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1.
Medicine (Baltimore) ; 99(19): e20189, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384512

RESUMO

We aim to explore the relationship between early-onset diabetes and proliferative diabetic retinopathy (PDR) in type 2 diabetes mellitus (T2DM) patients with microalbuminuria.A total of 461 T2DM patients with microalbuminuria were enrolled. Subjects were defined as early-onset or late-onset based on the age at which they were diagnosed with diabetes (<40 and ≥40 years, respectively). Medical history, anthropometry, and laboratory indicators were documented. PDR was defined as the presence of any of the following changes on fundus photography: neovascularization, vitreous hemorrhage, or preretinal hemorrhage.The prevalence of PDR was 6-fold higher in patients with early-onset than late-onset T2DM [(6.1% vs 1.0%), P = .004]. Univariate correlation analysis showed that early-onset diabetes, use of oral hypoglycemic drugs, and insulin therapy were risk factors for PDR. In multivariate logistic analysis, patients with early-onset diabetes exhibited a 7.00-fold [(95% confidence interval 1.40-38.26), P = .019] higher risk of PDR than subjects with late-onset diabetes after adjusting for sex; T2DM duration; systolic blood pressure; total triglyceride; glycated hemoglobin; insulin therapy; and the use of oral hypoglycemic drugs, antihypertensive drugs, and lipid-lowering drugs.In T2DM patients with microalbuminuria, early-onset diabetes is an independent risk factor for the development of PDR.


Assuntos
Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Albuminúria/classificação , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Pesos e Medidas Corporais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
2.
Adv Exp Med Biol ; 1177: 133-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32246446

RESUMO

Coronary artery disease (CAD) is one of the leading causes of death worldwide. It is well known that dyslipidemia is a major pathogenic risk factor for atherosclerosis and CAD, which results in cardiac ischemic injury and myocardial infarction. Lipid-modifying drugs can effectively improve lipid abnormalities including reducing low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) or increasing high-density lipoprotein cholesterol (HDL-C), and eventually decrease the incidence of cardiovascular events. This chapter will review basic principles of lipid metabolism and focus on the therapeutic strategies of lipids modifying drugs (statins, proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, niacin, polyunsaturated fatty acids, and so on) in patients with arteriosclerotic cardiovascular disease. Meanwhile, the challenges and perspectives of the lipid-lowering agents currently in clinical practice as well as their limitations will be outlined.


Assuntos
Hipolipemiantes/farmacologia , Lipídeos/sangue , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
4.
High Blood Press Cardiovasc Prev ; 27(2): 157-164, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32219670

