A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition.

This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-I, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .01). Simvastatin increased Lp A-I, but did not change Lp A-II:A-I, while fenofibrate decreased Lp A-I and increased Lp A-II:A-I. Lp E:B and Lp C-III:B were decreased with both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin. This study demonstrates that both drugs have beneficial effects on the parameters positively or negatively correlated with the atherosclerotic risk, with simvastatin being more effective in reducing some of them. These results suggest that the drugs led to different structural modifications of the lipoproteins, which would not be revealed by examination of lipoprotein density classes. These differences are probably related to the different mechanisms of action of the agents.

Telematic expert system Diabeto. New tool for diet self-monitoring for diabetic patients.

OBJECTIVE: To evaluate Diabeto, a computer-assisted diet education system. RESEARCH DESIGN AND METHODS: One hundred five patients with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM) were divided into two randomized groups to participate in the evaluation of Diabeto. With free access through Minitel, the French public videotex network, Diabeto helps diabetic patients self-monitor their diets and balance their meals with personalized counseling. RESULTS: During the first 6-mo study, group A (54 patients) used Diabeto, whereas group B (51 patients) were control subjects. For the second 6-mo study, group B used the system. Evaluation was based on patients' dietetic knowledge, dietary habits, and metabolic balance. CONCLUSIONS: Diabeto led to a significant improvement of dietetic, knowledge in group A (P less than 0.0005) and also to improved dietary habits; decreased caloric intake in patients initially overeating (P less than 0.05), increase of dietary carbohydrate from 39.7 +/- 0.7 to 42.9 +/- 0.9% in patients with an initial intake less than 45% carbohydrate, and decrease of fat intake from 41.9 +/- 0.9 to 37.4 +/- 1.1% in patients with an initial intake of greater than 35% fat (P less than 0.0005). In the second study, in addition to similar improvements to those observed in the first study, HbA1 decreased from 11.0 +/- 0.4 to 9.9 +/- 0.4% (P less than 0.005) and fructosamine from 5.00 +/- 0.17 to 4.57 +/- 0.17% (P less than 0.001). Diabeto appears to be an effective therapeutic tool in the control of metabolic diseases.

Lipoprotein particle analysis comparing simvastatin and fenofibrate.

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.d., if their total cholesterol and their LDL cholesterol remained above 7.60 mmol/l (300 mg/dl) and 4.95 mmol/l (195 mg/dl) after a 4-week placebo period. Simvastatin dosage was doubled at the end of 6 weeks of therapy if the LDL-cholesterol level remained above 3.55 mmol/l (140 mg/dl). Analyses were done after 6 and 10 weeks of therapy. Apolipoprotein AI was increased significantly only at week 10 with fenofibrate (+7.4%). Simvastatin had a more pronounced effect than fenofibrate on apolipoprotein B. There was a significant difference between drugs at weeks 6 and 10. No change was observed in the LpAII:AI level with simvastatin, whereas fenofibrate increased these particles quite significantly (+13.9 and +22.3%). The drugs had opposite effects on LpAI (+2.5 and +5.6% with simvastatin; -12.8 and -15.1% with fenofibrate). LP E:B (-33.0 and -40.8% with simvastatin; -53.8 and -52.2% with fenofibrate) and LpCIII:B (-23.8 and -31.8% with simvastatin; -35.1 and -43.5% with fenofibrate) were decreased by both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin at week 6. This study suggests that both drugs led to different structural modifications of the lipoproteins, which would not be revealed by total apolipoprotein analysis. These differences are probably related to the mechanisms of action of these drugs.

Heterogeneity of HDL in crossed immunoelectrophoresis with continuous gradient polyacrylamide gel in the first dimension and one or two antibody layers in the second dimension.

We describe a new method of immunoelectrophoresis with a continuous gradient polyacrylamide gel in the first dimension and an agarose-dextran gel in the second dimension with one or two layers of antibody. The use of a polyacrylamide gel in the first dimension allows better resolution of lipoproteins than with crossed immunoelectrophoresis using agarose gel in both dimensions. The use of two layers of antibody in the second dimension also enhances the specificity of characterization and the resolution of the separation. Thus, using a layer of anti-apo A-I combined with a layer of anti-apo A-II, three particles containing only apo A-I and three containing both apo A-I and A-II could be separated.

Discontinuous polyacrylamide gel-agarose gel immunoelectrophoresis for analysis of plasma lipoproteins.

