Reduction In LDL-cholesterol Concentrations Research Articles

Long-term outcomes of liver transplantation for homozygous familial hypercholesterolaemia in Australia and New Zealand

Background and aimsHomozygous familial hypercholesterolaemia (FH) causes severe cardiovascular disease from childhood. Conventional drug therapy is usually ineffective; lipoprotein apheresis (LA) is often required. Liver transplantation (LT) can correct the metabolic defect but is considered a treatment of last resort. Newer drugs including lomitapide and evinacumab might reduce the need for apheresis and LT. We sought to determine the long-term outcomes following LT in Australia and New Zealand. MethodsWe analysed demographic, biochemical and clinical data from all patients in Australia and New Zealand who have received LT for homozygous FH, identified from the Australia and New Zealand Liver and Intestinal Transplant Registry. ResultsNine patients (five female; one deceased; seven aged between 3 and 6 years at the time of LT and two aged 22 and 26 years) were identified. Mean follow-up was 14.1 years (range 4–27). Baseline LDL-cholesterol off all treatment was 23 ± 4.1 mmol/L. Mean LDL-cholesterol on medical therapy (including maximal statin therapy in all patients, ezetimibe in three and LA in five) was 11 ± 5.7 mmol/L (p < 0.001). After LT, mean LDL-cholesterol was 2.6 ± 0.9 mmol/L (p = 0.004) with three patients remaining on statin therapy and none on LA. One patient died from acute myocardial infarction (AMI) three years after LT. Two patients required aortic valve replacement, more than 10 years after LT. The remaining six patients were asymptomatic after eight to 21 years of follow-up. No significant adverse events associated with immunosuppression were reported. ConclusionsLT for homozygous FH was highly effective in achieving substantial long-term reduction in LDL-cholesterol concentrations in all nine patients. LT remains an option for severe cases of homozygous FH where drug therapy combined with apheresis is ineffective or unfeasible.

Identification of a PCSK9-LDLR disruptor peptide with in vivo function

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 1013invitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with invivo PCSK9-LDLR disruptor function.

Effect of phytosterol capsule supplementation associated with the National Cholesterol Education Program Step 2 diet on low-density lipoprotein in children and adolescents with dyslipidemia: A double-blind crossover trial.

To evaluate the effect of phytosterol capsule supplementation associated with the National Cholesterol Education Program (NCEP) Step 2 diet on LDL-C levels in children and adolescents with dyslipidemia. This is a randomized, double-blind, crossover trial conducted with children and adolescents (n = 31; mean ± SD, age 9.0 ± 2.22 years, BMI zscore 1.65 ± 1.47 kg/m2) with dyslipidemia. After a run-in period, the participants were randomly allocated to control or intervention groups. The intervention group received capsules containing 1.5 g/day of phytosterols, and the control group received capsules containing 2 g/day of sunflower oil for 8 weeks. Patients in both groups were instructed to follow the NCEP Step 2 diet during the study. The primary outcome was LDL-C and secondary outcomes were total cholesterol (TC), HDL-C, triglyceride, insulin, blood pressure, and anthropometric measures. Intention-to-treat analyses were performed using the proc mixed procedure in SAS. The rate of change for LDL-C was not different between intervention and control groups (p=0.30). No significant reduction was also observed for TC (p=0.47), HDL-C (p=0.97), insulin (p=0.27), triglycerides (p=0.38), systolic blood pressure (p=0.11), and diastolic blood pressure (p=0.57) compared to control group. Although we observed a high adherence to the capsule intake (95.7% in phytosterol and 93.8% in the control group), the low adherence to the diet may have contributed to explaining the results. Daily phytosterol capsules supplementation associated with the NCEP Step 2 diet did not reduce LDL-cholesterol concentrations in children and adolescents with dyslipidemia.

