and no patient was withdrawn from the study. CONCLUSION Lovastatin was well tolerated and effective in the treatment of familial hypercholesterolemia.

Lipids, Lipoproteins, and Sexual Maturation During Adolescence: The Princeton Maturation Study

Abstract This study encompassed a cross-sectional and longitudinal examination of schoolchildren as they entered into and passed through puberty, examining interrelationships between lipids, lipoproteins, and sexual maturation. In the first year of the study (1976), 529 schoolchildren in grades 5–12 participated; 203 were restudied in 1977, and 141 in 1978. At each yearly visit, the childrens stage of sexual maturation was assessed using the Tanner scale. Plasma cholesterol and triglyceride were quantitated each year; high, low, and very low density lipoprotein cholesterol (C-HDL, C-LDL, C-VLDL) levels were measured in the second and third years of the study. In males, cross-sectional decrements in plasma cholesterol were observed with increasing sexual maturation (Tanner stages 1–4), with an increment at Tanner 5 (sexual maturity); plasma triglyceride levels rose at all stages save Tanner 4. The mid-Tanner fall in plasma cholesterol appears (longitudinally) to be accounted for by reduction in C-HDL, while the rise in plasma cholesterol at Tanner 5 may be produced by an increase in C-LDL. Changes in age and Quetelet indices did not appear to relate closely to changes in C-VLDL in 12- and 13-yr-old males, but increasing age and Quetelet indices in 14–15-yr old males accompanied increasing C-VLDL. Cross-sectional studies in females revealed that plasma cholesterol fell at Tanner stages 3 and 4 and rose at stage 5; plasma triglyceride rose during all stages except Tanner 4. Longitudinal studies suggested that the decrements in plasma cholesterol in females may be partially accounted for by reductions in C-HDL; the increase in plasma cholesterol in late sexual development may be accounted for by an increase in C-LDL. In male children, we speculate that the fall in C-HDL and late rise in C-LDL as sexual maturation progresses is associated with increased testosterone production.

Plasma cholesterol and triglyceride levels in 6775 school children, ages 6–17

Associations of age, sex, and race with the distribution of fasting plasma cholesterol and triglyceride were studied in 6775 school children (4946 white and 1829 black students, ages 6–17 yr) in a biethnic school district. The target population included 8906 students with 84% of eligible white and 78% of eligible black children participating. In children ages 6–10, mean cholesterol and triglyceride levels varied only minimally. Females 6–10 yr old generally had higher mean plasma cholesterol and triglyceride than males, and blacks had higher mean cholesterol and lower mean triglyceride than whites, p < 0.001. In comparison to the cross-sectional stability of cholesterol and triglyceride over ages 6–10, plasma cholesterol began to fall at ages 11 and 12, continued to fall through ages 15–16, and rose at age 17. An inverse pattern was observed for mean triglycerides. The major increment in triglyceride levels occurred between the ages of 11 and 12, temporally concordant with decrements in cholesterol. Subsequently, in males mean triglycerides continued to rise through age 17, while in females mean triglycerides dipped sharply at ages 16 and 17. Withinrace comparisons of changes in triglyceride over age show the males first having lower triglyceride than females at ages 11–13, and the female levels falling below the male levels at ages 15–17. The decrements of cholesterol and increments in triglyceride during adolescence were also generally observed for the extremes of the distribution, the 5th and 95th percentiles. As was the case for 6–11-yr olds, in the 12–17-yr-old children, blacks had higher mean cholesterols and lower mean triglycerides than whites. Within the limitations of the cross-sectional nature of this study, the inverse changes of cholesterol and triglyceride suggest that hormonal and growth changes during adolescence may have a notable effect on plasma lipids. The availability of age-, sex-, and race-specific cholesterol and triglyceride distributions may allow more meaningful assessment of plasma cholesterol and triglyceride levels of any individual child.

Parent-offspring and sibling lipid and lipoprotein associations during and after sharing of household environments: the Princeton school district family study.

