Changes In Serum Low-density Lipoprotein Cholesterol Research Articles

Degree of serum LDL cholesterol reduction by simvastatin and ezetimibe is dependent on baseline LDL cholesterol concentration but not on baseline values and changes in cholesterol synthesis and absorption parameters.

We questioned whether the baseline status of low-density lipoprotein cholesterol (LDL-C), cholesterol synthesis and absorption, and the changes in these parameters determine the change in serum LDL-C under statin or ezetimibe treatment or under combination treatment. 37 mildly hypercholesterolemic healthy male subjects were studied under placebo, simvastatin (20mg/d), ezetimibe (10mg/d), and combination treatment. We correlated the change of LDL-C (ΔLDL-C) under treatment with the placebo end values of LDL-C (baseline), whole-body cholesterol synthesis, and hepatic cholesterol synthesis (serum lathosterol to cholesterol ratio) as well as fractional absorption rate (FAR) of cholesterol and serum campesterol to cholesterol ratio. The change in serum LDL-C was also correlated with the changes in synthesis and absorption parameters. ΔLDL-C was highly negatively related to baseline LDL-C under ezetimibe (p<0.0001), simvastatin (p<0.0001), and combination treatment (p<0.0001). Under combination treatment, LDL-C lowering appears possible from baseline values of 10 mg/dL upwards, while ΔLDL-C was independent of the baseline value (-50 to -60%). ΔLDL-C was positively associated with placebo FAR under ezetimibe (p=0.0106) and combination treatment (p=0.0457). No associations were found between ΔLDL-C and baseline values for synthesis nor between ΔLDL-C and changes in synthesis and absorption surrogate markers. Under ezetimibe, simvastatin, and combination treatment, ΔLDL-C is predominantly dependent on the baseline LDL-C concentration. We hypothesize that the concentration gradient between serum LDL-C and hepatic cellular cholesterol determines the efficiency of serum LDL-C lowering. Combination treatment is the preferred treatment.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic modeling of bempedoic acid and low-density lipoprotein cholesterol in healthy subjects and patients with dyslipidemia

Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70–100 kg) and high (> 100 kg vs. 70–100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC50 of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment.

Effect of rosuvastatin and eicosapentaenoic acid on neoatherosclerosis: the LINK-IT Trial.

We aimed to assess the effect of 10 mg/day of rosuvastatin plus eicosapentaenoic acid (EPA) versus 2.5 mg/day of rosuvastatin on the extent of neoatherosclerosis using optical coherence tomography (OCT). We randomly assigned 50 patients with non-obstructive neoatherosclerotic plaques detected on OCT to receive either rosuvastatin 10 mg/day and EPA 1,800 mg/day (intensive therapy group) or rosuvastatin 2.5 mg (standard therapy group). Follow-up OCT was performed one year later to evaluate serial changes in neoatherosclerosis. The serum low-density lipoprotein cholesterol (LDL-C) level decreased significantly from baseline to 12-month follow-up in the intensive therapy group (89 mg/dL to 70 mg/dL; p<0.001), while no change occurred in the standard therapy group. Lipid index change and percent changes in macrophage grade were significantly lower in the intensive therapy group than in the standard therapy group (-53.6 vs 310.1, p=0.001; -37.0% vs 35.3%, p<0.001; respectively). Percent changes in lipid index and macrophage grade were positively correlated with the changes in serum LDL-C and C-reactive protein levels, and negatively correlated with the change in serum EPA/arachidonic acid and 18-hydroxyeicosapentaenoic acid (EPA bioactive metabolite) level. Compared with rosuvastatin 2.5 mg/day, rosuvastatin 10 mg/day and EPA 1,800 mg/day significantly stabilised non-obstructive neoatherosclerotic plaques. UMIN ID: UMIN000012576. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014711.

Effect of atorvastatin on dyslipidemia and carotid intima-media thickness in children with refractory nephrotic syndrome: a randomized controlled trial.

