Treatment of familial hypercholesterolaemia. United Kingdom lipid clinics study of pravastatin and cholestyramine.

OBJECTIVE--To compare the efficacy and safety of cholestyramine, an anion exchange resin, and pravastatin, a new hydrophilic specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in the treatment of heterozygous familial hypercholesterolaemia. DESIGN--Double blind, double dummy, placebo controlled study with three parallel groups. SETTING--Six specialist lipid clinics in the United Kingdom. PATIENTS--128 patients aged 18-70 with heterozygous familial hypercholesterolaemia diagnosed on strict biochemical and clinical findings. MAIN OUTCOME MEASURES--Total plasma cholesterol, triglyceride, and lipoprotein subfractions and biochemical and haematological safety parameters. RESULTS--Pravastatin (40 mg/day) led to a 25% reduction in total plasma cholesterol concentration and a reduction in low density lipoprotein cholesterol concentration of 30%. Cholestyramine (24 g/day) led to similar reductions in concentrations of total cholesterol (23%) and low density lipoprotein cholesterol (31%). No consistent changes occurred in high density lipoprotein cholesterol values with either compound. Plasma triglyceride concentrations showed a small rise (18%) on resin therapy. No serious adverse drug reactions occurred during the study. CONCLUSIONS--Pravastatin seems to be a highly effective, well tolerated drug for severe hypercholesterolaemia. Patients chosen for this study were recruited on the basis that they could tolerate a full dose of cholestyramine, and in this situation cholestyramine was also highly effective in lowering plasma low density lipoprotein cholesterol concentrations.     

Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia

ObjectivesTo assess the feasibility of detecting new cases of heterozygous familial hypercholesterolaemia by using a nurse led genetic register.DesignCase finding among relatives of patients with familial hypercholesterolaemia.SettingTwo lipid clinics in central and south Manchester.Subjects259 (137 men and 122 women) probands and 285 first degree relatives.ResultsOf the 200 first degree relatives tested, 121 (60%) had inherited familial hypercholesterolaemia. The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. Concentrations of serum cholesterol were, respectively, 8.4 (1.7 SD) mmol/l and 8.1 (1.9 SD) mmol/l in affected men and women and 5.6 (1.0 SD) mmol/l and 5.6 (1.1 SD) mmol/l in unaffected men and women. Screening for risk factors as recommended in recent guidelines for coronary heart disease prevention would have failed to identify most of the affected relatives in whom hypertension, diabetes mellitus, cigarette smoking, and obesity were uncommon.ConclusionsBy performing cholesterol tests on 200 relatives, 121 new patients with familial hypercholesterolaemia were discovered. Because 1 in 500 people in the UK are affected by this condition, to detect a similar number by population screening over 60 000 tests would be required, and only a few of these patients would have been detected had cholesterol testing been restricted to those with other risk factors for coronary heart disease. A case exists for organising a genetic register approach, linking lipid clinics nationally.     

Biliary lipid secretion in patients with heterozygous familial hypercholesterolemia and combined hyperlipidemia. Influence of bezafibrate and fenofibrate

Serum and biliary lipid metabolism were examined in 13 patients with different types of hyperlipoproteinemia before and after 4 weeks of treatment with either bezafibrate or fenofibrate. In patients with heterozygous familial hypercholesterolemia (FH), bezafibrate (n = 5) and fenofibrate (n = 7) produced a similar significant reduction of total cholesterol, LDL-cholesterol, and triglycerides by 21, 23, and 32%, respectively. In patients with familial combined hyperlipidemia (CHL), only triglycerides decreased markedly. Biliary lipid secretion rates in patients with heterozygous FH were not different from those of young male volunteers, indicating that a reduction of hepatic LDL receptors did not affect hepatic elimination of cholesterol or bile acids. Biliary cholesterol secretion increased significantly from 57 to 75 mg/hr during bezafibrate therapy (n = 8) and from 62 to 71 mg/hr during fenofibrate therapy (n = 9). No consistent change in bile acid or phospholipid secretion was observed. The elevated output of biliary cholesterol increased cholesterol saturation significantly from 147 to 185% and from 152 to 173% during administration of bezafibrate and fenofibrate, respectively. The present study indicates that treatment with bezafibrate or fenofibrate is effective in lowering LDL cholesterol in patients with heterozygous FH, but both drugs increase cholesterol saturation of bile, which might enhance the risk of cholesterol gallstone formation.     

Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolemia

Patients with heterozygous familial hypercholesterolemia (n = 12) were treated either with pravastatin, a specific inhibitor of HMG-CoA reductase, or cholestyramine, followed by a period of combined treatment with both drugs. Initially, these patients had increased serum levels of low density lipoprotein (LDL) cholesterol (8.77 +/- 0.48 mmol/l; SEM), lathosterol (5.32 +/- 0.60 mg/l), and ubiquinone (0.76 +/- 0.09 mg/l), while the serum dolichol concentration was in the normal range. Cholestyramine treatment (n = 6) decreased the levels of LDL cholesterol (-32%) and increased lathosterol (+125%), but did not change dolichol or ubiquinone levels in a significant manner. Pravastatin treatment (n = 6) decreased LDL cholesterol (-27%), lathosterol (-46%), and ubiquinone (-29%). In this case, the amount of dolichol in serum also showed a small but statistically insignificant decrease (-16%) after 12 weeks of treatment. Combined treatment with cholestyramine and pravastatin (n = 6) resulted in changes that were similar to, but less pronounced than, those observed during pravastatin treatment alone. In no case was the ratio between ubiquinone and LDL cholesterol reduced. Possible effects on hepatic cholesterol, ubiquinone, and dolichol concentrations were studied in untreated (n = 2), cholestyramine-treated (n = 2), and pravastatin-treated (n = 4) gallstone patients and no consistent changes could be observed. The results indicate that treatment with pravastatin in familial hypercholesterolemia decreases serum ubiquinone levels in proportion to the reduction in LDL cholesterol.     

Contrasting patterns of coronary atherosclerosis in normocholesterolaemic smokers and patients with familial hypercholesterolaemia.

An angiographic comparison was made of the extent and severity of coronary artery disease in 25 patients with heterozygous familial hypercholesterolaemia and 25 normocholesterolaemic patients with coronary artery disease in whom heavy cigarette consumption was the chief risk factor. The patients with familial hypercholesterolaemia were younger and included a much higher proportion of women than the smokers. Significantly more patients with familial hypercholesterolaemia had disease of the main stem of the left coronary artery (eight v none, p less than 0.05) and triple-vessel disease (18 v four, p less than 0.05). Disease affecting only distal vessels occurred in five smokers, whereas all the patients with familial hypercholesterolaemia showed a combination of proximal and distal lesions. These findings suggest that cigarette smoking and familial hypercholesterolaemia predispose to different patterns of coronary atheroma. Early coronary angiography with a view to coronary artery bypass surgery seems desirable in symptomatic patients with familial hypercholesterolaemia because of the common association of this disorder with life-threatening left main-stem disease.     

Familial defective apolipoprotein B-100: a lesson from homozygous and heterozygous patients

Familial defective apolipoprotein B-100 (FDB) is a genetic disorder caused by a substitution of glutamine for arginine at residue 3500 of the apolipoprotein B-100 molecule. We have identified 23 heterozygotes and one homozygote for FDB (frequency 1:20) in a group of 510 patients with hypercholesterolemia. Mean age of the patients (18 females and 6 males) was 46 years. The diagnosis of FDB was based on point mutation PCR analysis of exon 26 of the apo B gene. Plasma lipids in heterozygous patients were: total cholesterol 8.76+/-1.2 mmol/l, triglycerides 1.42+/-0.5 mmol/l, HDL-cholesterol 1.43+/-0.3 mmol/l, LDL-cholesterol 6.69+/-1.2 mmol/l, apoB 1.69+/-0.4 g/l, Lp(a) 0.26+/-0.2 g/l. The most frequent apoE genotype was 3/3 (19 patients), apoE 3/4 genotype was found in 3 patients and one person had apoE 2/3. Xanthelasma palpebrarum was present in 4 patients and tendon xanthomas in 3 patients including the homozygote. Premature manifestation of coronary heart disease was revealed in 3 patients. Sixteen patients were treated with statins, a combination of statin and resin was used in 2 patients (including the homozygote), whereas six patients were treated with the diet only. We conclude that although the plasma lipid levels of total and LDL cholesterol in FDB patients are lower than in patients with familial hypercholesterolemia, the patients with FDB suffer from premature atherosclerosis. The therapeutic approach to FDB individuals and patients with familial hypercholesterolemia is very similar.     

