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A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9.
Zeitlinger, M, Bauer, M, Reindl-Schwaighofer, R, Stoekenbroek, RM, Lambert, G, Berger-Sieczkowski, E, Lagler, H, Oesterreicher, Z, Wulkersdorfer, B, Lührs, P, et al
European journal of clinical pharmacology. 2021;(10):1473-1484
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Abstract
PURPOSE AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. METHODS This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. RESULTS The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%. CONCLUSIONS Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. TRIAL REGISTRATION EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.
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Comparison of diets enriched in stearic, oleic, and palmitic acids on inflammation, immune response, cardiometabolic risk factors, and fecal bile acid concentrations in mildly hypercholesterolemic postmenopausal women-randomized crossover trial.
Meng, H, Matthan, NR, Wu, D, Li, L, Rodríguez-Morató, J, Cohen, R, Galluccio, JM, Dolnikowski, GG, Lichtenstein, AH
The American journal of clinical nutrition. 2019;(2):305-315
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Abstract
BACKGROUND Direct comparisons between SFAs varying in chain length, specifically palmitic acid (16:0) and stearic acid (18:0), relative to the latter's metabolic product, oleic acid (18:1), on cardiometabolic risk factors are limited. OBJECTIVE The aim of this study was to determine the relative comparability of diets enriched in palmitic acid, stearic acid, and oleic acid on inflammation and coagulation markers, T lymphocyte proliferation/ex-vivo cytokine secretion, plasma cardiometabolic risk factors, and fecal bile acid concentrations. METHODS Hypercholesterolemic postmenopausal women (n = 20, mean ± SD age 64 ± 7 y, BMI 26.4 ± 3.4 kg/m2, LDL cholesterol ≥ 2.8 mmol/L) were provided with each of 3 diets [55% energy (%E) carbohydrate, 15%E protein, 30%E fat, with ∼50% fat contributed by palmitic acid, stearic acid, or oleic acid in each diet; 5 wk/diet phase] using a randomized crossover design with 2-wk washouts between phases. Outcome measures were assessed at the end of each phase. RESULTS Fasting LDL-cholesterol and non-HDL-cholesterol concentrations were lower after the stearic acid and oleic acid diets than the palmitic acid diet (all P < 0.01). Fasting HDL-cholesterol concentrations were lower after the stearic acid diet than the palmitic acid and oleic acid diets (P < 0.01). The stearic acid diet resulted in lower lithocholic acid (P = 0.01) and total secondary bile acid (SBA) concentrations (P = 0.04) than the oleic acid diet. All other outcome measures were similar between diets. Lithocholic acid concentrations were positively correlated with fasting LDL-cholesterol concentrations (r = 0.33; P = 0.011). Total SBA, lithocholic acid, and deoxycholic acid concentrations were negatively correlated with fasting HDL cholesterol (r = -0.51 to -0.44; P < 0.01) concentrations and positively correlated with LDL cholesterol:HDL cholesterol (r = 0.37-0.54; P < 0.01) ratios. CONCLUSIONS Dietary stearic acid and oleic acid had similar effects on fasting LDL-cholesterol and non-HDL-cholesterol concentrations and more favorable ones than palmitic acid. Unlike oleic acid, the hypocholesterolemic effect of stearic acid may be mediated by inhibition of intestinal hydrophobic SBA synthesis. These findings add to the data suggesting there should be a reassessment of current SFA dietary guidance and Nutrient Facts panel labeling.This trial was registered at clinicaltrials.gov as NCT02145936.
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An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults.
