[Update of lipid lowering therapy]. / Update der lipidsenkenden Therapie.

Dyslipidemia is one of the most important cardiovascular risk factors. Accordingly preventive measures to normalize lipids are of great importance. The indication for a lipid lowering therapy according to current guidelines focuses on the identification of a patient's global risk, i.e. the contribution of all major cardiovascular risk factors. The selection of the lipid lowering therapy should be appropriate for the kind of lipid disorder. This may be a special challenge with respect to target values and safety aspects. Statins in monotherapy are generally considered safe drugs. Higher dosages may be associated with liver toxicity and muscle problems. Lifestyle management should underpin all lipid management strategies.

[Evaluating the efficacy and tolerance of atorvastatin in hyperlipidemia in general practice (SWITCH Study)]. / Prüfung der Wirksamkeit und Verträglichkeit von Atorvastatin bei Hyperlipidämie unter Praxisbedingungen (SWITCH-Studie).

Elevated levels of serum lipids and lipoproteins are known to play a major role in the development of atherosclerosis and subsequent coronary heart disease (CHD). In controlled clinical studies, atorvastatin (Sortis), a new 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA)-reductase inhibitor, proved to be a very effective and safe lipid-lowering agent. The aim of this open-label, multicentre study (without a control group) was to confirm the efficacy and safety of atorvastatin in a private practice group, including 181 Swiss cardiologists, internists, and general practitioners. A total of 877 hyperlipidaemic patients requiring treatment participated in this study. To evaluate the effectiveness of the treatment with atorvastatin over a period of 12 weeks, total plasma cholesterol (TC), HDL cholesterol, LDL cholesterol and triglycerides (TG) were determined every 4 weeks. The initial atorvastatin dose was 10 mg in 78% of patients and 20 mg in 22%. The dose was doubled every 4 weeks until the target values of TC < or = 5.2 mmol/l and TC/HDL < or = 5 were reached. After 12 weeks of treatment with atorvastatin the mean reduction in TC, TC/HDL, LDL and TG compared to baseline levels was 33, 37, 42, and 25% respectively. At the same time the HDL concentration was increased by 9%. These results were evidenced in patients with existing coronary heart disease, in high risk patients without manifest coronary heart disease and in patients with significantly elevated lipid levels (TC > 7.8 mmol/l, TC/HDL > 6.5). After treatment with atorvastatin for 12 weeks, 59% of patients had reached the therapeutic target of TC < or = 5.2 mmol/l. The target of TC/HDL < or = 5 was reached by 79%. Atorvastatin was almost without exception well tolerated, the most frequently reported side effects being nausea, myalgia, and headache. In this open-label multicentre study atorvastatin was found to be effective and well tolerated. The observed reduction in the lipid and lipoprotein concentration is in accordance with the results of published controlled studies. The lipid and lipoprotein concentrations were decreased significantly in patients with slight to moderate elevation of lipid levels as well as in those with significantly raised values.

[Pharmacoeconomic evaluation of pravastatin in coronary secondary prevention in patients with myocardial infarct or unstable angina pectoris. An analysis based on the LIPID Study]. / Pharmakoökonomische Bewertung von Pravastatin in der koronaren Sekundärprävention bei Patienten mit Myokardinfarkt oder instabiler Angina Pectoris. Eine Analyse auf der Grundlage der LIPID-Studie.

BACKGROUND: Secondary coronary prevention with lipid lowering drugs have become a major issue in health policy formulation due to the large upfront investment in drug therapy. The recently completed LIPID trial with pravastatin in secondary prevention immediately raise the question whether pravastatin might be cost-effective in Switzerland. METHODS: We conducted a cost-effectiveness analysis from the perspective of third party payers. The following costs were included in the analysis: daily treatment costs of pravastatin, non fatal myocardial infarction, coronary bypass operations and stroke. Life years gained was obtained by applying the declining exponential approximation of life expectancy. All calculations were standardized to 1000 treated patients. RESULTS: The net costs of treating 1000 patients (i.e. drug costs minus the costs of sequelae and interventions) are Fr. 3.6 Mio. In addition, a total of 430 life-years may be saved through treatment. The corresponding cost-effectiveness of pravastatin treatment is Fr. 8341 (nominal) Fr. 6985 (discounted). CONCLUSIONS: The results suggest that the cost-effectiveness of pravastatin in secondary prevention lie well within the threshold of other commonly accepted medical interventions and may be considered an economically viable approach for secondary coronary prevention.

Lipid screening in paediatrics for early detection of cardiovascular risks.