Diagnosing familial hypercholesterolaemia in childhood by measuring serum cholesterol.

The serum cholesterol concentrations of 134 children aged 1-16 years who had at least one first-degree relative with presumed familial hypercholesterolaemia showed a bimodal distribution, and, using the maximum likelihood technique, two overlapping curves could be fitted. The mean value of the affected children (heterozygotes) was 8-9 mmol/l and that of the unaffected 4-9 mmol/l. The two curves intersected at 6-77 mmol/l, and at this point 5% of the unaffected children had values over 6-77 mmol/l and 3-5% of the heterozygotes had values under 6-77 mmol/l. If this cholesterol concentration is used as a cut-off point 4-25% of cases would be misdiagnosed.     

Long term metabolic effects of two dietary methods of treating hyperlipidaemia.

OBJECTIVES--To compare the long term metabolic effects of two diets for treating hyperlipidaemia. DESIGN--Randomised controlled study: after three weeks of normal (control) diet, subjects were randomly allocated to one of two test diets and followed up for six months. SETTING--Lipid clinic of tertiary referral centre in Naples. SUBJECTS--63 subjects with primary type IIa and IIb hyperlipoproteinaemia entered the study, and 44 completed it. Exclusion criteria were taking drugs known to influence lipid metabolism, evidence of cardiovascular disease, homozygous familial hypercholesterolaemia, and body mass index over 30. INTERVENTIONS--Two test diets with reduced saturated fat (8%) and cholesterol (approximately 200 mg/day): one was also low in total fat and rich in carbohydrate and fibre, and the other was low in carbohydrate and fibre and rich in polyunsaturated and monounsaturated fats. MAIN OUTCOME MEASURES--Fasting plasma lipid and lipoprotein concentrations; blood glucose, insulin, and triglyceride concentrations before and after a test meal. RESULTS--In comparison with the control diet, both test diets induced significant and similar decreases in low density lipoprotein cholesterol concentrations (by a mean of 0.72 (SE 0.15) mmol/l, P < 0.001, for low total fat diet; by 0.49 (0.18) mmol/l, P < 0.05, for high unsaturated fat diet) and plasma triglyceride concentrations (by 0.21 (0.09) mmol/l, P < 0.05, for low total fat diet; by 0.39 (0.15) mmol/l, P < 0.05, for high unsaturated fat diet), while high density lipoprotein cholesterol concentrations after fasting and plasma glucose and insulin concentrations during test meals were not modified by either diet. CONCLUSIONS--Both test diets are suitable (alone or in combination) for treatment of hypercholesterolaemia.     

Sterol synthesis in vitro in freshly isolated blood mononuclear leukocytes from familial hypercholesterolemic patients treated with probucol

Sterol synthesis rates were measured in freshly isolated blood mononuclear leukocytes obtained from familial hypercholesterolemic patients undergoing treatment with either probucol alone or probucol plus cholestyramine. Subjects with heterozygous familial hypercholesterolemia on probucol had a significant 31% reduction in mononuclear cell sterol synthesis rates as compared to control patients; sterol synthesis in cells from homozygous familial hypercholesterolemic patients on probucol did not differ from that in control subjects. Addition of Cholestyramine to probucol therapy in heterozygous familial hypercholesterolemic patients caused an increase in sterol synthesis rates equal to but not greater than control values, thus negating the decreased mononuclear leukocyte sterol synthesis associated with probucol administration alone. Probucol treatment effectively decreased plasma cholesterol levels in both homozygous and heterozygous familial hypercholesterolemic subjects; however, the data suggest that the drug may exert different effects on sterol synthesis in peripheral tissues depending upon the presence or absence of cellular receptors for low-density lipoproteins.     

