Effects Of Lowering LDL Cholesterol Research Articles

LDL cholesterol-lowering effect of Daeshiho-tang in patients with dyslipidemia: A pilot randomized, double-blind, placebo-controlled trial

BackgroundDyslipidemia, a major risk factor for atherosclerotic cardiovascular disease, can be prevented by lowering low-density lipoprotein cholesterol (LDL-C) levels. The lipid improvement effects of Daeshiho-tang (DSHT), a herbal formula, have been proven through various preclinical studies based on anti-obesity and anti-inflammatory properties, however, clinical trials were few. This preliminary study aimed to assess the lipid-lowering effect of DSHT in patients with dyslipidemia and examine its safety profile. The study was a randomized, double-blind, placebo-controlled trial. The trial included 60 patients with untreated dyslipidemia: total cholesterol (TC) > 200 mg/dL, triglyceride (TG) > 150 mg/dL, LDL-C >130 mg/dL, or high-density lipoprotein cholesterol (HDL-C) <40 mg/dL. Participants (mean age, 44.7 ± 13.7 years) consumed DSHT extract or an equivalent placebo at a dose of 3 g, thrice a day for 8 weeks. Participants underwent blood tests assessing serum lipid and apolipoprotein (apo) levels, including LDL-C, HDL-C, TC, TG, apoA1, and apoB, at baseline and 4 and 8 weeks. Levels of biochemical safety markers, including AST, ALT, GGT, creatinine, and eGFR, were assessed throughout the study. Between the two groups, significant differences were observed in the changes of LDL-C, TC, and apoB concentrations from baseline to post-intervention. Compared with the placebo group, DSHT-administered participants showed significantly reduced LDL-C by 14.0 ± 4.66 mg/dL (p < 0.01), TC by 13.7 ± 4.73 mg/dL (p < 0.01) and apolipoprotein-B by 7.03 ± 3.23 mg/dL (p < 0.05). No significant changes were observed in the safety biochemical parameters in either group. DSHT treatment for 8 weeks improved LDL-C levels and reduced apoB concentrations without severe adverse events.

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Effect of alirocumab on coronary plaque in patients with coronary artery disease assessed by optical coherence tomography

BackgroundProprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been demonstrated to produce significantly greater reduction in LDL cholesterol levels and cardiovascular events than standard statin therapy. However, evidence on the impact of PCSK9 inhibitors on coronary plaque composition and morphology is limited.MethodsIn this open-label randomized study, eligible patients with intermediate coronary lesions and elevated LDL cholesterol values were randomized to either alirocumab 75 mg Q2W plus statin (atorvastatin 20 mg/day or rosuvastatin 10 mg/day) therapy or standard care. Optical coherence tomography (OCT) assessments for target lesions were obtained at baseline and at 36 weeks of follow-up.ResultsLDL cholesterol levels were significantly decreased in both the alirocumab and standard care arms, whereas the absolute reduction in LDL cholesterol was significantly greater in patients treated with alirocumab (1.72 ± 0.51 vs. 0.96 ± 0.59, P < 0.0001). Compared with standard care, the addition of alirocumab to statins was associated with significantly greater increases in minimum fibrous cap thickness (18.0 [10.8–29.2] μm vs 13.2 [7.4–18.6] μm; P = 0.029), greater increases in minimum lumen area (0.20[0.10–0.33] mm2 vs 0.13 [0.12–0.24] mm2; P = 0.006) and a greater diminution in maximum lipid arc (15.1̊ [7.8–24.5] vs. 8.4̊ [2.0–10.5]; P = 0.008).ConclusionsThe addition of alirocumab to statins can not only provide additional LDL cholesterol lowering effects but also have a potential role in promoting a more stable plaque phenotype.Trial registrationClinicalTrials.gov Identifier: NCT04851769. Registered 2 Mar 2019.

Effect of Oat β-Glucan on Affective and Physical Feeling States in Healthy Adults: Evidence for Reduced Headache, Fatigue, Anxiety and Limb/Joint Pains.