Dietary sugars and cardiometabolic risk factors: a network meta-analysis on isocaloric substitution interventions

There is controversy on the relevance of dietary sugar intake for cardiometabolic health. The aim of this network meta-analysis (NMA) was to assess how isocaloric substitutions of dietary sugar with other carbohydrates affect cardiometabolic risk factors, comparing different intervention studies. We included randomized controlled trials (RCTs) investigating the isocaloric effect of substituting dietary sugars (fructose, glucose, sucrose) with other sugars or starch on cardiometabolic risk markers, including LDL cholesterol, triacylglycerol (TG), fasting glucose (FG), glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR), uric acid, C-reactive protein (CRP), alanine transaminase (ALT), aspartate transaminase (AST), and liver fat content. To identify the most beneficial intervention for each outcome, random-effects NMA was conducted by calculating pooled mean differences (MDs) with 95% CIs, and by ranking the surface under the cumulative ranking curves (SUCRAs). The certainty of evidence was evaluated using the Confidence In Network Meta-Analysis tool. Thirty-eight RCTs, including 1383 participants, were identified. A reduction in LDL-cholesterol concentrations was shown for the exchange of sucrose with starch (MD: -0.23 mmol/L; 95% CI: -0.38, -0.07 mmol/L) or fructose with starch (MD: -0.22 mmol/L; 95% CI: -0.39, -0.05 mmol/L; SUCRAstarch: 98%). FG concentrations were also lower for the exchange of sucrose with starch (MD: -0.14 mmol/L; 95% CI: -0.29, 0.01 mmol/L; SUCRAstarch: 91%). Replacing fructose with an equivalent energy amount of glucose reduced HOMA-IR (MD: -0.36; 95% CI: -0.71, -0.02; SUCRAglucose: 74%) and uric acid (MD: -23.77 µmol/L; 95% CI: -44.21, -3.32 µmol/L; SUCRAglucose: 93%). The certainty of evidence was rated very low to moderate. No significant effects were observed for TG, HbA1c, CRP, ALT, and AST. Our findings indicate that substitution of sucrose and fructose with starch yielded lower LDL cholesterol. Insulin resistance and uric acid concentrations were beneficially affected by replacement of fructose with glucose. Our findings are limited by the very low to moderate certainty of evidence. This review was registered at www.crd.york.ac.uk/prospero as CRD42018080297.

Intensive LDL cholesterol-lowering treatment beyond current recommendations for the prevention of major vascular events: a systematic review and meta-analysis of randomised trials including 327 037 participants

The benefits of LDL cholesterol-lowering treatment for the prevention of atherosclerotic cardiovascular disease are well established. However, the extent to which these effects differ by baseline LDL cholesterol, atherosclerotic cardiovascular disease risk, and the presence of comorbidities remains uncertain. We did a systematic literature search (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, from inception up to June 15, 2019) for randomised controlled trials of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors with at least 1000 patient-years of follow-up. Random-effects meta-analysis and meta-regressions were done to assess for risk of major vascular events (a composite of cardiovascular mortality, non-fatal myocardial infarction, non-fatal ischaemic stroke, or coronary revascularisation) per 1 mmol/L (38·7 mg/dL) reduction in LDL cholesterol concentrations. 327 037 patients from 52 studies were included in the meta-analysis. Each 1 mmol/L reduction in LDL cholesterol was associated with a 19% relative risk (RR) reduction for major vascular events (RR 0·81 [95% CI 0·78-0·84]; p<0·0001). Similar reductions (per 1 mmol/L reduction in LDL cholesterol) were found in trials with participants with LDL cholesterol 2·60 mmol/L or lower, 2·61-3·40 mmol/L, 3·41-4·10 mmol/L, and more than 4·1 mmol/L (p=0·232 for interaction); and in a subgroup of patients who all had a baseline LDL cholesterol less than 2·07 mmol/L (80 mg/dL; RR 0·83 [95% CI 0·75-0·92]; p=0·001). We found greater RR reductions in patients at lower 10-year atherosclerotic cardiovascular disease risk (change in RR per 10% lower 10-year atherosclerotic cardiovascular disease 0·97 [95% CI 0·95-0·98]; p<0·0001) and in patients at younger age across a mean age of 50-75 years (change in RR per 10 years younger age 0·92 [0·83-0·97]; p=0·015). We found no difference in RR reduction for participants with or without diabetes (p=0·878 for interaction) and chronic kidney disease (p=0·934 for interaction). For each 1 mmol/L LDL cholesterol lowering, the risk reduction of major vascular events is independent of the starting LDL cholesterol or the presence of diabetes or chronic kidney disease. Patients at lower cardiovascular risk and younger age might have a similar relative reduction in risk with LDL-cholesterol lowering therapies and future studies should investigate the potential benefits of earlier intervention. None.

