Simvastatin treatment on postprandial hypertriglyceridemia in type 2 diabetes mellitus patients with combined hyperlipidemia

Recent studies have shown that statins are effective in reducing fasting low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels. However, it remains unknown if treatment with statins also lowers daily postprandial triglyceride concentrations, which may promote atherogenesis in type 2 diabetes subjects. Forty-one subjects with type 2 diabetes and combined hyperlipidemia who had stable glycemic control were randomly assigned to take simvastatin 20 mg (n = 27) or a placebo (n = 14) once daily for 12 weeks. The medication dosage was doubled after 4 weeks if a subject's LDL-C was not less than 130 mg/dL. Among these participants, 24 subjects (15 on simvastatin and 9 on placebo) agreed to take a meal tolerance test with isocaloric mixed meals (carbohydrate, 52%; fat, 33%, and protein, 15% of the daily caloric intake) and daytime hourly blood sampling from 8 AM to 4 PM. Simvastatin treatment reduced the fasting total cholesterol level from 237 +/- 5 to 178 +/- 6 mg/dL (-25%), the LDL cholesterol level from 150 +/- 6 to 87 +/- 5 mg/dL (-40%), and raised high-density lipoprotein-cholesterol (HDL-C) level from 36 +/- 2 to 40 +/- 2 mg/dL (+11%) (all P <.001). Fasting and daily ambient triglyceride concentrations from 8 AM to 4 PM decreased significantly in response to simvastatin administration (P <.001), but not to the placebo (P =.305). Simvastatin treatment not only decreased total cholesterol and LDL-C levels and increased HDL-C levels effectively, it also decreased fasting, as well as daily postprandial triglyceride concentrations, but had no effect on glycemic control in type 2 diabetes subjects with combined hyperlipidemia.     

Effects of estrogen and medroxyprogesterone acetate on subpopulations of triglyceride-rich lipoproteins and high-density lipoproteins

Hormonal replacement therapy (HRT) in postmenopausal women has been shown to increase both triglyceride (TG) and high-density lipoprotein (HDL) cholesterol levels. To better understand the effects of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), the 2 most commonly prescribed hormones in HRT, on the different subpopulations of TG-rich and HDL lipoproteins, we conducted a placebo-controlled, double-blind, randomized, crossover study consisting of 3 different phases in 14 postmenopausal women. The 3 phases, each 8-week long, included: (1) placebo, (2) CEE 0.625 mg/d, and (3) CEE 0.625 mg/d and MPA 2.5 mg/d. Slight and statistically nonsignificant elevations in TG levels were observed during the CEE treatment. While very-low-density lipoprotein (VLDL) cholesterol levels were not significantly affected by CEE and CEE + MPA, both HRT treatments lowered remnant lipoprotein (RLP) cholesterol (-14% and -37%, respectively). Compared with placebo, CEE caused a significant increase in HDL, HDL(2), apolipoprotein (apo) A-I, LpAI, alpha1, and prealpha1 levels (12%, 27%, 17%, 26%, 60%, and 102%, respectively). The combination therapy blunted the CEE effect on all HDL parameters, resulting in HDL, HDL(2), and LpAI levels being no longer significantly different from placebo. Apo A-I levels and alpha1, and prealpha1 levels were still significantly higher than placebo (+11%, +50%, and +112%, respectively). These results indicate that HRT has beneficial effects on RLP levels and that, while the estrogen component of HRT has a beneficial effect on the HDL subpopulations mostly associated with coronary heart disease (CHD) protection, MPA partially inhibits this effect.     

Effect on high-density lipoprotein cholesterol of maximum dose simvastatin and atorvastatin in patients with hypercholesterolemia: results of the Comparative HDL Efficacy and Safety Study (CHESS)

Background

Previous studies have shown that effects on high-density lipoprotein cholesterol (HDL-C) may differ among statins.

Methods

A multicenter, randomized, double-blind, parallel-dose study was conducted in 917 hypercholesterolemic patients to compare the efficacy of 80 mg/d simvastatin versus 80 mg/d atorvastatin on HDL-C and apolipoprotein (apo) A-I for 24 weeks. Efficacy was assessed as the means of weeks 6 and 12 and weeks 18 and 24. Prespecified subgroups analyzed were patients with low HDL-C levels and with the metabolic syndrome.

