Tatu A. Miettinen

Reduction of Serum Cholesterol with Sitostanol-Ester Margarine in a Mildly Hypercholesterolemic Population

BACKGROUND Dietary plant sterols, especially sitostanol, reduce serum cholesterol by inhibiting cholesterol absorption. Soluble sitostanol may be more effective than a less soluble preparation. We tested the tolerability and cholesterol-lowering effect of margarine containing sitostanol ester in a population with mild hypercholesterolemia. METHODS We conducted a one-year, randomized, double-blind study in 153 randomly selected subjects with mild hypercholesterolemia. Fifty-one consumed margarine without sitostanol ester (the control group), and 102 consumed margarine containing sitostanol ester (1.8 or 2.6 g of sitostanol per day). RESULTS The margarine containing sitostanol ester was well tolerated. The mean one-year reduction in serum cholesterol was 10.2 percent in the sitostanol group, as compared with an increase of 0.1 percent in the control group. The difference in the change in serum cholesterol concentration between the two groups was -24 mg per deciliter (95 percent confidence interval, -17 to -32; P < 0.001). The respective reductions in low-density lipoprotein (LDL) cholesterol were 14.1 percent in the sitostanol group and 1.1 percent in the control group. The difference in the change in LDL cholesterol concentration between the two groups was -21 mg per deciliter (95 percent confidence interval, -14 to -29; P < 0.001). Neither serum triglyceride nor high-density lipoprotein cholesterol concentrations were affected by sitostanol. Serum campesterol, a dietary plant sterol whose levels reflect cholesterol absorption, was decreased by 36 percent in the sitostanol group, and the reduction was directly correlated with the reduction in total cholesterol (r = 0.57, P < 0.001). CONCLUSIONS Substituting sitostanol-ester margarine for part of the daily fat intake in subjects with mild hypercholesterolemia was effective in lowering serum total cholesterol and LDL cholesterol.

Cholesterol-Lowering Therapy in Women and Elderly Patients With Myocardial Infarction or Angina Pectoris: Findings From the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those > or = 65 years of age, those < 65 years of age, women, and men. METHODS AND RESULTS The 4S cohort of 4444 CHD patients included 827 women and 1021 patients > or = 65 years of age. Total cholesterol at baseline was 5.5 to 8.0 mmol/L with triglycerides < or = 2.5 mmol/L. Patients were randomized to therapy with simvastatin 20 to 40 mg daily or placebo for a median follow-up period of 5.4 years. End points consisted of all-cause and CHD mortality, major coronary events (primarily CHD death and nonfatal myocardial infarction), other acute CHD and atherosclerotic events, hospitalizations for CHD and cardiovascular events, and coronary revascularization procedures. Mean changes in serum lipids were similar in the different subgroups. In patients > or = 65 years of age in the simvastatin group, relative risks (95% confidence intervals) for clinical events were as follows: all-cause mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83); major coronary events, 0.66 (0.52 to 0.84); any atherosclerosis-related event, 0.67 (0.56 to 0.81); and revascularization procedures, 0.59 (0.41 to 0.84). In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86 (0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51 (0.30 to 0.86), respectively. CONCLUSIONS Cholesterol lowering with simvastatin produced similar reductions in relative risk for major coronary events in women compared with men and in elderly (> or = 65 years of age) compared with younger patients. There were too few female deaths to assess the effects on mortality in women. Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older patients.

Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype.

Relationship between the efficiency of cholesterol absorption and apolipoprotein E (apoE) phenotype was studied in a random sample of middle-aged Finnish men. Subjects that were either heterozygous or homozygous for the allele epsilon 2 absorbed less and synthesized more cholesterol than those with the phenotype E4/3 and E4/4, the values for the individuals with the most frequent phenotype E3/3 (56% of the population sample) falling in between. Among the whole study group, the sum of the subscripts of apoE phenotype (e.g., E2/3 = 5) was correlated positively with the fractional absorption of cholesterol (r = 0.40; P less than 0.05) and negatively with the serum level of lathosterol, a cholesterol precursor sterol reflecting the activity of cholesterol synthesis (r = -0.48; P less than 0.01). Thus, apoE polymorphism appears to affect the efficiency of cholesterol absorption and may by this mechanism contribute to the variation in plasma total and low density lipoprotein cholesterol concentration.

