Greater Increase In High-density Lipoprotein Cholesterol Research Articles

Trajectories of lipids around the menopause transition in Chinese women: results of the Kailuan cohort study

To investigate changes in lipid parameters around the final menstrual period (FMP) in Chinese women. A prospective community-based cohort study. Three thousand seven hundred fifty six Chinese women from the Kailuan cohort study who participated in the first examination and reached their FMP by the end of the seventh examination. Health examinations were performed every 2 years. Multivariable piece-wise linear mixed-effect models were used for repeated measures of lipids as a function of time around FMP. Number of years before or after FMP at each examination. Lipids at each examination, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Total cholesterol, LDL-C, and TGs began to increase in early transition, regardless of baseline age. Moreover, TC and LDL-C had a maximum annual increase from 1 year before to 2 years after FMP; TGs had a maximum annual increase from early transition to the fourth-year after menopause. The trajectories in other postmenopause segments differed across subgroups of different baseline ages. Furthermore, HDL-C remained stable around FMP if baseline age was <45 years, whereas if baseline age was ≥45 years, HDL-C would first decline and then rise during postmenopause. Women with a higher body mass index (BMI) underwent less adverse changes in TC and TGs during postmenopause and had decline in HDL-C before menopause. A later FMP age was associated with less adverse changes in TC, LDL-C, and TGs and greater increase in HDL-C during postmenopause; it was associated with a greater increase in LDL-C during early transition. This repeated measurement cohort study of indigenous Chinese women demonstrated that, regardless of baseline age, the adverse effect of menopause on lipids was since early transition, and the most adverse change time was from 1 year before to 2 years after FMP; HDL-C decreased first and then increased during postmenopause in older women; BMI and FMP age affected lipid trajectory mainly during postmenopause. We highlighted positive lipid management during menopause to reduce the burden of postmenopausal dyslipidemia. For lipid stratification management in postmenopausal women, BMI and FMP age are important factors.

A Significant Increase of Estimated Glomerular Filtration Rate After Switching From Fenofibrate to Pemafibrate in Type 2 Diabetic Patients.

BackgroundDyslipidemia is one of the major risk factors for cardiovascular disease (CVD), along with hypertension, diabetes, smoking and obesity. Approximately 70% of CVD risk remains even after treatment of elevated low-density lipoprotein-cholesterol (LDL-C) by statins. High triglyceride (TG) and low high-density lipoprotein-cholesterol (HDL-C) level are potential therapeutic targets to prevent CVD. Fibrates were associated with a greater reduction in TG, and a greater increase in HDL-C. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). Fibrates improve atherogenic dyslipidemia by mediating PPARα. Pemafibrate is a novel member of the selective PPARα modulator (SPPARMα) family that was designed to have a higher PPARα agonistic activity and selectivity than previous fibrates. Here, we aimed to study the influences of the switching from fenofibrate to pemafibrate on metabolic parameters in type 2 diabetic patients.MethodsWe retrospectively picked up type 2 diabetic patients who had undergone the switching from fenofibrate to pemafibrate, and compared metabolic parameters before the switching with the data at 3, 6 and 12 months after the switching.ResultsWe found 15 patients with type 2 diabetes. Serum alanine aminotransferase significantly decreased at 6 months after the switching as compared with baseline. The estimated glomerular filtration rate (eGFR) significantly increased at 3, 6 and 12 months after the switching from fenofibrate to pemafibrate as compared with baseline. Serum uric acid (UA) levels significantly increased at 3 and 6 months after the switching as compared with baseline. We did not observe changes in other metabolic parameters after the switching.ConclusionWe observed a significant increase of eGFR and serum UA after the switching from fenofibrate to pemafibrate in type 2 diabetic patients. Recent evidences suggest that the improvement of eGFR is beneficially associated with the development of CVD in type 2 diabetic patients. Considering the impact on eGFR, pemafibrate may effectively reduce CVD as compared with fenofibrate.