The gastrointestinal (GI) side-effects of dietary fibers are recognized, but less is known about their effects on non-GI symptoms. We assessed non-GI symptoms in a trial of the LDL-cholesterol lowering effect of oat β-glucan (OBG). Participants (n = 207) with borderline high LDL-cholesterol were randomized to an OBG (1 g OBG, n = 104, n = 96 analyzed) or Control (n = 103, n = 95 analyzed) beverage 3-times daily for 4 weeks. At screening, baseline, 2 weeks and 4 weeks participants rated the severity of 16 non-GI symptoms as none, mild, moderate or severe. The occurrence and severity (more or less severe than pre-treatment) were compared using chi-squared and Fisher’s exact test, respectively. During OBG treatment, the occurrence of exhaustion and fatigue decreased versus baseline (p < 0.05). The severity of headache (2 weeks, p = 0.032), anxiety (2 weeks p = 0.059) and feeling cold (4 weeks, p = 0.040) were less on OBG than Control. The severity of fatigue and hot flashes at 4 weeks, limb/joint pain at 2 weeks and difficulty concentrating at both times decreased on OBG versus baseline. High serum c-reactive-protein and changes in c-reactive-protein, oxidized-LDL, and GI-symptom severity were associated with the occurrence and severity of several non-GI symptoms. These data provide preliminary, hypothesis-generating evidence that OBG may reduce several non-GI symptoms in healthy adults.

Prevention of Cardiovascular Events with Pitavastatin is Associated with Increased Serum Lipoprotein Lipase Mass Level: Subgroup Analysis of the TOHO-LIP.

Aim: To clarify the mechanism by which pitavastatin reduced cardiovascular (CV) events more effectively than atorvastatin in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), the changes in (Δ) non-heparinized serum level of lipoprotein lipase mass (LPL mass) during administration of the respective statins were investigated. Methods: From TOHO-LIP data, 223 hypercholesterolemic patients with any CV risks followed at Toho University Sakura Medical Center were analyzed. The patients were randomized to pitavastatin (2 mg/day) group ( n =107) or atorvastatin (10 mg/day) group ( n =116), and followed for 240 weeks. In this subgroup study, the primary and secondary end points were the same as those in TOHO-LIP, and 3-point major adverse cardiovascular events (3P-MACE) was added. The relationship between ΔLPL mass during the first year and the incidences of each end point was analyzed. Results: The lipid-lowering effect was not different between the two statins. Cumulative 240-week incidence of each end point was significantly lower in pitavastatin group (primary: 1.9% vs. 10.3%, secondary: 4.7% vs. 18.1%, 3P-MACE: 0.9% vs. 6.9%). Mean LPL mass (64.9 to 69.0 ng/mL) and eGFR (70.1 to 73.6 ml/min/1.73m 2 ) increased in pitavastatin group, but not in atorvastatin group during the first year. Cox proportional-hazards model revealed that ΔLPL mass (1 ng/mL or 1SD) contributed to almost all end points. Conclusions: Pitavastatin administration reduced CV events more efficaciously than atorvastatin despite similar LDL cholesterol-lowering effect of the two statins. Increased LPL mass during the first year by pitavastatin treatment may be associated with this efficacy.

A Moderate-Fat Diet with One Avocado per Day Increases Plasma Antioxidants and Decreases the Oxidation of Small, Dense LDL in Adults with Overweight and Obesity: A Randomized Controlled Trial

Background:Avocados are a nutrient-dense source of MUFAs and are rich in antioxidants. Avocados have an additional LDL cholesterol (LDL-C) lowering effect beyond that observed when their MUFAs are substituted for SFAs, especially on small, dense LDL (sdLDL) particles, which are susceptible to in vivo oxidation and associated with increased risk of cardiovascular disease (CVD). Objectives:We investigated whether a healthy diet with 1 avocado daily decreased the following secondary outcomes: circulating oxidized LDL (oxLDL) and related oxidative stress markers. Methods:A randomized, crossover, controlled feeding trial was conducted with 45 men and women, aged 21–70 y, with overweight or obesity and elevated LDL-C (25th–90th percentile). Three cholesterol-lowering diets were provided (5 wk each) in random sequences: a lower-fat (LF) diet (24% calories from fat—7% SFAs, 11% MUFAs, 6% PUFAs) and 2 moderate-fat (MF) diets (34% calories from fat—6% SFAs, 17% MUFAs, 9% PUFAs): the avocado (AV) diet included 1 Hass avocado (~136 g) per day, and the MF diet used high oleic acid oils to match the fatty acid profile of 1 avocado. A general linear mixed model was used to analyze the treatment effects. Results:Compared with baseline, the AV diet significantly decreased circulating oxLDL (—7.0 U/L, –8.8%, P = 0.0004)and increased plasma lutein concentration (19.6 nmol/L, 68.7%, P < 0.0001), and both changes differed significantlyfrom that after the MF and LF diets (P ≤ 0.05). The change in oxLDL caused by the AV diet was significantly correlatedwith the changes in the number of sdLDL particles (r = 0.32, P = 0.0002) but not large, buoyant LDL particles. Conclusions:One avocado a day in a heart-healthy diet decreased oxLDL in adults with overweight and obesity, and the effect was associated with the reduction in sdLDL. This trial was registered at http://www.clinicaltrials.gov as NCT01235832.