The purpose of the study was to try to detect at an early stage the important cardiovascular risk factors associated with increased concentrations of blood lipids, notably cholesterol. The trial was based on the screening of 102 families, including 219 children, 8-18 years of age and their parents. A group of young adults, 19-25 years of age, was included in the study. All subjects were derived from a paediatric practice. In addition to total cholesterol, VLDL-, LDL-, HDL-cholesterol and apolipoproteins A-I and B were also measured. The study identified a significant number of school-children and adolescents with hyperlipidaemia, predominantly hypercholesterolaemias type II-A. There was a close relationship between their blood lipids and those of their parents. The study demonstrates the importance of including parents in studies of this kind. Total cholesterol proved to be a reliable parameter for screening. The value of apolipoproteins in such screening is discussed.

Risk factor interactions for coronary heart disease.

There is now an increasing awareness of the atherogenicity of the individual lipoprotein subfractions. In addition, the effects of commonly used antihypertensive drugs has been a cause for concern. Thiazides and loop diuretics both increase LDL cholesterol, but indapamide and spironolactone have no apparent effects. Beta-blocker monotherapy may also increase triglycerides whilst post-synaptic alpha-blockers do not affect, or slightly lower triglycerides, total cholesterol, LDL and VLDL levels.

[Selective elimination of atherogenic lipoproteins using dextran-sulfate cellulose. Experiences in 2 patients with heterozygote familial hypercholesterolemia]. / Selektive Elimination atherogener Lipoproteine mit Dextransulfat-Cellulose. Erfahrungen bei 2 Patienten mit heterozygoter, familiärer Hypercholesterinämie.

Extracorporeal elimination of atherogenic lipoproteins with dextran-sulfate-cellulose for lowering of plasma cholesterol levels was tested in 2 patients with familial heterozygous hypercholesterolemia (untreated cholesterol values 12.9 +/- 1.5 and 12.5 +/- 1.2 respectively) in a longterm experiment. One patient was treated weekly for a period of 36 weeks and the other at fourteen days' intervals with simultaneous administration of 40 mg/day Simvastatin (synvinolin, MSD) for 8 weeks. The mean reduction in total cholesterol concentration was 41% in the first case and 54% in the second (combination with Simvastatin). The therapy was well tolerated without side effects.

Lipoprotein changes in familial hypercholesterolemia after extracorporeal immunoadsorption of low density lipoproteins.

The effects of extracorporeal immunoadsorption of LDL on the lipoprotein metabolism in two patients with familial hypercholesterolemia are reported. The immunoadsorbent consisted of F(ab')2 fragments of sheep anti-LDL antibodies, which had been coupled to Sepharose CL 4B. Within a time period of 3 to 3.5 hours a mean reduction of the level of total cholesterol by 76 +/- 4 p. cent could be obtained. The level of LDL cholesterol was reduced by 78 +/- 4 p. cent and the level of apo. B by 84 +/- 5 p. cent. Both LDL and VLDL were bound to the immunoadsorbent, while HDL was predominantly lowered by the plasma-dilution, which was in the order of 20 p. cent. The same was true for other serum proteins, not related to LDL or VLDL. The relative distribution of the different lipoprotein classes was again reached 3 days after the treatment, the initial lipid and apolipoprotein levels two to three weeks after the treatment. In a long-term therapy consisting of 45 treatments with a mean interval of 18 days between two treatments a mean cholesterol lowering of 42 p. cent could be achieved. No adverse effects and no sensitization to be heterologous protein were observed.

Alpha-1-adrenergic blockade and lipoprotein metabolism in essential hypertension.

The effect of the selective alpha 1-antagonist terazosin on serum lipoproteins and certain blood pressure-regulating factors was assessed in 15 patients with essential hypertension. Terazosin given during 8 weeks reduced arterial pressure (from 153/103 +/- 3/2 (SE) to 143/96 +/- 5/2 mm Hg; P less than 0.02) but did not modify body weight, heart rate, blood volume, plasma renin activity, aldosterone and catecholamine levels, or serum cholesterol, triglycerides, and their lipoprotein fractions. In nine of the patients, blood pressure control was not achieved with terazosin monotherapy and the diuretic methyclothiazide, 2.5 mg, was added. After 8 weeks of combined treatment, blood pressure decreased further (P less than 0.05); serum lipids and lipoprotein fractions did not change as compared with placebo or terazosin conditions. These findings indicate that terazosin in monotherapy does not unfavorably influence lipid metabolism.