A Significant Increase of Estimated Glomerular Filtration Rate After Switching From Fenofibrate to Pemafibrate in Type 2 Diabetic Patients

Background: Dyslipidemia is one of the major risk factors for cardiovascular disease (CVD), along with hypertension, diabetes, smoking and obesity. Approximately 70% of CVD risk remains even after treatment of elevated low-density lipoprotein-cholesterol (LDL-C) by statins. High triglyceride (TG) and low high-density lipoprotein-cholesterol (HDL-C) level are potential therapeutic targets to prevent CVD. Fibrates were associated with a greater reduction in TG, and a greater increase in HDL-C. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). Fibrates improve atherogenic dyslipidemia by mediating PPARalpha. Pemafibrate is a novel member of the selective PPARalpha modulator (SPPARMalpha) family that was designed to have a higher PPARalpha agonistic activity and selectivity than previous fibrates. Here, we aimed to study the influences of the switching from fenofibrate to pemafibrate on metabolic parameters in type 2 diabetic patients. Methods: We retrospectively picked up type 2 diabetic patients who had undergone the switching from fenofibrate to pemafibrate, and compared metabolic parameters before the switching with the data at 3, 6 and 12 months after the switching. Results: We found 15 patients with type 2 diabetes. Serum alanine aminotransferase significantly decreased at 6 months after the switching as compared with baseline. The estimated glomerular filtration rate (eGFR) significantly increased at 3, 6 and 12 months after the switching from fenofibrate to pemafibrate as compared with baseline. Serum uric acid (UA) levels significantly increased at 3 and 6 months after the switching as compared with baseline. We did not observe changes in other metabolic parameters after the switching. Conclusion: We observed a significant increase of eGFR and serum UA after the switching from fenofibrate to pemafibrate in type 2 diabetic patients. Recent evidences suggest that the improvement of eGFR is beneficially associated with the development of CVD in type 2 diabetic patients. Considering the impact on eGFR, pemafibrate may effectively reduce CVD as compared with fenofibrate. Cardiol Res. 2021;000(000):000-000 doi: https://doi.org/10.14740/cr1333

Effects of age, gender and statin dose on lipid levels: Results from the VOYAGER meta-analysis database

Background and aimsThe effectiveness of statins in the treatment of dyslipidaemia and reduction of cardiovascular risk is well established. However, the association of statin-mediated lipid effects with age and gender is unclear. This study aimed to determine whether age and gender are associated with statin-mediated changes in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and non-HDL-C. MethodsIndividual patient data (n = 32,258) were obtained from VOYAGER. Least-squares mean percentage change from baseline in LDL-C, non-HDL-C and HDL-C with atorvastatin 10–80 mg, rosuvastatin 5–40 mg or simvastatin 10–80 mg was estimated in women aged <70 years, women aged ≥70 years, men aged <70 years and men aged ≥70 years. ResultsAll statins and doses gave significant dose-dependent reductions in LDL-C and non-HDL-C, and increases in HDL-C, in all four patient groups. A 2.1% greater reduction in LDL-C was observed in women, compared with men (p < 0.0001). Patients aged ≥70 years experienced a 2.7% greater reduction in LDL-C compared with younger patients (p < 0.0001). Similar results were also observed for statin-mediated changes in non-HDL-C. Men experienced a significantly greater increase in HDL-C than women, and patients aged ≥70 years achieved a significantly greater increase than younger patients (both p = 0.001). ConclusionsWhile statins improve the lipid profile in all gender and age groups analysed, the improvements are greater in women than in men and in those aged ≥70 years compared with those aged <70 years.

