Changes In Triglyceride Levels Research Articles

Effect of simvastatin on endothelial function in cardiac syndrome X patients

Patients with cardiac syndrome X with mild hypercholesterolemia were randomized to placebo (n = 20) or simvastatin 20 mg/day (n = 20). In the simvastatin group, there was a significant (26%; p < 0.0001) decrease in total cholesterol, a 38% (p < 0.0001) decrease in low-density lipoprotein cholesterol levels, and 7% a (p < 0.0001) increase in high-density lipoprotein cholesterol levels, without significant changes in triglyceride levels. Brachial artery flow-mediated dilation increased significantly (52% relative increase, p < 0.0001), and the time to > 1-mm ST-segment depression during stress testing was longer by the end of the study (p < 0.0001).

Impact of adjunctive thiazolidinedione therapy on blood lipid levels and glycemic control in patients with type 2 diabetes

SUMMARYObjective: This study was undertaken to assess the effect of pioglitazone hydrochloride and rosiglitazone maleate on blood lipid levels and glycemic control when these drugs are used as adjunctive therapy in type 2 diabetes.Research design and methods: Patients with type 2 diabetes receiving metformin and/or sulfonylurea (n = 829) were evaluated in this national, multicenter, retrospective study. Medical records from 318 endocrinology practices in the USA were randomly selected and screened for study inclusion. Data related to patient demographics and laboratory data were extracted from medical records and analyzed for primary and secondary outcomes.Main outcome measures: The primary study outcome was the mean change in plasma triglyceride (TG) levels. Secondary outcome measures included mean changes in total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations and hemoglobin A1C levels.Results:With pioglitazone, TG levels declined by a mean of 51.5 mg/dl (P < 0.001), HDL-C levels rose by 3.3 mg/dl (P < 0.001), and no change was seen in LDL-C or TChol. Treatment with rosiglitazone was associated with no significant change in TG levels and a 1.5 mg/dl mean increase in HDL-C (P < 0.001). Furthermore, rosiglitazone therapy was associated with an 8 mg/dl mean increase in TChol (P < 0.001), and a 5.8 mg/dl mean increase in LDL-C (P < 0.001). Hemoglobin A1C levels were significantly reduced by approximately 1% within thiazolidinedione (TZD) cohorts (P < 0.001), but were not significantly different between study groups (P = 0.257).Conclusions: Results from this study suggest that pioglitazone has a more favorable effect on lipid profiles of patients with type 2 diabetes compared with rosiglitazone. In particular, differences were observed in TG and LDL-C levels. Both TZDs were equivalent at reducing hemoglobin A1C levels. These differences in lipid effects may have an impact on cardiovascular outcomes. The full clinical importance of these lipid alterations must be further assessed in prospective trials.

Progression of coronary atherosclerosis relates to the onset of myocardial infarction in an animal model of spontaneous myocardial infarction (WHHLMI rabbits).

Recently, we developed myocardial infarction-prone WHHLMI rabbits from coronary atherosclerosis-prone WHHL rabbits (WHHLCA rabbits) by selective breeding. In this study, we examined the relation of atherosclerotic plaques to the onset of myocardial infarction. We examined myocardial lesions of 378 WHHL rabbits born between 1992 and 2000, and atherosclerosis lesions of 93 WHHLCA and 82 WHHLMI rabbits. The aortic lesions were evaluated as percent surface lesion area. The coronary lesions were evaluated as cross sectional narrowing using sections prepared at 500 or 1,000 microm intervals. Serum lipid levels were assayed with enzymatic methods. The cumulative incidence of fatal myocardial infarction between 11 and 35 months old was 90% in WHHLMI rabbits and 21% in WHHLCA rabbits, respectively. Selective breeding increased the serum cholesterol levels by about 200 mg/dl despite there being no changes in triglyceride levels. Aortic and coronary atherosclerosis progressed markedly in WHHLMI rabbits compared to WHHLCA rabbits. Especially, WHHLMI rabbits over 15 months old showed more than 90% cross sectional narrowing of the left circumflex arteries, main stem of the left coronary artery, and the origin portion of the right coronary artery. In addition, there were no gender differences in atherosclerotic lesions of both aortas and coronary arteries. In conclusion, the present study showed that marked progression of coronary atherosclerosis was probably associated with spontaneous development of myocardial infarction in WHHLMI rabbits.