Dyslipidemia is an important cardiovascular risk factor in steroid-resistant nephrotic syndrome (SRNS). Efficacy of statins for treatment of hyperlipidemia in children with SRNS is unclear. This prospective, randomized, double-blind, placebo-controlled, parallel-group clinical trial enrolled 30 patients with SRNS, aged 5-18years, with serum low-density lipoprotein cholesterol (LDL-C) levels between 130 and 300mg/dl, to receive a fixed dose of atorvastatin (n= 15, 10mg/d) or placebo (n= 15) by block randomization in a 1:1 ratio. Primary outcome was change in serum LDL-C at 12months. Change in levels of other lipid fractions, carotid intima-media thickness (cIMT), flow-mediated dilation (FMD) of the brachial artery, and adverse events were also evaluated. At the end of 12months, atorvastatin was not superior to placebo in reducing plasma LDL-C levels, median percentage reduction 15.8% and 9.5% respectively, in atorvastatin and placebo arms (n = 14 in each; P = 0.40). Apolipoprotein B levels significantly declined with atorvastatin in modified intention-to-treat analysis (P = 0.01) but not in the per-protocol analysis. There was no significant effect on other lipid fractions, cIMT and FMD. Adverse events were similar between groups. Change in serum albumin was negatively associated with change in serum LDL-C, very low-density lipoprotein cholesterol, total cholesterol, triglyceride, and apolipoprotein B (P < 0.001), irrespective of receiving atorvastatin, age, gender, body mass index, and serum creatinine. Atorvastatin, administered at a fixed daily dose of 10mg, was not beneficial in lowering lipid levels in children with SRNS; rise in serum albumin was associated with improvement in dyslipidemia.

Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis

ObjectivesPatients with rheumatoid arthritis (RA) have reduced serum low-density lipoprotein cholesterol (LDL-c), which increases following therapeutic IL-6 blockade. We aimed to define the metabolic pathways underlying these lipid changes.MethodsIn the...

Oral Supplementation With ProbioticL. reuteriNCIMB 30242 Increases Mean Circulating 25-Hydroxyvitamin D: A Post Hoc Analysis of a Randomized Controlled Trial

Low serum 25-hydroxyvitamin D is a risk factor for osteoporosis, cardiovascular disease, diabetes, and cancer. Disruption of noncholesterol sterol absorption due to cholesterol-lowering therapies may result in reduced fat-soluble vitamin absorption. We have previously reported on the cholesterol-lowering efficacy and reduced sterol absorption of probiotic bile salt hydrolase active Lactobacillus reuteri NCIMB 30242; however, the effects on fat-soluble vitamins was previously unknown and the objective of the present study. DESIGN, SETTINGS, PATIENTS, AND INTERVENTION: The study was double-blind, placebo-controlled, randomized, parallel-arm, multicenter lasting 13 weeks. A total of 127 otherwise healthy hypercholesterolemic adults with low-density lipoprotein-cholesterol >3.4 mmol/L, triglycerides <4.0 mmol/L, and body mass index of 22 to 32 kg/m² were included. Subjects were recruited from 6 private practices in Prague, Czech Republic, and randomized to consume L. reuteri NCIMB 30242 or placebo capsules over a 9-week intervention period. The primary outcome measure was the change in serum low-density lipoprotein-cholesterol over the 9-week intervention. Analysis of fat-soluble vitamins at weeks 0 and 9 were performed post hoc. There were no significant differences between L. reuteri NCIMB 30242 and placebo capsule groups in serum vitamin A, vitamin E, or β-carotene or dietary intake over the intervention period (P > .05). L. reuteri NCIMB 30242 increased serum 25-hydroxyvitamin D by 14.9 nmol/L, or 25.5%, over the intervention period, which was a significant mean change relative to placebo of 17.1 nmol/L, or 22.4%, respectively (P = .003). To our knowledge, this is the first report of increased circulating 25-hydroxyvitamin D in response to oral probiotic supplementation.

Alternate-day versus daily atorvastatin in coronary artery disease: a randomized study

We sought to compare the effect of alternate-day versus daily atorvastatin 10 mg, on serum low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP) in patients with coronary artery disease (CAD) and controlled serum LDL-C by daily atorvastatin. The study was prospective, randomized, single-blinded, two-armed. Randomization was performed by a computer-generated randomization list. We randomized 60 patients with CAD and controlled serum LDL-C to receive either atorvastatin in the standard-dose of 10 mg daily (Group A=30 patients), or the same medication every other day (Group B=30 patients). Primary efficacy criterion included changes in serum LDL-C and hs-CRP from the initial to the 6-week follow-up values. The mean age was 54.5±7.7 years, (70% males). LDL-C was significantly lower in Group A as compared with group B at 6-week follow-up (88±21 versus 105±26 mg/dl, respectively, p=0.008). Similarly, the mean percent increase of LDL-C from baseline to final assessment was significantly lower in Group A as compared with Group B (1.5±0.2 versus 32.8±6.2%, respectively, p<0.0001). However, the mean percent change of hs-CRP value was statistically similar between the two groups (p=0.108). Patients reported no side effects attributable to the medication. The current pilot study demonstrated that in patients with CAD who have achieved target LDL-C level, maintenance on alternate-day atorvastatin 10 mg was inferior to daily atorvastatin in keeping LDL-C below the target level; however, it produced a similar effect on hs-CRP.