Cerivastatin for lowering lipids.

Cerivastatin was the most potent statin until it was withdrawn from the market due to a number of fatalities due to rhabdomyolysis, however, the dose-related magnitude of effect of cerivastatin on blood lipids is not known. Primary objective To quantify the effects of various doses of cerivastatin on the surrogate markers: LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides in children and adults with and without cardiovascular disease. The aim of this review is to examine the pharmacology of cerivastatin by characterizing the dose-related effect and variability of the effect of cerivastatin on surrogate markers. Secondary objectives To quantify the effect of various doses of cerivastatin compared to placebo on withdrawals due to adverse effects. To compare the relative potency of cerivastatin with respect to fluvastatin, atorvastatin and rosuvastatin for LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides. The Cochrane Hypertension Information Specialist searched the following databases for RCTs up to March 2019: CENTRAL (2019, Issue 3), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov.We also searched the European Patent Office, FDA.gov, and ProQuest Dissertations & Theses, and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. RCTs and controlled before-and-after studies evaluating the dose response of different fixed doses of cerivastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without cardiovascular disease. Two review authors independently assessed eligibility criteria for trials to be included and extracted data. We entered data from RCTs and controlled before-and-after studies into Review Manager 5 as continuous and generic inverse variance data respectively. We collected information on withdrawals due to adverse effects from the RCTs. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases. Fifty trials (19 RCTs and 31 before-and-after studies) evaluated the dose-related efficacy of cerivastatin in 12,877 participants who had their LDL cholesterol measured. The participants were of any age with and without cardiovascular disease and the trials studied cerivastatin effects within a treatment period of three to 12 weeks. Cerivastatin 0.025 mg/day to 0.8 mg/day caused LDL cholesterol decreases of 11.0% to 40.8%, total cholesterol decreases of 8.0% to 28.8% and triglyceride decreases of 9.0% to 21.4%. We judged the certainty of evidence for these effects to be high. Log dose-response data over doses of 2.5 mg to 80 mg revealed strong linear dose-related effects on LDL cholesterol, total cholesterol and triglycerides. When compared to fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250-fold more potent than fluvastatin, 20-fold more potent than atorvastatin and 5.5-fold more potent than rosuvastatin at reducing LDL cholesterol; 233-fold more potent than fluvastatin, 18-fold more potent than atorvastatin and six-fold more potent than rosuvastatin at reducing total cholesterol; and 125-fold more potent than fluvastatin, 11-fold more potent than atorvastatin and 13-fold more potent than rosuvastatin at reducing triglycerides. There was no dose-related effect of cerivastatin on HDL cholesterol, but overall cerivastatin increased HDL cholesterol by 5%. There was a high risk of bias for the outcome withdrawals due to adverse effects, but a low risk of bias for the lipid measurements. Withdrawals due to adverse effects were not different between cerivastatin and placebo in 11 of 19 of these short-term trials (risk ratio 1.09, 95% confidence interval 0.68 to 1.74). The LDL cholesterol, total cholesterol, and triglyceride lowering effect of cerivastatin was linearly dependent on dose. Cerivastatin log dose-response data were linear over the commonly prescribed dose range. Based on an informal comparison with fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250-fold more potent than fluvastatin, 20-fold more potent than atorvastatin and 5.5-fold more potent than rosuvastatin in reducing LDL cholesterol, and 233-fold greater potency than fluvastatin, 18-fold greater potency than atorvastatin and six-fold greater potency than rosuvastatin at reducing total cholesterol. This review did not provide a good estimate of the incidence of harms associated with cerivastatin because of the short duration of the trials and the lack of reporting of adverse effects in 42% of the RCTs.

