Changes In High-density Lipoprotein Cholesterol Levels Research Articles

IS APELIN A PROMISING TARGET IN DIABETES MELLITUS OF RATS: TYPE I VS. TYPE II?

Background: Apelin is a novel adipokine identified as an endogenous ligand of receptor APJ. Apelin and its receptor APJ are expressed in a wide variety of tissues including heart, brain, kidneys and lungs. Apelin in human physiology acts as a regulating peptide of cardiovascular, hypothalamus-hypophysis, metabolic, gastrointestinal and immune systems. Objective: The present study was carried out to assess the value of apelin in management of type II vs. type I diabetes mellitus in rats. Design: A total number of 60 healthy adult male albino rats were used. Rats were divided into 2 groups: group I (n=40) Streptozotocin induced diabetic group; model of type I diabetes and group II (n=20) high fat diet induced obesity and diabetic group; model of type II diabetes. Group I was subdivided into 4 equal subgroups (saline treated control, an insulin treated, an apelin treated and an apelin and insulin treated subgroups), while group II was further subdivided into 2 equal subgroups (a saline treated control and an apelin treated groups). In all groups the body weight, nose to anus length were measured, and these data were used to calculate the body mass index (BMI). In addition, serum glucose, insulin, triglycerides, total cholesterol, LDL and HDL cholesterol were estimated and used to calculate the homeostasis model assessment as a measure of insulin resistance (HOMA-IR) and the homeostasis model assessment as a measure of β cell function (HOMA-β). Results: This study revealed that an intraperitoneal injection of apelin induced insignificant changes in most of parameters measured in animals of group I when compared with insulin treated subgroup. On the other hand, animals of group II showed a significant decrease in serum levels of glucose and insulin when compared with saline treated controls with resulting a significant decrease in HOMA-IR and a significant increase in HOMA- β. Furthermore, apelin injection induced a significant increase in serum triglyceride, total cholesterol and LDL cholesterol levels and insignificant changes in HDL cholesterol levels in group II rats. Conclusion: In models of type II diabetes, apelin significantly induced amelioration of serum glucose level and enhance insulin sensitivity that was denoted by a significant reduction in HOMA-IR, this was not the case in rats of type I diabetes, so it is promising therapeutic target in management of obesity induced type II diabetes rather than type I. Key words: Apelin, type II diabetes, high fat diet (HFD), Streptozotocin induced diabetes, HOMA-IR, HOMA-β, obesity.

Cholesterol Efflux Capacity

High-density lipoprotein cholesterol (HDL-C) levels represent a robust and well-integrated biomarker of cardiovascular risk. The prevalence of low HDL-C is high and likely to increase in coming years in parallel with the epidemic of obesity and type 2 diabetes mellitus. However, the clinical efficacy of raising plasma HDL-C levels to achieve cardiovascular risk reduction has been difficult to prove. Recently published outcomes trials involving the addition of niacin or dalcetrapib to standard low-density lipoprotein cholesterol reduction therapy failed to demonstrate clinical benefit despite increases in HDL-C.1,2 Furthermore, genetic variants associated with increased HDL-C, thus conferring lifelong exposure to higher circulating levels, are not consistently associated with improved vascular outcomes.3 These findings have reinforced the idea that changes in HDL-C levels are an inadequate surrogate for therapeutic use. See accompanying article on page 1696 The notion of HDL functionality has circulated in the field for years based on known heterogeneity in lipid content, protein cargo, and size across HDL particles.4 For example, assays that quantify apoptotic pathway activation, endothelial vasomotor effects, and antioxidant properties have suggested HDL functional impairment in cardiometabolic disease states.5–7 Although the relative mechanistic contributions of HDL-mediated atheroprotection remain unclear, the role of HDL in macrophage reverse cholesterol transport is thought to play a key role. This pathway involves efflux of cholesterol from macrophages (such as those within atherosclerotic plaque) to HDL acceptor particles for ultimate return to the liver and biliary excretion.8 Animal studies have suggested that flux through this pathway is a better predictor of the atherosclerotic impact of various genetic and pharmacological perturbations than static, mass-based quantification of circulating HDL-C.9 Rothblat et al10 pioneered methodologies allowing assessment of the cholesterol efflux capacity of human serum or HDL, the basic premise of which is that …

Longitudinal changes in high‐density lipoprotein cholesterol and cardiovascular events in older adults