Effect of a Dietary Portfolio of Cholesterol-Lowering Foods Given at 2 Levels of Intensity of Dietary Advice on Serum Lipids in Hyperlipidemia

Combining foods with recognized cholesterol-lowering properties (dietary portfolio) has proven highly effective in lowering serum cholesterol under metabolically controlled conditions. To assess the effect of a dietary portfolio administered at 2 levels of intensity on percentage change in low-density lipoprotein cholesterol (LDL-C) among participants following self-selected diets. A parallel-design study of 351 participants with hyperlipidemia from 4 participating academic centers across Canada (Quebec City, Toronto, Winnipeg, and Vancouver) randomized between June 25, 2007, and February 19, 2009, to 1 of 3 treatments lasting 6 months. Participants received dietary advice for 6 months on either a low-saturated fat therapeutic diet (control) or a dietary portfolio, for which counseling was delivered at different frequencies, that emphasized dietary incorporation of plant sterols, soy protein, viscous fibers, and nuts. Routine dietary portfolio involved 2 clinic visits over 6 months and intensive dietary portfolio involved 7 clinic visits over 6 months. Percentage change in serum LDL-C. In the modified intention-to-treat analysis of 345 participants, the overall attrition rate was not significantly different between treatments (18% for intensive dietary portfolio, 23% for routine dietary portfolio, and 26% for control; Fisher exact test, P = .33). The LDL-C reductions from an overall mean of 171 mg/dL (95% confidence interval [CI], 168-174 mg/dL) were -13.8% (95% CI, -17.2% to -10.3%; P < .001) or -26 mg/dL (95% CI, -31 to -21 mg/dL; P < .001) for the intensive dietary portfolio; -13.1% (95% CI, -16.7% to -9.5%; P < .001) or -24 mg/dL (95% CI, -30 to -19 mg/dL; P < .001) for the routine dietary portfolio; and -3.0% (95% CI, -6.1% to 0.1%; P = .06) or -8 mg/dL (95% CI, -13 to -3 mg/dL; P = .002) for the control diet. Percentage LDL-C reductions for each dietary portfolio were significantly more than the control diet (P < .001, respectively). The 2 dietary portfolio interventions did not differ significantly (P = .66). Among participants randomized to one of the dietary portfolio interventions, percentage reduction in LDL-C on the dietary portfolio was associated with dietary adherence (r = -0.34, n = 157, P < .001). Use of a dietary portfolio compared with the low-saturated fat dietary advice resulted in greater LDL-C lowering during 6 months of follow-up. clinicaltrials.gov Identifier: NCT00438425.

Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia

ABSTRACT Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or eprotirome at a dose of 25, 50, or 100 μg reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.

Longevity-associated NADH dehydrogenase subunit-2 237 Leu/Met polymorphism modulates the effects of daily alcohol drinking on yearly changes in serum total and LDL cholesterol in Japanese men.

Reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism, is reportedly associated with longevity in the Japanese population. The ND2-237Met genotype may exert resistance to atherogenic diseases, such as myocardial infarction or cerebrovascular disorders. To investigate whether ND2-237 Leu/Met polymorphism is associated with yearly changes in serum lipid levels, we conducted a longitudinal study of 107 healthy Japanese male subjects. Analysis of covariance revealed that the interaction between the ND2-237 Leu/Met genotypes and habitual drinking was significantly associated with yearly changes in serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels (p=0.036 and p=0.006, respectively). In multiple regression analysis, daily drinking was significantly and positively associated with yearly changes in serum LDLC levels in men with ND2-237Met (p=0.026). After adjusting for covariates, yearly changes in serum LDLC levels were significantly lower in non-daily drinkers with ND2-237Met than in those with ND2-237Leu (p=0.047). These results suggest that ND2-237Met has a beneficial impact on yearly changes in serum LDLC in non-daily drinkers but not in daily drinkers.