Effects of continuous combined conjugated estrogen/medroxyprogesterone acetate and 17β-estadiol/norethisterone acetate on lipids and lipoproteins

Objectives: Various estrogen/progestogen combinations used in hormonal replacement therapy (HRT) have been reported to influence lipid and lipoprotein fractions differently. This motivated a comparative study where the two continuous combined regimens most commonly used in Sweden during the 1990s have been studied regarding effects on lipid profile. Methods: In a 1-year prospective, double-blind study, 62 post-menopausal women were randomized to conjugated estrogen (CE), 0.625 mg, and medroxyprogesterone acetate (MPA), 5 mg, or 17β-estradiol (E2), 2 mg, and norethisterone acetate (NETA), 1 mg. Serum concentrations of lipids and lipoproteins were measured at baseline and after 1 year of treatment. Results: Both treatment groups significantly lowered the lipoprotein(a) (Lp(a)) levels. The CE/MPA group showed no significant changes in total cholesterol (TC), high-density (HDL) and low-density lipoprotein (LDL), but a significant increase of triglyceride (TG) levels. The E2/NETA group developed a significant lowering of total cholesterol, HDL, and LDL, but no significant changes of TG levels. The magnitude of change in serum concentrations of total cholesterol, HDL and TG differed significantly between the two treatment groups. Conclusions: Continuous combined treatment with CE/MPA and E2/NETA equally lowered Lp(a), an important risk factor for cardiovascular disease in women. Apart from this, the two treatments produced different effects on lipids and lipoproteins, findings that are more delicate to interpret.

Effects of atorvastatin on electrophoretic characteristics of LDL particles among subjects with heterozygous familial hypercholesterolemia

The effects of the HMG CoA reductase inhibitor atorvastatin on electrophoretic characteristics of LDL particles were evaluated in 46 patients (28 males and 18 females) with heterozygous familial hypercholesterolemia (FH) aged 20–61 carrying either a negative or a defective LDL receptor gene mutation. Following a 6 week drug-free baseline period, FH heterozygotes were treated with atorvastatin (median dose: 20 mg/day, range 10–80 mg/day)) for 6 months to maintain their plasma LDL–cholesterol concentrations between 4.0 and 5.0 mmol/l. Atorvastatin treatment significantly reduced plasma total cholesterol, LDL–cholesterol and triglyceride levels and increased plasma HDL–cholesterol. Furthermore, atorvastatin treatment significantly increased LDL peak particle diameter (LDL-PPD) by 0.5% (from 255.0±6.2 to 256.4±5.5 Å, P=0.004) and reduced the absolute concentration of cholesterol among small (<255 Å) and large (>260 Å) LDL particles by 35% ( P<0.001). Changes in LDL-PPD and plasma triglyceride levels were inversely correlated ( R=−0.34; P=0.02). Stepwise multiple linear regression analyses showed that 41.6% of the variation in the LDL-PPD response to atorvastatin was attributable to the initial LDL-PPD (14.4%, P=0.003), the apo E polymorphism (12.4%, P=0.02), the nature of the LDL receptor gene mutation (9.6%, P=0.01) and change in triglyceride levels (5.2%, P=0.04). Moreover, the reduction in the cholesterol content of LDL <255 Å was directly correlated with the daily dosage of atorvastatin ( P=0.05). Results of the present study showed that atorvastatin alters significantly LDL heterogeneity in patients at high risk of coronary heart disease (CHD) such as FH heterozygotes. These results also suggest that genetic and metabolic factors may be important determinants of atorvastatin-induced changes of LDL particle size and distribution among FH heterozygotes.

Triglyceride, cholesterol and weight changes among risperidone-treated youths. A retrospective study.