[Cyclosporin A and hyperlipidemia after kidney transplantation. Prospective study]. / Cyclosporin A und Hyperlipidämie nach Nierentransplantation. Eine prospektive Untersuchung.

Hyperlipidemia is common after renal transplantation and has been attributed, at least in part, to corticosteroid therapy. We therefore studied serum lipids in a group of nondiabetic transplant recipients on conventional immunosuppression with azathioprin and prednisone (Aza/P), in comparison with a transplanted group on cyclosporin A monotherapy (CyA) without steroids. Frequency and degree of hyperlipidemia in the two groups showed no significant difference. Atherogenic hypercholesteremia was found as frequently in patients on CyA as in those on Aza/P. Possible factors preventing normalization are discussed.

[Management of hypercholesteremia by extracorporeal immune adsorption]. / Behandlung einer Hypercholesterinämie durch extrakorporale Immunadsorption.

Reduction of plasma cholesterol by extracorporeal immune elimination of low density lipoproteins (LDL) as an efficient approach to the treatment of familial hypercholesterolemia is described. LDL was removed from the plasma by immune adsorption on Sepharose-bound sheep antibodies against apo B, the protein fraction of LDL. To prevent the possibility of sensitization by the sheep antibodies, F(ab')2 fragments were used and the antibody containing Sepharose was underlaid by LDL containing Sepharose. Within a treatment time of 4 1/2-5 hours a reduction of the total plasma cholesterol by 70-80% was obtained. The mean reduction of the cholesterol concentration was more than 40% with a 14-day interval between two treatments. The concentration of other plasma proteins was not affected. The 11 treatments achieved so far were well tolerated and no side effects could be observed.

Quantitation of apolipoprotein B by polyclonal and monoclonal antibodies.

A non-competitive sandwich enzyme linked immunosorbent assay for the quantitation of apolipoprotein B with polyclonal and monoclonal antibodies was developed. Polyclonal antibodies were used as 'coater'. In the assay with polyclonal antibodies, the same antibody was used as conjugate with alkaline phosphatase. For studies with monoclonal antibodies, enzyme conjugated anti-mouse immunoglobulin had to be used, since monoclonal antibodies lost their reactivity upon enzyme conjugation. Two murine monoclonal antibodies were employed: MAB B-1 with specificity for apolipoproteins (Apo) B-48 and B-100 and MAB B-5 with specificity for B-100 (Radioimmunoassay Inc.). In a reference group Apo B values of 0.82 +/- 0.20 g/l were measured with polyclonal antibodies, 0.68 +/- 0.19 g/l and 0.95 +/- 0.33 g/l with MAB B-1 and MAB B-5. In pure hypercholesterolemia, a similar increase was found with all three antibodies, while in combined hyperlipoproteinemia MAB B-5 gave greater than 40% lower values. Differences were also found with respect to the correlation between Apo B and cholesterol or triglycerides.

Serum lipoproteins during treatment with the antihypertensive agent indapamide.

Considering the documented, potentially undesirable influence of various thiazide-type or loop diuretics on serum lipoproteins, we prospectively investigated in 69 men (mean age +/- SEM, 32 +/- 1 years) the metabolic effects of the new diuretic-antihypertensive compound indapamide. Compared to placebo, indapamide (2.5 mg/day) given for 6 to 8 weeks lowered (p less than 0.02 to less than 0.001) blood pressure (supine values from 148/98 +/- 3/2 to 137/93 +/- 3/2) in 29 men with mild to moderate essential hypertension, but not in 40 healthy men. In both groups, significant (p less than 0.05 to less than 0.001) decreases in body weight (-0.8 kg) and plasma potassium (-0.6 mmol/L), and increases in plasma uric acid (+20%), renin activity (+200%), and aldosterone documented good compliance. There were no significant changes in total cholesterol (in all subjects, from 208 +/- 6 to 213 +/- 6 mg/dl), low- or very low-density lipoprotein (VLDL) cholesterol (127 +/- 6 to 129 +/- 6 and 21 +/- 1 to 21 +/- 2 respectively), high-density lipoprotein cholesterol (50 +/- 1 to 51 +/- 1 mg/dl), total triglycerides (Tg) (108 +/- 5 to 112 +/- 6 mg/dl), VLDL-Tg, apoproteins A1 and A2, plasma glucose, epinephrine, norepinephrine, sodium, calcium, magnesium, and creatinine; apoprotein B (84 +/- 2 to 88 +/- 3 mg/dl) and plasma insulin after glucose loading dose tended to be increased minimally. The absence of distinct lipoprotein alterations after short-term indapamide treatment may be of clinical and epidemiological interest.