RESUMO

INTRODUCTION: Cardiovascular diseases (CVD) represent the first cause of mortality in western countries. Hypertension and dyslipidemia are strong risk factors for CVD, and are prevalent either alone or in combination. Although effective substances for the treatment of both factors are available, there is space for optimization of treatment regimens due to poor patient's adherence to medication, which is usually a combination of several substances. Adherence decreases with the number of pills a patient needs to take. A combination of substances in one single-pill (single pill combination, SPC), might increase adherence, and lead to a better clinical outcome. AIM: We conducted a meta-analysis to compare the effect of SPC with that of free-combination treatment (FCT) in patients with either hypertension, dyslipidemia or the combination of both diseases under conditions of daily practice. METHODS: Studies were identified by searching in PubMed from November 2014 until February 2015. Search criteria focused on trials in identical hypertension and/or dyslipidemia treatment as FCT therapy or as SPC. Adherence and persistence outcome included proportion-of-days-covered (PDC), medication possession ratio (MPR), time-to treatment gap of 30 and 60 days and no treatment gap of 30 days (y/n). Clinical outcomes were all cause hospitalisation, hypertension-related hospitalisation, all cause emergency room visits, hypertension-related emergency room visits, outpatient visits, hypertension-related outpatient visits, and number of patients reaching blood pressure goal. Randomized clinical studies were excluded because they usually do not reflect daily practice. RESULTS: 11 out of 1.465 studies met the predefined inclusion criteria. PDC ≥ 80% showed an odds ratio (OR) of 1.78 (95% CI: 1.30-2.45; p = 0.004) after 6 months and an OR of 1.85 (95% CI: 1.71; 2.37; p < 0.001) after ≥ 12 months in favour to the SPC. MPR ≥ 80% after 12 months also was in favour to SPC (OR 2.13; 95% CI: 1.30; 3.47; p = 0.003). Persistence was positively affected by SPC after 6, 12, and 18 months. Time to treatment gap of 60 days resulted in a hazard ratio (HR) of 2.03 (95% CI: 1.77; 2.33, p < 0.001). The use of SPC was associated with a significant improvement in systolic blood pressure reduction, leading to a higher number of patients reaching individual blood pressure goals (FCT vs SPC results in OR = 0.77; 95% CI: 0.69; 0.85, p < 0.001). Outpatient visits, emergency room visits and hospitalisations, both overall and hypertension-related were reduced by SPC: all-cause hospitalisation (SPC vs FCT: 15.0% vs 18.2%, OR 0.79, 95% CI 0.67; 0.94, p = 0.009), all-cause emergency room visits (SPC vs FCT: 25.7% vs 31.4%, OR 0.75, 95% CI 0.65; 0.87, p = 0.001) and hypertension related emergency room visits (SPC vs FCT: 9.7% vs 14.1%, OR 0.65, 95% CI 0.54; 0.80, p < 0.001). CONCLUSIONS: SPC improved medication adherence and clinical outcome parameter in patients suffering from hypertension and/or dyslipidemia and led to a better clinical outcome compared to FCT under conditions of daily practice.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Lipídeos/sangue , Adesão à Medicação , Administração Oral , Idoso , Anti-Hipertensivos/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Esquema de Medicação , Combinação de Medicamentos , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Comprimidos , Fatores de Tempo , Resultado do Tratamento
5.
Rev Med Suisse ; 16(684): 438-443, 2020 Mar 04.
Artigo em Francês | MEDLINE | ID: mdl-32134222

RESUMO

Experts' guidelines for the management of dyslipidemias differ from country to country, with important differences between medical societies of Europe and the United States. Recently, new American and European guidelines have been established. These guidelines mainly differ for cardiovascular risk stratification in secondary prevention, and for LDL-cholesterol (LDL-c) goals to achieve. Similitudes between guidelines include the global strategy to initiate lipid-lowering drugs, which is based first on the global cardiovascular risk, then on the LDL-c level. We are here presenting a comparison and an interpretation of these guidelines.


Assuntos
LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/uso terapêutico , Guias de Prática Clínica como Assunto , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/complicações , Europa (Continente) , Humanos , Fatores de Risco , Estados Unidos
6.
PLoS One ; 15(3): e0229541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130251

RESUMO

BACKGROUND: Hyperlipidemia and hypertension are modifiable risk factors for Alzheimer's disease and related dementias (ADRD). Approximately 25% of adults over age 65 use both antihypertensives (AHTs) and statins for these conditions. While a growing body of evidence found statins and AHTs are independently associated with lower ADRD risk, no evidence exists on simultaneous use for different drug class combinations and ADRD risk. Our primary objective was to compare ADRD risk associated with concurrent use of different combinations of statins and antihypertensives. METHODS: In a retrospective cohort study (2007-2014), we analyzed 694,672 Medicare beneficiaries in the United States (2,017,786 person-years) who concurrently used both statins and AHTs. Using logistic regression adjusting for age, socioeconomic status and comorbidities, we quantified incident ADRD diagnosis associated with concurrent use of different statin molecules (atorvastatin, pravastatin, rosuvastatin, and simvastatin) and AHT drug classes (two renin-angiotensin system (RAS)-acting AHTs, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers (ARBs), vs non-RAS-acting AHTs). FINDINGS: Pravastatin or rosuvastatin combined with RAS-acting AHTs reduce risk of ADRD relative to any statin combined with non-RAS-acting AHTs: ACEI+pravastatin odds ratio (OR) = 0.942 (CI: 0.899-0.986, p = 0.011), ACEI+rosuvastatin OR = 0.841 (CI: 0.794-0.892, p<0.001), ARB+pravastatin OR = 0.794 (CI: 0.748-0.843, p<0.001), ARB+rosuvastatin OR = 0.818 (CI: 0.765-0.874, p<0.001). ARBs combined with atorvastatin and simvastatin are associated with smaller reductions in risk, and ACEI with no risk reduction, compared to when combined with pravastatin or rosuvastatin. Among Hispanics, no combination of statins and RAS-acting AHTs reduces risk relative to combinations of statins and non-RAS-acting AHTs. Among blacks using ACEI+rosuvastatin, ADRD odds were 33% lower compared to blacks using other statins combined with non-RAS-acting AHTs (OR = 0.672 (CI: 0.548-0.825, p<0.001)). CONCLUSION: Among older Americans, use of pravastatin and rosuvastatin to treat hyperlipidemia is less common than use of simvastatin and atorvastatin, however, in combination with RAS-acting AHTs, particularly ARBs, they may be more effective at reducing risk of ADRD. The number of Americans with ADRD may be reduced with drug treatments for vascular health that also confer effects on ADRD.