Stimulation of Fecal Steroid Excretion After Infusion of Recombinant Proapolipoprotein A-I Potential Reverse Cholesterol Transport in Humans

BACKGROUND Apolipoprotein (apo) A-I is the major protein component of HDL, a cholesterol transport particle that protects against atherosclerosis. Apo A-I is believed to promote reverse cholesterol transport, transferring cholesterol from peripheral cells to the liver for subsequent elimination. To test this hypothesis in humans, we measured fecal steroid excretion before and after the intravenous infusion of human proapo A-I (precursor of apo A-I) liposome complexes. METHODS AND RESULTS Four subjects with heterozygous familial hypercholesterolemia w re studied under standardized conditions. The fecal excretion of bile acids and neutral sterols was determined for 9 days before and 9 days after an intravenous infusion of recombinant human proapo A-I (4 g protein) liposome complexes. Plasma apoA-I and HDL cholesterol levels increased transiently (mean peak concentrations were 64% and 35% above baseline, respectively) during the first 24 hours. Mean lipoprotein lipid and apolipoprotein levels were not different during the 2 collecting periods, however. Serum lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, was also unchanged. The fecal excretion of cholesterol (neutral sterols and bile acids) increased in all subjects (mean increase, +39% and +30%, respectively), corresponding to the removal of approximately 500 mg/d excess cholesterol after infusion. Control infusions with only liposomes in 2 of the patients did not influence lipoprotein pattern or cholesterol excretion. CONCLUSIONS Infusion of proapoA-I liposomes in humans promotes net cholesterol excretion from the body, implying a stimulation of reverse cholesterol transport. This mechanism may prove useful in the treatment of atherosclerosis.

Fatty-acid composition of serum lipids predicts myocardial infarction.

During a follow-up of five to seven years 33 out of 1222 middle-aged men initially free of coronary heart disease sustained fatal or non-fatal myocardial infarction or died suddenly. The fatty-acid composition of serum triglycerides, phospholipids, and cholesterol esters had been measured at the start of the surveillance in these men and in a control group of 64 men matched for age, serum cholesterol and triglyceride concentrations, blood pressure, obesity, smoking, and one-hour glucose tolerance. Palmitic and stearic acids of phospholipids were significantly higher and linoleic and most polyunsaturated fatty acids, including arachidonic acid and eicosapentaenoic acid, of phospholipids were lower in the subjects who sustained coronary events compared with the controls. Linoleic acid tended to correlate negatively with blood pressure while other polyunsaturated fatty acids, especially eicosapentaenoic acid, exhibited a negative correlation with blood pressure and relative body weight in the controls but not in the subjects who sustained coronary events. These findings suggest that the fatty-acid pattern of serum phospholipids is an independent risk factor for coronary heart disease.

Reduction of Serum Cholesterol in Postmenopausal Women With Previous Myocardial Infarction and Cholesterol Malabsorption Induced by Dietary Sitostanol Ester Margarine Women and Dietary Sitostanol

BACKGROUND Reduction of serum cholesterol decreases mortality in primary and especially in secondary prevention. We investigated how effectively postmenopausal women with a previous myocardial infarction reduced their serum cholesterol with dietary means by using sitostanol ester rapeseed oil margarine, alone and in combination with statins, and to what extent cholesterol metabolism was affected. METHODS AND RESULTS The first study group consisted of 22 randomly chosen women with angiographically documented coronary artery disease. Baseline studies on home diet were followed by double-blind, randomized, cross-over studies on margarine without and with sitostanol (3 g/d) ester for 7 weeks in random order. A second group of 10 women on simvastatin consumed sitostanol ester margarine for 12 weeks. Sitostanol ester margarine lowered serum total cholesterol by 13% (P<.05) and LDL cholesterol by 20% (P<.01). Sitostanol ester margarine reduced total cholesterol in all patients, LDL cholesterol <2.6 mmol/L (<100 mg/dL) in 32%, and <3.4 mmol/L (<133 mg/dL) in 73% versus none and 27% during the home diet (P<.01 for both). Combined with simvastatin, sitostanol still reduced total and LDL cholesterol by 11+/-3% and 16+/-5% (P<.01 for both). Sitostanol reduced absorption (-45%), increased fecal elimination (+45% as neutral sterols), and stimulated synthesis (+39%) of cholesterol. High cholestanol and plant sterol (high cholesterol absorption) and low baseline precursor sterol proportions (low cholesterol synthesis) predicted high decreases in serum cholesterol. CONCLUSIONS Dietary use of sitostanol ester margarine normalizes LDL cholesterol in about one third of women with previous myocardial infarction, especially in those with high baseline absorption and low synthesis of cholesterol, and in combination with statins reduces the needed drug dose.

Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study

Abstract Objectives: To investigate whether baseline serum cholestanol:cholesterol ratio, which is negatively related to cholesterol synthesis, could predict reduction of coronary events in the Scandinavian simvastatin survival study. Design: Follow up of patients with coronary heart disease in whom baseline ratios were related to major coronary events. Setting: Four universities in Finland. Subjects: A subgroup of 868 patients with coronary heart disease selected from the Scandinavian simvastatin survival study. Intervention: Treatment with simvastatin or placebo. Main outcome measures: Serum concentrations of low density lipoprotein and high density lipoprotein cholesterol, total triglyceride concentration, and cholesterol:cholestanol ratio. Major coronary events. Results: With increasing baseline quarter of cholestanol distribution the reduction in relative risk increased gradually from 0.623 (95% confidence interval 0.395 to 0.982) to 1.166 (0.791 to 1.72). The risk of recurrence of major coronary events increased 2.2-fold (P<0.01) by multiple logistic regression analysis between the lowest and highest quarter of cholestanol. The ratio of cholestanol was related inversely to the body mass index and directly to high density lipoprotein cholesterol and triglyceride concentrations but their quarters of distribution were not related to risk reduction. Conclusions: Measurement of serum cholestanol concentration revealed a subgroup of patients with coronary heart disease in whom coronary events were not reduced by simvastatin treatment. Thus, patients with high baseline synthesis of cholesterol seem to be responders whereas those with low synthesis of cholesterol are non-responders.

Phytosterolaemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis

Abstract. A fourth case is described in which phytosterolaemia, earlier diagnosed as familial hypercholes‐terolaemia, was associated with normocholesterol‐aemia, hypersplenism and premature atherosclerotic arterial disease requiring a three‐vessel coronary bypass at the age of 29 years. During a follow‐up of 5 years 22–26% and 27–30% of serum and bile sterols were plant sterols, respectively. In addition to campes‐terol and β‐sitosterol, stigmasterol and a fourth major plant sterol, tentatively identified as avenasterol, were found in bile, and in free and esterified forms in all serum lipoproteins. Analysis of faecal steroids and measurement of biliary lipid secretion indicated that in addition to enhanced absorption of plant sterols their decreased biliary secretion contributed to the development of phytosterolaemia. Impaired biliary cholesterol secretion was compensated for by a markedly reduced cholesterol but normal bile acid synthesis and resulted in bile undersaturated with respect to cholesterol, in a reduced intestinal cholesterol pool and in a very low faecal excretion of cholesterol as neutral sterols. Cholestyramine brought about a modest increase in cholesterol elimination as bile acids, increased cholesterol synthesis as evidenced by the sterol balance value and the increased cholesterol precursors squalene and methyl sterols in plasma and bile, and reduced the plasma cholesterol by 21% and plant sterols by 16%, but had no effect on the biliary composition of main sterols.

Cholesterol Production in Obesity

Sterol-balance studies were performed in 10 control subjects, 10 normolipidemic obese patients, and 10 hypertriglyceridemic (type IV, mostly obese) patients on a low-cholesterol solid-food diet. Fecal elimination of cholesterol was markedly elevated in the overweight patients and tended to be high in the hypertriglyceridemic subjects also. A significant correlation was found between body weight and fecal excretion of neutral, acidic, and total steroids, indicating that the greater the body weight the higher was the rate of cholesterol synthesis. Sterol-balance data in obese subjects showed that excess daily cholesterol production roughly amounted to 20 mg/kg of adipose tissue. The control subjects produced only 12 mg/kg of body weight daily. Thus, obesity is associated with an increased rate of cholesterol synthesis in man. However, the correlation between serum cholesterol concentration and cholesterol production was low, suggesting that the overall rate of cholesterol synthesis was not the only factor determining the serum cholesterol level. That enhanced cholesterol production is not an irreversible phenomenon in obese subjects was indicated by the normalization of sterol-balance values in three overweight patients after their weights had been reduced by total fast followed by a low-calorie diet.

Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment

SummaryCholesterol absorption and metabolism and LDL and HDL kinetics were investigated in 11 hypercholesterolaemic non-insulin-dependent diabetic men off and on a hypolipidaemic treatment with sitostanol ester, (3 g sitostanol daily) dissolved in rapeseed oil margarine, by a double-blind crossover study design. Serum total, VLDL and LDL cholesterol and apoprotein B fell significantly by 6±2, 12±6, 9±3 and 6±2%, mean ±SEM, and HDL cholesterol was increased by 11±4% (p<0.05) by sitostanol ester. LDL cholesterol and apoprotein B were significantly decreased in the dense (1.037–1.055 g/ml), but not light, LDL subfraction due to a significantly diminished transport rate for LDL apoprotein B, while the fractional catabolic rate was unchanged. HDL kinetics, measured with autologous apoprotein AI, was unaffected by sitostanol ester. Cholesterol absorption efficiency was markedly reduced from 25±2 to 9±2% (p<0.001) during sitostanol ester followed by proportionately decreased serum plant sterol proportions. Cholesterol precursor sterol proportions in serum, fecal neutral sterol excretion, and cholesterol synthesis, cholesterol transport, and biliary secretion were all significantly increased by sitostanol ester. We conclude that the sitostanol ester-induced decrease in cholesterol absorption compensatorily stimulated cholesterol synthesis, had no effect on fractional catabolic rate, but decreased transport rate for LDL apoprotein B so that serum total, VLDL and LDL cholesterol levels were decreased. Dietary rapeseed oil margarine rich in sitostanol ester was well tolerated, appears to be safe from the nutritional point of view and effective for lowering VLDL and LDL cholesterol and increasing HDL cholesterol in hypercholesterolaemic non-insulin-dependent diabetic subjects.