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1.
Cerebrotendinous xanthomatosis, sitosterolemia, Smith-Lemli-Opitz syndrome and the seminal contributions of Gerald Salen, MD (1935-2020).
Schaefer, EJ, Tint, GS, Duell, PB, Steiner, RD
Journal of clinical lipidology. 2021;(4):540-544
Abstract
Cerebrotendinous xanthomatosis (CTX), sitosterolemia, and Smith-Lemli Opitz syndrome (SLOS) are rare inborn errors of metabolism. The diagnoses of CTX and sitosterolemia are often delayed for many years because of lack of physician awareness, often resulting in significant and unnecessary progression of disease. CTX may present with chronic diarrhea, juvenile onset cataracts, strikingly large xanthomas, and neurologic disease in the setting of a normal serum cholesterol, but markedly elevated serum or plasma cholestanol levels. These patients have a defect in producing the bile acid chenodoxycholate, and oral chenodeoxycholate therapy is essential for these patients in order to prevent neurologic complications. Sitosterolemia can present with xanthomas, anemia, thrombocytopenia, splenomegaly, very premature heart disease, and serum cholesterol levels that may be normal or elevated, along with marked elevations of plasma β-sitosterol. These patients have a defect causing overabsorption of β-sitosterol, and the treatment of choice is oral ezetimibe. SLOS presents with growth delay, intellectual disability, multiple structural anomalies, and low serum cholesterol levels, and the defect is reduced cholesterol production. Treatment consists of dietary cholesterol supplementation and oral bile acid therapy which raises serum cholesterol levels and may improve symptoms. The metabolic and genetic defects in these disorders have been defined. There is no one in our field that has contributed more to the diagnosis and treatment of these disorders than Gerald Salen, MD, who died in late 2020 at 85 years of age. He will be greatly missed by his family, friends, and colleagues from around the world.
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2.
An overview of rosuvastatin/ezetimibe association for the treatment of hypercholesterolemia and mixed dyslipidemia.
Strilchuk, L, Tocci, G, Fogacci, F, Cicero, AFG
Expert opinion on pharmacotherapy. 2020;(5):531-539
Abstract
Introduction: Although statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe.Areas covered: This paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)).Expert opinion: The additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.
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3.
Population Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis of LY3015014, a Monoclonal Antibody to Protein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Healthy Subjects and Hypercholesterolemia Patients.
Shen, T, James, DE, Krueger, KA
Pharmaceutical research. 2017;(1):185-192
Abstract
PURPOSE LY3015014 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to the catalytic domain of PCSK9 and reduce low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia that is poorly controlled by maximally tolerated statin therapy. The objective of this pharmacokinetic/pharmacodynamics (PK/PD) analysis was to characterize the PK and PD properties of LY3015014 and assess the effect of covariates on the LY3015014 PK-PD profiles. METHODS Single and multiple dose data from three phase1 studies in healthy subjects (n = 133), as well as a phase 2 study in hypercholesterolemia patients (n = 527) were combined into a single dataset for analysis. In this dataset, healthy subjects received single intravenous (IV) doses of 0.03 to 10 mg/kg, or multiple subcutaneous (SC) doses of 1.0 to 3.0 mg/kg, administered every 2 to 4 weeks, while patients received 20 to 300 mg every 4 weeks or 100 to 300 every 8 weeks. PK/PD analysis was performed using NONMEM (ICON, software version 7.0 level 3). PK and PD modeling were conducted sequentially, with PK parameters fixed during the development of the PK/PD model. PD parameters and estimated intersubject and intrasubject variability were obtained based on pharmacological drug exposure-response relationships. Age, baseline total PCSK9, body weight, diabetes diagnosis, hypercholesterolemia disease status, dose, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and satin administration were evaluated as potential covariates in the PK model. Baseline total PCSK9, baseline LDL-C, diabetes diagnosis, disease status, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and Statin administration were evaluated as potential covariates in the PD model. RESULTS LY3015014 PK profile was consistent across all the studies and between healthy subjects and hypercholesterolemia patients. The PK time course data were well described by a two compartment PK model with first order absorption, and covariates identified for PK parameters included weight on both clearance (CL) and central volume (V2), dose on CL, race on bioavailability (F), and age on V2. The PD (LDL-C) was described using an indirect response model with LY3015014 acting to stimulate the elimination of LDL-C. Covariates identified to have a statistically significant impact on PD were coadministration of statins, baseline LDL-C, metabolic syndrome status and gender. CONCLUSIONS The population PK/PD model adequately describes the PK and PD profiles of LY3015014. Identification of clinically significant covariates will support the design and dose selection for the pivotal registration studies, ensuring that patients are dosed appropriately.