Results

Simvastatin increased HDL-C and apo A-I values significantly more than did atorvastatin for the mean of weeks 6 and 12 (8.9% vs 3.6% and 4.9% vs −0.9%, respectively) and the mean of weeks 18 and 24 (8.3% vs 4.2% and 3.7% vs −1.4%). These differences were observed across both baseline HDL-C subgroups (<40 mg/dL, ≥40 mg/dL) and in patients with the metabolic syndrome. Low-density lipoprotein cholesterol and triglyceride reductions were greater with atorvastatin. Consecutive elevations >3× the upper limit of normal in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) occurred in significantly fewer patients treated with simvastatin than with atorvastatin (2/453 [0.4%] vs 13/464 [2.8%]), with most elevations observed in women taking atorvastatin (11/209 [5.3%] vs 1/199 [0.5%] for simvastatin).

Conclusions

Simvastatin (80 mg) increased HDL-C and apo A-I significantly more than did atorvastatin (80 mg) in patients with hypercholesterolemia. This advantage was observed regardless of HDL-C level at baseline or the presence of the metabolic syndrome. Significantly fewer consecutive elevations >3× the upper limit of normal in ALT and/or AST occurred in patients receiving simvastatin.     

Influence of cholesteryl ester transfer protein, peroxisome proliferator-activated receptor α, apolipoprotein E, and apolipoprotein A-I polymorphisms on high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I:A-II concentrations: the Prospective Epidemiological Study of Myocardial Infarction study

The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (≤28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (≥73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the ?2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively.     

Dose-response effects of atorvastatin and simvastatin on high-density lipoprotein cholesterol in hypercholesterolaemic patients: a review of five comparative studies

Epidemiological evidence and clinical trials with fibrate therapy show a clear relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular risk. In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), the hydroxy-methylglutaryl-coenzyme A reductase inhibitors (statins), also raise the levels of HDL-C. This review summarizes the results of five randomized, multicenter studies in hypercholesterolaemic patients in which multiple doses of atorvastatin and simvastatin were compared for their effects on lipids and lipoproteins including HDL-C. Both statins reduced LDL cholesterol and achieved parallel decreases in TG, with atorvastatin showing a slight overall superiority in these studies. Both HDL-C and apolipoprotein (Apo) A-I, its associated apoprotein, were significantly and consistently increased by all doses of simvastatin. However, atorvastatin had a different dose-response effect from simvastatin on both lipid parameters. Whereas HDL-C and Apo A-I were elevated by low doses of atorvastatin, the effect diminished markedly with increasing dose suggesting a possible negative dose-response effect. At higher doses, simvastatin increased HDL-C and Apo A-I significantly more than atorvastatin. These data indicate that statins may not be identical in all their clinical properties relevant to reducing the risks of atherosclerosis.     

Post-prandial effects of gemfibrozil vs simvastatin in hypercholesterolemic subjects with borderline hypertriglyceridemia

BACKGROUND AND AIM: Impaired triglyceride-rich lipoprotein metabolism is most probably related to an enhanced cardiovascular risk, and may be associated with a pro-coagulant state. A double-blind, randomized study was undertaken to evaluate two widely utilized hypolipidemic drugs in the post-prandial phase and their impact on lipid, coagulation and fibrinolytic parameters. METHODS AND RESULTS: Thirty middle-aged men selected according to their low density lipoprotein-cholesterol (LDL-C) > or = 160 and < or = 240 mg/dl and borderline hypertriglyceridemia (110-220 mg/dl) after at least one month of a lipid-lowering diet received gemfibrozil (600 mg bid) or simvastatin (20 mg qd) and the corresponding placebo. On enrollment and after 2 months of drug treatment, they were tested with a standard oral fat load (OFL) (35 g fat/m2 body surface). On both occasions plasma total-cholesterol, LDL-C, HDL-C, triglycerides, lipoprotein[a] (Lp[a]), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), antithrombin-III (AT-III), plasminogen and fibrinogen were determined just before the meal (t0) and at times 2 hours, 4 h, 6 h, 8 h after it (t2-t8). A two-factor (time and visit) multivariate analysis for repeated measurements was performed to evaluate the data. Total cholesterol, and LDL-C were significantly diminished 2 months after both gemfibrozil and simvastatin, the latter being more active. Plasma triglycerides showed a marked reduction with gemfibrozil at all times, while simvastatin regimen yielded only minor modifications. HDL-C was only slightly increased by simvastatin; Lp[a] plasma levels were almost unaffected. Small fibrinogen (t0, t2, t6, t8), PAI-1 (t6) and AT III (t0-t8) increases were observed after gemfibrozil, while simvastatin did not significantly modify these parameters. CONCLUSIONS: In the post-prandial phase, gemfibrozil and simvastatin induce different metabolic effects that beneficially influence the lipid pattern, whereas fibrinolytic and coagulative parameters display minor variations of undetermined significance.     