Reformulation and priorities for reducing energy density; a survey on fat content in cakes and biscuits sold in British supermarkets

AbstractCakes and biscuits are widely consumed foods and are important contributors of energy, total and saturated fat and sugar in British diets. So far, the UK government has prompted the food industry to reduce energy density in cakes and biscuits mainly through sugar reformulation. However, a government led evaluation has shown that reducing only sugar has lowered energy density minimally. To assess whether total and saturated fat reformulation could be an additional and more effective mechanism for reducing product energy density we conducted a cross-sectional survey of pre-packed cakes and biscuits available in nine UK supermarkets. We collected nutrition information from product packaging. In cakes (n = 381), the mean total fat content was 17.9 ± 5.2g/100 g (39% of the overall energy); range (1.4–35.6g/100g). The average saturated fat content in cakes was 5.9 ± 3.4g/100 g (13% of the overall energy); range (0.3–20g/100g). The average sugar content in cakes was 36.6 ± 7.6 (34% of the overall energy); range (11.3–62.0g/100g). In biscuits (n = 481) the mean total fat content was 21.8g ± 6.3g/100 g (40% of the overall energy); range (0.7–38.9g/100g) and the average saturated fat content was 11.4 ± 4.9 g/100 g (23% of the overall energy); range (0.3–22.3g/100g). The average sugar content in biscuits was 30.0 ± 9.2 (23% of the overall energy); range (12.0–74.0g/100g). In both cakes and biscuits total and saturated fat, but not sugar content, was positively correlated with energy density. According to the nutrient profiling system used by the government, 57% of cakes and 75% of biscuits would receive a red (high) label for total fats; 54% of cakes and 88% of biscuits and would receive a red label for saturated fat.Our results show that cakes and biscuits sold in UK supermarkets are high in total and saturated fat, and that fat content contributes substantially to product energy density. We observed a large variation in total and saturated fat content within each product category. This finding indicates that reformulation to reduce total and saturated fat and energy density is possible as some manufacturers are already producing cake and biscuits with a more healthful nutrient composition and lower energy density. Fat reformulation in cakes and biscuits and similar products would effectively reduce energy density and calorie intake and thereby prevent obesity. We recommend that fat reformulation should be implemented simultaneously with sugar reformulation and to be focussed where possible on saturated fat, as this will have the additional and independent beneficial effect of lowering LDL cholesterol.

Almond snack consumption improves endothelial function in adults with moderate risk of cardiovascular disease: a randomised, controlled, parallel trial

AbstractEndothelial dysfunction is a predictor for cardiovascular disease risk and is a key feature of atherosclerosis. Poor diet quality, including consumption of saturated fat-rich, high-refined carbohydrate snack foods, may have adverse effects on endothelial function. Thus, snack foods, which contribute an average of 20% of energy intake in the UK adult population, present an easily identifiable target to improve vascular health. Almonds are nutrient-dense foods that are rich in unsaturated fats, fibre, minerals and non-nutrient bioactives (NNB), and may have health benefits by displacing snacks high in refined carbohydrates, enriching the diet with micronutrients and NNB, and/or low lipid bioaccessibility. Human clinical trials have demonstrated LDL cholesterol-lowering effects of daily almond consumption, yet the effects on endothelial function are unclear. This study aimed to investigate whether replacing habitual snacks (20% estimated daily energy requirements) with almonds had any impact on endothelium-dependent vasodilation, measured by flow-mediated dilatation (FMD) using ultrasound imaging of the brachial artery following reactive hyperaemia. A randomised, controlled, parallel trial in adult regular snack consumers aged 30–70 y at moderate risk of cardiovascular disease was conducted, including a 2-week run-in period with control snacks and a 6-week intervention period. Control sweet and savoury mini muffin snacks were developed to replicate the average UK snack nutrient profile, which was calculated from snack foods identified in the UK National Diet and Nutrition Survey (NDNS) database (55% energy from carbohydrate, 36% total fat (14% saturated fat), and 10% protein). One hundred and nine volunteers (77 females and 32 males; mean age 56 y) were enrolled in the study and 107 were randomised to isocaloric treatments, 1) control muffins, or 2) dry roasted whole almonds; 105 participants completed the study. Almonds significantly increased FMD relative to control (mean difference 3.6%, 95% CI 1.7, 5.5; P &lt; 0.001), indicating improved endothelial function, and LDL-cholesterol (mean difference -0.25 mmol/L, 95% CI -0.47, -0.03; P = 0.030) significantly decreased adjusted with sex, age and baseline BMI and baseline dependent outcome values. Snacking on whole almonds as a replacement for snacks high in refined starch and sugar, and low in fibre and unsaturated fatty acids, improves endothelial function. The results of this study provide further evidence for the importance of nuts in dietary strategies to reduce risk of cardiovascular disease.