Effect of pectin on cholesterol distribution in the lipoproteins of streptozotocin-diabetic rats fed cholesterol diet

In rats fed a semisynthetic diet, streptozotocin-induced diabetes [45 mg/kg, 17 days] led to hypertriglyceridaemia [6.4 mmol/l], to a marked increase in the proportion of plasma cholesterol present in the very low density lipoproteins [VLDL] [to 40 %] and to a decrease in the amount present in the high density lipoproteins [HDL] [to 34 %]. The addition of 0.25 % cholesterol to the above diet led in healthy rats to hypercholesterolaemia [4.3 mmol/l] and to similar changes in the distribution of cholesterol in the lipoproteins. In diabetic rats, the same diet led to pronounced hypertriglyceridaemia [13.8 mmol/l] and hypercholesterolaemia [18.9 mmol/l], while the proportion of HDL-borne plasma cholesterol fell still further to 6 % and rose in the VLDL to 70 %. The addition of pectin to the diet in 6 % concentration markedly inhibited triglyceridaemia [3.3 mmol/l] and cholesterolaemia [4.4 mmol/l] and raised the proportion of HDL plasma cholesterol to 47 %.     

Screening for a prevalent LDL receptor mutation in patients with severe hypercholesterolaemia

Summary A rapid new method for the diagnosis of familial hypercholesterolaemia (FH) detects the deletion extending from intron 15 to exon 18 in the low density lipoprotein (LDL) receptor gene, i.e. the FH-Helsinki mutation responsible for a major portion of FH in Finland. Amplification of the DNA sequences flanking the deletion in the mutant allele generated an abnormal 391-bp product that could be detected by photographing the ethidium-bromide-stained agarose gel after electrophoresis. Up to 50 samples can be analysed in about 8h. The method was validated by comparison with a routine Southern blot technique. The deletion was found in 23 out of 37 patients with a clinical diagnosis of FH (62%) and in 2 out of 73 with primary hypercholesterolaemia without a clinical diagnosis of FH within a series of 110 consecutvie patients with severe hypercholesterolaemia (serum cholesterol > 8mmol/l). The data indicate that DNA techniques may provide a supplementary aid for the routine diagnosis of FH and suggest that the polymerase chain reaction in particular may offer major advantages because of its simplicity and rapidity.     

Lipid screening: is it enough to measure total cholesterol concentration?

OBJECTIVES--To determine whether measurement of total cholesterol concentration is sufficient to identify most patients at lipoprotein mediated risk of coronary heart disease without measurement of triglyceride and high density lipoprotein (HDL) cholesterol concentrations. DESIGN--Cross sectional screening programme. SETTING--Six general practices in Oxfordshire. PATIENTS--1901 Men and 2068 women aged 25-59. MAIN OUTCOME MEASURE--Cardiovascular risk as assessed by fasting venous plasma concentrations of total cholesterol, triglyceride, and HDL cholesterol. RESULTS--2931 Patients (74% of those screened) had a total cholesterol concentration of less than 6.5 mmol/l. If the triglyceride concentration had not been measured in these patients isolated hypertriglyceridaemia (greater than or equal to 2.3 mmol/l) would have remained undetected in 185. Among these 185 patients, however, 123 were overweight or obese and only 18 (0.6% of those screened) had an increased risk associated with both a raised triglyceride concentration (greater than or equal to 2.3 mmol/l) and a low HDL cholesterol concentration (less than 0.9 mmol/l). Conversely, in the 790 patients with predominant hypercholesterolaemia (cholesterol concentration greater than or equal to 6.5 mmol/l and triglyceride concentration less than 2.3 mmol/l) measurement of HDL cholesterol concentration showed that 348 (9% of those screened) had only a moderately increased risk with a ratio of total to HDL cholesterol of less than 4.5 and 104 had a low risk with a ratio of less than 3.5. CONCLUSIONS--Fasting triglyceride and HDL cholesterol concentrations identify few patients at increased risk of coronary heart disease if the total cholesterol concentration is less than 6.5 mmol/l. HDL cholesterol and triglyceride concentrations should, however, be measured in patients with a total cholesterol concentration exceeding this value. Total cholesterol concentration alone may overestimate risk in a considerable number of these patients, and measurement of HDL cholesterol concentration allows a more precise estimate of risk. Measurement of the triglyceride concentration is required to characterise the lipoprotein abnormality. A patient should not be started on a drug that lowers lipid concentrations without having had a full lipoprotein assessment including measurement of HDL cholesterol concentration.     