Abstract 18754: Genetic Predisposition to Coronary Artery Disease and Changes in Lipid Profile in Response to 2-year Weight-loss Diet Intervention: The Pounds Lost Trial

Introduction: Dyslipidemia is a major risk factor of coronary artery disease (CAD), and is affected by interaction between genetic and environmental factors, such as diets. Weight-loss diet intervention has been widely used to improve lipids to mitigate cardiovascular complications of obesity. Hypothesis: We hypothesize that the genetic predisposition to CAD may modify lipids metabolism in response to diets. Methods: We calculated a genetic risk score (GRS) based on 19 CAD-associated single nucleotide polymorphisms in 744 adults from a 2-year diet intervention study: the POUNDS Lost trial. We examined the changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides by the GRS and diet intervention. Results and Conclusions: We found significant interaction between the GRS and dietary fat intake on changes in total cholesterol, HDL and LDL cholesterol (P-interaction=0.02, 0.01 and 0.02, respectively) after the 2-year intervention. Overall, both low- and high-fat diets decreased total cholesterol, LDL cholesterol and triglycerides, but increased HDL cholesterol. At 2 years, in the highest tertile of the GRS, participants eating the low-fat diet showed a greater decrease in total cholesterol and LDL cholesterol than those eating the high-fat diet; whereas participants eating the high-fat diet showed a greater increase in HDL cholesterol than those eating the low-fat diet (all P&lt;0.001). In lower tertiles of the GRS, the difference in lipids changes between the two diet groups was not significant. In conclusion, genetic predisposition to CAD might modify the dietary fat induced lipids changes. Our data suggest that in participants with higher genetic risk, low-fat diet may lower total cholesterol and LDL cholesterol, while high-fat diet may improve HDL cholesterol. And in participants with lower genetic risk, the two diets showed similar effects on improvement of lipid profile.

Systematic review and meta-analysis of randomised controlled trials testing the effects of vitamin C supplementation on blood lipids

Randomised controlled trials (RCTs) in humans revealed contradictory results regarding the effect of vitamin C supplementation on blood lipids. We aimed to conduct a systematic review and meta-analysis of RCTs investigating the effect of vitamin C supplementation on total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides and to determine whether the effects are modified by the participants' or intervention characteristics. Four databases (PubMed, Embase, Scopus and Cochrane Library) were searched from inception until August 2014 for RCTs supplementing adult participants with vitamin C for≥2 weeks and reporting changes in blood lipids. Overall, vitamin C supplementation did not change blood lipids concentration significantly. However, supplementation reduced total cholesterol in younger participants (≤52 years age) (-0.26mmol/L, 95% CI:-0.45,-0.07) and LDL-C in healthy participants (-0.32mmol/L, 95% CI:-0.57,-0.07). In diabetics, vitamin C supplementation reduced triglycerides significantly (-0.15mmol/L, 95% CI:-0.30,-0.002) and increased HDL-C significantly (0.06mmol/L, 95% CI: 0.02, 0.11). Meta-regression analyses showed the changes in total cholesterol (β:-0.24, CI:-0.36,-0.11) and in triglycerides (β:-0.17, CI:-0.30,-0.05) following vitamin C supplementation were greater in those with higher concentrations of these lipids at baseline. Greater increase in HDL-C was observed in participants with lower baseline plasma concentrations of vitamin C (β:-0.002, CI:-0.003,-0.0001). Overall, vitamin C supplementation had no significant effect on lipid profile. However, subgroup and sensitivity analyses showed significant reductions in blood lipids following supplementation in sub-populations with dyslipidaemia or low vitamin C status at baseline. PROSPERO Database registration: CRD42014013487, http://www.crd.york.ac.uk/prospero/.

Future of Cholesteryl Ester Transfer Protein (CETP) Inhibitors: A Pharmacological Perspective

In almost 30years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in phase III clinical trials. Because of off-target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone, leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on cardiovascular risk especially in patients with a greater increase in HDL-C and apolipoprotein A-1 (apoA-1) levels. The phase III clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C levels but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors, including torcetrapib, anacetrapib, and evacetrapib, while dalcetrapib only affects the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors, with a smaller molecular weight and a lack of trifluoride moieties. Moreover, dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in phase III clinical trials. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib remains to be confirmed upon the completion of phase III clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered a biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exists between HDL-C levels and the risk of coronary artery diseases. The most crucial role for HDL is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL particle size, charge, and composition, the mere concentration of HDL-C may not be a good surrogate marker for HDL functionality. Recent clinical studies have reported that increased HDL functionality inversely correlates with the development of atherosclerotic plaque. Future development of CETP inhibitors may therefore benefit from the use of biomarkers of HDL functionality.

