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Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a new specific vascular inflammation biomarker that is carried by the lipoproteins in the blood and plays a prominent role in the pathogenesis of atherosclerosis. Increased Lp-PLA2 levels and impaired Lp-PLA2 distribution across high-density lipoprotein (HDL) and non-HDL lipoproteins have been reported in diabetic patients, which is associated with the increase in cardiovascular disease (CVD) risk. This study is aimed at investigating the effect of alpha lipoic acid (ALA), as an antioxidant with potential cardioprotective properties, on the Lp-PLA2 mass and its distribution in diabetic patients. In a double-blind, randomized, placebo-controlled clinical trial, seventy diabetic patients were randomly allocated to ALA (1200 mg ALA as two 600 mg capsules/day) and placebo (two maltodextrin capsules/day) groups. The serum levels of total Lp-PLA2 mass, HDL-Lp-PLA2, oxidized low-density lipoproteins (ox-LDL), apolipoprotein A1 (apo A1), lipid profiles, fasting blood sugar (FBS), and insulin were measured, and apolipoprotein B- (apoB-) associated Lp-PLA2 and homeostasis model of assessment index (HOMA-IR) were calculated at the baseline and after 8 weeks of intervention. ALA significantly decreased the ox-LDL, total Lp-PLA2 mass, apoB-associated Lp-PLA2, and percent of apoB-associated Lp-PLA2 and triglyceride and increased the percent of HDL-Lp-PLA2 compared with the placebo group but had no significant effect on HDL-Lp-PLA2 mass, apo A1, lipid profiles, and glycemic indices. There was a positive correlation between the reduction in the ox-LDL level and total Lp-PLA2 mass in the ALA group. In conclusion, ALA may decrease the CVD risk by reducing the ox-LDL and Lp-PLA2 mass and improving the Lp-PLA2 distribution among lipoproteins in type 2 diabetic patients.

BackgroundCardiovascular disease (CVD) is the leading cause of death in children with chronic kidney disease (CKD) and accounts for 40% of all deaths among pediatric patients with stage 5 chronic kidney disease (CKD 5). Dyslipidemia is common in children with CKD and is considered one of the major causes of CVD in these patients. As carnitine plays a key role in lipid metabolism and because plasma levels are reduced in hemodialysis patients, the aim of this study was to determine the effects of L-carnitine supplementation on serum lipid profiles, apolipoproteins, and free carnitine (FC) levels.MethodsA total of 30 children on hemodialysis (6–18 years) were enrolled and 24 completed the study. Twelve patients received 50 mg/kg/day L-carnitine, while the other 12 patients received placebo for 10 weeks. Serum FC, total cholesterol (TC), LDL-C, HDL-C, TG, Apolipoprotein B (ApoB), and Apolipoprotein A1 (ApoA1) were determined at the baseline and after the intervention. One-way repeated measures analysis was used to evaluate the effects of L-carnitine supplementation.ResultsOral L-carnitine supplementation led to decreased ApoB levels and ApoB/ApoA1 ratio, but these changes were not significant compared to placebo. Meanwhile, L-carnitine supplementation significantly reduced serum LDL-C and TC and increased serum FC compared to placebo. No significant changes were observed in serum TG and HDL-C levels.ConclusionGiven the significant reduction in LDL-C and TC levels, L-carnitine supplementation had positive effects on improving hyperlipidemia in children receiving hemodialysis. For more decisive results, studies with longer duration of L-carnitine therapy on children receiving hemodialysis with significant dyslipidemia are recommended.Trial registrationWe registered the present trial in the Iranian Registry of Clinical Trials website (available at: http://www.irct.ir, identifier: IRCT20170202032367N2).