Assuntos
Doença de Alzheimer/prevenção & controle , Anti-Hipertensivos/administração & dosagem , Demência/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Estudos de Coortes , Demência/epidemiologia , Demência/etiologia , Quimioterapia Combinada , Feminino , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Incidência , Modelos Logísticos , Masculino , Medicare , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
7.
Int J Nanomedicine ; 15: 705-715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099359

RESUMO

Background: Bezafibrate is a BCS class II drug as it presents very low solubility in water; therefore, its bioavailability after oral administration is very poor. The aim of this work was to enhance solubility and dissolution rate of bezafibrate in water in order to enhance its oral bioavailability. Methods: Several formulations were prepared using PVP K30 and Cremophor ELP employing the solvent-evaporation method and the electrospraying technique. Solubility, release rate, bioavailability in male Sprague Dawley rats, and lipid profile attributes in Wistar rats were assessed in comparison with bezafibrate plain powder. Solid-state characterization was carried out using X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). Results: All the formulations exerted positive effect towards the desired goal. In particular, the optimized formulation furnished about 14-fold enhanced solubility and 85.48 ± 10.16% drug was released in 10 min as compared with bezafibrate alone (4.06 ± 2.59%). The drug existed in the amorphous state in the prepared sample as confirmed by XRD and DSC, whilst no drug-excipient interactions were observed through FTIR analysis. Moreover, SEM revealed smooth-surfaced spherical particles of the optimized formulation. A 5.5-fold higher oral bioavailability was achieved with the optimized formulation in comparison with bezafibrate plain powder. Also, TG, LDL and TC were decreased, and HDL was increased considerably in HFD-treated rats. Conclusion: The optimized formulation consisting of bezafibrate, PVP K30 and cremophor ELP (1/12/1.5, w/w/w) might be a capable drug delivery system for orally administering poorly water-soluble bezafibrate with improved bioavailability and antihyperlipidemic effects.


Assuntos
Bezafibrato/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Hipolipemiantes/farmacologia , Nanosferas/química , Polímeros/química , Administração Oral , Animais , Bezafibrato/administração & dosagem , Bezafibrato/sangue , Bezafibrato/farmacocinética , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Interações Hidrofóbicas e Hidrofílicas , Hipolipemiantes/administração & dosagem , Hipolipemiantes/sangue , Hipolipemiantes/farmacocinética , Lipídeos/química , Masculino , Nanosferas/ultraestrutura , Polietilenoglicóis/química , Povidona/química , Pós , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
8.
Metabolism ; 105: 154188, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32084431