Impact of Restrictive (Sleeve Gastrectomy) vs Hybrid Bariatric Surgery (Roux-en-Y Gastric Bypass) on Lipid Profile

Few studies have evaluated the impact of hybrid versus purely restrictive bariatric surgery on lipid profile, with the results being contradictory. The effect of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) on lipid profile was compared. A nonrandomized prospective cohort study was conducted on severely obese patients undergoing bariatric surgery. Indication for the type of surgical procedure was based on clinical criteria. Patients on lipid-lowering drugs and those that could not be matched for age, sex, and body mass index were excluded. Finally, 51 patients who underwent LSG and 51 undergoing LRYGB completed this study. During the first year post-surgery, no differences in percentage of excess weight loss and triglyceride reduction were found between groups. After LRYGR, low-density lipoprotein (LDL) cholesterol concentrations fell significantly (125.9 ± 29.3 to 100.3 ± 26.4mg/dl, p < 0.001), whereas no significant changes were observed in the LSG group (118.6 ± 30.7 to 114.6 ± 33.5mg/dl, p = 0.220). High-density lipoprotein (HDL) cholesterol increase was significantly greater after LSG (15.4 ± 13.1mg/dl) compared with LRYGB (9.4 ± 14.0mg/dl, p = 0.032). Factors independently associated with LDL cholesterol reduction were higher baseline total cholesterol and undergoing LRYGB. A greater increase in HDL cholesterol was associated with LSG, older age, and baseline HDL cholesterol. LRYGB produces an overall improvement in lipid profile, with a clear benefit in all lipid fractions. Although LSG does not alter LDL cholesterol levels, its effect on HDL cholesterol is comparable to or greater than that obtained with malabsorptive techniques.

Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol

Interest remains high in cholesteryl ester transfer protein (CETP) inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins. To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia. Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe. Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks. The co-primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment. The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of -0.7 mg/dL (-3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of -20.5 to -51.4 mg/dL (-13.6% to -35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of -67.1 to -75.8 mg/dL (-11.2% to -13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed. Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation. clinicaltrials.gov Identifier: NCT01105975.

Effects of Diet on High-Density Lipoprotein Cholesterol

Multiple dietary factors have been shown to increase high-density lipoprotein cholesterol (HDL-C) concentrations, and HDL-C has been inversely associated with coronary heart disease (CHD) risk. Replacement of dietary carbohydrate with polyunsaturated, monounsaturated and saturated fat has been associated with progressively greater increases in HDL-C (7-12%) in addition to other lipid changes. Added sugars, but not high glycemic carbohydrates, have been associated with decreased HDL-C. Alcohol consumption has been associated with increased HDL-C (9.2%) independent of changes in other measured lipids. Modest effects on HDL-C (~4-5%) among other lipid and non-lipid CHD risk factors have also been observed with weight loss by dieting, omega-3 fatty acids, and a Mediterranean diet pattern. The CHD benefit of increasing HDL-C is unclear given the inconsistent evidence from HDL-raising pharmacologic trials. Furthermore, pleiotropic effects of diet preclude attribution of CHD benefit specifically to HDL-C. Investigation into functional or other properties of HDL may lend further insight.

Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials

This post hoc analysis compared the lipid-altering efficacy and safety of ezetimibe 10 mg plus statin (EZE/statin) vs. statin monotherapy in hypercholesterolaemic patients with and without diabetes. A pooled analysis of 27 previously published, randomized, double-blind, active- or placebo-controlled clinical trials comprising 21 794 adult patients with (n = 6541) and without (n = 15253) diabetes receiving EZE/statin or statin alone for 4-24 weeks evaluated percentage change from baseline in lipids and other parameters. Consistency of the treatment effect across the subgroups was tested using treatment × subgroup interaction. No multiplicity adjustments were made. Treatment effects within both subgroups were generally consistent with the overall population. EZE/statin was more effective than statin alone in improving low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), non-HDL-C, apolipoprotein (apo) B and high-sensitivity C-reactive protein (hs-CRP) in the overall population and both subgroups. Patients with diabetes achieved significantly larger reductions in LDL-C, TC and non-HDL-C compared with non-diabetic patients. Incidences of adverse events or creatine kinase elevations were similar between groups. A small but significantly higher incidence of alanine aminotransferase or aspartate aminotransferase elevations was seen in patients receiving EZE/statin (0.6%) vs. statin monotherapy (0.3%) in the overall population. Treatment with EZE/statin vs. statin monotherapy provided significantly larger reductions in LDL-C, TC, TG, non-HDL-C, apo B and hs-CRP and significantly greater increases in HDL-C, with a similar safety profile in patients with and without diabetes. Reductions in LDL-C, TC and non-HDL-C were larger in patients with diabetes than in patients without diabetes.

New evidence on pitavastatin: efficacy and safety in clinical studies

Importance of the field: Many clinical trials of pitavastatin have been done since its launch. New insights on pitavastatin from these trials are summarized and evaluated.Areas covered in this review: The results of clinical studies using pitavastatin, from 2008 to 2009, the LIVES study, the JAPAN-ACS study, the CHIBA study, the PIAT study and Phase III clinical trials in the West are reviewed.What the reader will gain: In the LIVES study, pitavastatin showed significant and continuous elevation of high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR), as well as potential decrease in low-density lipoprotein cholesterol (LDL-C), in addition to long-term safety. Non-inferiority of pitavastatin against atorvastatin in the percentage change in plaque volume was proved in the JAPAN-ACS study. Also, comparable effects on LDL-C reduction rate of pitavastatin versus atorvastatin were confirmed in the CHIBA study and Phase III clinical trials in the West, and a greater increase in HDL-C was observed than with atorvastatin in the PIAT study.Take home message: Pitavastatin is a useful potent statin in raising HDL-C as well as in lowering of LDL-C, though a large-scale, clinical trial to confirm prevention of cardiovascular events is needed in the future.

Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women.

A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the oestrogen receptor alpha gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT. Subjects Postmenopausal Caucasian women (n = 208) participating in a placebo-controlled randomized trial of 3.2 years of hormone therapy (HT). Plasma triglyceride (TG), remnant lipoprotein cholesterol (RLP-C), and high-density lipoprotein cholesterol (HDL-C) levels and HDL subpopulations were assessed at baseline and at follow up. Single nucleotide polymorphisms (SNPs) in ESR1 and in the ATP binding cassette A1 (ABCA1), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), and scavenger receptor class B type I (SRB1) genes were assessed for their association with baseline plasma levels and HT-related changes in levels of RLP-C and HDL subpopulations. Carriers of the ESR1 PvuII or IVS1-1505 variants had lower plasma TG concentrations and higher plasma HDL-C and alpha-1 and prealpha-1 HDL particle levels at baseline and showed greater increases in HDL-C, apo A-I and alpha-1 particle levels after HT than wild-type carriers. Carriers of the N291S and D9N variants in the LPL gene had significantly higher remnant lipoproteins and lower alpha-2 HDL particle levels at baseline. The CETP TaqIB SNP was a significant determinant of baseline plasma HDL-C and HDL subpopulation profile. Single nucleotide polymorphisms in ESR1, CETP and LPL had significant effects on baseline plasma levels of TG-rich and HDL subpopulations. With the exception of ESR1 SNPs, variation in genes involved in lipid metabolism has a very modest effect on lipoprotein response to HT.

Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis

Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis. Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P =0.02), and lowered serum potassium (0.11±0.02 mmol/L, P &lt;0.0001). Despite substantial increases in HDL-C, no effect was found of torcetrapib on percent atheroma volume. In torcetrapib-treated patients, an inverse relationship was observed between changes in HDL-C and percentage atheroma volume ( r =−0.17, P &lt;0.001). Participants with regression had greater increases in HDL-C (mean±SE, 62.9±37.4% versus 54.0±39.1%, P =0.002). Compared with the lowest quartile, torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (−0.31±0.27 versus 0.88±0.27%, P =0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (−0.69±0.27%, P =0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression ( P =0.001). Conclusions— The majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression.