Costabile, A, Buttarazzi, I, Kolida, S, Quercia, S, Baldini, J, Swann, JR, Brigidi, P, Gibson, GR
PloS one. 2017;(12):e0187964
Abstract
UNLABELLED Coronary heart disease (CHD) is one of the major causes of death and disability in industrialised countries, with elevated blood cholesterol an established risk factor. Total plasma cholesterol reduction in populations suffering from primary hypercholesterolemia may lower CHD incidence. This study investigated the cholesterol reducing capacity of Lactobacillus plantarum ECGC 13110402, a strain selected for its high bile salt hydrolase activity, in 49 normal to mildly hypercholesterolaemic adults. Primary efficacy outcomes included effect on blood lipids (total cholesterol (TC), low density lipoproteins (LDL-C), high density lipoproteins (HDL-C) and triacylgycerides (TAG), inflammatory biomarkers and occurrence/severity of gastrointestinal side effects to establish safety and tolerance of the intervention. Secondary outcomes included blood pressure, immune biomarkers, gut microbiota characterisation and metabonome changes. The study was run in a parallel, double blind, placebo controlled, randomised design in which the active group ingested 2x109 CFU encapsulated Lactobacillus plantarum ECGC 13110402 twice daily. Daily ingestion of the active treatment resulted in a statistically significant reduction in LDL-C in volunteers with baseline TC<5mM during the 0-12 week period (13.9%, P = 0.030), a significant reduction in TC in volunteers with baseline TC≥6mM in the 0-6 week period (37.6%, P = 0.045), a significant decrease in TAG (53.9% P = 0.030) and an increase in HDL-C (14.7%, P = 0.007) in the over 60 years population in the 6-12 week period. A statistically significant reduction in systolic blood pressure was also observed across the active study group in the 6-12-week period (6.6%, P = 0.003). No impact on gastrointestinal function and side effects was observed during the study. Similar to blood and urine metabonomic analyses, faecal metagenomics did not reveal significant changes upon active or placebo intake. The results of this study suggest that Lactobacillus plantarum ECGC 13110402 is a well-tolerated, natural probiotic, that may be used as an alternative or supplement to existing treatments to reduce cardiovascular risk. TRIAL REGISTRATION Clinical trials.gov NCT03263104.
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Influence of Phenol-Enriched Olive Oils on Human Intestinal Immune Function.
Martín-Peláez, S, Castañer, O, Solà, R, Motilva, MJ, Castell, M, Pérez-Cano, FJ, Fitó, M
Nutrients. 2016;(4):213
Abstract
Olive oil (OO) phenolic compounds (PC) are able to influence gut microbial populations and metabolic output. Our aim was to investigate whether these compounds and changes affect the mucosal immune system. In a randomized, controlled, double blind cross-over human trial, for three weeks, preceded by two-week washout periods, 10 hypercholesterolemic participants ingested 25 mL/day of three raw virgin OO differing in their PC concentration and origin: (1) an OO containing 80 mg PC/kg (VOO); (2) a PC-enriched OO containing 500 mg PC/kg from OO (FVOO); and (3) a PC-enriched OO containing a mixture of 500 mg PC/kg from OO and thyme (1:1, FVOOT). Intestinal immunity (fecal immunoglobulin A (IgA) and IgA-coated bacteria) and inflammation markers (C-reactive protein (CRP) and fecal interleukin 6 (IL-6), tumor necrosis factor α (TNFα) and calprotectin) was analyzed. The ingestion of high amounts of OO PC, as contained in FVOO, tended to increase the proportions of IgA-coated bacteria and increased plasma levels of CRP. However, lower amounts of OO PC (VOO) and the combination of two PC sources (FVOOT) did not show significant effects on the variables investigated. Results indicate a potential stimulation of the immune system with very high doses of OO PC, which should be further investigated.
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Effects of simvastatin on carotenoid status in plasma.
Rydén, M, Leanderson, P, Kastbom, KO, Jonasson, L
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2012;(1):66-71
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Abstract
BACKGROUND AND AIMS Carotenoids are potent antioxidants mainly transported in the low density lipoprotein (LDL) fraction. They may also influence the immune response and inverse associations with inflammatory markers have been reported. We investigated whether simvastatin, by exerting both lipid-lowering and anti-inflammatory effects, altered the carotenoid status in plasma. METHODS AND RESULTS A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. Lipids, oxidized LDL (ox-LDL), C-reactive protein (CRP), interleukin (IL)-6, oxygenated carotenoids (lutein, zeaxanthin, β-cryptoxanthin) and hydrocarbon carotenoids (α-carotene, β-carotene, lycopene) were measured in plasma. Simvastatin use was associated with significant reductions in total cholesterol, LDL, ox-LDL and CRP. Simvastatin therapy also resulted in reduced plasma levels of both oxygenated and hydrocarbon carotenoids. However, when adjusted for lipids, all carotenoids except β-cryptoxanthin showed significant increases after simvastatin therapy. Both crude and lipid-adjusted carotenoids were inversely correlated with CRP and IL-6 in plasma but the change in carotenoid status during simvastatin therapy was not specifically related to any changes in inflammatory markers. CONCLUSIONS To summarize, the change in carotenoid status during simvastatin therapy was mainly attributed to the lowering of cholesterol and not to the suppression of inflammatory activity. After adjustment for lipids, the levels of lutein, lycopene, α-carotene and β-carotene were significantly increased by simvastatin suggesting an increased ratio of carotenoids per particle.