While low high-density lipoprotein cholesterol (HDL-C) is associated with increased risk of cardiovascular (CV) events, there are limited data evaluating the association of longitudinal change in HDL-C with CV event risk in older populations. The aim of this study was to examine the association between within-subject changes in HDL-C levels and CV events in an older population. Observational cohort study. 1293 men and 1422 women age ≥50 years, with ≥2 consecutive HDL measurements, and no prior CVD as part of Framingham Offspring Study. A clinical CV event was defined as the first occurrence of any of the following: coronary heart disease (coronary death, myocardial infarction, coronary insufficiency and angina), cerebrovascular event, peripheral artery disease or heart failure. Median total follow-up time across subjects was 9·6 years. Change in HDL-C was evaluated as between-exam (approximately 3·5 years) percentage change in HDL-C, categorized as ≥10% decrease, <10% change (stable) and ≥10% increase. Crude and adjusted sex-specific Cox hazards regression models with change in HDL-C as a time-dependent covariate quantified the association with CV events. Mean baseline age of the analysis sample was 53 years. There were 233 and 111 CV events among men and women, respectively. Change in HDL-C was not significantly associated with CVD incidence in men or women, without or with adjustment for confounders including baseline HDL-C or use of relevant medications. In conclusion, relatively short-term (3·5 years) changes in HDL-C levels do not affect CV events in men and women.

Association of disease activity and anti-rheumatic treatment in juvenile idiopathic arthritis with serum lipid profiles: A prospective study

Patients with juvenile idiopathic arthritis (JIA) have abnormal serum lipid profiles. This study aimed to explore the association of disease activity and anti-rheumatic treatment with serum lipid profiles in a JIA cohort. Fifty-eight patients newly diagnosed with JIA who had not been treated with corticosteroids or disease-modifying anti-rheumatic drugs were enrolled. We measured their serum lipid profiles at baseline and 18 months later, and determined whether there were differences in lipid levels and atherogenic indices between patients who were in inactive disease and those who were not. For a case-control comparison at 18 months, control subjects from a population-based study cohort (NAHSIT study) were selected. Thirty-one of the 58 patients achieved inactive disease status after 18-month treatment. In these patients, high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) levels increased significantly (p = 0.001 and p = 0.044); whereas the ratios of low-density lipoprotein cholesterol (LDL-C) to HDL-C and TC to HDL-C decreased with borderline significance (p = 0.066 and p = 0.080). The overall changes in HDL-C levels, LDL-C/HDL-C and TC/HDL-C ratio between baseline and 18 months were correlated with those in C-reactive protein levels (p = 0.005, p = 0.001, and p = 0.002, respectively). There were also significant differences among inactive, active and control subjects in HDL-C and TC levels (p = 0.021 and p = 0.013) but not in LDL, LDL-C/HDL-C, TC/HDL-C ratio, and triglyceride levels. Abnormal lipid levels and atherogenic indices were associated with disease activity in JIA and improved substantially following effective anti-rheumatic treatment. This improvement may reduce the risk of cardiovascular disease in JIA.

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The clinical relevance of dysfunctional HDL in patients with coronary artery disease: A 3-year follow-up study