Abstract The specific aim of this report was to determine whether, and to what degree, parent-offspring and sibling associations for lipids and lipoproteins outlast the period of shared household environment. Intrafamilial lipid-lipoprotein associations were assessed in two and three generation kindreds in the Cincinnati Lipid Research Clinics Princeton School District Family Study. Intrafamilial lipid-lipoprotein associations were evaluated in parents and their pediatric (

Effects of fenofibrate on lipids, lipoproteins, and apolipoproteins in 33 subjects with primary hypercholesterolemia

The effects of fenofibrate on lipids, lipoproteins, and apolipoproteins in 33 subjects with primary hypercholesterolemia were assessed in a 6-month parallel group study, placebo (n = 15) versus fenofibrate 300 mg/day (n = 18), followed by an open label 6-month treatment period. After stabilization on an isocaloric low fat (less than 35% total calories) diet with less than 250 mg cholesterol/day and a P/S ratio of 1, and maintenance of LDL-cholesterol (LDL-C) levels greater than or equal to 175 mg/dl, subjects received placebo for 6 weeks and were then randomized into placebo or fenofibrate groups for 6 months, followed by open label treatment for 6 months. During the 6-month double-blind period, compared to the placebo group, the treatment group had significant reductions in total cholesterol, LDL-C, total apo B, and triglyceride, and increments in HDL-cholesterol, apolipoprotein A-I and apolipoprotein A-II (P less than 0.01 for all comparisons). Compared to placebo baseline, therapy with fenofibrate resulted in a reduction of LDL-C, apo B, and the LDL-C/HDL-C ratio of 15%, 13%, and 18% respectively; HDL-C, apo A-I, and apo A-II increased respectively 12%, 13% and 30% (P less than 0.01 for all comparisons). Mean adherence during the double blind phase of the trial was 95% in the drug group and 96% in the placebo group. An additional 6 months of open label fenofibrate therapy maintained the reduced total and LDL-C as well as the elevated HDL-C, apo A-I and apo A-II in the drug-drug group.(ABSTRACT TRUNCATED AT 250 WORDS)

Black-white differences in plasma lipids and lipoproteins in adults: The Cincinnati lipid research clinic population study☆

Black—white lipoprotein differences were studied in 43 pairs of adult males and 51 pairs of adult females to test the hypothesis that in a heterogeneous suburban biethnic setting, blacks have higher levels of high density lipoprotein cholesterol (C-HDL), lower levels of low density lipoprotein cholesterol (C-LDL), and lower levels of triglyceride (TG) when pair-matched by total plasma cholesterol, age, and sex with whites. With essentially identical total plasma cholesterol levels and comparable degrees of ponderosity, black males had lower plasma TG (P < 0.05) and higher plasma C-HDL levels (P < 0.005). There were no significant male black—white differences in C-LDL, but the ratio of C-LDL to C-HDL was lower in black males (P < 0.01). There were no significant differences in any lipoprotein fractions or the C-LDL/C-HDL ratio between black and white females, although black females had slightly lower plasma TG and slightly higher C-HDL than white females.

Cigarette smoking, alcohol intake, and oral contraceptives: Relationships to lipids and lipoproteins in adolescent school-children

The effects of cigarette smoking, alcohol intake, and oral contraceptives on plasma cholesterol, triglyceride, high density lipoprotein cholesterol (C-HDL), and low density lipoprotein cholesterol (C-LDL) were assessed in 965 12--19-year-old school-children in the Cincinnati Lipid Research Clinics Princeton school survey. After pair matching for age, sex, race, and total plasma cholesterol, adolescent children who smoked had mean C-HDL 6.1 mg/dl lower, and mean C-LDL 4.1 mg/dl higher, than nonsmokers (p less than 0.01). These findings for C-HDL were replicated by covariance analysis, adjusting for age, race, sex, alcohol intake, and triglyceride levels. Adolescents who drank alcohol had higher C-HDL and triglyceride levels and lower C-LDL than nondrinkers, but the differences were not significant. Adolescent females taking oral contraceptives had higher triglyceride, C-HDL, and C-LDL levels than matched controls, but the differences were not significant. If a portion of smokings contribution to coronary heart disease risk is mediated through its inverse association with C-HDL, and if smoking habits initiated in adolescence continue into adulthood, this report provides additional physiologic data relevant to programs designed to prevent, reduce, or stop cigarette smoking in the adolescent years.

Black-white similarities in cord blood lipids and lipoproteins.