The purpose of this retrospective chart review was to assess triglyceride, cholesterol and weight changes among risperidone-treated youths. The charts of 22 child and adolescent inpatients were abstracted. The sample's mean (+/- SD) age was 12.8 (+/- 2.6) years, daily risperidone dose 2.7 (+/- 2.2) mg, and average length of exposure 4.9 (+/- 1.0) months. Repeated measures analysis of variance revealed statistically and clinically significant weight gain averaging 7.0 (+/- 4.7) kg (95% confidence interval [CI] for the mean = 4.9,9.1; F = 49.421, df = 1,21, p < 0.001). No significant changes in serum triglyceride or cholesterol levels were seen in the group as a whole. Triglyceride levels and weight were strongly correlated with each other: almost 25% of the variance in triglyceride level changes could be explained by weight gain alone (R2 = 0.22, F = 5.526, p = 0.029), although such association weakened when excluding subjects (N=5) concurrently treated with lithium or divalproex (R2 = 0.06, p > 0.05). On the basis of this preliminary report it seems prudent to be clinically vigilant and conservative, recommending regular laboratory monitoring until a clearer picture emerges regarding lipid dysregulation associated with risperidone and other atypical antipsychotic use in children and adolescents.

A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients

Objective: The objective of the present study was to compare the effects of a 16-week pharmacotherapy with fenofibrate (200 mg) or pravastatin (initially 20 mg for 8-weeks and, if necessary, increased to 40 mg) on low density lipoprotein (LDL) particle size assessed by gradient gel electrophoresis among patients with type IIa dyslipidemia. Methods: For that purpose, type IIa dyslipidemic patients (cholesterol, 7.45±1.18 (S.D.) mmol/l; LDL cholesterol, 5.57±1.16 mmol/l; triglycerides (TGs), 1.66±0.43 mmol/l) were randomized to either fenofibrate ( n=36) or pravastatin ( n=43) therapy for 16 weeks. Fasting plasma lipoprotein levels as well as the LDL peak particle size (using 2–16% polyacrylamide gel electrophoresis) were assessed at baseline and after the 16-week treatment period. Results: Whereas significant improvements in the plasma lipoprotein–lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased with fenofibrate therapy (+2.11±5.18 Å, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size ( r=−0.54, P<0.0007), whereas no such association was found in pravastatin-treated patients. The prevalence of patients with small, dense LDL particles (as defined by LDL particle diameter <255.5 Å) was reduced from 69.4 to 30.6% ( P<0.05) among fenofibrate-treated patients as opposed to 81.4 to 72.1% (NS) in patients who received pravastatin. Conclusion: As pravastatin treatment had no effect on LDL size, it is suggested that the additional effect of fenofibrate therapy on LDL size may contribute to reduce the risk of coronary heart disease (CHD) beyond what can be expected from the reduction in LDL cholesterol concentration in type IIa dyslipidemic patients.

A comparison of the effects of two continuous HRT regimens on cardiovascular risk factors

In a study comparing the effects of two continuous HRT regimens on cardiovascular risk markers, 43 postmenopausal women were randomly assigned to receive either tibolone 2.5 mg/day ( n=20) or 0.625 mg/day conjugated equine oestrogens plus continuous medroxyprogesterone acetate 5 mg/day ( n=23). Serum lipoprotein levels, including LDL and HDL subfractions, oxidisability of LDL and serum nitrate/nitrite levels were determined before and during 12 weeks of therapy. Tibolone significantly reduced triglycerides (17.1%, P<0.01), HDL cholesterol (22.2%, P<0.001), and the ratio HDL 2/HDL 3 cholesterol (20.2%, P<0.01). Total LDL cholesterol levels did not change significantly, although there was a downward trend in the LDLIII subfraction (12.0% reduction; P=0.06), percentage changes being positively correlated with percentage changes in triglyceride levels ( r=0.60, P<0.01). Susceptibility of LDL to oxidation was significantly decreased ( P<0.001), changes in lag-time being highly negatively correlated with percentage changes in levels of both LDLIII ( r=−0.68, P<0.01) and triglycerides ( r=−0.63, P<0.01). Nitrate/nitrite levels did not change. In contrast, the combined therapy caused a significant reduction in LDL cholesterol levels (11.1%; P<0.01) as a result of a significant decrease in the LDLI+II subfraction (12.8%; P<0.05). Changes in LDLI+II and LDLIII were correlated with changes in triglyceride levels ( r=−0.52, P<0.05 and r=0.63, P<0.01, respectively). No other parameter was significantly modified. Between treatment effects were significantly different on triglycerides ( P<0.01), HDL cholesterol ( P<0.001), LDL oxidation ( P<0.01) and LDLI+II:LDLIII ratio ( P<0.05). The reduction in LDL induced by the continuous combined therapy is likely to be beneficial, despite the apparent shift towards the LDLIII subfraction. Changes in oxidisability and subfraction profile of LDL indicate that tibolone may have a more favourable effect on cardiovascular risk than previously suggested.