The well known atheroprotective effects of high density lipoprotein cholesterol (HDL) are based on reverse cholesterol transport as well as anti-inflammatory properties [1,2]. Primary prevention studies have confirmed that HDL levels are strongly associated with reduced cardiovascular events [3]. However, recent evidence supports the notion that HDL functionality may be impaired under certain conditions [4,5]. Ansell and colleagues reported that HDL isolated from subjects with coronary artery disease (CAD) had less antiinflammatory activity than HDL derived from healthy controls, thus providing the first evidence that HDL may be dysfunctional in this setting [6]. Interestingly, in CAD patients HDL has shown to be even proinflammatory, thus increasing monocyte chemiotaxis, reactive oxygen species production, endothelial dysfunction and cellular apoptosis [6,7]. Hence, HDL may not be protective in secondary prevention of coronary artery disease. This issue needs to be rapidly clarified since therapies that raise HDL levels are being investigated for the treatment of CAD patients [8,9]. In the present study we sought to determine whether higher HDL levels maintain their protective effects also in patients with CAD. From March 2006 to April 2009 we consecutively enrolled 184 patients with a first manifestation of CAD (mean age 62±10 years, male/female ratio 3:1). All patients taking lipid-lowering agents or other cardiovascular medications at admission were excluded from the study. Moreover, patients with relevant comorbidities (renal failure, COPD, infective or inflammatory diseases, autoimmune disorders, cancer) were also not considered. All subjects underwent coronary angiography and routine blood chemistry including high sensitivity C-reactive protein (hs-CRP) and lipid profile comprehensive of ApoB-100 and ApoA1 determination. The study was approved by our Institute Committee and all patients signed an informed consent. The study population was divided into groups with higher (N50 for women, N40 formen) and lower HDL levels (≤50 for women, ≤40 for men, Table 1), according to ATPIII criteria [10]. Groups did not significantly differ for demographic and antropometric characteristics as well as for the prevalence of cardiovascular risk factors and left ventricular ejection fraction (EF). Serum creatinine, fasting plasma glucose, uric acid and Pro-BNP were similar in the two groups. HDL and ApoA1 were significantly different but the groups did not differ with regard to LDL and ApoB-100 levels (Table 1). Patients with high HDL had significantly lower triglycerides and hs-CRP values (Table 1). Notably, statin treatment and dose were similar between the two groups (Table 2). Cardiovascular end-points were assessed by clinic visits and programmed phone contacts up to 3 years after the first admission. Determinations of lipid fractions were performed both at baseline and follow-up. No significant changes in HDL levels were observed during follow-up either in patients with high or low HDL (Fig. 1A,B). Major adverse cardiovascular events (MACE) consisted of: (1) mortality for all causes; (2) myocardial infarction (MI); (3) revascularization by percutaneous coronary intervention or by-pass surgery; (4) cerebrovascular events including transient ischemic attack and stroke. Data analysis was performed with SPSS 13.0 software package (SPSS Inc., Chicago). Numerical data are reported as

Influence of mitochondrial DNA 5178 C/A polymorphism on serum cholesterol changes: a short-term follow-up in middle-aged Japanese men

The mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) polymorphism is reportedly associated with longevity in the Japanese population, and the Mt5178A genotype may exert anti-atherogenic effects. The aim of this study was to determine whether there were longitudinal differences in serum lipid levels between carriers of the Mt5178C genotype and those of the Mt5178A genotype and to assess the impact of these genotypes on serum cholesterol levels. The serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), and low-density lipoprotein cholesterol (LDLC) were measured and the Mt5178 C/A genotypes determined in 110 Japanese men aged 41-66 (mean 52.3) years who had received medical checkups twice in the period 1999-2005. The longitudinal changes of TC, HDLC, and LDLC were calculated according to genotype. The serum levels of TC at baseline and follow-up were significantly different, whereas those of HDLC and LDLC were not. The changes in HDLC differed significantly between the two Mt5178 C/A genotype groups, with the changes in HDLC level being significantly greater in the Mt5178A genotype group than in the Mt5178C group (p = 0.015). The Mt5178 C/A genotype may modify longitudinal changes in serum TC and HDLC levels in middle-aged Japanese men.

Effect of Statins on C-reactive Protein, Lipoprotein(a) and Fibrinogen in Hypercholesterolemic Patients

Objective: C-reactive protein (CRP), lipoprotein (a)[Lp(a)], and fibrinogen are associated with systemic inflammatory reactions. Statins have anti-inflammatory effects. However, the effect of statins on these parameters is inconsistent. We evaluated the effect of statins on inflammatory markers and variables related to changes in these markers. Methods: A total of 390 hypercholesterolemic patients were enrolled. Atorvastatin (n=112), lovastatin (n=25), pitavastatin (n=49), rosuvastatin (n=20), and simvastatin (n=184) were administered. Lipids, CRP, Lp(a), and fibrinogen levels were measured before and after 2 months of the therapy. Results: Statins reduced cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride levels by -28.9±9.1% (P=0.000), -41.4±12.4% (P=0.000), and -11.6±39.4% (P=0.000), respectively and increased high density lipoprotein (HDL) cholesterol level by 2.56±13.2% (P=0.014). CRP levels decreased from 1.23±1.30 to 1.14±1.29 mg/L (P=0.000). Lp(a) levels were not changed (P=0.91) and fibrinogen levels increased from 277.8±54.4 to 282.6±56.9 mg/dL (P=0.042). Changes in CRP levels were associated with baseline CRP levels (r=-0.56, P=0.000) and changes in HDL cholesterol levels (r=-0.14, P=0.005). Changes in Lp(a) levels were associated with changes in triglyceride (r=-0.24, P=0.000) and baseline aspartate aminotransferase level (r=0.12, P=0.015). Changes in fibrinogen levels were associated with baseline fibrinogen levels (r=-0.40, P=0.000), sex (r=0.18, P=0.001), and changes in HDL cholesterol levels (r=-0.15, P=0.003). Conclusion: Inflammatory markers showed different responses to statins and changes in these markers were associated with different parameters. This finding suggests that anti-inflammatory effect of statin is confined to a specific pathway of inflammation.