Estrogen treatment improves arterial distensibility, fibrinolysis, and metabolic profile in postmenopausal women with type 2 diabetes mellitus

The effects of isolated estrogen therapy on the hemostatic system and arterial distensibility were determined in postmenopausal females with type 2 diabetes mellitus. This was a prospective nonrandomized study of 19 subjects (age, 56.2 +/- 4.7 years; body mass index, 27.8 +/- 2.4 kg/m(2) [mean +/- SD]). Inclusion was done after 2 months of glycemic and blood pressure control. The study consisted of 4 months of placebo treatment immediately followed by an equal period of oral conjugated equine estrogens (CEE) 0.625 mg/d. Measures included anthropometrics, a metabolic profile (oral glucose tolerance test and fasting glycated hemoglobin, total cholesterol and fractions, and triglyceride levels), and coagulation and fibrinolytic factors at the end of the placebo period and after 4 months of oral CEE. Conjugated equine estrogen therapy decreased plasminogen activator inhibitor 1 (placebo x CEE: 16.33 +/- 9.11 x 13.08 +/- 8.87 UI/mL, P < .03) and increased factor VIII activity (134.11% +/- 46.18% x 145.33% +/- 42.04%, P < .04). An increase in high-density lipoprotein cholesterol levels (placebo x CEE: 42.47 +/- 6.80 x 53.32 +/- 11.89 mg/dL, P < .01), and a decrease in glycated hemoglobin (8.45% +/- 1.30% vs 7.58% +/- 1.06%, P < .02) and in fasting glucose levels (121.51 +/- 21.05 x 111.21 +/- 20.74 mg/dL, P = .02) followed CEE therapy. Pulse wave velocity and augmentation index were performed by applanation tonometry and were obtained at the end of the placebo period (placebo), again after an intravenous load of 1.25 mg of CEE (short-term), and after 4 months of oral CEE (long-term). A significant decrease in central (carotid-femoral) pulse wave velocity was seen both after short- and long-term CEE (placebo vs short-term vs long-term: 9.36 +/- 2.58 vs 8.26 +/- 2.20 vs 7.98 +/- 1.90 m/s, respectively [analysis of variance, P < .03]; placebo vs short-term, P < .05; placebo vs long-term, P < .01), whereas augmentation index decreased only after long-term CEE (placebo vs short-term vs long-term: 39.14% +/- 6.94% vs 37.48% +/- 8.67% vs 34.3.3% +/- 8.11% [analysis of variance, P < .05], respectively; placebo vs long-term, P < .05). Long-term administration of CEE leads to an improvement in fibrinolysis and arterial distensibility, associated with an increase of the intrinsic coagulation pathway in postmenopausal women with type 2 diabetes mellitus.     

Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia

PURPOSE: To examine the efficacy and safety of colesevelam hydrochloride, a novel, nonsystemic, lipid-lowering agent, when coadministered with starting doses of simvastatin in a multicenter, randomized, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Subjects with hypercholesterolemia (plasma low density lipoprotein [LDL] cholesterol level > 160 mg/dL and triglyceride level < or = 300 mg/dL) were randomly assigned to receive daily doses of placebo (n = 33), colesevelam 3.8 g (recommended dose, n = 37), simvastatin 10 mg (n = 35), colesevelam 3.8 g with simvastatin 10 mg (n = 34), colesevelam 2.3 g (low dose, n = 36), simvastatin 20 mg (n = 39), or colesevelam 2.3 g with simvastatin 20 mg (n = 37), for 6 weeks. RESULTS: Mean LDL cholesterol levels decreased relative to baseline in the placebo group (P < 0.05) and in all active treatment groups (P < 0.0001). For groups treated with combination therapy, the mean reduction in LDL cholesterol level was 42% (-80 mg/dL; P < 0.0001 compared with baseline), which exceeded the reductions for simvastatin 10 mg (-26%, -48 mg/dL) or 20 mg (-34%, -61 mg/dL) alone, or for colesevelam 2.3 g (-8%, -17 mg/dL) or 3.8 g (-16%, -31 mg/dL) alone (P < 0.001). The effects of combination therapy on serum HDL cholesterol and triglyceride levels were similar to those for simvastatin alone. Side effects were similar among treatment groups, and there were no clinically important changes in laboratory parameters. CONCLUSION: Coadministration of colesevelam and simvastatin was effective and well tolerated, providing additive reductions in LDL cholesterol levels compared with either agent alone.     

Effect of body mass index on apolipoprotein A-I kinetics in middle-aged men and postmenopausal women

The effect of body mass index (BMI) and obesity on apolipoprotein (apo) A-I levels and kinetics was examined by gender. Apo A-I kinetics were determined with a primed, constant infusion of deuterated leucine in the fed state in 19 men and 13 postmenopausal women. Compared with nonobese men, nonobese women had a higher level of high-density lipoprotein cholesterol (HDL-C) and apo A-I due to a 48% higher apo A-I production rate (PR) (P = .05). Obesity had no significant effects on apo A-I kinetics in women. In contrast, compared with nonobese men, obese men had a 9% lower apo A-I level due to a 64% higher fractional catabolic rate (FCR) partially offset by a 47% higher PR. Obese women had a 52% higher HDL-C than obese men (50 vs 33 mg/dL, respectively; P = .012), a finding related to the faster apo A-I FCR in obese men. BMI was directly correlated with apo A-I FCR (r = 0.84, P < .001) and PR (r = 0.79, P < .001) in men but not in women. Sixty-two percent of the variability in PR and 71% of the variability in FCR were due to BMI in men and only 3% and 23%, respectively, in women. In conclusion, BMI has a significant effect on apo A-I PR and FCR in men but not in women.     

Comparison of intermittent with continuous simvastatin treatment in hypercholesterolemic patients with end stage renal failure

Coronary artery disease is the most important cause of morbidity and mortality in patients with end-stage renal failure (RF). Hypercholesterolemia is an important risk factor for coronary heart disease. Patients with chronic renal failure (CRF) have difficulties in compliance with their care and treatment. Intermittent simvastatin treatment may help to increase compliance and can be a treatment alternative in patients with CRF at risk of coronary artery disease. We investigated the effects of simvastatin and compared intermittent with continuous simvastatin treatment in hypercholesterolamic patients with CRF. The study group included 40 of 422 CRF patients on dialysis in our clinic. The inclusion criterion was low density lipoprotein cholesterol (LDL-C) of 130 mg/dL or more. Twenty patients received simvastatin 10 mg/day (continuous group) and 20 patients received simvastatin 20 mg three times a week (only dialysis days- intermittent group) for four months. Nineteen patients served as controls and they were given a prescribed diet only. Total cholesterol (TC) and LDL-C decreased markedly in patients receiving intermittent and continuous simvastatin compared to controls. Continuous simvastatin decreased TC by 23% (P < 0.001) and LDL-C by 39% (P < 0.001). Intermittent simvastatin decreased TC by 26% (P < 0.001) and LDL-C by 40% (P < 0.001). The atherogenic index ratios in both the continuous and intermittent groups (TC/High density lipoprotein-cholesterol (HDL-C) and LDL-C/HDL-C) decreased significantly. There was no significant difference in patient compliance between the two groups. Intermittent simvastatin is as effective and reliable as continuous simvastatin treatment and can be an alternative treatment in hypercholesterolemic patients on dialysis.     

Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL

One strategy for treating coronary artery disease (CAD) patients with low HDL cholesterol (HDL-C) is to maximally increase the HDL-C to LDL-C ratio by combining lifestyle changes with niacin (N) plus a statin. Because HDL can prevent LDL oxidation, the low-HDL state also may benefit clinically from supplemental antioxidants. Lipoprotein changes over 12 months were studied in 153 CAD subjects with low HDL-C randomized to take simvastatin and niacin (S-N), antioxidants (vitamins E and C, beta-carotene, and selenium), S-N plus antioxidants (S-N+A), or placebo. Mean baseline plasma cholesterol, triglyceride, LDL-C, and HDL-C levels of the 153 subjects were 196, 207, 127, and 32 mg/dL, respectively. Without S-N, lipid changes were minor. The S-N and S-N+A groups had comparably significant reductions (P相似文献   

Serum lipoproteins, sex hormones and sex hormone binding globulin in middle-aged men of different physical fitness and risk of coronary heart disease

Serum concentrations of lipoproteins, apolipoprotein A-I (Apo A-I), androgens, including biologically active free testosterone (free T), and sex hormone binding globulin (SHBG) and their associations were studied in 3 groups of men of different physical fitness and risk of CHD, consisting of male CHD patients, joggers and healthy controls. Of the 3 study groups, men with angiographically assessed CHD had the lowest HDL-C (P less than 0.002) and highest LDL-C and triglyceride (TG) levels (P = 0.05 and P less than 0.001) and lower 5 alpha-dihydrotestosterone (5 alpha-DHT) levels than joggers (P less than 0.02). Joggers had the highest serum high density lipoprotein cholesterol (HDL-C), Apo A-I and SHBG levels and lowest serum low density lipoprotein cholesterol (LDL-C) compared to the other groups (P less than 0.01). In correlation analysis 5 alpha-DHT was the most significant positive determinant of HDL-C and Apo A-I levels in CHD patients (r = 0.56 and r = 0.55, respectively, P less than 0.05). Moreover, SHBG was significantly positively correlated to both HDL-C and Apo A-I levels in patients, in the whole study group and in healthy men separately (r = 0.37-0.52, P less than 0.01). These significant correlations were also confirmed when age variation and differences in body mass index and smoking were controlled in multivariate analysis and in addition, in multivariate analysis both serum free and total testosterone were inversely related to serum triglyceride (TG) levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gemfibrozil, nicotinic acid and combination therapy in patients with isolated hypoalphalipoproteinemia: a randomized, open-label, crossover study

OBJECTIVES: To assess the effects of nicotinic acid (NA), gemfibrozil and combination therapy on the lipid profile of patients with clinical atherosclerotic disease and isolated hypoalphalipoproteinemia. BACKGROUND: Isolated hypoalphalipoproteinemia (low high density lipoprotein cholesterol [HDL-C] alone) accounts for a significant percentage of patients with premature atherosclerosis. However, it remains unclear whether currently available pharmacotherapy has the ability to favorably affect the lipid profile and therefore potentially reduce clinical events. METHODS: Twenty-three patients with clinically well-defined atherosclerosis and isolated hypoalphalipoproteinemia were prospectively randomized to receive gemfibrozil, NA or combination therapy in an open-label, crossover design trial to assess the effects on serum lipids. Lipid profiles and other relevant laboratory variables were monitored while the patients were on and off pharmacologic lipid-modulating therapy. RESULTS: In those 14 patients able to tolerate all forms of pharmacotherapy, HDL-C of 0.89 +/- 0.17 mmol/liter (34.5 +/- 6.5 mg/dl) increased by 15%, to 1.02 +/- 0.18 mmol/liter (39.7 +/- 7.1 mg/dl), while taking gemfibrozil (1,200 mg/day); by 35%, to 1.20 +/- 0.21 mmol/liter (46.5 +/- 8.1 mg/dl), while taking NA (mean dose 2,250 mg/day); and by 45%, to 1.29 +/- 0.19 mmol/liter (50.0 +/- 7.5 mg/dl), while taking combination therapy of gemfibrozil plus NA (p < 0.001 for all interventions as compared with baseline/washout; p < 0.005 NA vs. gemfibrozil; p < 0.001 combination therapy vs. gemfibrozil alone; p = 0.088 combination therapy vs. NA alone). Statistically significant favorable alterations were also observed with low density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C, non-HDL-C/HDL-C, apolipoprotein (Apo) B and Apo B/Apo A1. CONCLUSIONS: In the majority of patients with clinical atherosclerotic disease and isolated hypoalphalipoproteinemia, pharmacologic therapy to raise HDL-C is not only feasible but is also effective with currently available agents, particularly when used in combination.     