A modification of crossed immunoelectrophoresis for the analysis of plasma lipoproteins is described and is called polyacrylamide gel-crossed immunoelectrophoresis. The incorporation of albumin in the first-dimensional gel facilitates the transfer of the larger lipoproteins containing apolipoprotein B from the first-dimensional gel to the second dimension. Furthermore, under this condition the quantitation of total apolipoprotein B by polyacrylamide gel-crossed immunoelectrophoresis is in good agreement with the results obtained by rocket immunoelectrophoresis or nephelometry. The correlation between polyacrylamide gel-crossed immunoelectrophoresis and rocket immunoelectrophoresis is good for total apolipoprotein B (p greater than 0.001) and apolipoprotein A-I (p greater than 0.001). Polyacrylamide gel-crossed immunoelectrophoresis also offers interesting aspects to study the plasma lipoprotein classes and subclasses in different cases: normal plasma, current and complex dyslipoproteinemias in the presence or absence of lipoprotein small a. In a case of dyslipoproteinemia of Fredrickson's Type V polyacrylamide gel-crossed immunoelectrophoresis demonstrates the presence of a small-sized Lp (a) major peak in the low density lipoprotein (LDL) zone and of a large-sized Lp (a) minor peak in the very low density lipoprotein (VLDL) zone.

[Use of 6 serum pools in standardization of the determination of apolipoproteins AI and B in the human serum]. / Utilisation de 6 calibrants sériques pour standardiser les dosages des apolipoprotéines AI et B dans le sérum humain.

The proliferation of commercial immunoassays for the determination of apolipoproteins AI and B as parameters of risk for coronary heart disease and the discordance between the values obtained with the systems have made more urgent than ever the need for standardization of these assays. The authors report here the results of a collaborative study on the standardization of the values between the "Comité Française de Coordination des Recherches sur l'Athérosclérose et le Cholestérol (ARCOL)" and 13 Companies providing 15 different analytical systems. The results show that standardized measurements are not possible using a "consensus international standard" and that the major problem is related to the enormous variability of the analytical systems. In contrast, the present study demonstrates that six different serum pools containing increasing amounts of apolipoproteins AI and B can be used to generate a common reference curve which permits calibration of all immunoassays and standardization of results.

[Peripheral thyroid insufficiency. Criteria of equilibrium in treatment with L-thyroxine]. / Insuffisance thyroïdienne périphérique. Critères d'équilibre du traitement par L-thyroxine.

During treatment of primary hypothyroidism, the respective values of hormonal assays (total and free T4 and T3, ultrasensitive TSH assay, TRH test) and of the serum markers from peripheral tissue response to thyroid hormones used to detect overdosage are matter to debate. Thirty-four female patients with hypothyroidism, aged 38 +/- 7 years (mean +/- SD) were studied. the mean dose of L-thyroxine required to obtain clinical euthyroidism was 100 +/- 35 micrograms/day. Thyroid hormone and TSH concentrations were measured 20 to 24 hours after the last dose of L-thyroxine and after fasting overnight and were compared with the concentrations obtained in 45 euthyroid controls aged 32 +/- 10 years.

Plasminogen activator inhibitor in plasma is related to testosterone in men.

Low plasma testosterone and high levels of the rapid inhibitor of plasminogen activator (PA-I) have been proposed as risk factors for myocardial infarction. In this study, the relationship between testosterone and PA-I activity levels in middle-aged men without thrombotic antecedent was investigated. In 54 normogonadic men (testosterone, 7.3 to 29.1 nmol/L), PA-I was related positively to body mass index (BMI) and triglycerides and negatively to testosterone. When these variables were controlled, the relation between PA-I and testosterone remained significant (P less than .01). In the 41 normogonadic men with BMI less than 25, testosterone was the only variable to influence PA-I. Fibrinolytic activity was evaluated by the euglobulin lysis plate method and the specific measurement of functional tissue plasminogen activator. The basal fibrinolytic activity and the response to venous occlusion were essentially controlled by PA-I but were not significantly related to testosterone. In 17 men with severe hypogonadotrophinic hypogonadism (testosterone less than 3 nmol/L), PA-I was significantly increased (18.5 +/- 1.8 AU/mL, mean +/- SE) compared with 9.5 +/- 0.8 AU/mL in 41 normogonadic men of normal weight (P less than .001). However, 14 hypogonadic men had a hypertriglyceridemia or a BMI greater than 25, which could explain high PA-I levels. This study shows that the level of the inhibitor of plasminogen activator is partly dependent on hormonal status in men and provides a link between independently established epidemiologic data.

[Cardiovascular risk factors in the population of 2 regions covered by the MONICA-France regions: Strasbourg and Toulouse]. / Facteurs de risque cardio-vasculaire dans la population de deux régions couvertes par les registres MONICA-France: Strasbourg et Toulouse.

Cardiovascular risk factors were studied from 1985 to 1987 in two population samples from the French regions of the Bas-Rhin (BR) (Strasbourg) and the Haute-Garonne (HG) (Toulouse). 1,257 men and women in the BR and 1,323 in the HG, aged 35-64, participated in the survey. A common investigation methodology in harmony with the MONICA protocol, was used. The mean weight was higher among the male (5 kg) and female (6 kg) populations living in the BR than in the HG. Even after age, body mass index and tobacco consumption adjustments, arterial systolic blood pressure was higher in the male population of the BR (145 mm Hg) than in the HG (133 mm Hg). Similar differences were observed among the female population. A higher proportion of hypertensive subjects whatever the sex and the age group was noted in the BR. The proportion of smokers, and the quantity of tobacco they smoked, did not differ between the two centers. Adjusted total cholesterolemia was higher in the HG, with mean differences of 0.32 mmol/l among the men and 0.35 mmol/l among the women. In the case of HDL cholesterol, the differences were 0.23 mmol/l among the men and 0.34 mmol/l among the women, explaining in large part the differences of the mean levels of total cholesterol.