Association between change in HDL-C and vascular events in patients treated with statins: Report from the UK general practice research database

Dyslipidemia, including low levels of high-density lipoprotein cholesterol (HDL-C), is a relatively well-established risk factor for cardiovascular disease. However, the independent association between changes in HDL-C and the subsequent risk of cardiovascular events has not been well studied. The retrospective cohort analysis was conducted to evaluate the association between changes in HDL-C and cardiovascular (CV) and/or cerebrovascular (CB) events among statin-treated patients. Patient demo-graphics, clinical characteristics, laboratory data, and CV/CB events, were collected from the UK General Practice Research Database. The association between the risk of an incident event and changes in patients’ HDL-C was estimated using multivariate Cox pro-portional hazards models. Among 17,923 statin-treated patients with an average follow-up of 1.9 years, there were 815 CV events and 220 CB events. The average change in HDL-C experienced was 0.4 mg/dL, ranging from 11 mg/dL average decrease in the lowest change quartile to 12 mg/dL average increase in the highest change quartile. CV events occurred at an average overall rate of 21 per 1000 person-years and 17 per 1000 person-years among individuals in the highest quartile of change in HDL-C levels. Fully adjusted Cox regression estimated a 6% decrease in hazards (HR, 0.94; 95% CI, 0.90, 0.98) of a subsequent CV event associated with each 5 mg/dL increase in HDL-C. Similar results (HR: 0.95, 95% CI, 0.92, 0.98) were observed when assessing the association with changes in HDL-C and the composite outcome of CV/CB event. Among statin-treated patients from UK clinical practices, increases in HDL-C were associated with a significantly decreased relative risk of experiencing CV/CB events with a more pronounced effect on CV events. Therefore, a more aggressive treatment to increase HDL-C could benefit patients by reducing the risk of CV/CB events.

HMG-CoA Reductase Inhibitor (Statin) Therapy and Coronary Atherosclerosis in Japanese Subjects

The level of serum low-density lipoprotein cholesterol (LDL-C) achieved and change in serum LDL-C level in response to HMG-CoA reductase inhibitor (statin) therapy may not be reflected in coronary plaque regression in Japanese subjects, and plaque regression has occurred in many cases in the absence of any marked decrease in serum LDL-C level. We hypothesized that the indicators of coronary plaque regression in response to statin therapy in a Japanese population are different from the indicators in Western populations. The purpose of this study was to investigate the predictors of coronary plaque regression in Japanese patients with coronary artery disease (CAD) using a receiver-operating-characteristic (ROC) analysis. A 6-month prospective observational study to identify predictors of regression of coronary plaque as assessed by volumetric intravascular ultrasound was conducted on 113 CAD patients receiving usual doses of pravastatin at Nihon University Surugadai Hospital, Tokyo, Japan. The mean pravastatin dose was 12.5 ± 3.2 mg/day. After 6 months of therapy, the average change in plaque volume was -9.9% (p < 0.0001 vs baseline). Body mass index (BMI) before pravastatin therapy was significantly lower in the plaque regression group than in the plaque progression group (23.5 ± 2.8 kg/m2 vs 25.3 ± 2.5 kg/m2, p < 0.01). Furthermore, significant increases in serum levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo) A-1, and decreases in LDL-C/HDL-C, apoB/apoA-1, and monocyte count were observed in the plaque regression group (n = 90) in comparison with the plaque progression group (n = 23), while there were no differences in achieved LDL-C levels between the groups (101 ± 25 mg/dL vs 101 ± 24 mg/dL). The changes in plaque volume correlated with the changes in serum levels of HDL-C (r = -0.496, p < 0.0001), LDL-C/HDL-C (r = 0.361, p < 0.0001), apoA-1 (r = -0.362, p = 0.0005), apoB/apoA-1 (r = 0.314, p = 0.0003), monocyte count (r = 0.325, p = 0.0004), and with baseline BMI (r = 0.278, p = 0.003), but not with the change in LDL-C level (r = 0.023, p = 0.860). Moreover, an ROC analysis showed that the change in HDL-C level was better than any other parameter in terms of evaluating the predictor of plaque regression because it had a larger area under the ROC curve (0.751; sensitivity: 76.9%; specificity: 60.9%; cut off value: ±0%). Even with modest LDL-C lowering to maintain the serum LDL-C level at only 100 mg/dL, we demonstrated that reduction of the coronary plaque volume can be achieved by elevation of the serum HDL-C. The results suggest that the ameliorating action of statins on lipid metabolism and sensitivity to their inhibitory effect on the progression of coronary plaque may be different in Japanese and Western populations.