Proprotein convertase subtilisin/kexin type 9 inhibitors for reduction of cardiovascular events.

The efficacy, safety, and place in therapy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for lipid lowering are reviewed. PCSK9 inhibitors are injectable monoclonal antibodies that increase the availability of low-density lipoprotein (LDL) receptors, resulting in a reduction in serum LDL cholesterol (LDL-C). The currently available PCSK9 inhibitors alirocumab and evolocumab were shown to reduce LDL-C concentrations by approximately 55-60% relative to placebo use when used as monotherapy or added to other lipid-lowering therapies. A large randomized controlled trial of evolocumab demonstrated a reduction in cardiovascular events that translated to a 16% relative risk reduction per 1-mmol/L (39-mg/dL) reduction in LDL-C over 2 years, nearly identical to risk reductions reported with use of statins for LDL-C lowering. Another large outcome trial with alirocumab is ongoing. PCSK9 inhibitors are well tolerated, and minor injection-site reaction is the only known adverse effect. Routine use of these agents in all patients with cardiovascular disease is not cost-effective at the current annual cost of therapy of approximately $14,000 in the United States and $7,000 in other Western countries. Careful patient selection may increase the benefit-to-cost ratio of these agents. The PCSK9 inhibitors alirocumab and evolocumab, as adjuncts to oral lipid-lowering agents or as monotherapy, lower serum LDL-C concentrations and reduce the risk of cardiovascular events. These agents are safe and well tolerated, but high cost and lack of cost-effectiveness limit their routine use.

Effect of dietary cholesterol and plant sterol consumption on plasma lipid responsiveness and cholesterol trafficking in healthy individuals.

Dietary cholesterol and plant sterols differentially modulate cholesterol kinetics and circulating cholesterol. Understanding how healthy individuals with their inherent variabilities in cholesterol trafficking respond to such dietary sterols will aid in improving strategies for effective cholesterol lowering and alleviation of CVD risk. The objectives of this study were to assess plasma lipid responsiveness to dietary cholesterol v. plant sterol consumption, and to determine the response in rates of cholesterol absorption and synthesis to each sterol using stable isotope approaches in healthy individuals. A randomised, double-blinded, crossover, placebo-controlled clinical trial (n 49) with three treatment phases of 4-week duration were conducted in a Manitoba Hutterite population. During each phase, participants consumed one of the three treatments as a milkshake containing 600 mg/d dietary cholesterol, 2 g/d plant sterols or a control after breakfast meal. Plasma lipid profile was determined and cholesterol absorption and synthesis were measured by oral administration of [3, 4-13C] cholesterol and 2H-labelled water, respectively. Dietary cholesterol consumption increased total (0·16 (sem 0·06) mmol/l, P=0·0179) and HDL-cholesterol (0·08 (sem 0·03) mmol/l, P=0·0216) concentrations with no changes in cholesterol absorption or synthesis. Plant sterol consumption failed to reduce LDL-cholesterol concentrations despite showing a reduction (6 %, P=0·0004) in cholesterol absorption. An over-compensatory reciprocal increase in cholesterol synthesis (36 %, P=0·0026) corresponding to a small reduction in absorption was observed with plant sterol consumption, possibly resulting in reduced LDL-cholesterol lowering efficacy of plant sterols. These data suggest that inter-individual variability in cholesterol trafficking mechanisms may profoundly impact plasma lipid responses to dietary sterols in healthy individuals.

Phytosterol and its esters as novel food ingredients: A review

Phytosterols or stanols are large group of compounds found exclusively in plants. These are naturally present in plants and are structurally similar to cholesterol. A daily intake of 3 g of phytosterol (or their reduced form stanols) is associated with consistent and reproducible reduction in LDL cholesterol concentrations upto 10% and reduces the risk of coronary heart disease by 20% over a lifetime. Studies have concluded that the effective doses for reduction of cholesterol are between 1.5 and 3g/day, leading to decrease in 8% and 15% of LDL-cholesterol. The principal mechanism of action is based on interference with the solubilization of the cholesterol in the intestinal mucosa. Several studies have validated the cholesterol lowering effect of phytosterols and stanols along with its role in prevention of coronary heart diseases. Plant sterols and stanols appear to be unhazardous to health in a large number of human studies and no evidence of toxicity even at high dose levels has been reported. Changing lifestyle, constant stress and risk towards various diseases have necessitated the need of such vital neutraceuticals to be incorporated in diet and daily food items. Such new foods and formulations should pave the way for greater use of phytosterols in heart health promotion, increasing the long term potential for the creation of innovative functional foods containing plant sterols and their derivatives.

Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies)

We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses (50, 75, 150mg) on low-density lipoprotein cholesterol (LDL-C) reduction in patients with primary hypercholesterolemia on atorvastatin. A randomized, single ascending-dose study of alirocumab (100, 150, 250, or 300mg) or placebo (3:1 ratio), administered subcutaneously, was conducted in 32 healthy Japanese men. The phase 2, randomized, double-blind, placebo-controlled, parallel-group study was performed in patients with primary hypercholesterolemia (defined as calculated LDL-C ≥100mg/dl [2.6mmol/l]) who were on a stable dose of atorvastatin (5to 20mg). Patients were randomized to alirocumab (50, 75, or 150mg) or placebo (in single 1.0-ml injection volumes) administered every 2weeks (Q2W) for 12weeks; the primary outcome was the mean percent change in calculated LDL-C from baseline to week 12. Single subcutaneous administration of alirocumab in healthy subjects was well tolerated over 15weeks and resulted in highest mean percent reductions in LDL-C from baseline of approximately 40% to 60%. In the multiple-dose study, least-square mean (SE) changes in calculated LDL-C concentrations from baseline to week 12 were-54.8% (3.1%) for alirocumab 50mg,-62.3% (3.1%) for alirocumab 75mg, and-71.7% (3.1%) for alirocumab 150mg, with a least-square mean (SE) difference versus placebo of-52.2% (4.3%),-59.6% (4.3%), and-69.1% (4.3%), respectively (all p <0.0001). In conclusion, alirocumab was well tolerated and significantly reduced LDL-C concentrations in Japanese patients with primary hypercholesterolemia on atorvastatin.

Can phototherapy associated with an aerobic exercise on treadmill change the cardiovascular risk in obese women?

s / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375 365 insulin resistance (IR), glucose intolerance, dyslipidemia and systemic arterial hypertension (SAH). The aim of this study was evaluate the effects of aerobic exercise associated with phototherapy on cardiovascular risk factors in obesewomen.Women (20–40 years; BMI ≥30kg/m2) were divided into 2 groups: Phototherapy (P) and Sham (S). They trained aerobic exercise on treadmill, 1 h, 3 times/week during 16 week. Phototherapy was applied after each exercise session for 16min, infrared laser, wavelength 808nm, continuous output, and power 100mW, energy delivery 50 J. The area of visceral fat was measured with Bioimpedance InBody® and the lipoproteins concentrations (HDL and LDL-cholesterol) were performed in the clinical laboratory. Statistical analysis was performed using the program STATISTICA version 7.0 for Windows (StatSoft Inc., Tulsa, OK, USA). Comparing the effects between groups the association of the Phototherapy plus Aerobic Exercise was more effective in change the cardiovascular risk. This effect can be observed through the reduction in LDL-cholesterol concentrations and visceral fat area as well as increasing the HDL-cholesterol concentration. http://dx.doi.org/10.1016/j.pdpdt.2015.07.155 Laser therapy and biomembrane in treatment of venous ulcer Vitoria H. Maciel, Dora Patricia Ramirez Angarita, Vanderlei S. Bagnato Sao Carlos Institute of Physics, University of Sao

Effects of low-level laser therapy (LLLT) on muscle gene expression and cardiac autonomic control in rats

s / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375 365 insulin resistance (IR), glucose intolerance, dyslipidemia and systemic arterial hypertension (SAH). The aim of this study was evaluate the effects of aerobic exercise associated with phototherapy on cardiovascular risk factors in obesewomen.Women (20–40 years; BMI ≥30kg/m2) were divided into 2 groups: Phototherapy (P) and Sham (S). They trained aerobic exercise on treadmill, 1 h, 3 times/week during 16 week. Phototherapy was applied after each exercise session for 16min, infrared laser, wavelength 808nm, continuous output, and power 100mW, energy delivery 50 J. The area of visceral fat was measured with Bioimpedance InBody® and the lipoproteins concentrations (HDL and LDL-cholesterol) were performed in the clinical laboratory. Statistical analysis was performed using the program STATISTICA version 7.0 for Windows (StatSoft Inc., Tulsa, OK, USA). Comparing the effects between groups the association of the Phototherapy plus Aerobic Exercise was more effective in change the cardiovascular risk. This effect can be observed through the reduction in LDL-cholesterol concentrations and visceral fat area as well as increasing the HDL-cholesterol concentration. http://dx.doi.org/10.1016/j.pdpdt.2015.07.155 Laser therapy and biomembrane in treatment of venous ulcer Vitoria H. Maciel, Dora Patricia Ramirez Angarita, Vanderlei S. Bagnato Sao Carlos Institute of Physics, University of Sao

New clinical application of light: Synergic effects of laser and ultrasound in the rehabilitation of people with hands osteoarthritis

s / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375 365 insulin resistance (IR), glucose intolerance, dyslipidemia and systemic arterial hypertension (SAH). The aim of this study was evaluate the effects of aerobic exercise associated with phototherapy on cardiovascular risk factors in obesewomen.Women (20–40 years; BMI ≥30kg/m2) were divided into 2 groups: Phototherapy (P) and Sham (S). They trained aerobic exercise on treadmill, 1 h, 3 times/week during 16 week. Phototherapy was applied after each exercise session for 16min, infrared laser, wavelength 808nm, continuous output, and power 100mW, energy delivery 50 J. The area of visceral fat was measured with Bioimpedance InBody® and the lipoproteins concentrations (HDL and LDL-cholesterol) were performed in the clinical laboratory. Statistical analysis was performed using the program STATISTICA version 7.0 for Windows (StatSoft Inc., Tulsa, OK, USA). Comparing the effects between groups the association of the Phototherapy plus Aerobic Exercise was more effective in change the cardiovascular risk. This effect can be observed through the reduction in LDL-cholesterol concentrations and visceral fat area as well as increasing the HDL-cholesterol concentration. http://dx.doi.org/10.1016/j.pdpdt.2015.07.155 Laser therapy and biomembrane in treatment of venous ulcer Vitoria H. Maciel, Dora Patricia Ramirez Angarita, Vanderlei S. Bagnato Sao Carlos Institute of Physics, University of Sao

Laser therapy and biomembrane in treatment of venous ulcer

s / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375 365 insulin resistance (IR), glucose intolerance, dyslipidemia and systemic arterial hypertension (SAH). The aim of this study was evaluate the effects of aerobic exercise associated with phototherapy on cardiovascular risk factors in obesewomen.Women (20–40 years; BMI ≥30kg/m2) were divided into 2 groups: Phototherapy (P) and Sham (S). They trained aerobic exercise on treadmill, 1 h, 3 times/week during 16 week. Phototherapy was applied after each exercise session for 16min, infrared laser, wavelength 808nm, continuous output, and power 100mW, energy delivery 50 J. The area of visceral fat was measured with Bioimpedance InBody® and the lipoproteins concentrations (HDL and LDL-cholesterol) were performed in the clinical laboratory. Statistical analysis was performed using the program STATISTICA version 7.0 for Windows (StatSoft Inc., Tulsa, OK, USA). Comparing the effects between groups the association of the Phototherapy plus Aerobic Exercise was more effective in change the cardiovascular risk. This effect can be observed through the reduction in LDL-cholesterol concentrations and visceral fat area as well as increasing the HDL-cholesterol concentration. http://dx.doi.org/10.1016/j.pdpdt.2015.07.155 Laser therapy and biomembrane in treatment of venous ulcer Vitoria H. Maciel, Dora Patricia Ramirez Angarita, Vanderlei S. Bagnato Sao Carlos Institute of Physics, University of Sao

The Role of Dietary Cholesterol in Lipoprotein Metabolism and Related Metabolic Abnormalities: A Mini-review