Lipoprotein fractions, lipoprotein lipase and hepatic triglyceride lipase during short-term and long-term uptake of ethanol in healthy subjects.

In short-term experiments, healthy fasting persons were given a basic dose of 0.5 g of ethanol/kg body weight, followed by hourly maintenance doses of 0.15 g of ethanol/kg body weight. After 10 h there was a significant increase of triglycerides in the VLDL, LDL, and HDL, the main rise (from 42 to 92 mg/dl) being found in the VLDL triglycerides. Other subjects, who received nourishment isocaloric with ethanol, likewise showed a significant rise of triglycerides in all lipoprotein fractions. Chylomicron triglycerides increased from 9.3 to 35.5 mg/dl. There was no significant change in postheparin HTGL, but postheparin LPL activity decreased after 10 h from 17.9 to 12.2 mmol FFA/ml/h in the fasting subjects, and from 28.5 to 10.2 mmol/FFA/ml/h in the persons receiving food. In long-term experiments after 4 weeks of 70 - 80 g of ethanol and isocaloric food daily, triglycerides increased, especially in the VLDL (from 50 to 82 mg/dl). The increase in the HDL, however, was also significant. After 4 weeks of ethanol, the chylomicron triglycerides in the plasma of the fasting subjects reached a value of 29.3 mg/100 ml, LDL cholesterol decreased, and HDL cholesterol increased. After 4 weeks of ethanol there was an increase in the lipoprotein lipase of the adipose tissue.

Diurnal lipid and lipoprotein profiles with bezafibrate and clofibrate in healthy volunteers.

Diurnal lipid and lipoprotein profiles were measured in 28 healthy volunteers after 10-day treatment periods with placebo, bezafibrate (200 mg 3-times daily) or clofibrate (500 mg 3-times daily) in a double-blind, parallel trial. The two drugs lowered fasting triglyceride and cholesterol levels (p less than or equal to 0.05 for cholesterol with bezafibrate vs placebo). Diurnal triglyceride profiles were lowest with bezafibrate due to lowest fasting triglycerides. Alimentary lipaemia with placebo was mild and due to increased VLDL-triglycerides, while the other lipoprotein lipids and total plasma cholesterol remained virtually unchanged during the day. Bezafibrate (half-life 2 hours) and clofibrate (half-life 15 hours) gave similar diurnal triglyceride patterns. The diurnal values were dependent on the fasting values. Changes in the cholesterol/phospholipid ratio during the day may be related to altered post-prandial composition of HDL.

Effects of the dopaminergic agonist cianergoline on blood pressure, the renin-angiotensin-aldosterone axis and the sympathetic nervous system in patients with essential hypertension.

Cianergoline is a new dopaminergic agonist with a predominant cardiovascular action. Its effects on blood pressure, the renin-angiotensin-aldosterone axis, the sympathetic nervous system and lipid metabolism were assessed in 20 patients with benign essential hypertension. Cianergoline given in increasing doses for 4 weeks (maximum daily dose 12 +/- 2 mg (SD)) and placebo both caused a slight decrease in arterial pressure, (from 159/104 to 152/98 mm Hg and from 154/104 to 149/103 mm, respectively; difference not significant). Supine and upright plasma renin activity, plasma aldosterone, norepinephrine, epinephrine and dopamine levels, urinary catecholamine excretion rates as well as serum prolactin, low and high density cholesterol and triglyceride concentrations were not changed after cianergoline or placebo. Total serum cholesterol and triglyceride levels decreased significantly after placebo, but were unchanged after cianergoline. 3 out of 10 patients in the cianergoline group complained of nausea. The findings indicate that the new dopaminergic agonist cianergoline exerts only a mild blood pressure lowering effect in patients with essential hypertension and does not modify the release of prolactin, lipid metabolism or the basal activity or postural responsiveness of the renin-angiotensin-aldosterone axis and of the sympathetic nervous system.

[Cardiovascular risk factors: an intervention program for general practice]. / Kardiovaskuläre Risikofaktoren: ein Interventionsprogramm für die Praxis.

A new multiple risk factor intervention program, combining a comprehensive, stepwise and health education-based approach, was tested in an outpatient setting. In the first 47 patients (aged 17-55, referred by their physicians) total cardiovascular risk (estimated by Framingham index) was reduced within the first 12 months by an average of 32.5%. This improvement derived from significant reductions in all major risk factors. These findings demonstrate the feasibility and potential, yet unexploited, benefit of a more comprehensive risk factor, approach in general medical practice.