Effect of Supplementation With High-Selenium Yeast on Plasma Lipids

High selenium status has been linked to elevated blood cholesterol levels in cross-sectional studies. To investigate the effect of selenium supplementation on plasma lipids. Randomized, placebo-controlled, parallel-group study stratified by age and sex. Participants, research nurses, and persons assessing outcomes were blinded to treatment assignment. (International Standard Randomised Controlled Trial Number Register registration number: ISRCTN25193534) 4 general practices in the United Kingdom. 501 volunteers aged 60 to 74 years. Participants received selenium, 100 mcg/d (n = 127), 200 mcg/d (n = 127), or 300 mcg/d (n = 126), as high-selenium yeast or a yeast-based placebo (n = 121) for 6 months. Total and high-density lipoprotein (HDL) cholesterol concentrations were measured in nonfasting plasma samples stored from participants in the UK PRECISE (United Kingdom PREvention of Cancer by Intervention with SElenium) Pilot Study at baseline (n = 454) and at 6 months (n = 394). Non-HDL cholesterol levels were calculated. Mean plasma selenium concentration was 88.8 ng/g (SD, 19.2) at baseline and increased statistically significantly in the treatment groups. The adjusted difference in change in total cholesterol levels for selenium compared with placebo was -0.22 mmol/L (-8.5 mg/dL) (95% CI, -0.42 to -0.03 mmol/L [-16.2 to -1.2 mg/dL]; P = 0.02) for 100 mcg of selenium per day, -0.25 mmol/L (-9.7 mg/dL) (CI, -0.44 to -0.07 mmol/L [-17.0 to -2.7 mg/dL]; P = 0.008) for 200 mcg of selenium per day, and -0.07 mmol/L (-2.7 mg/dL) (CI, -0.26 to 0.12 mmol/L [-10.1 to 4.6 mg/dL]; P = 0.46) for 300 mcg of selenium per day. Similar reductions were observed for non-HDL cholesterol levels. There was no apparent difference in change in HDL cholesterol levels with 100 and 200 mcg of selenium per day, but the difference was an adjusted 0.06 mmol/L (2.3 mg/dL) (CI, 0.00 to 0.11 mmol/L [0.0 to 4.3 mg/dL]; P = 0.045) with 300 mcg of selenium per day. The total-HDL cholesterol ratio decreased progressively with increasing selenium dose (overall P = 0.01). The duration of supplementation was limited, as was the age range of the participants. Selenium supplementation seemed to have modestly beneficial effects on plasma lipid levels in this sample of persons with relatively low selenium status. The clinical significance of the findings is unclear and should not be used to justify the use of selenium supplementation as additional or alternative therapy for dyslipidemia. This is particularly true for persons with higher selenium status, given the limitations of the trial and the potential additional risk in other metabolic dimensions. The Cancer Research Campaign (now Cancer Research UK) and the University of Surrey.

Association of GWAS-Based Candidate Genes with HDL-Cholesterol Levels before and after Bariatric Surgery in the Swedish Obese Subjects Study

The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study. Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance. In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2-4.2% (P < 10(-14)) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R(2) = 0.4-1.1%; 3.8 × 10(-6) < P < 3 × 10(-3)), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10(-4) < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C. SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.