Utility of the Arg/Gln polymorphism of the factor VII (FVII) gene, serum lipid levels and body mass index in the prediction of the FVII:C and FVII:Ag in North Karelia; a cross-sectional and prospective study

The arginine/glutamine (Arg/Gln) polymorphism of the factor VII (FVII) gene is associated with variation in coagulation activity (FVII:C) and antigen concentration (FVII:Ag) of the FVII protein. We estimated frequency distributions of the Arg and Gln alleles and respective genotypes in North Karelia, and evaluated the utility of this polymorphism, serum lipids, and body mass index (BMI) in the prediction of the distributions of FVII:C and FVII:Ag in a cross-sectional study and in a prospective cohort study. The sample comprised 203 males and 262 females (aged 45-64 years) who were seen twice, in 1992 and 1995. The Arg/Arg genotype and the Arg allele frequencies were among the highest reported so far (86 and 93% respectively, in men; and 89 and 94% respectively, in women). Intragenotypic means of both FVII:C and FVII:Ag were significantly higher in the Arg/Arg genotype than in the Arg/Gln genotype in both genders. Also, intragenotypic variances were different in different genotypes in females. Regression relationships between the FVII:C and FVII:Ag and serum triglyceride, and total cholesterol levels and BMI were positive in both genotypes in both genders, which has not been found in other populations. In prospective analyses, average changes in the FVII:C and FVII:Ag were genotype specific in both genders, as were also regression relationships between these changes and changes in triglyceride level in females (P = 0.065 for FVII:C and P = 0.061 for FVII:Ag). A consequence of these complex genetic architectures is that predictive utility of the Arg/Gln genotypes depends on population, gender, serum lipid levels, and BMI, and changes in these factors over time.

Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: A randomized, placebo-controlled study

Background: Their complimentary mechanisms of action suggest that a combination of pioglitazone hydrochloride and metformin may have clinically beneficial effects in the treatment of patients with type 2 diabetes. Objective: This study was undertaken to assess the efficacy and tolerability of pioglitazone in combination with metformin in patients with type 2 diabetes mellitus. Methods: This was a 16-week, double-blind study with the option of enrollment in a separate open-ended, open-label study. It included patients with poorly controlled diabetes mellitus (glycated hemoglobin [HbA 1c] ≥8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for ≥30 days. Patients with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or kidney function; or unstable cardiovascular or cerebrovascular conditions were excluded. Patients were randomized to receive once-daily pioglitazone 30 mg + metformin or placebo + metformin. Patients in the open-label extension received pioglitazone 30 mg (with optional titration to 45 mg) + metformin. Results: Three hundred twenty-eight patients were randomized to treatment (168 pioglitazone + metformin, 160 placebo + metformin), and 249 completed the study. Of these, 154 elected to enter the open-label extension study. Patients' mean age was 56 years; most (84%) were white and slightly more than half (57%) were male. Patients receiving pioglitazone 30 mg + metformin had statistically significant mean decreases in HbA 1c (−0.83%) and fasting plasma glucose (FPG) levels (−37.7 mg/dL) compared with placebo + metformin ( P ≤ 0.05). Decreases in FPG levels occurred as early as the fourth week of therapy, the first time point at which FPG was measured. The pioglitazone + metformin group had significant mean percentage changes in levels of triglycerides (−18.2%) and high-density lipoprotein cholesterol (+8.7%) compared with placebo + metformin ( P ≤ 0.05). Mean percentage increases were noted in low-density lipoprotein cholesterol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) and total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metformin), with no significant differences between groups. In the extension study, patients treated with open-label pioglitazone + metformin for 72 weeks had mean changes from baseline of −1.36% in HbA 1c and −63.0 mg/dL in FPG. The incidence of adverse events was similar in both groups. Throughout the study, no patient in either treatment group had an alanine aminotransferase (ALT) value ≥3 times the upper limit of normal, a commonly used marker of potential liver damage. Thus, no evidence of drug-induced hepatotoxicity or drug-induced elevations in serum ALT was observed. Conclusions: In this study in patients with type 2 diabetes mellitus, pioglitazone + metformin significantly improved HbA 1c and FPG levels, with positive effects on serum lipid levels and no evidence of drug-induced hepatotoxicity. These effects were maintained for >1.5 years, including the open-label extension.