A 52-Week, Randomized, Open-Label, Parallel-Group Comparison of the Tolerability and Effects of Pitavastatin and Atorvastatin on High-Density Lipoprotein Cholesterol Levels and Glucose Metabolism in Japanese Patients with Elevated Levels of Low-Density Lipoprotein Cholesterol and Glucose Intolerance

Background: Statin therapy has been found to produce substantial reductions in low-density lipoprotein cholesterol (LDL-C) levels, resulting in a reduced risk for cardiovascular events. Recently, research interest has focused on modification of high-density lipoprotein cholesterol (HDL-C) levels for the potential prevention of cardiovascular events. The effects of pitavastatin and atorvastatin on HDL-C have not been directly compared. Objectives: This study compared the effects of pitavastatin and atorvastatin on HDL-C and other lipids and glucose metabolism in Japanese patients with elevated LDL-C levels and glucose intolerance. The tolerability of the 2 treatments was also compared. Methods: This was a multicenter, open-label, parallelgroup trial. Patients with LDL-C levels ≥ 140 mg/dL and glucose intolerance (defined according to Japanese criteria for borderline diabetes and World Health Organization criteria for impaired fasting glucose and impaired glucose tolerance) were randomly assigned to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d for 52 weeks. Levels of serum lipids and lipoproteins and measures of glucose metabolism (fasting insulin, fasting glucose, glycosylated hemoglobin, and homeostasis model assessment for insulin resistance) were obtained at baseline and at 8, 26, and 52 weeks of treatment. The effect of study drug on glucose metabolism was evaluated as a tolerability outcome. Tolerability was further assessed based on adverse events, either spontaneously reported or elicited by questioning; physical examination findings; and clinical laboratory test results. Study physicians rated the relationship of adverse events to study medication as unrelated, suspected, or probable. Results: Two hundred seven patients were enrolled in the study, and efficacy was evaluated in 173 patients (88 pitavastatin, 85 atorvastatin). Thirty-four patients were excluded for reasons including failure to start medication or lack of ≥ 6 months of follow-up. Women accounted for 62% (108/173) of the evaluable population, which had a mean age of 63.3 years and a mean weight of 63.0 kg; 89% (154/173) had diabetes mellitus. The percent change in HDL-C levels was significantly greater in the pitavastatin group compared with the atorvastatin group (8.2 vs 2.9, respectively; P = 0.031), as was the percent change in apolipoprotein (Apo) A-I (5.1 vs 0.6; P = 0.019). The percent change in LDL-C levels was significantly lower with atorvastatin compared with pitavastatin (−40.1 vs −33.0, respectively; P = 0.002), as were the percent changes in non-HDL-C (−37.4 vs −31.1; P = 0.004), Apo B (−35.1 vs −28.2; P < 0.001), and Apo E (−28.1 vs −17.8; P < 0.001). The significant results for these parameters were unchanged when all 189 subjects who received ≥ 1 dose of study medication were included in the analysis, using last-value-carried-forward methodology. There were no significant differences between treatments with respect to the measures of glucose metabolism. Both statins appeared to be well tolerated. Adverse events occurred in 9% (9/96) of the pitavastatin group and 14% (13/93) of the atorvastatin group ( P = NS). Two patients in the pitavastatin group and none in the atorvastatin group had an alanine aminotransferase value >3 times the upper limit of normal ( P = NS). Conclusions: In these patients with elevated LDL-C levels and glucose intolerance, 52 weeks of treatment with pitavastatin 2 mg/d was associated with significantly greater increases in HDL-C and Apo A-I levels than atorvastatin 10 mg/d. Both treatments were well tolerated.