Risperidone and serum lipid profile changes in child and adolescent patients

Objectives Atypical antipsychotics (AAPs) have been reported to cause metabolic dysregulation that can cause AAPs-related weight gain. The purpose of this study was to assess triglyceride, cholesterol, and weight changes among risperidone-treated children and youths. Methods Eighty-one subjects treated with risperidone for any psychiatric disturbances were included in the study. Fasting total low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG) levels were measured at the baseline and at the sixth month of treatment. Results TG, TC and LDL-C levels increased over time and reached statistical significance but there has been no change in HDL-C levels. Seven subjects (8.64%) crossed the threshold into clinically significant hypertriglyceridemia, four subjects (4.94%) crossed the threshold into clinically significant hypercholesterolemia, defined as going over the 95th percentile of published age normed plasma TG and TC levels, respectively. There was a positive correlation between TG and TC elevations and weight gain. There was no significant association with age, gender, diagnoses, risperidone dose and changes of serum TG, TC or LDL-C levels. Conclusion The present study identified significant associations between lipid dysregulation and risperidone treatment. Since there is little research available on long-term lipid profile follow-up with atypical antipsychotics treatment in children and youths, controlled studies in larger samples should be carried out to reveal the relationship between risperidone use and plasma lipid parameters in the pediatric population.

Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial

HIV infection and its treatment with protease inhibitors, especially when boosted with ritonavir, can cause lipid disorders. Statins, with the exception of fluvastatin, pravastatin and rosuvastatin, interact with protease inhibitor metabolism via CYP450. Pravastatin is recommended for patients with protease inhibitor-associated dyslipidemia. Rosuvastatin is the statin most effective on low-density lipoprotein cholesterol (LDL-c) in non-HIV patients. HIV-1-infected patients treated with boosted protease inhibitor were randomized to receive either rosuvastatin 10 mg/day or pravastatin 40 mg/day for dyslipidemia (LDL-c >4.1 mmol/l and triglycerides <8.8 mmol/l). The percentage change in LDL-c, triglyceride and high-density lipoprotein-cholesterol levels, measured in a central laboratory, was determined after 45 days of statin treatment. Eighty-eight patients were randomized and 83 took the study drugs, 41 rosuvastatin and 42 pravastatin. The median duration of prior antiretroviral treatment was 9 years. At baseline, the median LDL-c level was 4.93 mmol/l, the triglyceride level 2.29 mmol/l, and the high-density lipoprotein-cholesterol level 1.27 mmol/l. The median percentage changes in the rosuvastatin and pravastatin arms were -37 and -19% for LDL-c (P < 0.001), respectively, and -19 and -7% for triglycerides (P = 0.035), respectively. The change in the high-density lipoprotein-cholesterol level was not significantly different between the two arms. None of the four severe adverse events was attributed to the statins; in particular, there were no renal, hepatic or muscular events. Rosuvastatin 10 mg/day was more effective than pravastatin 40 mg/day on LDL-c and triglyceride levels in HIV-1-infected patients receiving a boosted protease inhibitor.

Evaluation of a Pharmacist-Managed Telephone Lipid Clinic at a Veterans Affairs Medical Center

Heart disease is one of the leading causes of death and disability in the US, with dyslipidemia being a significant risk factor. Pharmacist-managed lipid clinics have been shown to be effective in lowering low-density lipoprotein cholesterol (LDL-C) values in the veteran population. In addition, telephone-managed clinics are known to be an effective method to manage anticoagulation therapy. This type of appointment is very convenient; it reduces travel and waiting times, costs, and potential no-show rates. To assess changes in LDL-C levels from baseline to follow-up and number of patients attaining LDL-C goals during enrollment in the pharmacist-managed telephone lipid clinic (PMTLC). A retrospective chart review was conducted on all patients enrolled in the clinic who had follow-up laboratory data available. Baseline LDL-C values were compared with values obtained at follow-up. Patients' total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) values were also collected and analyzed for improvement. The agents used, number of antidyslipidemic medications, and the incidence of adverse drug reactions prior to and during clinic enrollment were also collected. Patients in the PMTLC had a mean +/- SD reduction in LDL-C of 44.3 +/- 45.2 mg/dL (p < 0.001). In addition, 10 (28%) patients achieved the LDL-C goal (p = 0.002). Mean reductions in TC and TG levels were 44 mg/dL (18%) and 14.6 mg/dL (8%), respectively. There was no significant change in HDL-C levels. The PMTLC at the Erie, PA, Veterans Affairs Medical Center demonstrated statistically significant reduction in patients' LDL-C levels and increase in the number of patients attaining LDL-C goal.