The hypolipidemic action of bezafibrate therapy in hypertriglyceridemia is mediated by upregulation of lipoprotein lipase: no effects on VLDL substrate affinity to lipolysis or LDL receptor binding

Fibrates are regarded as drugs of choice in hypertriglyceridemia (HTG). Downregulation of apolipoprotein (apo) C-III gene expression and upregulation of lipoprotein lipase (LPL) gene expression have been suggested to explain the hypolipidemic action of fibrates. This study was designed to study the effects of bezafibrate therapy on very low density lipoprotein (VLDL) susceptibility to lipolysis, VLDL binding to the low density lipoprotein (LDL) receptor and postheparin LPL activities in patients with HTG. VLDL lipolysis was studied with heparan sulfate proteoglycan-bound LPL. Binding affinity of VLDL to the LDL receptor was determined in J774 cells with 125I-labeled control LDL. Eighteen HTG patients were randomized to receive, in a double-blind placebo-controlled cross-over fashion, 400 mg bezafibrate once daily for 6 weeks. In response to bezafibrate therapy, plasma triglyceride and apoC-III levels decreased by 69 and 42%, respectively. HTG VLDL was lipolyzed less efficiently compared to control VLDL, and lipolysis did not improve by bezafibrate therapy. VLDL binding affinity to the LDL receptor was comparable between the control group and HTG group, and did not change upon bezafibrate therapy. However, the post-heparin LPL activity in the HTG patients increased from 153 to 192 U/l ( P=0.025). A strong inverse relation was observed between the change in LPL activities and the change in triglyceride levels ( r=−0.62, P=0.006). In conclusion, the hypolipidemic action of bezafibrate therapy in HTG may be attributed to increased LPL activity, whereas VLDL susceptibility to lipolysis and LDL receptor binding are not affected.

Absence of association between individual thymidine analogues or nonnucleoside analogues and lipid abnormalities in HIV-1-infected persons on initial therapy.

Changes in levels of triglycerides and cholesterol during antiretroviral therapy raise concerns regarding an increased future risk of atherogenic disease and may precede the appearance of fat redistribution. Hypotheses regarding the impact of nucleoside analogues on adipocytes provide a possible explanation for metabolic and clinical fat disturbances. It is unclear whether the choice of nucleoside analogue combination or coadministration of nonnucleoside agents influences change in lipids. We performed a cross-sectional analysis of 135 persons receiving their first nucleoside analogue plus nonnucleoside-based combination antiretroviral regimen for at least 1 month and for whom cholesterol and triglyceride values were available on therapy. Univariate and multivariate regression models were used to explore the relation between cholesterol and triglycerides, as continuous variables with other variables. Both significant and nonsignificant variables from univariate analyses were evaluated in multivariate models to limit possible confounders. No association with drug choice was observed, either when comparing thymidine analogues (stavudine or zidovudine), all nucleoside analogue combinations or choice of either efavirenz or nevirapine as nonnucleoside. Age and triglyceride levels were found in a multivariate analysis to be associated with higher cholesterol. Only higher cholesterol was associated with higher triglyceride levels. In conclusion, no differences were observed between choice of drug or combination on cholesterol or triglyceride values during therapy. Older individuals may be more likely to have elevated cholesterol values.