LDL-cholesterol lowering effect of hydroxytyrosol (HTEssenceandreg;): A randomized double-blind, placebo-controlled parallel study

Background: Nutraceuticals containing hydroxytyrosol have been shown to exert a wide range of beneficial effects on the cardiovascular system like lipid modification and cholesterol reduction. The aim of this randomized doubleblind, placebo-controlled parallel study was to investigate the effects of a pure, synthetic form of hydroxytyrosol (HTEssence®) on the lipid profile in subjects with elevated LDL-cholesterol level. Methods: 92 subjects underwent a 12-week intervention with hydroxytyrosol or placebo. At baseline, after 6 and 12 weeks of intervention the lipid profile of the subjects was assessed.The study was conducted in accordance with the guidelines for Good Clinical Practice (GCP) andwas registered in the German Clinical Trials Register (DRKS00015251). Results: A significant delta change of LDL-cholesterol levels was observed in the hydroxytyrosol group after 12 weeks of intervention comparedto the placebo group (p=0.0454). The absolute difference between placebo and hydroxytyrosol accounted for 8.46mg/dL.With regard to the changes within the intervention groups after 12 weeks, a slight decrease of LDL-cholesterol could be observed in the hydroxytyrosol group (-2.70 mg/dL, 95% CI: -8.15- 2.75) and, in contrast, an increase of this parameter in the placebo group (5.76 mg/dL, 95% CI: 0.23– 11.28). Regarding the other parameters of lipid status including total cholesterol, HDL-cholesterol, LDL/HDL-ratio and triglycerides, no lipid modifying effects were observed. Conclusion: Data of the current clinical study support the evidence for hydroxytyrosol being a nutraceutical with anti-atherogenic effects.

Effect of mushroom polysaccharides from Pleurotus eryngii on obesity and gut microbiota in mice fed a high-fat diet.

Mushrooms are reported to have a variety of health-promoting activities. However, little information is available on the effects of intake of polysaccharides from Pleurotus eryngii on obesity. In this study, we investigated the effects of P. eryngii polysaccharides on obesity and gut microbiota in mice fed a high-fat diet. Soluble polysaccharides were extracted from P. eryngii using hot water. C57BL/6J mice were fed a standard diet (ST), a high-fat diet (HF), or HF with 1% or 5% P. eryngii polysaccharide fraction (LP or HP) for 16weeks. Adipose tissues were weighed and blood parameters were measured. Expression of genes involved in fatty acid and cholesterol metabolism was assessed by real-time quantitative PCR. The gut microbiota composition was analysed by 16S rRNA gene sequencing. Body weight gain and mesenteric fat tissue were lower in the HP group than in the HF group. In the HP group, serum total cholesterol and LDL cholesterol levels decreased, and lipid and total bile acids in faeces increased. Mice in the HP group showed increased expression of the LDLR gene in the liver and GPR43 in fat. The relative abundance of Firmicutes was significantly higher in the HF and HP groups than in the ST group. The abundance of some short-chain fatty acid-producing gut bacteria was altered by P. eryngii polysaccharides. These results provide the first evidence that P. eryngii polysaccharides have anti-obesity and LDL cholesterol-lowering effects in obese mice through increased excretion of bile acids and lipids and altered microbiota.

Inclisiran Durably Lowers Ldl-C And Pcsk9 Expression In Subjects With Homozygous Familial Hypercholesterolaemia: The Orion-2 Pilot Study

Background and Aims: Homozygous familial hypercholesterolaemia (HoFH) is a genetic disorder characterised by severely elevated plasma LDL cholesterol (LDL-C) levels and development of premature atherosclerotic cardiovascular disease. Robust and durable LDL-C lowering is essential, but additional reductions beyond what can be achieved with statins and ezetimibe are required. We evaluated the LDL-C–lowering effect and safety of inclisiran in an open-label, single-arm, multicentre pilot study in HoFH patients receiving high-intensity statin plus ezetimibe.

Reformulation and Priorities for Reducing Energy Density; Results from a Cross-Sectional Survey on Fat Content in Pre-Packed Cakes and Biscuits Sold in British Supermarkets.