Comparison of sequential rosuvastatin doses in hypercholesterolaemia: a meta-analysis of randomised controlled trials

Background:Rosuvastatin is an effective treatment for patients with hypercholesterolaemia. However, the incremental benefit and risk of increasing through the licensed dose range have not been comprehensively assessed across all available clinical trials.Research design and methods:The literature databases CENTRAL, EMBASE, and MEDLINE were searched in April 2008 for trials with comparisons of sequential licensed rosuvastatin dosages: 5 vs. 10 mg/day, 10 vs. 20 mg/day, and 20 vs. 40 mg/day. Clinical trial registries were also searched. For benefit outcomes, weighted mean differences were derived using the inverse variance method. For risk outcomes, the Mantel–Haenszel method was used to calculate a summary relative risk.Results:The meta-analysis included 26 trials. The results demonstrated significantly favourable changes in low-density lipoprotein cholesterol level with increasing dosage (by 6.25, 5.84, and 5.03 percentage points for 10 vs. 5 mg/day, 20 vs. 10 mg/day, and 40 vs. 20 mg/day, respectively), and also in the ratios of total cholesterol to high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B to apolipoprotein A-I (all p < 0.00001). In addition, a significantly favourable change in HDL-C level was found with 20 mg/day over 10 mg/day (p = 0.02). Among the primary tolerability comparisons, no significant differences in risk were seen for muscular, hepatic, or renal adverse events, with only one exception: the risk of proteinuria by urine dipstick testing was significantly higher with rosuvastatin 40 mg/day than 20 mg/day (p = 0.01).The efficacy outcomes assessed in this meta-analysis are limited to surrogate markers of morbidity and mortality.Conclusions:This meta-analysis provides evidence for improved efficacy in treating patients with hypercholesterolaemia with each sequential titration of rosuvastatin and a generally consistent tolerability profile across the dose range.

HDL as a biomarker, potential therapeutic target, and therapy.

Emerging evidence suggests that HDL function is not always accurately predicted by HDL cholesterol levels. The functions of HDL include reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of the innate immune system. In healthy individuals, in the absence of systemic oxidative stress and inflammation, HDL is anti-inflammatory. However, in those with chronic illnesses such as diabetes that are characterized by systemic oxidative stress and inflammation, HDL may actually promote the inflammatory response (i.e., it may become proinflammatory). HDL may be thought of as a shuttle. The size of the shuttle can be estimated by HDL cholesterol levels. The shuttle's cargo can change dramatically from one that efficiently promotes reverse cholesterol transport and is anti-inflammatory to one that is less effective in promoting reverse cholesterol transport and is also proinflammatory without any change in the size of the shuttle (i.e., these changes in HDL cargo can occur without any change in HDL cholesterol levels). Understanding these issues may lead to improved use of HDL as a biomarker and may also lead to new therapeutic targets and therapies. ### HDL can modulate LDL oxidation. Lipoproteins evolved to facilitate the extracellular transport of lipids in multicellular organisms. The major protein in LDL is apolipoprotein (apo)-B. This protein contains a binding domain that causes LDL to be deposited in the extracellular matrix of many tissues, particularly in arteries that are predisposed to atherosclerosis. As a result of the binding of apoB-containing proteins to extracellular matrix molecules, the concentration of apoB in the subendothelial space of even normal arteries is twofold higher than in plasma (1). The deposition of LDL in the extracellular matrix of the subendothelial space predisposes it to oxidation. The oxidized lipids that result evoke a tissue response similar to that which occurs in response to a Mycobacterium (2, …

Evaluating the Incremental Benefits of Raising High-Density Lipoprotein Cholesterol Levels During Lipid Therapy After Adjustment for the Reductions in Other Blood Lipid Levels

The role of high-density lipoprotein cholesterol (HDL-C) as a therapeutic target to prevent cardiovascular (CV) events remains unclear. We examined data from the Framingham Offspring Study from 1975 through 2003 to determine whether increases in HDL-C levels after lipid therapy was started were independently associated with a reduction in CV events. Using Cox proportional-hazards regression, we evaluated the risk of a CV event associated with changes in blood lipid levels among individuals who started lipid therapy. The independent effect of HDL-C levels on future CV risk (average follow-up, 8 years) was estimated after adjustment for changes in low-density lipoprotein cholesterol, plasma triglycerides, and pretreatment blood lipid levels. Potential confounders (eg, smoking status, weight, and the use of beta-blockers) were then added to the model. Interactions between blood lipid levels were also explored. The change in HDL-C level was a strong independent risk factor for CV events (hazard ratio, 0.79 per 5-mg/dL increase; 95% confidence interval, 0.67-0.93) after adjustment for the other lipid changes associated with treatment. This relationship remained stable across a wide range of patient subgroups and did not appear to be associated with a specific drug class. An important interaction was observed: the lower the pretreatment low-density lipoprotein cholesterol level, the greater the impact of raising the HDL-C. Raising HDL-C levels with commonly used lipid medications appears to be an important determinant of the benefits associated with lipid therapy. These results support the further evaluation of therapies to raise HDL-C levels to prevent CV events.