Absence of Association Between Individual Thymidine Analogues or Nonnucleoside Analogues and Lipid Abnormalities in HIV-1–Infected Persons on Initial Therapy

Changes in levels of triglycerides and cholesterol during antiretroviral therapy raise concerns regarding an increased future risk of atherogenic disease and may precede the appearance of fat redistribution. Hypotheses regarding the impact of nucleoside analogues on adipocytes provide a possible explanation for metabolic and clinical fat disturbances. It is unclear whether the choice of nucleoside analogue combination or coadministration of nonnucleoside agents influences change in lipids. We performed a cross-sectional analysis of 135 persons receiving their first nucleoside analogue plus nonnucleoside-based combination antiretroviral regimen for at least 1 month and for whom cholesterol and triglyceride values were available on therapy. Univariate and multivariate regression models were used to explore the relation between cholesterol and triglycerides, as continuous variables with other variables. Both significant and nonsignificant variables from univariate analyses were evaluated in multivariate models to limit possible confounders. No association with drug choice was observed, either when comparing thymidine analogues (stavudine or zidovudine), all nucleoside analogue combinations or choice of either efavirenz or nevirapine as nonnucleoside. Age and triglyceride levels were found in a multivariate analysis to be associated with higher cholesterol. Only higher cholesterol was associated with higher triglyceride levels. In conclusion, no differences were observed between choice of drug or combination on cholesterol or triglyceride values during therapy. Older individuals may be more likely to have elevated cholesterol values.

Relation of body weight change to changes in atherogenic traits; a study of middle-aged Japanese obese male office workers.

We examined the effect of body weight change on the modification of atherogenic risk factors in 296 middle-aged obese male office workers without medication for hypertension, dyslipidemia, hyperuricemia or diabetes mellitus. During a 1-year education program, 39.2% of the participants could reduce their weight, and the percentage of those who lost 2 kg or more was only 17.7%. Concomitant with the decrease of weight, however, the levels of systolic and diastolic blood pressures, total cholesterol, triglyceride, uric acid and hemoglobin A1c and the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol decreased significantly, whereas the HDL cholesterol level increased significantly. In a multivariate regression analysis, in addition to the initial risk-factor level, weight change was an important factor determining the changes in atherogenic risk factors. Changes in alcohol consumption were significantly associated with the changes in systolic blood pressure and HDL cholesterol levels. Changes in cigarettes smoking also showed significant associations with the changes in triglyceride level and the ratio of total cholesterol to HDL cholesterol. These results suggest that although the education program for controlling weight may have limited success, weight reduction exhibits beneficial changes in the atherogenic risk-factor profile in middle-aged obese men.

Visceral adipose tissue and low-density lipoprotein particle size in middle-aged versus young men.

Age is associated with increased deposition of visceral adipose tissue. We examined whether this age-related change in regional adipose tissue distribution had an impact on low-density lipoprotein (LDL) particle size. For this purpose, the plasma lipoprotein-lipid profile, including LDL peak particle diameter as determined by gradient gel electrophoresis, was assessed in 38 young men (aged 26.4 +/- 4.2 years, mean +/- SD) and compared with 40 middle-aged men (55.9 +/- 6.2 years). Middle-aged men had higher values for total body fat and visceral adipose tissue area as measured by computed tomography than young men (P < .001). Although significant differences were noted between the two age groups for plasma cholesterol, triglyceride (TG), apolipoprotein B (apo B), LDL cholesterol, and LDL apo B, as well as the cholesterol to high-density lipoprotein (HDL) cholesterol ratio (P < .001), no difference was found for LDL peak particle size between young and middle-aged men. While visceral adipose tissue was a significant correlate of plasma lipoprotein levels, the fasting TG concentration was the best predictor of LDL particle size, and the regression of TG levels on LDL peak particle diameter was not different between the two age groups. These results suggest that middle-aged men are characterized by an increased concentration of LDL particles (reflected by increased LDL apo B levels) but not by a reduced LDL peak particle size compared with young men. It is therefore proposed that in the absence of an important age-related change in TG levels, age per se is associated with an increased concentration of atherogenic LDL particles rather than a reduction of LDL particle diameter.

Selective estrogen receptor modulators.