Comparison of cardiovascular risk factor levels in two French populations: Haute-Garonne (Toulouse) and Bas-Rhin (Strasbourg).

Cardiovascular risk factors were studied from 1985 to 1987 in population samples in two French regions with different ischaemic heart disease mortality rates in Bas-Rhin (Strasbourg MONICA centre) and in Haute-Garonne (Toulouse MONICA centre). These rates were, among men, 109/100,000 in Bas-Rhin, and 72/100,000 in Haute-Garonne. 1,253 and 1,319 men and women aged 35-64 participated in the survey. In each region, identical investigation methodology was used, according to MONICA protocol. The average weight in both sexes was higher in Bas-Rhin than in Haute-Garonne (5 Kg more for men and 6 Kg more for women). After adjustment for age, body mass index and tobacco consumption, arterial systolic blood pressure was higher for men in Bas-Rhin (145 mm Hg) than in Haute-Garonne (133 mm Hg). Similar differences were observed in women. Higher proportions of hypertensive participants of both sexes and in all age groups were registered in Bas-Rhin than in Haute-Garonne. The number of smokers and the amount of tobacco consumption did not differ between the two centres. Mean serum cholesterol was higher in Haute Garonne (5.95 mmol/L for men and 5.88 mmol/L for women) than in Bas-Rhin (5.57 mmol/L for men and 5.51 mmol/L for women). Also high-density lipoprotein (HDL)-cholesterol values were higher in Haute-Garonne, and can partly explain the regional difference in total cholesterol.

Effects of a low-energy diet associated with egg supplementation on plasma cholesterol and lipoprotein levels in normal subjects: results of a cross-over study.

1. The influence of a low-energy diet when associated with high-cholesterol intake was investigated in seventeen normal men during an 8-week cross-over study. The subjects were given a daily supplement of two whole eggs and two egg yolks (approximately 1 g cholesterol) either with their usual diet for 4 weeks or with a low-energy diet for 4 weeks. Each subject took part randomly in both dietary periods. 2. During the first part of the study, no changes occurred in the plasma cholesterol of the subjects with egg supplementation of the usual diet. 3. In contrast, the low-energy diet and associated weight loss markedly decreased tolerance to high-cholesterol intake resulting in increased plasma cholesterol. The mean rise was 22.7% but with wide individual variations in the response. This was almost completely normalized when the subjects returned to their usual energy intake indicating the involvement of weight reduction in the increase observed. 4. Changes in low-density-lipoprotein (LDL) cholesterol were parallel to those of total plasma cholesterol with an increase following the low-energy diet and normalization after body-weight recovery. 5. The opposite effect was shown with the low-energy diet after previous adaptation to the consumption of four eggs per day. This dietary regimen resulted in a decrease in plasma cholesterol although it was not significant. Moreover, the lipoprotein profile was improved with a decrease in very-low-density-lipoprotein (VLDL) cholesterol and an increase in high-density-lipoprotein (HDL) cholesterol. 6. High-cholesterol intake induced significant changes in lipoprotein composition whatever the energy ration. LDL and HDL were enriched in cholesterol esters as early as the 1st month of egg supplementation of the diet. 7. Taken together, the results emphasize the possible adverse effect of slimming diets when associated with high-cholesterol intake. The existence of 'high-responders' to these dietary conditions calls for special attention to be paid to the cholesterol content of restricted diets.

Fluorescence quenching by iodide ions of low density lipoproteins from normolipidemic and hypercholesterolemic type IIa subjects. Effect of low density lipoprotein-cholesterol and low density lipoprotein non-apolipoprotein-B.

In order to evaluate the effect of hypercholesterolemia on the surface properties of low density lipoproteins (LDL), the quenching by iodide ions of the native fluorescence of human plasma LDL was studied on normolipidemic and hypercholesterolemic type IIa subjects. A significant difference (P less than 0.001) was found between these two groups (20 patients with type IIa hyperlipoproteinemia, 18 normolipidemic subjects). Furthermore, the fluorescence quenching (F0-F1)/F0 (F0 and F1 fluorescence intensity respectively in the absence and in the presence of iodide ions is negatively correlated with the relative LDL-cholesterol level (LDL-cholesterol/LDL-apoprotein). In contrast, this quenching is positively correlated with the relative LDL-non-apo-B level (LDL-non-apo-B/LDL apo). It is suggested that the greater the LDL-cholesterol level, the more embedded are the tryptophyl residues in the hydrophobic core. In contrast, the greater the LDL-non-apo-B level, the more exposed are the tryptophyl to the aqueous environment. Thus, a significant conformation change of the superficial apolipoproteins occurs, which could affect the immunological properties of the LDL and their affinity to the LDL receptors.