Prevalence and phenotypic distribution of dyslipidemia in type 1 diabetes mellitus: effect of glycemic control

BACKGROUND: Data on the prevalence of dyslipidemia in type 1 diabetes mellitus are scarce and are based on total triglyceride and total cholesterol concentrations alone. OBJECTIVE: To assess the effect of glycemic optimization on the prevalence of dyslipidemia and low-density lipoprotein cholesterol (LDL-C) concentrations requiring intervention in patients with type 1 diabetes. PATIENTS: A total of 334 adults with type 1 diabetes and 803 nondiabetic control subjects. METHODS: Levels of glycosylated hemoglobin, total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-C), and LDL-C were assessed at baseline and after 3 to 6 months of intensive therapy with multiple insulin doses. RESULTS: Levels of LDL-C greater than 4.13 mmol/L (>160 mg/dL) and total triglyceride greater than 2.25 mmol/L (>200 mg/dL) and low HDL-C levels (<0.9 mmol/L [<35 mg/dL] in men or <1.1 mmol/L [<45 mg/dL] in women) were found in 16%, 5%, and 20% of patients and 13%, 6%, and 9% of controls, respectively (P<.001 for HDL-C). Diabetic women showed more hypercholesterolemia than nondiabetic women (15.6% vs 8.5%; P =.04). After glycemic optimization (mean +/- SD glycosylated hemoglobin decrease, 2.2 +/- 1.96 percentage points), the prevalence of LDL-C levels greater than 4.13 mmol/L (>160 mg/dL) became lower in diabetic men than in nondiabetic men (9.7% vs 17.5%; P =.04), but women showed frequencies of dyslipidemia similar to their nondiabetic counterparts. The proportion of patients with LDL-C concentrations requiring lifestyle (>2.6 mmol/L [>100 mg/dL]) or drug (>3.4 mmol/L [>130 mg/dL]) intervention decreased from 78% and 42% to 66% and 26%, respectively. CONCLUSIONS: Low HDL-C is the most frequent dyslipidemic disorder in patients with poorly controlled insulin-treated type 1 diabetes, and a high proportion show LDL-C levels requiring intervention. Less favorable lipid profiles could explain the absence of sex protection in diabetic women. The improvement caused by glycemic optimization puts forward intensive therapy as the initial treatment of choice for dyslipidemia in poorly controlled type 1 diabetes.     

Relationships of serum lipoproteins and apoproteins to sex hormones and to the binding capacity of sex hormone binding globulin in healthy Finnish men

We have determined the levels of serum sex hormones, the binding capacity of sex hormone binding globulin (SHBG), urinary estrogens, serum lipids, lipoproteins, and apolipoproteins A-I, A-II, and B in 30 healthy middle-aged Finnish men with similar dietary habits. Serum levels of total testosterone, free testosterone, 5 alpha-dihydrotestosterone (5 alpha-DHT), and the binding capacity of SHBG were all positively correlated to high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I) (r = .43 to .80, P less than 0.05 to 0.001). Total testosterone and 5 alpha-DHT showed a positive correlation to the ratio of apo A-I to Apo A-II (r = .37, P less than 0.05 and r = .58, P less than 0.01, respectively). Serum estradiol levels were negatively correlated to serum total cholesterol, low density lipoprotein cholesterol (LDL), and Apo B (r = -.51 to -.56, P less than 0.01). Moreover, serum free estradiol was negatively correlated to HDL-C and Apo A-I (r = -.46 and r = -.50, P less than 0.01). In multiple linear regression analysis, 5 alpha-DHT was the most significant independent determinant of HDL-C and apo A-I levels when androgens, luteinizing hormone, estradiol, binding capacity of SHBG, and exogenous factors such as age, body mass index (BMI), smoking, alcohol consumption, and diet were taken into account. Multivariate analysis also demonstrated that both total and free estradiol were inversely related to serum Apo B levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation of the -514C/T polymorphism in the hepatic lipase gene to serum HDL and LDL cholesterol levels in postmenopausal women under hormone replacement therapy