Selective estrogen receptor modulators are a growing class of nonsteroidal compounds with estrogen-like actions in bone, lipid metabolism, and antiestrogenic actions in the breast. Tamoxifen and its derivatives have a weak estrogenic action in the uterus and are responsible for endometrial hyperplasia. Raloxifene does not stimulate endometrial growth but is less effective than tamoxifen for the treatment of patients with breast cancer. The duality of selective estrogen receptor modulators and 1 7B-estradiol actions is explained by several hypotheses referring to the molecular biology of estrogen receptor. Clinical trials are conducted with raloxifene in post-menopausal women. The results show a significant decrease in vertebral fracture risk and a decrease of low-density lipoprotein cholesterol, with no change in triglyceride levels. Endometrial thickness does not change. Interestingly, the risk for newly diagnosed breast cancer decreases significantly with no change in risk for estrogen receptor-negative tumors. Selective estrogen receptor modulators might change the way we manage hormone replacement therapy of postmenopausal women.

Comparison of Statins in Hypertriglyceridemia

In 1996, the first 2 studies using 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (“statin”) therapy in hypertriglyceridemic subjects were published. In subjects with isolated triglyceride elevations who were treated with atorvastatin 5, 20, and 80 mg/day, large and dose-related reductions were noted. In subjects with combined hyperlipidemia treated with 10 mg simvastatin, triglyceride reduction similar to that reported for the 5 mg atorvastatin dose was seen. In response to these findings, we conducted comparative assessments to determine whether all statins are effective in lowering triglyceride levels and whether their effect on triglycerides is related to factors such as drug, dose, and baseline triglyceride levels. To standardize these assessments, we devised a ratio that related changes in triglyceride levels to the known predictable response of low-density lipoprotein (LDL) cholesterol to statins. This triglyceride/LDL cholesterol ratio was obtained by dividing the percent change from baseline in the triglyceride level by the percent change from baseline in the LDL cholesterol level. The triglyceride/LDL cholesterol ratio was initially applied to several published studies, and found to be approximately 1.0 and 0.5 in hypertriglyceridemic and nonhypertriglyceridemic populations, respectively. We then assessed the effect of various statins on triglycerides using a pooled laboratory database of 2,689 subjects who had participated in 7 separate studies with similar designs. All of the studies had a placebo run-in followed by a randomized, double-blind, active treatment phase of at least 4 weeks with a statin. Entry into these studies required a triglyceride level of <400 mg/dL. In subjects with baseline triglyceride >250 mg/dL, significant and dose-dependent reductions in triglyceride of 22–45% were seen with all statins. When baseline triglyceride was <150 mg/dL, no significant or dose-dependent effect on triglyceride was seen. The triglyceride/LDL cholesterol ratio was evaluated using a linear model that included baseline triglyceride level, drug, and dose. Only the baseline triglyceride level was significantly (p <0.001) related to this ratio. Moreover, the triglyceride/LDL cholesterol ratio was fairly constant across all statins and doses for patients with baseline triglyceride levels of <150 mg/dL, 150–250 mg/dL, and >250 mg/dL, at 0.0 ± 0.3, 0.5 ± 0.2, and 1.2 ± 0.3, respectively. We conclude that all statins are effective in decreasing triglyceride levels, but only in hypertriglyceridemic patients. Due to the relatively constant triglyceride/LDL cholesterol ratio, our analysis indicates that the more effective the statin is in decreasing LDL cholesterol, the more effective it will also be in decreasing triglyceride levels in patients with hypertriglyceridemia.

The severity of coronary atherosclerosis in type 2 diabetes mellitus is related to the number of circulating triglyceride-rich lipoprotein particles.

The presence or absence of coronary artery disease (CAD) in diabetic patients has been related to the level of circulating plasma lipoproteins. This study examines whether there is a relationship between the actual severity of CAD and the plasma concentration of major classes of plasma lipoproteins (HDL, LDL, triglyceride-rich lipoproteins (TRL), and their Sf 12 to 60 and Sf 60 to 400 subfractions), particularly the numbers of lipoprotein particles, in men and women with type 2 diabetes. 174 diabetic patients (136 men, 38 women) who underwent angiography were studied. Nine specific coronary segments were scored. The population was divided into tertiles according to the angiographic severity of their coronary disease: mild CAD: coronary score 1 to 10; moderate CAD: coronary score 11 to 13; or severe CAD: coronary score 14 to 22. The main findings were that the numbers of particles (as reflected by the apoB levels) of the TRL were greater in those with moderate and severe disease than in those with mild disease (P = .001). There was a significant correlation between the coronary score and the apoB in TRL (P = .006). There were parallel but nonsignificant changes in triglyceride levels. ApoA-I was lower in patients with moderate and severe disease (P = .01). These differences were more striking in women than they were in men. There were no differences in plasma, LDL, or HDL cholesterol or in LDL apoB or Lp(a). Multiple linear regression analysis, when adjusted for sex, age, and BMI, showed that three lipid variables (TRL apoB, LDL cholesterol, and plasma apoA-I) significantly and independently predicted the coronary score. This study demonstrates that in type 2 diabetes, the severity of angiographically evaluated CAD is positively related to the numbers of TRL particles in the plasma. This relationship is stronger in women than in men, and it is independent of HDL and LDL.