Cholesterol plays a vital role in cell biology. Dietary cholesterol or “exogenous” cholesterol accounts for approximately one-third of the pooled body cholesterol, and the remaining 70% is synthesized in the body (endogenous cholesterol). Increased dietary cholesterol intake may result in increased serum cholesterol in some individuals, while other subjects may not respond to dietary cholesterol. However, diet-increased serum cholesterol levels do not increase the low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio, nor do they decrease the size of LDL particles or HDL cholesterol levels. Elevated levels of LDL cholesterol, reduced HDL cholesterol levels, and small, dense LDL particles are independent risk factors for coronary artery disease. Dietary cholesterol is the primary approach for treatment of conditions such as the Smith–Lemli–Opitz syndrome. Recent studies have highlighted mechanisms for absorption of dietary cholesterol. These studies have help understand how dietary and/or pharmaceutical agents inhibit cholesterol absorption and thereby reduce LDL cholesterol concentrations. In this article, various aspects of cholesterol metabolism, including dietary sources, absorption, and abnormalities in cholesterol metabolism, have been summarized and discussed.

Effects of Plant Sterol and Stanol Consumption on Blood Pressure and Endothelial Function.

The cholesterol lowering effects of plant sterols and stanols are a well-established complementary means by which to reduce blood cholesterol concentrations. The average reduction in LDL cholesterol concentrations is approximately -10% following a 28-day supplementation protocol. There is very little known regarding what, if any, effect plant sterols and stanols have on other cardiometabolic risk factors such as blood pressure and endothelial function. Here we review the available literature on this topic and attempt to draw conclusions regarding any benefit or risk for blood pressure and endothelial function linked to plant sterol and stanol supplementation. Generally there has been very little work focusing on changes in blood pressure or endothelial function following plant sterol or stanol intervention, but these factors have been measured in some cases as secondary outcomes. Overall, there is little evidence to support either positive or negative effects of plant sterol or stanol supplementation of blood pressure and the data surrounding endothelial function is quite inconclusive. This area of research would benefit from well controlled mechanistic studies in animals and primary interventions in humans which focus on ambulatory blood pressure, central blood pressure and endothelial function.

Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study

Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18-80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI -39·5 to -32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [-1·2 to 8·6], with a difference in percentage change between anacetrapib and placebo of -39·7% (95% CI -45·7 to -33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. Merck & Co, Inc.

Abstract 239: LDL Apheresis Is Associated With a Reduction in Markers of Chronic Inflammation in Patients With Familial Hypercholesterolemia

Background: Familial Hypercholesterolemia is an inherited disease characterized by severely elevated levels of LDL cholesterol (LDL-C) and associated with premature coronary artery disease (CAD). LDL apheresis (LA) is indicated for management of CAD patients with LDL-C&gt;200 mg/dl despite medical therapy. LA may reduce LDL-C concentrations by up to 70%; this in turn has been associated with regression of atherosclerosis. NMR measurement of signals corresponding to methyl group protons of glycoproteins (GlycA and GlycB) has recently been validated in prediction of atherosclerosis and chronic systemic inflammation. Studies have demonstrated a reduction in inflammatory cytokines with LA, but no study to date has evaluated the impact of LA on levels of glycoproteins as markers of chronic inflammation. Objective: To determine the effect of LA on plasma levels of glycoproteins using a novel NMR based technique, and to correlate these findings with changes in lipoprotein subclasses. Methods: Comprehensive NMR lipoprotein analysis was performed on serum obtained from seven subjects prior to and following LA sessions performed at two-week intervals (N = 47 paired samples). Three subjects had homozygous FH, three had heterozygous FH with CAD and/or LDL-C &gt; 200 mg/dL, one patient had severe mixed dyslipidemia with CAD and LDL-C &gt; 200 mg/dL. Results: Mean GlycA and GlycB levels were 335±91 μmol/L and 125±31 μmol/L respectively prior to LA. Following LA treatment, there was a significant reduction in GlycA to 277±73 μmol/L (P&lt;0.001) and in GlycB to 102±28 μmol/L (P&lt;0.001). The reduction in GlycA was strongly correlated with a decrease in total small LDL particle number (r = 0.68, p &lt; 0.001) and with a reduction in medium VLDL particle number (r = 0.52, P &lt; 0.001). GlycB level was weakly correlated with small LDL (r = 0.39, P = 0.007) and IDL particle numbers (r = 0.32, P = 0.028). In addition, GlycA and GlycB levels were correlated to each other (r = 0.49, P &lt; 0.001). Conclusion: This is the first report of NMR detection of glycoproteins as inflammatory biomarkers in patients with severe dyslipidemia undergoing LA. LA was associated with a significant reduction in levels of both GlycA and GlycB, which correlated with reductions in LDL and VLDL particle number.