Cakes and biscuits contribute to energy, total and saturated fat and sugar in British diets. So far, the UK government has prompted manufacturers to reduce energy density in these products through a reduction of their sugar content. We conducted a cross-sectional survey of the fat content of cakes and biscuits available in nine UK supermarket chains. In cakes (n = 381), the mean total fat content was 17.9 ± 5.2 g/100 g (39% of the overall energy); range (1.4–35.6 g/100 g) and the average saturated fat content in cakes was 5.9 ± 3.4 g/100 g (13% of the overall energy); range (0.3–20 g/100 g). In biscuits (n = 481), the mean total fat content was 21.8 g ± 6.3 g/100 g (40% of the overall energy); range (0.7–38.9 g/100 g) and the average saturated fat content was 11.4 ± 4.9 g/100 g (23% of the overall energy); range (0.3–22.3 g/100 g). In both cakes and biscuits, total and saturated fat content was positively correlated with energy density. Our results show that cakes and biscuits sold in UK supermarkets are high in total and saturated fat, and that fat content contributes substantially to product energy density. Fat reformulation in these products would effectively reduce energy density, calorie intake and help prevent obesity. Fat reformulation should be implemented simultaneously with sugar reformulation and be focused on saturated fat, as this will have the additional effect of lowering LDL cholesterol.

LDL-Cholesterol Lowering of Plant Sterols and Stanols-Which Factors Influence Their Efficacy?

The LDL-cholesterol (LDL-C) lowering effect of plant sterols/stanols (PSS) is summarized in several meta-analyses showing a dose-response relationship with intakes of 1.5 to 3 g/day lowering LDL-C by 7.5% to 12%. This review summarizes evidence for the impact of various factors potentially influencing the LDL-C-lowering efficacy of PSS. PSS are efficacious in all food formats and in food supplements. Some factors related to food format, e.g., solid vs. liquid foods, seem to impact efficacy, while there is no difference between free PSS and esters. Compared to multiple daily intakes, once-a-day intake of PSS, especially in the morning with light breakfast, leads to a sub-optimal LDL-C lowering. However, intake frequency seems influenced by intake occasion, i.e., with or without a meal, and time of day. Meal intake is a critical factor for an optimal LDL-C lowering efficacy of PSS. While age has no impact, gender is suggested to influence the LDL-C lowering effect of PSS with greater reductions reported for men than women; but overall evidence is inconclusive and larger studies show no gender by treatment interaction. In conclusion, PSS are efficacious in all foods and food supplements; for optimal efficacy they should be consumed with a (main) meal and twice daily.

Statement for Appropriate Clinical Use of PCSK9 Inhibitors.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that promotes the degradation of LDL receptors. Evolocumab (Repatha®), a recombinant human IgG2 antibody, and alirocumab (Praluent ®), a recombinant human IgG1 antibody, are new types of drug that lower blood LDL cholesterol (LDL-C) by inhibiting PCSK9 and increasing the number of LDL receptors on the surface of hepatocytes. In combination with statins, PCSK9 inhibitors achieve a very strong LDL-C lowering effect making them a powerful option for patients with insufficient LDL-C management with existing drugs. However, the drugs are expensive. Therefore, from the viewpoints of medical and medical economics, it is an urgent issue to identify the types of patients who really need them and would be benefitted greatly from their use. In this regard, the Japan Atherosclerosis Society would like to express its views in accordance with the JAS Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases 20171).

LDL-cholesterol lowering effect of a new dietary supplement: an open label, controlled, randomized, cross-over clinical trial in patients with mild-to-moderate hypercholesterolemia