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4.
Low-carbohydrate and high-fat intake can manage obesity and associated conditions: occasional survey.
Noakes, TD
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. 2013;(11):826-30
Abstract
This study analyses 127 communications from individuals self-reporting their weight change following adoption of a low-carbohydrate, high-fat (LCHF) eating plan. Total combined self-reported weight loss was 1 900 kg (range 5 kg gain to 84 kg loss). The mean ± standard deviation weight loss of 15 (±12) kg is among the largest yet described. Sixteen subjects reported the LCHF 'cured' (i.e. medications no longer required) one or more of their medical conditions, most commonly type 2 diabetes mellitus (T2DM) (n=14), hypertension (n=8) and hypercholesterolaemia (n=7). Another 9 subjects with either type 1 diabetes mellitus or T2DM reduced medications as did 7 patients with hypertension; 8 no longer suffered from irritable bowel syndrome. These data show that significant and rapid weight loss is possible on an unsupervised eating plan that severely restricts daily carbohydrate intake to approximately <75 g/day. Better weight loss on a carbohydrate-restricted LCHF eating plan than on an iso-caloric high-carbohydrate, low-fat (HCLF) diet is well described in the literature, probably due to a paradoxical reduction of hunger by carbohydrate restriction. A randomised controlled clinical trial is urgently required to disprove the hypothesis that the LCHF eating plan can reverse cases of T2DM, metabolic syndrome and hypertension without pharmacotherapy.
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5.
Key points for maximum effectiveness and safety for cholesterol-lowering properties of plant sterols and use in the treatment of metabolic syndrome.
Rondanelli, M, Monteferrario, F, Faliva, MA, Perna, S, Antoniello, N
Journal of the science of food and agriculture. 2013;(11):2605-10
Abstract
According to the American Diabetes Association and the Adult Treatment Panel III, the starting point for treating metabolic syndrome (MS) is a change of lifestyle. In addition, action on the main symptoms of MS by means of dietary supplements, can be helpful in view of the chronic course of the disease. The term 'phytosterols' refers to sterols and stanols composed of lipophilic triterpenes, a family that is widely distributed in the plant kingdom and whose cholesterol-lowering properties have been amply demonstrated. In the light of the recent literature, the key points for maximum effectiveness and safety of sterols are the following. (A) Plant sterols should be taken with meals: clinical trials have shown that when plant sterols are consumed close to mealtimes, low-density lipoprotein cholesterol may decrease by 9.4%, while when they are taken between meals, the reduction is about 6%. (B) The optimal dosage is 2-2.5 g day(-1) in a single dose. More than 3 g day(-1) has not been found to have any additional beneficial effect and increases the risk of side effects. (C) The food matrix used to dissolve the phytosterols should contain a certain amount of fat. A milk-based matrix appears optimal from this point of view.
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6.
[An inhibitor of intestinal cholesterol transporter].