Statin therapy on glycaemic control in type 2 diabetes: a meta-analysis

Objective: Randomised controlled trials (RCTs) indicate that statin therapy has cardiovascular benefit among patients with type 2 diabetes. Recently, statins were reported to increase risk of diabetes by 9%. The aim was to investigate by a meta-analysis whether statins deteriorate glycaemic control in type 2 diabetes.Methods: Medline, EMBASE and Cochrane Central Register of Controlled Trials from 1966 to 2012 were searched for RCTs of statins. Included were only trials with type 2 diabetes.Main outcome measures: The I2 statistic was used to measure heterogeneity between trials and calculated mean differences for glycaemic parameters with random-effect meta-analysis.Results: 26 eligible studies were identified with 3232 participants. Statin therapy had no remarkable influence on HbA1c (WMD 0.04%, 95% CI -0.08 to 0.16, I² = 45.7%, n = 3070), FPG (2.25 mg/dl, 95% CI -3.50 to 7.99, I² = 46%, n = 1176), BMI, fasting insulin or HOMA-IR. However, subgroup analysis showed significant, detrimental effect of atorvastatin on HbA1c, whereas simvastatin presented an ameliorative effect. Meta-regression presented that neither baseline age nor relative reduction in LDL-cholesterol concentrations accounted for residual heterogeneity.Conclusion: Statin therapy showed non-significant effect on glycaemic control in type 2 diabetes. Statin therapy need not change among them with moderate or high cardiovascular risk or existing cardiovascular disease.

Scientific Opinion on the substantiation of a health claim related to the consumption of 2 g/day of plant stanols (as plant stanol esters) as part of a diet low in saturated fat and a two‐fold greater reduction in blood LDL‐cholesterol concentrations compared to the consumption of a diet low in saturated fat alone pursuant to Article 14 of Regulation (EC)

Following an application from McNeil Nutritionals and Raisio Nutrition Ltd, submitted for authorisation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of the United Kingdom, the Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to the consumption of 2 g/day of plant stanols (as plant stanol esters) as part of a diet low in saturated fat and a two-fold greater reduction in blood LDL-cholesterol concentrations compared to the consumption of a diet low in saturated fat alone. The food that is the subject of the health claim, plant stanol esters, is sufficiently characterised. The applicant provided five human intervention studies for the scientific substantiation of the claim. The Panel notes that the design of the studies submitted did not allow an evaluation of the quantitative effects of diets low in saturated fat per se on blood LDL-cholesterol concentrations. Therefore, the effect of consuming 2 g/day plant stanols as part of a diet low in saturated fat relative to the effect of consuming a diet low in saturated fat alone cannot be determined on a quantitative basis. The Panel considers that the evidence provided by the applicant does not establish that the consumption of 2 g/day of plant stanols (as plant stanol esters) as part of a diet low in saturated fat results in a two-fold greater reduction in LDL-cholesterol concentrations compared with consuming a diet low in saturated fat alone. A claim on plant stanol esters and reduction of blood LDL-cholesterol concentrations (irrespective of the background diet) has already been authorised in the European Union.

Does the Benefit from Statin Therapy Extend Beyond 5 Years?

Large randomized trials have shown that lowering the concentration of LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, with further benefit emerging during each year of treatment allocation. But, limited evidence is available about the long-term efficacy and safety of statin treatment. Long-term follow-up of surviving trial participants allows direct assessment of the benefits (and any hazards) of a sustained reduction in LDL cholesterol concentration during the post-trial period. Post-trial follow-up of several large statin trials (of which the Heart Protection Study was the largest) confirms that the substantial absolute benefits and cost-effectiveness of statin therapy were, in fact, underestimated in previous analyses restricted to the "in-trial" periods of randomized studies. Reassuringly, no adverse effects on cancer incidence or non-vascular mortality emerged during the extended follow-up of the Heart Protection Study. These findings support the prompt initiation and long-term continuation of statin therapy in individuals at increased vascular risk.