BackgroundHypercholesterolemia is a major risk factor for cardiovascular disorders and requires specific intervention through an adequate lifestyle (diet and physical exercise) and, if necessary, an appropriate drug treatment. Lipid-lowering drugs, although generally efficacious, may sometimes cause adverse events. A growing attention has been devoted to the correction of dyslipidemias through the use of dietary supplements. The aim of this study was to assess the lipid-lowering activity and safety of a dietary supplement containing monacolin K, L-arginine, coenzyme Q10 and ascorbic acid, named Argicolina (A), compared to a commercially available product containing monacolin K and coenzyme Q10, Normolip 5 (N).MethodsThis was a single center, controlled, randomized, open-label, cross-over clinical study enrolling 20 Caucasian outpatients aged 18–75 years with serum LDL-C between 130 and 180 mg/dL. Patients assumed two different dietary supplements (A and N) both containing monacolin K 10 mg for 8 weeks each, separated by a 4-week wash-out period. Evaluated parameters were: Total cholesterol (Tot-C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting blood glucose, aspartate aminotransferase, alanine aminotransferase, creatinekinase, gamma-glutamyl-transpeptidase, brachial arterial pressure and heart rate, measured at the start and at the end of each treatment period. Safety was monitored through the study.ResultsLDL-C decreased by 23.3% during treatment with N (p < 0.0001) and by 25.6% during treatment with A (p < 0.0001); the LDL-C mean reduction was 36.4 (95% CI: 45,6–27,1) mg/dL during N treatment and 40.1 (95% CI: 49.2–30,9) mg/dL during A treatment. Tot-C decreased significantly (p < 0.0001) within each treatment period. HDL-C increase was negligible during A whereas it was significant during N. TG diminished markedly during A and not significantly during N. The difference between treatments was not statistically significant for all variables. No serious or severe adverse events occurred during the study.ConclusionsOur results confirm the clinically meaningful LDL-C lowering properties of monacolin K. At variance with a supplement already in the market (N), the novel association (A) of monacolin K with L-arginine, coenzime Q10 and ascorbic acid also produces a significant reduction of triglycerides without significant effects on HDL.Trial registrationClinicalTrials.gov ID: NCT03425630.

A low-fat spread with added plant sterols and fish omega-3 fatty acids lowers serum triglyceride and LDL-cholesterol concentrations in individuals with modest hypercholesterolaemia and hypertriglyceridaemia

PurposeThe primary and secondary objectives were to investigate the triglyceride (TG) and LDL-cholesterol (LDL-C) lowering effects of a spread with added plant sterols (PS) and fish oil as compared to a placebo spread.MethodsThis study had a randomized, double-blind, placebo-controlled, parallel group design with two intervention arms. Following a 2-week placebo run-in period, 260 healthy individuals with modestly elevated blood TG (≥ 1.4 mmol/L) and LDL-C (≥ 3.4 mmol/L) concentrations consumed either the placebo or intervention spread for 4 weeks. The intervention spread contained 2.0 g/day PS and 1.0 g/day eicosapentaenoic acid (EPA) + docosahexanoic acid (DHA) from fish oil. Fasting serum lipids and apolipoproteins (Apo) (exploratory) were measured at the end of the run-in and intervention phases.ResultsFour-week consumption of the intervention spread resulted in significantly lower TG (− 10.6%, 95% CI − 16.0 to − 4.9%; P < 0.001) and LDL-C concentrations (− 5.2%; 95% CI − 7.8 to − 2.4%) as compared to placebo. Total cholesterol (− 3.9%; 95% CI − 6.1 to − 1.5%), non-HDL-C (− 5.4%; 95% CI − 8.1 to − 2.7%), remnant-cholesterol (− 8.1%; 95% CI − 3.4 to − 12.5%), ApoAII (− 2.9%; 95% CI − 5.5 to − 0.2%), ApoCIII (− 7.7%; 95% CI − 12.1 to − 3.1%) and ApoB (− 3.2%; 95% CI − 5.9 to − 0.4%) concentrations were also significantly lower, as compared to placebo. No significant treatment effects were found for HDL-cholesterol, ApoAI, ApoCII, Apo E or ApoB/ApoAI.ConclusionsFour-week consumption of the intervention spread led to significant and clinically relevant decreases in serum TG, LDL-C and other blood lipid concentrations. The study was registered at clinicaltrials.gov (NCT 02728583).

Residual Cardiovascular Risk—Is Inflammation the Primary Cause?