Sano, M
Nihon rinsho. Japanese journal of clinical medicine. 2013;(9):1661-6
Abstract
Ezetimibe is a unique inhibitor of intestinal cholesterol absorption. Ezetimibe selectively inhibits intestinal cholesterol absorption by blocking Niemann-Pick C1-like 1 (NPCIL1). Ezetimibe accelerates VLDL and TG degradation. Therefore, ezetimibe ameliorates postprandial hyperlipidemia. Ezetimibe inhibited the progression of nonalcoholic fatty liver disease (NAFLD) by correcting insulin resistance and decreasing small dense LDL-C in human subjects. In clinical study, ezetimibe administration combined with statin failed to inhibit progression of IMT thickness in ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) study. In this study baseline IMT thickness (0.7 mm) of patients was within normal range. Therefore only two years observation was too short to demonstrate anti-atherogenic effects of ezetimibe. SEAS(Simvastatin and Ezetimibe in Aortic Stenosis) trial examined effects of combination therapy with ezetimibe and statin in patients with aortic stenosis. Combination therapy could not inhibit progression of aortic stenosis. However, events of ischemic heart disease, especially CABG were significantly decreased only in combination group. Statin was not reported to reduce CVD(cardiovascular disease) in moderate to severe CKD patients. In SHARP(Study of Heart and Renal Protection) study, patients with severe renal disease were allocated either for statin alone group or combination therapy group with statin and ezetimibe. Combination therapy significantly decreased non-hemorrhagic stroke by 25 % compared with statin alone group in severe CKD and HD(hemodialysis) patients. Ezetimibe has unique lipid lowering profile increasing HDL-C concomitant with decreasing LDL-C and TG. Ezetimibe should be initiated first in patients with insulin resistant metabolic syndrome. Ezetimibe should be combined with statin to reduce not only LDL-C but RLP-C(remnant like lipoprotein particle choletserol) in type IIb dyslipidemia.
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7.
Effects of ezetimibe on visceral fat in the metabolic syndrome: a randomised controlled study.
Takase, H, Dohi, Y, Okado, T, Hashimoto, T, Goto, Y, Kimura, G
European journal of clinical investigation. 2012;(12):1287-94
Abstract
BACKGROUND Although visceral obesity, a key abnormality in the metabolic syndrome, is an important risk for cardiovascular diseases, reduction in visceral fat is hard to achieve despite intensive efforts directed at lifestyle modification. The present study was designed to investigate whether ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1, reduces visceral fat in patients with metabolic syndrome. MATERIALS AND METHODS Seventy-eight outpatients (63·7 ± 10·4 years old) with metabolic syndrome were enroled and randomly assigned to receive either ezetimibe (10 mg/day) or nothing for 6 months. Changes in visceral fat were assessed by computed tomography. RESULTS Treatment with ezetimibe significantly improved lipid profiles. Visceral fat was decreased 7·2%, from 161·3 ± 58·6 cm(2) to 148·4 ± 52·7 cm(2) (P < 0·05), and adiponectin was increased 7·7%, from 3·61 ± 3·10 μg/mL to 3·86 ± 3·62 μg/mL (P < 0·05), after ezetimibe therapy; these beneficial effects were not observed in the control group. The increase in the adiponectin level was correlated with the reduction in visceral fat after ezetimibe treatment. Furthermore, ezetimibe reduced fasting insulin levels (P < 0·05) and improved the homoeostasis model assessment of insulin resistance (HOMA-IR) (P < 0·05). CONCLUSIONS Ezetimibe reduces visceral fat with beneficial effects on adiponectin and insulin resistance in patients with metabolic syndrome, suggesting a new therapeutic approach in such patients.
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8.
Lipid disorders in uremia and dialysis.
Bakris, GL
Contributions to nephrology. 2012;:100-105
Abstract
Treatment of cholesterol in people with advanced stage chronic kidney disease (CKD) clearly reduces cardiovascular risk; however, it does not significantly slow nephropathy progression. Moreover, cholesterol reduction does not reduce mortality in people on dialysis. In general, cholesterol reduction is very important for reducing cardiovascular risk in people with GFR values >15 ml/min who are not on dialysis. There are many reasons for the lack cardiovascular risk reduction with cholesterol lowering in dialysis patients including a defective HDL and higher than usual oxidation rates of LDL. The reviews some of the biochemistry of lipids in uremia and discusses the randomized trial data that support these statements and provides greater detail regarding use of statin in patients with stages 4 and 5 CKD. Caution should be used in dosing statins in stage 3b or higher CKD. Specifically, all statins except for atorvastatin and pravastatin need dose reductions due to safety issues. Given the more 'metabolic syndrome like' profile of lipids in stage 5 CKD adjunctive methods such as fibrates and omega-3 is discussed, however no good data are available in this group on outcomes with these agents.