Effect of Antioxidant Vitamins on the Transient Impairment of Endothelium—Dependent Brachial Artery Vasoactivity Following a Single High-Fat Meal

Much has been written about the potential role of antioxidants in the prevention of atherosclerosis. To assess the short-term effect of a single high-fat meal with and without pretreatment with antioxidant vitamins on endothelial function in healthy, normocholesterolemic subjects. Observer-blinded randomized trial. University hospital. Twenty healthy, normocholesterolemic (total and low-density lipoprotein cholesterol <5.2 mmol/L and <3.4 mmol/L [<200 mg/dL and <130 mg/ dL], respectively), male (7) and female (13) hospital employee volunteers, aged 24 to 54 years. Three randomly administered breakfasts: (1) a high-fat meal (3766 J [900 calories], 50 g of fat); (2) a low-fat meal (3766 J [900 calories], 0 g of fat); and (3) a high-fat meal and pretreatment with oral administration of vitamins C (1 g) and E (800 IU) (high-fat meal with vitamins). A subgroup of 10 subjects also ate the low-fat meal with the same vitamin pretreatment (low-fat meal with vitamins). High-resolution ultrasound assessed flow-mediated (endothelium-dependent) brachial artery vasodilation measured as percent diameter change before and hourly for 6 hours following each meal. Flow-mediated vasodilation fell from a mean+/-SD of 20%+/-8% before to 12%+/-6%, 10%+/-6%, and 8%+/-9% at 2, 3, and 4 hours, respectively, after the high-fat meal (P<.001). No significant changes in flow-mediated vasodilation occurred after the low-fat meal, high-fat meal with vitamins, or low-fat meal with vitamins. The change in flow-mediated vasodilation after the low-fat and high-fat meals correlated inversely with the 2-hour postprandial change in triglyceride levels (r=-0.54; P<.001). A single high-fat meal transiently reduces endothelial function for up to 4 hours in healthy, normocholesterolemic subjects, probably through the accumulation of triglyceride-rich lipoproteins. This decrease is blocked by pretreatment with antioxidant vitamins C and E, suggesting an oxidative mechanism.

Effects of chemotherapy-induced castration on serum lipids and apoproteins in premenopausal women with node-positive breast cancer.

The purpose of this study was to determine the effect of adjuvant chemotherapy on serum lipids and lipoproteins in premenopausal nonmetastatic breast cancer patients. Fifty-nine premenopausal breast cancer patients were treated with adjuvant chemotherapy comprising cyclophosphamide, methotrexate, and 5-fluorouracil. Levels of serum FSH, LH, and estradiol; fasting plasma levels of total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglyceride, and apolipoprotein A-I, A-II, and B levels; and lipoprotein(a) [Lp(a)] were measured before treatment and 12 months after the beginning of chemotherapy. The changes in serum lipids after chemotherapy correlated significantly to changes in menstruation. Total cholesterol, LDL, and HDL cholesterol levels increased significantly only in patients with chemotherapy-induced ovarian dysfunction. Changes in apo B paralleled those in LDL and apo A-I and A-II HDL cholesterol. The serum concentration of Lp(a) increased significantly only in patients who developed permanent amenorrhea. There were no significant changes in triglyceride levels. Chemotherapy per se has no effect on serum lipids unless associated with induction of ovarian dysfunction. Ovarian failure after chemotherapy has an unfavorable effect on serum total and LDL cholesterol, apo B, and Lp(a) levels, but a favorable effect on HDL cholesterol.