The Relationships of ABCB1 3435C&gt;T and CYP2B6 516G&gt;T With High-Density Lipoprotein Cholesterol in HIV-Infected Patients Receiving Efavirenz

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are associated with a favorable increase in high-density lipoprotein cholesterol (HDL-c) level. Isolated studies have found a direct correlation between efavirenz (EFV) exposure and HDL-c level changes. Here we explore the impact that drug disposition variants associated with EFV exposure have on changes in HDL-c level. Seventy-six patients on first-line EFV-based regimens were genotyped for CYP2B6 516G>T and ABCB1 3435C>T. There was a 37% increase (+0.32 mmol/l, P < 0.001) in mean HDL-c level over 48 weeks, and this was univariately associated with gender (male +0.26 mmol/l, female +0.55 mmol/l; P = 0.03), ABCB1 3435C>T (CC +0.26 mmol/l, CT +0.16 mmol/l, TT +0.54 mmol/l; P(ANOVA) = 0.003) and CYP2B6 516 G>T (GG +0.27 mmol/l, GT +0.29 mmol/l, TT +0.72 mmol/l; P(ANOVA) = 0.08). There was a significant association between the cumulative number of predictive genotypes (CYP2B6 516TT or ABCB1 3435TT) and mean HDL-c level change: (group 0 +0.20 mmol/l, group 1 +0.47 mmol/l, group 2 +1.00 mmol/l; P(ANOVA) < 0.0001). These findings need to be validated in independent cohorts.

Does Baseline High Density Lipoprotein Cholesterol Influence Post-exercise Change Associated With Acute Exercise?

PURPOSE: The purpose of this study was to determine if baseline levels of high density lipoprotein cholesterol (HDL) affects the change in HDL levels associated with an acute bout of exercise of varying energy expenditure. METHODS: Two groups of healthy untrained male volunteers participated in this study. Subjects were assigned to one of two groups according to their baseline HDL levels. The LOW HDL group consisted of 13 subjects with clinically low HDL (< 40mg/dl) and the NORMAL HDL group consisted of 14 subjects with normal HDL (≥ 45mg/dl). Age, diet, VO2max and anthropometric data were collected prior to initiation of the experimental protocol and were similar for both groups. Age, height, weight, BMI, VO2max and resting HDL for LOW were 21.9 ± 2.0 yrs, 1.8 ± 0.1 m, 80.9 ± 7.9 kg, 25.2 ± 2.2 kg/m2, 45.8 ± 5.1 ml/kg/min and 35.7 ± 2.7 mg/dl, respectively while characteristics of the NORMAL group were 23.4 ± 7.1yrs, 1.8 ± 0.1 m, 78.6 ± 7.6 kg, 24.3 ± 2.5 kg/m2, 47.5 ± 4.8 ml/kg/min and 53.9 ± 5.8 mg/dl. Subjects completed two nonconsecutive exercise sessions (on separate days) expending 500 and 700 kcals while running on a treadmill at 65% of VO2max. Venous blood was collected pre-exercise, immediately post-exercise (IPE), and 24 hours post-exercise (+24) and analyzed for HDL and subfractions of HDL (HDL2and HDL3) and corrected for any shift in plasma volume. RESULTS: No differences in HDL or HDL subfractions were observed between NORMAL and LOW HDL groups at any post-exercise times. With both groups pooled HDL was significantly increased (p<0.05) by 2.5mg/dl (5.6%) at IPE, but not at +24 when compared to pre-exercise values. The increase in HDL post exercise was due for the most part to increased HDL3 (3.5mg/dl, 13.6%) whereas the HDL2 subfraction remained statistically unchanged. CONCLUSIONS: Baseline HDL status does not appear to affect the magnitude of post-exercise HDL-C alterations in untrained men. Furthermore, post-exercise increases in HDL associated with acute exercise appear due to increased HDL3 and not HDL2 in the subjects of this study.