Regulation of cholesterol biosynthesis in sitosterolemia: effects of lovastatin, cholestyramine, and dietary sterol restriction.

We investigated the effects of lovastatin, cholestyramine, and dietary sterol restriction on cholesterol synthesis and low density lipoprotein receptor function in freshly isolated mononuclear leukocytes from two unrelated sitosterolemic families. Total plasma sterol concentrations were elevated in the two homozygous sitosterolemic subjects (343 and 301 vs. 185 mg/dl in controls) and contained increased amounts of plant sterols and 5 alpha-saturated stanols (20% and 8% vs. less than 1% in controls), but were not significantly different from controls in the two heterozygous subjects. The rates of conversion of acetate to cholesterol by mononuclear leukocytes were subnormal in all homozygous and heterozygous subjects and correlated with markedly reduced microsomal 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity. In the two homozygous subjects, cholestyramine treatment decreased plasma sterols 29% and 35%, and yet was associated with a paradoxical decline in mononuclear leukocyte HMG-CoA reductase activity. In contrast, plasma sterol concentrations decreased 14% and 5%, and mononuclear leukocyte HMG-CoA reductase activities increased 13% and 46% in three control and one heterozygous subjects treated with cholestyramine, respectively. Plasma sterol concentrations in the homozygous subjects unexpectedly failed to decline during treatment with lovastatin or a low sterol diet. In distinction, plasma sterol concentrations in three control and one heterozygous subjects dropped 28% and 31%, respectively, during treatment with lovastatin. Both cholestyramine and low dietary sterols stimulated low density lipoprotein receptor function. These results demonstrate a marked abnormality in cholesterol homeostasis in patients with homozygous sitosterolemia with xanthomatosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of cholesterol absorption by the combination of dietary plant sterols and ezetimibe: effects on plasma lipid levels

Consumption of plant sterols and treatment with ezetimibe both reduce cholesterol absorption in the intestine. However, the mechanism of action differs between the two treatments, and the consequences of combination treatment are unknown. Therefore, we performed a double-blind, placebo-controlled, crossover study for the plant sterol component with open-label ezetimibe treatment. Forty mildly hypercholesterolemic subjects were randomized to the following treatments for 4 weeks each: 10 mg/day ezetimibe combined with 25 g/day control spread; 10 mg/day ezetimibe combined with 25 g/day spread containing 2.0 g of plant sterols; 25 g/day spread containing 2.0 g of plant sterols; and placebo treatment consisting of 25 g/day control spread. Combination treatment of plant sterols and ezetimibe reduced low density lipoprotein cholesterol (LDL-C) by 1.06 mmol/l (25.2%; P < 0.001) compared with 0.23 mmol/l (4.7%; P = 0.006) with plant sterols and 0.94 mmol/l (22.2%; P < 0.001) with ezetimibe monotherapy. LDL-C reduction conferred by the combination treatment did not differ significantly from ezetimibe monotherapy (-0.12 mmol/l or -3.5%; P = 0.13). Additionally, the plasma lathosterol-to-cholesterol ratio increased with all treatments. Sitosterol and campesterol ratios increased after plant sterol treatment and decreased upon ezetimibe and combination therapy. Our results indicate that the combination of plant sterols and ezetimibe has no therapeutic benefit over ezetimibe monotherapy in subjects with mild hypercholesterolemia.     

Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, on corticosteroid metabolism in patients with heterozygous familial hypercholesterolemia.