Hepatic lipase (HL) is a lipolytic enzyme that catalyzes hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. Recently, a -514C/T polymorphism in the promoter region of the HL gene was found to be associated with variations in hepatic lipase activity and serum high density lipoprotein cholesterol (HDL-C) levels. Postmenopausal hormone replacement therapy (HRT) has known favorable effects on serum lipid and lipoprotein levels. In this study, we examined the relation between the -514C/T polymorphism and serum lipid and lipoprotein levels in postmenopausal women prior to and after 3 months of HRT. Significant associations between the -514 C/T polymorphism and HDL-C, low density lipoprotein cholesterol (LDL-C) and apolipoprotein A-I (apo A-I) levels were observed before and/or after 3 months of HRT. With HRT, serum total cholesterol (TC), LDL-C and apolipoprotein B (apo B) levels were reduced significantly (P=0.0001), and HDL-C and apo A-I levels were increased significantly (P=0.0001). However, the degrees of change in lipid and lipoprotein levels due to HRT did not differ significantly between the HL genotypes.     

Longitudinal serum lipoprotein changes in white males during adolescence: the Bogalusa Heart Study

Determinants of follow-up levels of low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and the ratio of LDL-C to HDL-C were analyzed in a longitudinal study. White boys (n = 81) aged 11 to 12 years, when examined in 1973-1974 (year 1) were reexamined in 1978-1979 (year 6) at ages 16 to 17 years. During follow-up, mean levels of LDL-C increased from 87.6 mg/dL to 89.8 mg/dL, mean levels of HDL-C decreased from 67.0 mg/dL to 48.4 mg/dL and the mean LDL-C/HDL-C ratio increased from 1.45 to 2.12. Cross-sectional associations between the serum lipoproteins and weight, triceps skinfold thickness, and ponderosity (wt/ht3) were stronger in year 6 than in year 1. A persistence of ranks was observed between year 1 and year 6 for LDL-C (r = 0.61), HDL-C (r = 0.51), and LDL-C/HDL-C (r = 0.50). Multiple linear regression indicated that year 6 LDL-C levels were positively related to year 1 LDL-C, year 1 Tanner stage (an indication of sexual maturation), and the change in skinfold thickness during follow-up. Follow-up LDL-C/HDL-C was related both to change in height (negatively) and to change in weight (positively), after controlling for year 1 LDL-C/HDL-C. These longitudinal findings were similar to those obtained from earlier cross-sectional analyses and were further verified on an independent cohort of white boys also followed for five years (1976-1977 through 1981-1982).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic hypothyroidism induces abnormal structure of high-density lipoproteins and impaired kinetics of apolipoprotein A-I in the rat

Abnormal levels of plasma high-density lipoproteins (HDL) commonly reflect altered metabolism of the major HDL-apolipoprotein A-I (apo A-I). It is well known that thyroid hormones are involved in the regulation of lipoprotein metabolism, inducing significant changes in the concentration, size, and composition of plasma HDL. The purpose of this study was to evaluate the mechanisms responsible of the decreased HDL-apo A-I in chronic thyroidectomized rats (Htx) and to assess the role of HDL structure in apo A-I turnover. Htx rats were found to have a 3-fold increase in low-density lipoprotein-cholesterol (LDL-C), whereas HDL-C and apo A-I showed a 25.9% and 22.6% decrease compared to controls (P <.05), thus suggesting a defect in HDL metabolism. Turnover studies of apo A-I incorporated into normal HDL, using exogenous (125)I-radiolabeling, confirmed an altered fractional catabolic rate (FCR) in Htx rats (0.097 +/- 0.009 d(-1) v 0.154 +/- 0.026 d(-1) for Htx and control rats, respectively, P <.005). Apo A-I production rates calculated with autologous HDL data showed that apo A-I synthesis was decreased to a higher extent than the already reduced apo A-I catabolism, thus explaining the low apo A-I plasma levels in Htx rats. Composition analysis of HDL-Htx revealed increased phospholipid and apo E content, whereas apo A-IV was diminished. Such structural changes contribute to the reduced apo A-I catabolism as demonstrated with further kinetic turnover studies in normal rats treated with (125)I-radiolabeled apo A-I reincorporated into HDL isolated from plasma of Htx rats (FCR, 0.102 +/- 0.017 v 0.154 +/- 0.026 d(-1), for Htx and normal rats, respectively, P <.005). In summary, chronic hypothyroidism in rat a species that lacks cholesteryl ester transfer protein (CETP) activity is characterized by low HDL-C and apo A-I plasma levels as a result of a low apo A-I production rate that exceeds a decreased FCR. Both structural abnormalities of HDL and changes induced in the animal that affect HDL catabolism contribute to the low FCR of apo A-I in the hypothyroid state.     