Clinically favorable effects of raloxifene on bone mineral density and serum lipids: population assessment via bivariate analysis

Introduction: Raloxifene is a nonsteroidal benzothiophene derivative that is classified as a selective estrogen receptor modulator (SERM). It has clinical promise because of its actions as an estrogen-agonist on bone and serum lipids and an estrogen-antagonist on the breast and uterus. Objectives: To determine the percentage of women who respond to raloxifene therapy with regard to bone mineral density (BMD) and serum low density lipoprotein cholesterol (LDL-C) concentration in a large population of healthy postmenopausal women. Methods: Pooled 24-month interim data from two multicenter, placebo-controlled, double-blind phase III studies were used in this analysis. The study population included 1145 healthy women, 45–60 years of age and 2–8 years postmenopausal, randomized to receive either placebo, raloxifene (RLX) 30 mg/day, RLX 60 mg/day, or RLX 150 mg/day. Changes in BMD, measured by dual x-ray absorptiometry, and serum LDL-C concentration, measured by enzymatic assay, were analyzed simultaneously by plotting the median percentage change (baseline to endpoint) in BMD of the lumbar spine and total hip on the y-axis against the corresponding median percentage change in serum LDL-C on the x-axis for each subject in the placebo group and each of the raloxifene groups. The data localized to one of four quadrants on the plot, the upper-left quadrant representing clinically favorable shifts (increased BMD and decreased LDL-C) and the lower-right quadrant representing clinically unfavorable shifts (decreased BMD and increased LDL-C). The bivariate mean, 50th and 95th percentile ellipses, and the percentage of patients improving in one, both, or neither of the measured parameters are displayed. Results: At the end of 24 months, the bivariate mean and the 50th and 95th percentile ellipses of the placebo group for lumbar spine BMD and LDL-C were shifted to the clinically unfavorable quadrant of the plot, reflecting a decrease in BMD and an increase in LDL-C. In contrast, the bivariate mean for all raloxifene groups had shifted to the clinically favorable quadrant of the plot, reflecting an increase in BMD and a decrease in LDL-C. There was a statistically significant difference (Hotelling-Lawley test, P < .001) in the bivariate mean for all doses of raloxifene compared to placebo. Only 19.1% of subjects in the placebo group exhibited improvement in both lumbar spine BMD and LDL-C, whereas 43.5%, 47.4%, and 49.8% of subjects in the RLX 30, RLX 60, and RLX 150 group, respectively, exhibited improvement in both of these variables. Furthermore, 35.9% of subjects in the placebo group exhibited no improvement in either lumbar spine BMD or LDL-C, whereas only 13.7%, 10.1%, and 11.6% of subjects in the RLX 30, RLX 60, and RLX 150 groups, respectively, exhibited no improvement in either of these variables. Similar results were obtained comparing total hip BMD and LDL-C. Conclusions: Compared with placebo, raloxifene has beneficial effects on BMD and LDL-C in a large sample of healthy postmenopausal women. Thus, insofar as these intermediate endpoints predict disease outcomes, long-term therapy with raloxifene may be beneficial in the prevention of osteoporosis and cardiovascular diseases.

Oral contraceptives and lipids.

Many studies have demonstrated a correlation between serum lipid concentrations and the high risk of developing cardiovascular disease. Further, oral contraceptives (OCs) are known to change lipid metabolism. The extent of the change depends on the dose and structure of the estrogen and gestagen, however. Many researchers studying the effect of OCs on lipid metabolism have encountered numerous sources of variability in their studies, such as age of the subjects, smoking, daily variations in serum lipid concentration, and whether samples were stored before analysis and for how long. Since there are many sources of variability, the results of any study should not be accepted uncritically. Published studies of OCs with 30ug ethinyl-estradiol and 150 ug levonorgestrel, serum low density lipoprotein (LDL) cholesterol concentration was lowered in 12 and unchanged in 13. On the other hand, results of studies for the triphasic OC containing ethinyl-estradiol and levonorgestrel were more consistent--this triphasic OC produced no change in either serum LDL cholesterol or high density lipoprotein (HDL) cholesterol concentrations. As for ethinyl-estradiol combined with 150 ug desogestrel, 15 studies showed an increase in serum HDL cholesterol concentration and 4 with no change, and 9 reported no change in serum LDL cholesterol concentration and 2 with a decrease. Further, research shows that changes in lipid metabolism appear not to be progressive with continued use of OCs, and the lipids revert to their pretreatment concentrations after stopping OC use. Despite inconclusive evidence of increased cardiovascular risk with OC use, physicians should prescribe formulations containing the lowest dose consistent with efficacy and acceptability.