Cord blood lipoproteins were quantitated in 117 neonates (58 white, 50 black) to assess for potential early expression of racial lipid distinctions. In comparison of black and white neonates there were no differences in total cholesterol (TC), highdensity lipoprotein cholesterol (C-HDL), low-density lipoprotein cholesterol (C-LDL), C-HDLC-LDL, or C-HDLTC. Cord blood triglycerides were slightly higher in black neonates (p = 0.02). Unlike certain adult black-white comparisons and within the limits of “genicity” as exeressed by cord blood lipoproteins, there were no racial differences in C-HDL, C-LDL, and total cholesterol.

Parental history of coronary heart disease, hypertension, diabetes, and stroke: Relationship to coronary heart disease risk factor variables in their adult children

Abstract Relationships of parental (familial) history of coronary heart disease, stroke, hypertension, and diabetes to major coronary heart disease (CHD) risk factors were examined in 738 adults (average age, 40 years) in the Cincinnati Lipid Research Clinics Princeton School study. Men reporting parental CHD had higher plasma triglyceride and higher systolic and diastolic blood pressure than comparison group men reporting no parental CHD, stroke, hypertension, or diabetes. Women reporting parental CHD had higher plasma triglycerides than comparison group women reporting no parental CHD, stroke, hypertension, or diabetes. Men reporting stroke in one parent had higher total plasma cholesterol and triglyceride levels than comparison men. Women reporting stroke in one parent had higher triglyceride levels than comparison group women. Women reporting hypertension in one parent had higher mean triglyceride and systolic blood pressure than comparison women. Men and women reporting diabetes in one parent had higher triglyceride than comparison adults. Matching men whose fathers had died of CHD with those whose fathers were free of CHD revealed significant increments in triglyceride levels, systolic, and diastolic blood pressure in the men with positive family history of CHD. Matching women whose fathers had died of CHD with those whose fathers were free of CHD revealed higher total plasma cholesterol, low-density lipoprotein cholesterol, and Quetelet index. In men, categorical assessment by CHD risk factor levels (low, intermediate, high), revealed that plasma triglycerides and systolic blood pressure were positively associated with a parental history of CHD, while high-density lipoprotein cholesterol was inversely related. In women, similar observations were made for triglycerides. Family history is a practical tool for identification of risk to CHD, hypertension, stroke, and diabetes. Serial risk factor measurements in offspring from CHD-, hypertension-, stroke-, and diabetes-positive families should have considerable utility in early recognition and documentation of CHD risk factor levels which, in turn, should facilitate primary intervention designed to ameliorate or prevent the development of CHD.

Nutrient intake: relationships with lipids and lipoproteins in 6--19-year-old children--the Princeton School District study.

Relationships between nutrient intakes and plasma lipids and lipoproteins were studied in 949 randomly selected children, ages 6--19, in the biracial, suburban, Princeton School District. While nutrient intake increased with age in males, such age-associated increases in nutrient ingestion were much less consistent or were not significant for females. Primarily in the 6--9 and 10--12 yr age groups, white children ingested more total calories, more saturated fat, and a lower ratio of polyunsaturated to saturated (P/S) fat, more total carbohydrates, sucrose, starch, and other carbohydrates, and more protein than black children. After adjusting for age, race, sex, weight, and height, several nutrient-lipid and lipoprotein partial correlation coefficients were significant, but of relatively low magnitude. There were weak but significant inverse correlations between dietary P/S ratios and dietary carbohydrates with both total (r = -.07, -0.7) and low-density lipoprotein cholesterol (C-LDL), (r = -.07, -.08). Plasma high-density lipoprotein cholesterol (C-HDL) was inversely and significantly correlated with dietary sucrose (r = -.07); plasma triglyceride correlated positively with dietary sucrose (r = .08). Potential relationships between nutrients and lipids-lipoproteins were also examined in children at the extremes of, and in the middle of, lipid-lipoprotein distributions. After covariance adjustment for age, sex, race, and Quetelet index, children having the highest levels of C-HDL had the lowest intake of dietary carbohydrate and total calories. After further covariance adjustment for total calories, children at the highest end of the plasma cholesterol distribution had a greater intake of cholesterol and total protein than did children in the lowest end of the distribution. Nutrient intake may play a small but significant role relative to lipids and lipoproteins in children, and as such, may have importance relative to pediatric precursors of atherosclerosis.