PC-1 Genotype and IRS Response to Exercise Training

The purpose of this study was to investigate whether the efficacy of exercise training as a means of insulin resistance syndrome (IRS) treatment is dependent on the PC-1 gene K121Q variants. A population of 84 abdominally obese Korean women was analyzed prospectively. Before and after a 12-week exercise (walking) training program, indices of body fatness including body mass index, percent body fat, and waist circumference, and cardiorespiratory fitness were measured. Total cholesterol (TC), triacylglycerol, high-density lipoprotein cholesterol (HDLC), glucose, and insulin were measured in fasting venous blood. At baseline, KK individuals had significantly lower waist circumference (p = 0.019) and TC (p = 0.001) than KQ/QQ individuals did. In particular, compared with KQ/QQ individuals, KK individuals had significantly greater reductions in body weight (p = 0.002), BMI (p = 0.032), and fasting insulin (p = 0.042), and a greater increase in HDLC (p = <0.001), following the 12-week walking exercise program. This study suggests that the PC-1 gene K121Q polymorphism may modulate responses of IRS to exercise training, at least in this population.

Changes in plasma lipids and lipoproteins following 10-days of prolonged walking: influence of age and relationship to physical activity level

The aim of the present study was to examine (1) the influence of 10 days of prolonged walking on plasma total-cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) concentrations, (2) the effect of age on any changes in plasma cholesterol and lipoprotein concentration, and (3) whether any changes in cholesterol and lipoprotein concentrations are correlated to the participants' physical activity level (PAL). Seventeen male participants were divided into two groups according to their age. The nine participants in group 1 constituted the younger group (age 24 ± 3 (SD) years), whereas eight older participants were in group 2 (age 56 ± 3 years). Both groups completed 10 consecutive days of high-intensity hill walking. Mean (range) daily distances and ascent were 21 km (10–35 km) and 1,160 m (800–2,540 m), respectively. Identical distances and ascents were covered by each group. For each participant, PAL was calculated from energy expenditure, assessed by the doubly-labeled water technique, divided by the individual's basal metabolic rate. Venous blood was sampled immediately prior to, and following, the 10 consecutive days of walking. Following these 10 days, the older group showed a greater decrease in both TC (−25 ± 11% vs. −10 ± 11%; P < 0.05) and LDL-C (−26 ± 12% vs. −4 ± 13%; P < 0.05) when compared with the young. Likewise, the older group showed a greater increase in HDL-C (38 ± 15%; P < 0.05), after the 10 days, whereas no significant change was evident in the younger group. In the older participants, there were strong positive relationships between PAL and the decreases in TC (r = 0.79, P < 0.05) and LDL-C (r = 0.74, P < 0.05). Conversely, in the younger group there were strong negative relationships between PAL and the decreases in TC (r = −0.74, P < 0.05) and LDL-C (r = −0.86, P < 0.01). These correlations persisted when changes in lipid concentrations were corrected for changes in plasma volume. These data suggest an ‘age-dependant’ threshold for PAL, rather than a specific exercise intensity or duration, may be critical for inducing favourable changes in HDL-C, LDL-C and TC.

Dose-comparison Study of the Combination of Ezetimibe and Simvastatin (Vytorin) Versus Atorvastatin in Patients With Hypercholesterolemia: The Vytorin Versus Atorvastatin (VYVA) Study

Background Low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target in the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines. This study tested the hypothesis that ezetimibe/simvastatin, a lipid-lowering agent that inhibits both intestinal cholesterol absorption and cholesterol synthesis, provides greater LDL-C reductions than atorvastatin across dose ranges. Methods This multicenter, double-blind, 6-week parallel-group study randomized 1902 patients with LDL-C above ATP III goal to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40, or 10/80 mg). Patients were stratified by prerandomization LDL-C level. Results At each milligram-equivalent statin dose comparison, and averaged across doses, ezetimibe/simvastatin provided greater LDL-C reductions (47%-59%) than atorvastatin (36%-53%). Ezetimibe/simvastatin 10/40 and 10/80 mg also provided significantly greater high-density lipoprotein cholesterol (HDL-C) increases than atorvastatin 40 and 80 mg. Triglyceride reductions were similar for all comparisons. More ezetimibe/simvastatin than atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of Conclusions Ezetimibe/simvastatin was more effective than atorvastatin in lowering LDL-C at each dose comparison and provided greater increases in HDL-C at the 40- and 80-mg statin dose. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment option for hypercholesterolemic patients.

Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: The Vytorin Versus Atorvastatin (VYVA) Study

Low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target in the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines. This study tested the hypothesis that ezetimibe/simvastatin, a lipid-lowering agent that inhibits both intestinal cholesterol absorption and cholesterol synthesis, provides greater LDL-C reductions than atorvastatin across dose ranges. This multicenter, double-blind, 6-week parallel-group study randomized 1902 patients with LDL-C above ATP III goal to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40, or 10/80 mg). Patients were stratified by prerandomization LDL-C level. At each milligram-equivalent statin dose comparison, and averaged across doses, ezetimibe/simvastatin provided greater LDL-C reductions (47%-59%) than atorvastatin (36%-53%). Ezetimibe/simvastatin 10/40 and 10/80 mg also provided significantly greater high-density lipoprotein cholesterol (HDL-C) increases than atorvastatin 40 and 80 mg. Triglyceride reductions were similar for all comparisons. More ezetimibe/simvastatin than atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of <100 mg/dL and the optional LDL-C target of <70 mg/dL. C-reactive protein reductions were similar between treatment groups. Consecutive elevations in alanine aminotransferase and/or aspartate aminotransferase occurred in significantly more atorvastatin patients than ezetimibe/simvastatin patients. No myopathy or liver-related adverse events led to study discontinuation with either drug. Ezetimibe/simvastatin was more effective than atorvastatin in lowering LDL-C at each dose comparison and provided greater increases in HDL-C at the 40- and 80-mg statin dose. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment option for hypercholesterolemic patients.

Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels

Patients with combined hyperlipidemia and low high-density lipoprotein (HDL) cholesterol levels may benefit from combination therapy with a statin and niacin; therefore, we assessed the efficacy and safety of rosuvastatin and extended-release (ER) niacin alone and in combination in 270 patients with this atherogenic dyslipidemia. Men and women ≥18 years with fasting total cholesterol levels ≥200 mg/dl, triglycerides 200 to 800 mg/dl, apolipoprotein B ≥110 mg/dl, and HDL cholesterol <45 mg/dl were randomized to 1 of 4 treatments in this 24-week, open-label, multicenter trial: rosuvastatin 10 to 40 mg; ER niacin 0.5 to 2 g; rosuvastatin 40 mg/ER niacin 0.5 to 1 g; or rosuvastatin 10 mg/ER niacin 0.5 to 2 g. Percent changes from baseline in low-density lipoprotein (LDL) cholesterol, non-HDL cholesterol, and other lipid measurements at week 24 were determined by analysis of variance, with statistical testing performed separately between the rosuvastatin monotherapy group and each remaining treatment group. Daily doses of rosuvastatin 40 mg reduced LDL and non-HDL cholesterol significantly more than either ER niacin 2 g or rosuvastatin 10 mg/ER niacin 2 g (−48% vs −0.1% and −36% for LDL cholesterol and −49% vs −11% and −38% for non-HDL cholesterol, respectively; p <0.01 for all comparisons); no additional reduction in LDL or non-HDL cholesterol was observed with the combination of rosuvastatin 40 mg/ER niacin 1.0 g (−42% and −47%; p = NS). Triglyceride reductions ranged from −21% (ER niacin monotherapy) to −39% (rosuvastatin 40 mg/ER niacin 1 g), but no observed differences were statistically significant. Compared with rosuvastatin alone, rosuvastatin 10 mg/ER niacin 2 g produced significantly greater increases in HDL cholesterol (11% vs 24%, p <0.001) and apolipoprotein A-I (5% vs 11%, p <0.017). Similar increases in HDL cholesterol and apolipoprotein A-I were noted between the monotherapy groups. Over 24 weeks, rosuvastatin alone was better tolerated than either ER niacin alone or the combinations of rosuvastatin and ER niacin.