Activation of Peroxisome Proliferator–Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men Ulf Risérus 1 , Dennis Sprecher 2 , Tony Johnson 2 , Eric Olson 2 , Sandra Hirschberg 2 , Aixue Liu 3 , Zeke Fang 4 , Priti Hegde 5 , Duncan Richards 6 , Leli Sarov-Blat 5 , Jay C. Strum 5 , Samar Basu 7 , Jane Cheeseman 1 , Barbara A. Fielding 1 , Sandy M. Humphreys 1 , Theodore Danoff 3 , Niall R. Moore 8 , Peter Murgatroyd 9 , Stephen O'Rahilly 10 , Pauline Sutton 1 , Tim Willson 11 , David Hassall 12 , Keith N. Frayn 1 and Fredrik Karpe 1 1 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K 2 Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 3 Human Target Validation, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 4 Statistics, GlaxoSmithKline, King of Prussia, Pennsylvania 5 Clinical Pharmacology and Discovery Medicine/Cardiovascular and Urogenital (CPDM CVU) Unit, GlaxoSmithKline, King of Prussia, Pennsylvania 6 Addenbrooke's Centre for Clinical Investigation (ACCI) Unit, GlaxoSmithKline, Cambridge, U.K 7 Department of Public Health, University of Uppsala, Uppsala, Sweden 8 Department of Radiology, Churchill Hospital, University of Oxford, Oxford, U.K 9 Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital, Cambridge, U.K 10 Department of Clinical Biochemistry and Medicine, University of Cambridge, Cambridge, U.K 11 GlaxoSmithKline, Research Triangle Park, North Carolina 12 GlaxoSmithKline, Stevenage, U.K Address correspondence and reprint requests to Dr. F. Karpe, Churchill Hospital, Oxford OX3 7LJ, U.K. E-mail: fredrik.karpe{at}ocdem.ox.ac.uk Abstract OBJECTIVE— Pharmacological use of peroxisome proliferator–activated receptor (PPAR)δ agonists and transgenic overexpression of PPARδ in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS— The PPARδ agonist (10 mg o.d. GW501516), a comparator PPARα agonist (20 μg o.d. GW590735), and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS— Treatment with GW501516 showed statistically significant reductions in fasting plasma triglycerides (−30%), apolipoprotein B (−26%), LDL cholesterol (−23%), and insulin (−11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content ( P < 0.05) and 30% reduction in urinary isoprostanes ( P = 0.01) were also observed. Except for a lowering of triglycerides (−30%, P < 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO 2 directly originating from the fat content of the meal was increased ( P < 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b ( CPT1b ) was also significantly increased. CONCLUSIONS— The PPARδ agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle. Apo, apolipoprotein AST, aspartate aminotransferase AUC, area under the curve γGT, γ-glutamyltransferase LCM, laser capture microdissection LPL, lipoprotein lipase MRI, magnetic resonance imaging NEFA, nonesterified fatty acid TTR, tracer-to-tracee ratio Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 16 November 2007. DOI: 10.2337/db07-1318. U.R. and D.S. contributed equally to this work. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1318 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 10, 2007. Received September 14, 2007. DIABETES

The present study was designed to evaluate the independent and interactive effects of a once-a-day yoghurt drink providing 2 g plant sterols/d and capsules providing 2 g fish oil n-3 long-chain (LC) PUFA/d on plasma lipids, apolipoproteins and LDL particle size. Following a 2-week run-in period, 200 mildly hypercholesterolaemic Indian adults aged 35–55 years were randomised into one of four groups of a 2 × 2 factorial, double-blind controlled trial. The 4-week treatments consisted of (1) control yoghurt drink and control capsules, (2) control yoghurt drink and fish oil capsules, (3) plant sterol-enriched yoghurt drink and control capsules, or (4) plant sterol-enriched yoghurt drink and fish oil capsules. Blood was drawn before and after the 4-week intervention. Changes in health status, lifestyle and dietary habits, and daily compliance were recorded. The main effects of plant sterols were a 4·5 % reduction in LDL-cholesterol and a 15 % reduction in TAG without a significant change in HDL-cholesterol. Overall, fish oil n-3 LC-PUFA did not significantly affect cholesterol concentrations but reduced TAG by 15 % and increased HDL-cholesterol by 5·4 %. The combination significantly lowered TAG by 15 % v. control. No significant interaction between plant sterols and n-3 LC-PUFA was observed on plasma cholesterol concentrations. In conclusion, once-a-day intake of 2 g plant sterols/d in a yoghurt drink, 2 g fish oil n-3 LC-PUFA/d in capsules, and their combination had beneficial effects on the lipid profile of mildly hypercholesterolaemic Indian adults. The potent hypotriacylglycerolaemic effect of plant sterols observed in the present study and this population warrants additional investigation.

OBJECTIVE:--We hypothesized that simvastatin may reduce adiponectin levels and insulin sensitivity in hypercholesterolemic patients. RESEARCH DESIGN AND METHODS--This was a randomized, double-blind, placebo-controlled, parallel study. Age, sex, and BMI were matched. Thirty-two patients were given placebo, and 30, 32, 31, and 31 patients were given daily 10, 20, 40, and 80 mg simvastatin, respectively, during a 2-month treatment period. RESULTS:--Simvastatin doses of 10, 20, 40, and 80 mg significantly reduced total cholesterol (mean changes 27, 25, 37, and 38%), LDL cholesterol (39, 38, 52, and 54%), and apolipoprotein B levels (24, 30, 36, and 42%) and improved flow-mediated dilation (FMD) (68, 40, 49, and 63%) after 2 months of therapy compared with baseline (P < 0.001 by paired t test) or compared with placebo (P < 0.001 by ANOVA). Simvastatin doses of 10, 20, 40, and 80 mg significantly decreased plasma adiponectin levels (4, 12, 5, and 10%) and insulin sensitivity (determined by the Quantitative Insulin-Sensitivity Check Index [QUICKI]) (5, 8, 6, and 6%) compared with baseline (P < 0.05 by paired t test) or compared with placebo (P = 0.011 for adiponectin and P = 0.034 for QUICKI by ANOVA). However, the magnitudes of these percent changes (FMD, adiponectin, and QUICKI) were not significantly different among four different doses of simvastatin despite dose-dependent changes in the reduction of apolipoprotein B levels. CONCLUSIONS:--Simvastatin significantly improved endothelium-dependent dilation, but reduced adiponectin levels and insulin sensitivity in hypercholesterolemic patients independent of dose and the extent of apolipoprotein B reduction.