Every cardiovascular clinical trial that has examined the beneficial effects of lowering LDL cholesterol to prevent cardiovascular events has demonstrated residual cardiovascular risk in the interventional treatment group. Residual risk is the term applied to the cardiovascular events (e.g., myocardial infarction, stroke, and cardiovascular death) that occur in spite of being on “optimal” medical therapy. This term is usually applied to secondary intervention studies, i.e., lipid lowering treatments in subjects who have already had at least one cardiovascular event. Studies that described residual risk have attributed it, at least in part, to the fact that the LDLc has not been lowered sufficiently to stop atherosclerotic plaque formation and rupture into the arterial lumen. However, a recent cardiovascular intervention clinical trial which achieved a very low group median LDLc of 30 mg/dl still demonstrated significant residual risk. Of more importance to reducing residual risk may be addressing the ongoing inflammation in the coronary arteries that results in cellular liberation of cytokines and proteases that attack the atherosclerotic plaque’s fibrous cap. Recent studies have shown that inflammation may act independently of LDL to cause cardiovascular events. This article provides evidence that inflammation is the primary cause of residual risk and will need to be treated as aggressively as LDL lowering if CVD events in the post treatment period are to be significantly reduced. Addressing major risk factors including obesity, diabetes, smoking, hypertension and hyperlipidemia are critical to reducing inflammation. Statins and aspirin are the mainstay medications to reduce ongoing inflammation. However, newer pharmaceuticals may also be required to reduce inflammation to undetectable levels. Targeting inflammation to eradicate residual cardiovascular risk will be the next therapeutic challenge facing primary care physicians.

Antisense oligonucleotide and thyroid hormone conjugates for obesity treatment

Using the principle of antibody-drug conjugates that deliver highly potent cytotoxic agents to cancer cells for cancer therapy, we here report the synthesis of antisense-oligonucleotides (ASO) and thyroid hormone T3 conjugates for obesity treatment. ASOs primarily target fat and liver with poor penetrance to other organs. Pharmacological T3 treatment increases energy expenditure and causes weight loss, but is contraindicated for obesity treatment due to systemic effects on multiple organs. We hypothesize that ASO-T3 conjugates may knock down target genes and enrich T3 action in fat and liver. Two established ASOs are tested. Nicotinamide N-methyltransferase (NNMT)-ASO prevents diet-induced obesity in mice. Apolipoprotein B (ApoB)-ASO is an FDA approved drug for treating familial hypercholesterolemia. NNMT-ASO and ApoB-ASO are chemically conjugated with T3 using a non-cleavable sulfo-SMCC linker. Both NNMT-ASO-T3 (NAT3) and ApoB-ASO-T3 (AAT3) enhance thyroid hormone receptor activity. Treating obese mice with NAT3 or AAT3 decreases adiposity and increases lean mass. ASO-T3 enhances white fat browning, decreases genes for fatty acid synthesis in liver, and shows limited effects on T3 target genes in heart and muscle. Furthermore, AAT3 augments LDL cholesterol-lowering effects of ApoB-ASO. Therefore, ASO and hormone/drug conjugation may provide a novel strategy for obesity and hyperlipidemia treatment.

Effects of Antrodia Camphorata Mycelia Extract Containing Antroquinonol on Lowering Low-Density Lipoprotein Cholesterol: A Randomized Double-Blind Study

Objective: Antrodia camphorata is a type of true fungus that grows only on Cinnamomum camphora trees, also known as Cinnamomum kanehirae (“kashi”) in Taiwan. Antroquinonol is a characteristic component of A. camphorata mycelia extract and was previously shown to exhibit antitumor action and lower blood cholesterol (total cholesterol and low-density lipoprotein [LDL] cholesterol) in cellular and animal models. So, This study examined the ability of A. camphorata mycelia extract to reduce LDL cholesterol in humans. Methods: We conducted a randomized double-blind trial in 26 subjects with either borderline LDL cholesterol (120–139 mg/dL; n = 11) or mildly elevated LDL cholesterol (140–159 mg/dL; n = 15). Participants ingested tablets containing either 25 mg of A. camphorata mycelia extract (antroquinonol: 0.68 mg; n = 14) or a placebo (n = 12) for 12 weeks. Results: The test group showed a significant reduction in LDL cholesterol when compared with the placebo group after 12 weeks of tablet ingestion (p &lt; 0.05), demonstrating the effects of A. camphorata mycelia extract on LDL cholesterol. A. camphorata mycelia extract also tended to reduce total cholesterol when compared with the placebo (p &lt; 0.10). The borderline LDL cholesterol and mildly elevated LDL cholesterol subgroups showed a significant reduction in LDL cholesterol in subjects who ingested A. camphorata mycelia extract compared with those who ingested the placebo, again demonstrating the LDL cholesterol-lowering effect of the extract. Conclusion: A. camphorata mycelia extract lowers LDL cholesterol in individuals with somewhat high LDL cholesterol levels. This clinical trial was registered with the University Hospital Medical Information Network (UMIN no. # 000019670).