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9.
A Mediterranean-style low-glycemic-load diet improves variables of metabolic syndrome in women, and addition of a phytochemical-rich medical food enhances benefits on lipoprotein metabolism.
Jones, JL, Fernandez, ML, McIntosh, MS, Najm, W, Calle, MC, Kalynych, C, Vukich, C, Barona, J, Ackermann, D, Kim, JE, et al
Journal of clinical lipidology. 2011;(3):188-196
Abstract
BACKGROUND The high prevalence of metabolic syndrome (MetS) has highlighted the need for effective dietary interventions to combat this growing problem. OBJECTIVE To assess the impact of a Mediterranean-style low-glycemic-load diet (control arm, n = 44) or the same diet plus a medical food containing phytosterols, soy protein, and extracts from hops and acacia (intervention arm, n = 45) on cardiometabolic risk variables in women with MetS. METHODS In this 12-week, 2-arm randomized trial, baseline, week 8 and 12, fasting blood samples were drawn to measure plasma lipids, apolipoproteins, and homocysteine. Dietary records were also collected and analyzed. RESULTS There were decreases in fat and sugar intake (P < .001 for both) and increases in docosahexaenoic acid and eicosapentaenoic acid intake (P < .001 for both) over time, consistent with the prescribed diet. Regarding MetS variables, there were decreases in waist circumference, systolic and diastolic blood pressure, and plasma triglycerides in all subjects (P < .001 for all) with no differences between arms. Plasma low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein (apo) B, and apo B/apo A1 were reduced over time but to a greater extent in the intervention arm (P < .05 for all), indicating the medical food had a greater effect in altering lipoprotein metabolism. Further, medical food intake was associated with reduced plasma homocysteine (P < .01) compared to the control arm. CONCLUSION A Mediterranean-style low-glycemic-load diet effectively reduces the variables of MetS. Addition of the medical food results in a less atherogenic lipoprotein profile and lower plasma homocysteine.
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10.
Metabolic syndrome and changes in body fat from a low-fat diet and/or exercise randomized controlled trial.
Camhi, SM, Stefanick, ML, Katzmarzyk, PT, Young, DR
Obesity (Silver Spring, Md.). 2010;(3):548-54
Abstract
It is difficult to identify the successful component(s) related to changes in metabolic syndrome (MetS) from lifestyle interventions: the weight loss, the behavior change, or the combination. The purpose of this study is to determine the effects of a weight-stable randomized controlled trial of low-fat diet and exercise, alone and in combination, on MetS. Men (n = 179) and postmenopausal women (n = 149) with elevated low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) were randomized into a 1-year, weight-stable trial with four treatment groups: control (C), diet (D), exercise (E), or diet plus exercise (D+E). MetS was defined using a continuous score. Changes in MetS score (DeltaMetS) were compared between groups using analysis of covariance, stratified by gender and using two models, with and without baseline and change in percent body fat (DeltaBF) as a covariate. In men, DeltaMetS was higher for D vs. C (P = 0.04), D+E vs. C (P = 0.0002), and D+E vs. E (P = 0.02). For women, DeltaMetS was greater for D vs. C (P = 0.045), E vs. C (P = 0.02), and D+E vs. C (P = 0.004). After adjusting for DeltaBF, all differences between groups were attenuated and no longer significant. DeltaMetS were associated with DeltaBF for both men (P < 0.0001) and women (P = 0.004). After adjustment for DeltaBF, low-fat diet alone and in combination with exercise had no effect on MetS. The key component for MetS from low-fat diet and/or increased physical activity appears to be body fat loss.