The present study examined whether hypolipidemic therapy with a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, influences corticosteroid metabolism in patients with heterozygous familial hypercholesterolemia (FH). Urinary excretion of tetrahydrocortisone, tetrahydrocortisol, 6 beta-hydroxycortisol and free cortisol were determined in 22 patients with heterozygous FH before and after pravastatin administration (10 mg/day for 2 months). Pravastatin induced a statistically significant decrease in serum total cholesterol in patients with heterozygous FH from 6.9 +/- 0.1 to 5.9 +/- 0.1 mmol/l (p less than 0.05). No significant changes were seen in the urinary tetrahydrocortisone, tetrahydrocortisol and free cortisol levels before and after pravastatin therapy. Urinary excretion of 6 beta-hydroxycortisol was significantly (p less than 0.05) increased after pravastatin administration. These results suggest that the hypolipidemic effect of pravastatin in patients with heterozygous FH does not influence the corticosteroid metabolism. The increase in urinary 6 beta-hydroxycortisol may be caused by pravastatin-induced hepatic microsomal 6 beta-hydroxylase induction.     

A therapeutic trial of bezafibrate on patients with hyperlipidemia with or without diabetes mellitus

Bezalip (bezafibrate), at an oral dosage of 200 mg three times a day, has been used on 12 patients with idiopathic hyperlipidemia, and on 12 patients with hyperlipidemia superimposed with diabetes mellitus. Each patient received bezafibrate for 3 months and placebo for 3 months. Blood glycosylated hemoglobin (HbA1) and fasting plasma glucose (FPG) were used as indices of diabetic control. Serum triglyceride (TG), total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C), and TC/HDL-C ratio were measured and calculated in order to compare the antilipemic effects of bezafibrate with that of placebo. Non-parametric Wilcoxon test was used for statistical analysis. In both the idiopathic group and diabetic group, bezafibrate significantly lowered the serum levels of TG and TC/HDL-C, as well as elevated the level of HDL-C. The serum TC levels were not significantly altered in either of the groups. These effects could not be ascribed to an improved diabetic control, since the percent changes of HbA1 were not different between the bezafibrate periods and the placebo periods. There were no significant facial flushing, nor other side effects during the treatment with bezafibrate. It is concluded that bezafibrate has antilipemic effects, and may be helpful in reducing the atherogenic risks.     

Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. Oxford Cholesterol Study Group.

OBJECTIVE--To evaluate the effects on mood of a substantial and prolonged reduction in total cholesterol concentration. DESIGN--Randomised placebo controlled comparison of patients who had been allocated to receive simvastatin 20 mg or 40 mg daily versus those allocated matching placebo in a ratio of 2:1. Follow up at an average of 152 weeks after randomisation. SUBJECTS--Men and women aged between 40 and 75 years at entry with blood total cholesterol of 3.5 mmol/l or greater, who were considered to be at higher than average risk of coronary heart disease based on medical history. MAIN OUTCOME MEASURES--The shortened profile of mood states questionnaire, reported use of psychotropic medication, and symptoms possibly related to mood. RESULTS--Simvastatin reduced total cholesterol by 1.9 mmol/l (26.7%) at the time of follow up. Among all 621 patients randomised to simvastatin (414 patients) or placebo (207 patients) there were no significant differences in the use of psychotropic medication or in reports of symptoms possibly related to mood. Of these patients, 491 (334 simvastatin, 157 placebo) completed the mood questionnaire, and there were no significant differences between the treatment groups in total or subscale scores, even when patients with low baseline cholesterol concentrations or elderly subjects were considered separately. CONCLUSION--These results do not support the hypothesis that treatment to lower cholesterol concentration causes mood disturbance.     

Efficacy of potassium and magnesium in essential hypertension: a double-blind,placebo controlled,crossover study.

OBJECTIVE--To evaluate the antihypertensive activity of potassium given alone or in combination with magnesium in patients with mild hypertension. DESIGN--A double blind, randomised, placebo controlled, crossover trial of 32 weeks'' duration. SETTINGS--Cardiology outpatient department, Sassoon General Hospitals, Pune, India. PATIENTS--37 Adults with mild hypertension (diastolic blood pressure less than 110 mm Hg). INTERVENTION--Patients received either placebo or potassium 60 mmol/day alone or in combination with magnesium 20 mmol/day in a crossover design. No other drug treatment was allowed. MEASUREMENTS--Blood pressure and heart rate assessed at weekly intervals and biochemical parameters at monthly intervals. RESULTS--Potassium alone or in combination with magnesium produced a significant reduction in systolic and diastolic blood pressures (p less than 0.001) and a significant reduction in serum cholesterol concentration (p less than 0.05); other biochemical variables did not change. Magnesium did not have an additional effect. Urinary potassium excretion increased significantly in the groups who received potassium alone or in combination with magnesium. The drug was well tolerated and compliance was satisfactory. CONCLUSION--Potassium 60 mmol/day lowers arterial blood pressure in patients with mild hypertension. Giving magnesium as well has no added advantage.     