The effect of endurance exercise training on plasma lipoprotein AI and lipoprotein AI:AII concentrations in sedentary adults

The effect of 6 months of endurance exercise training on plasma concentrations of lipoprotein (Lp)AI and LpAI:AII was determined in 39 sedentary subjects (17 men, 22 women, average age, 57 years) with abnormal cholesterol concentrations (total cholesterol [TC] > 200 mg/dL, or high-density lipoprotein-cholesterol [HDL-C] < 35 mg/dL). Following exercise training, plasma LpAI concentrations increased (+5.9 +/- 1.2 mg/dL; P <.001), but there was no change in total apolipoprotein (apo) A-I or LpAI:AII concentrations. The change in plasma LpAI concentration was positively correlated to changes in total HDL-C (r =.495, P =.001), the sum of HDL4-C(nmr) + HDL5-C(nmr) (r =.417, P =.008), and average HDL particle size (r =.415, P =.009), but not to changes in body composition or Vo2max. In the 8 subjects with the greatest change in LpAI concentration following training, the size distribution of LpAI and LpAI:AII particles in plasma also was measured before and after training. In these subjects, the size distribution of LpAI:AII particles did not change with training, but there was a significant increase (0.1 nm; P =.048) in the peak size of the "medium" (7.8 to 9.8 nm) LpAI particles after training. In 7 subjects who served as age- and weight-matched sedentary controls, plasma concentrations of total apo A-I, the LpAI and LpAI:AII subfractions, and plasma lipoprotein-lipids did not differ significantly between baseline and final testing. These data indicate that endurance exercise training increases the average size and plasma concentrations of LpAI, but not LpAI:AII, particles, which may represent possible enhancements of reverse cholesterol transport and may provide insight into the role that exercise plays in reducing cardiovascular disease risk.     

A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia

We report a large family in which four members showed a plasma lipid profile consistent with the clinical diagnosis of familial combined hyperlipidemia (FCHL). One of these patients was found to have markedly reduced HDL cholesterol (HDL-C) (0.72 mmol/l) and Apo A-I (72 mg/dl) levels, a condition suggestive of the presence of a mutation in one of the HDL-related genes. The analysis of APOA1 gene revealed that this patient was heterozygous for a cytosine insertion in exon 3 (c.49–50 ins C), resulting in a frame-shift and premature stop codon at position 26 of pro-Apo A-I (Q17PFsX10). This novel mutation, which prevents the synthesis of Apo A-I, was also found in four family members, including three siblings and the daughter of the proband. Carriers of Apo A-I mutation had significantly lower HDL-C and Apo A-I than non-carriers family members (0.77 ± 0.15 mmol/l vs. 1.15 ± 0.20 mmol/l, P < 0.005; 71.4 ± 9.1 mg/dl vs. 134.0 ± 14.7 mg/dl, P < 0.005, respectively). Two of the APOA1 mutation carriers, who were also heavy smokers, had fibrous plaques in the carotid arteries causing mild stenosis (20%). The intimal-media thickness in the two other adult carriers was within the normal range. The other non-carriers family members with FCHL had either overt vascular disease or carotid atherosclerosis at ultrasound examination. This observation suggests that the low HDL-C/low Apo A-I phenotype may result from a genetic defect directly affecting HDL metabolism, even in the context of a dyslipidemia which, like FCHL, is associated with low plasma HDL-C.