The aim of this study was to assess the effects of 1 and 2 mg 17beta-estradiol on serum lipid profile. Beneficial effects have been clearly established in previous studies with a 2 mg dose; further evidence was required to confirm the beneficial effects of a 1 mg dose. This double-blind, placebo-controlled study involved 579 postmenopausal women randomized to oral treatment with placebo, 1 mg/day 17beta-estradiol sequentially combined with 5 or 10 mg/day dydrogesterone for the last 14 days of each 28-day cycle, or 2 mg/day 17beta-estradiol sequentially combined with 10 or 20 mg/day dydrogesterone for the last 14 days of each 28-day cycle. Treatment was continued for 26 cycles. High density lipoprotein (HDL) cholesterol levels were significantly (p<0.05) increased after 26 cycles in all active treatment groups compared with placebo. In addition, low density lipoprotein (LDL) cholesterol and lipoprotein(a) levels were significantly reduced, and apolipoprotein A1 and triglyceride levels were significantly increased, in all active treatment groups after 13 and 26 cycles. The results of this study clearly indicate that sequential combinations of either 1 or 2 mg 17beta-estradiol with dydrogesterone are associated with long-term, favorable changes in the serum lipid profile. There was no evidence that dydrogesterone compromised the 17beta-estradiol-induced improvements in lipid profile.

The APOE ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease and the APOE ε2 allele the strongest genetic protective factor after multiple large scale genome-wide association studies and genome-wide association meta-analyses. However, no therapies directed at APOE are currently available. Although initial studies causally linked APOE with amyloid-β peptide aggregation and clearance, over the past 5 years our understanding of APOE pathogenesis has expanded beyond amyloid-β peptide-centric mechanisms to tau neurofibrillary degeneration, microglia and astrocyte responses, and blood–brain barrier disruption. Because all these pathological processes can potentially contribute to cognitive impairment, it is important to use this new knowledge to develop therapies directed at APOE. Several therapeutic approaches have been successful in mouse models expressing human APOE alleles, including increasing or reducing APOE levels, enhancing its lipidation, blocking the interactions between APOE and amyloid-β peptide, and genetically switching APOE4 to APOE3 or APOE2 isoforms, but translation to human clinical trials has proven challenging.

Aims/hypothesis In addition to its efficacy in reducing LDL-cholesterol, rosuvastatin has been shown to significantly decrease plasma triacylglycerol. The use of rosuvastatin may be beneficial in patients with type 2 diabetes, who usually have increased triacylglycerol levels. However, its effects on the metabolism of triacylglycerol-rich lipoproteins in type 2 diabetic patients remains unknown. Methods We performed a randomised double-blind crossover trial of 6-week treatment with placebo or rosuvastatin 20 mg in eight patients with type 2 diabetes who were being treated with oral glucose-lowering agents. In each patient, an in vivo kinetic study of apolipoprotein B (ApoB)-containing lipoproteins with [¹³C]leucine was performed at the end of each treatment period. A central randomisation centre used computer-generated tables to allocate treatments. Participants, caregivers and those assessing the outcomes were blinded to group assignment. Results Rosuvastatin 20 mg significantly reduced plasma LDL-cholesterol, triacylglycerol and total ApoB. It also significantly reduced ApoB pool sizes of larger triacylglycerol-rich VLDL particles (VLDL1; p = 0.011), smaller VLDL particles (VLDL2; p = 0.011), intermediate density lipoprotein (IDL; p = 0.011) and LDL (p = 0.011). This reduction was associated with a significant increase in the total fractional catabolic rate of VLDL1-ApoB (6.70 ± 3.24 vs 4.52 ± 2.34 pool/day, p = 0.049), VLDL2-ApoB (8.72 ± 3.37 vs 5.36 ± 2.64, p = 0.011), IDL-ApoB (7.06 ± 1.68 vs 4.21 ± 1.51, p = 0.011) and LDL-ApoB (1.02 ± 0.27 vs 0.59 ± 0.13, p = 0.011). Rosuvastatin did not change the production rates of VLDL2-, IDL- or LDL-, but did reduce VLDL1-ApoB production rate (12.4 ± 4.5 vs 19.5 ± 8.4 mg kg⁻¹ day⁻¹, p = 0.035). No side effects of rosuvastatin were observed during the study. Conclusions/interpretation In type 2 diabetic patients rosuvastatin 20 mg not only induces a significant increase of LDL-ApoB catabolism (73%), but also has favourable effects on the catabolism of triacylglycerol-rich lipoproteins, e.g. a significant increase in the catabolism of VLDL1-ApoB (48%), VLDL2-ApoB (63%) and IDL-ApoB (68%), and a reduction in the production rate of VLDL1-ApoB (-36%). The effects of rosuvastatin on the metabolism of triacylglycerol-rich lipoproteins may be beneficial for prevention of atherosclerosis in type 2 diabetic patients. Trial registration: ClinicalTrials.gov NCT00658463 Funding: This study was supported by a grant from AstraZeneca.