Correlation between plasma levels of 7alpha-hydroxy-4-cholesten-3-one and cholesterol 7alpha-hydroxylation rates in vivo in hyperlipidemic patients

BACKGROUND/AIM: Hepatic bile acid synthesis is the main mechanism whereby the organism can degrade cholesterol. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one have been reported to reflect bile acid synthesis and the expression or activity of the limiting enzyme of the main biosynthetic pathway, cholesterol 7alpha-hydroxylase. Aim of this study was to correlate the levels of this metabolite with the rates of cholesterol 7alpha-hydroxylation in vivo, a direct measurement of bile acid synthesis, in hyperlipidemic patients. DESIGN: Concentrations of 7alpha-hydroxy-4-cholesten-3-one were assayed by gas-liquid chromatography: mass spectrometry in plasma samples obtained in 18 patients with primary hyperlipoproteinemia who previously underwent determination of cholesterol 7alpha-hydroxylation rates in vivo by tritium release analysis. Both determinations were performed in basal conditions and after treatment with hypolipidemic drugs (the fibric acid derivatives gemfibrozil and bezafibrate, cholestyramine alone or associated with simvastatin). RESULTS: Changes in plasma 7alpha-hydroxy-4-cholesten-3-one profile closely reflected in vivo cholesterol 7alpha-hydroxylation rates during treatment with fibrates, cholestyramine and cholestyramine plus simvastatin. When plotting determinations from all studies (n=40), a very strict correlation was disclosed between plasma 7alpha-hydroxy-4-cholesten-3-one and cholesterol 7alpha-hydroxylation rates (r=0.81, P<0.001). CONCLUSIONS: Plasma 7alpha-hydroxy-4-cholesten-3-one closely mirrors measurements of cholesterol 7alpha-hydroxylation rates in vivo in hyperlipidemic subjects and therefore stands as a reliable marker of global bile acid synthesis. In view of the correlation observed, these data may help to interpret changes of plasma levels of this metabolite in terms of cholesterol balance quantification.     

Cost effectiveness of incremental programmes for lowering serum cholesterol concentration: is individual intervention worth while?

OBJECTIVE--To evaluate the relative cost effectiveness of various cholesterol lowering programmes. DESIGN--Retrospective analysis. SETTING--Norwegian cholesterol lowering programme in Norwegian male population aged 40-49 (n = 200,000), whose interventions comprise a population based promotion of healthier eating habits, dietary treatment (subjects with serum cholesterol concentration 6.0-7.9 mmol/l), and dietary and drug treatment combined (serum cholesterol concentration greater than or equal to 8.0 mmol/l). MAIN OUTCOME MEASURE--Marginal cost effectiveness ratios--that is, the ratio of net treatment costs (cost of treatment minus savings in treatment costs for coronary heart disease) to life years gained and to quality of life years (QALYs) saved. RESULTS--The cost per life year gained over 20 years of a population based strategy was projected to be 12 pounds. For an individual strategy based on dietary treatment the cost was about 12,400 pounds per life year gained and 111,600 pounds if drugs were added for 50% of the subjects with serum cholesterol concentrations greater than or equal to 8.0 mmol/l. CONCLUSIONS--The results underline the importance of marginal cost effectiveness analyses for incremental programmes of health care. The calculations of QALYs, though speculative, indicate that individual intervention should be implemented cautiously and within more selected groups than currently recommended. Drugs should be reserved for subjects with genetic hypercholesterolaemia or who are otherwise at very high risk of arteriosclerotic disease.