Apolipoprotein (apo)C-III is a constituent of HDL (HDL apoC-III) and of apoB-containing lipoproteins (LpB:C-III). It slows the clearance of triglyceride-rich lipoproteins (TRLs) by inhibition of the activity of the enzyme lipoprotein lipase (LPL) and by interference with lipoprotein binding to cell-surface receptors. Elevated plasma LpB:C-III is an independent risk factor for cardiovascular disease. We studied the effect of atorvastatin on plasma LpB:C-III and HDL apoC-III. We studied the effect of 30 weeks' treatment with 10 and 80 mg atorvastatin on plasma apoC-III levels in a randomized, double-blind, placebo-controlled trial involving 217 patients with type 2 diabetes and fasting plasma triglycerides between 1.5 and 6.0 mmol/l. Baseline levels of total plasma apoC-III, HDL apoC-III, and LpB:C-III were 41.5 +/- 10.0, 17.7 +/- 5.5, and 23.8 +/- 7.7 mg/l, respectively. Plasma apoC-III was strongly correlated with plasma triglycerides (r = 0.74, P < 0.001). Atorvastatin 10- and 80-mg treatment significantly decreased plasma apoC-III (atorvastatin 10 mg, 21%, and 80 mg, 27%), HDL apoC-III (atorvastatin 10 mg, 22%, and 80 mg, 28%) and LpB:C-III (atorvastatin 10 mg, 23%, and 80 mg, 28%; all P < 0.001). The decrease in plasma apoC-III, mainly in LpB:C-III, strongly correlated with a decrease in triglycerides (atorvastatin 10 mg, r = 0.70, and 80 mg, r = 0.78; P < 0.001). Atorvastatin treatment also leads to a reduction in the HDL apoC-III-to-HDL cholesterol and HDL apoC-III-to-apoA-I ratios, indicating a change in the number of apoC-III per HDL particle (atorvastatin 10 mg, -21%, and 80 mg, -31%; P < 0.001). Atorvastatin treatment resulted in a significant dose-dependent reduction in plasma apoC-III, HDL apoC-III, and LpB:C-III levels in patients with type 2 diabetes. These data indicate a potentially important antiatherogenic effect of statin treatment and may explain (part of) the triglyceride-lowering effect of atorvastatin.

Plasma phospholipid transfer protein (PLTP) plays an important role in lipoprotein metabolism. PLTP activity is elevated in patients with diabetes, a condition with strongly elevated risk for coronary heart disease. The aim of this study was to test the hypothesis that statins reduce PLTP activity and to examine the potential role of apolipoprotein E (apoE). PLTP activity and apoE were measured in patients with type 2 diabetes from the DALI (Diabetes Atorvastatin Lipid Intervention) Study, a 30-week randomized double-blind placebo-controlled trial with atorvastatin (10 and 80 mg daily). At baseline, PLTP activity was positively correlated with waist circumference, HbA(1c), glucose, and apoE (all P < 0.05). Atorvastatin treatment resulted in decreased PLTP activity (10 mg atorvastatin: -8.3%, P < 0.05; 80 mg atorvastatin: -12.1%, P < 0.002). Plasma apoE decreased by 28 and 36%, respectively (P < 0.001). The decrease in apoE was strongly related to the decrease in PLTP activity (r = 0.565, P < 0.001). The change in apoE remained the sole determinant of the change in PLTP activity in a multivariate model. The activity of PLTP in type 2 diabetes is decreased by atorvastatin. The association between the decrease in PLTP activity and apoE during statin treatment supports the hypothesis that apoE may prevent PLTP inactivation.