RESUMO

OBJECTIVES: Lipoprotein lipase (LPL) catalyzes the hydrolysis of circulating triglycerides into free fatty acids (FFA) and thereby promotes FFA uptake in peripheral tissues. LPL is negatively regulated by angiopoietin-like protein 4 (ANGPTL4) presumably by an FFA-dependent mechanism. Growth hormone (GH) suppresses LPL activity, but it is unknown whether this is mediated by FFA and ANGPTL4. Therefore, we investigated the concerted effect of GH on ANGPTL4 and LPL in the presence and absence of lipolysis in two in vivo studies in human subjects. METHODS: In a randomized, placebo-controlled, cross-over study, nine obese men were examined after injection of 1) a GH bolus, and 2) a GH-receptor antagonist followed by four adipose tissue biopsies obtained over a 5-h period. In a second study, nine hypopituitary men were examined in a 2 × 2 factorial design including GH and acipimox (an anti-lipolytic agent), with biopsies from adipose tissue and skeletal muscle obtained during a basal period and a subsequent hyperinsulinemic-euglycemic clamp. The mRNA expression of ANGPTL4 and LPL as well as LPL activity were analyzed in the biopsies. RESULTS: In both studies, GH increased serum FFA levels, upregulated ANGPTL4 mRNA expression and suppressed LPL activity. In study 2, acipimox completely suppressed FFA levels and antagonized the effects of GH on ANGPTL4 and LPL. CONCLUSIONS: These human in vivo studies demonstrate that GH upregulates ANGPTL4 mRNA and suppresses LPL activity via an FFA-dependent mechanism.


Assuntos
Proteína 4 Semelhante a Angiopoietina/biossíntese , Ácidos Graxos/metabolismo , Hormônio do Crescimento Humano/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Estudos Cross-Over , Ácidos Graxos não Esterificados/sangue , Hormônio do Crescimento Humano/antagonistas & inibidores , Humanos , Hipolipemiantes/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia , Pirazinas/uso terapêutico , RNA Mensageiro/biossíntese , Método Simples-Cego , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
9.
PLoS One ; 15(1): e0228004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990936

RESUMO

Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.


Assuntos
Apolipoproteína B-48/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Pirimidinas/uso terapêutico , Adiponectina/sangue , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Dislipidemias/sangue , Jejum/sangue , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
10.
N Engl J Med ; 382(3): 244-255, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31893580

RESUMO

BACKGROUND: Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS: The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS: APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Lipoproteína(a)/sangue , Oligonucleotídeos/administração & dosagem , Adulto , Idoso , Doenças Cardiovasculares/sangue , Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Hipolipemiantes/uso terapêutico , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/efeitos adversos , Fatores de Risco
11.
Expert Opin Pharmacother ; 21(1): 107-120, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31738617

RESUMO

Introduction: Hypertriglyceridemia is associated with both the development of cardiovascular disease (CVD) when mild-to-moderate and high risk of pancreatitis when more severe. The residual CVD risk after low-density lipoprotein cholesterol (LDL-C) lowering is, in part, attributed to high triglyceride (TG) levels. Therefore, there appears to be a need for effective TG-lowering agents.Areas covered: This review presents the most recent advances in hypertriglyceridemia treatment; specifically, it discusses the results of clinical trials and critically comments on apolipoprotein C-III inhibitors, angiopoietin-like 3 inhibitors, alipogene tiparvovec, pradigastat, pemafibrate and novel formulations of omega-3 fatty acids.Expert opinion: In the era of extreme lowering of LDL-C levels with several agents, there seems to be space for novel therapeutic options to combat parameters responsible for residual CVD risk, among which are elevated TGs. Furthermore, a significant number of individuals have very high TG levels and encounter the risk of acute pancreatitis. The most recently developed TG-lowering drugs appear to have a role in both conditions; the choice is mainly based on baseline TG levels. Dyslipidemia guidelines are likely to change in the near future to include some of these agents. Of course, long-term data regarding their safety and efficacy in terms of CVD outcomes and pancreatitis are warranted.


Assuntos
Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Doença Aguda , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Pancreatite/prevenção & controle , Triglicerídeos/sangue
12.
Arterioscler Thromb Vasc Biol ; 40(1): 255-266, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578080

RESUMO

OBJECTIVE: High Lp(a) (lipoprotein[a]) cause cardiovascular disease (CVD) in a primary prevention setting; however, it is debated whether high Lp(a) lead to recurrent CVD events. We tested the latter hypothesis and estimated the Lp(a)-lowering needed for 5 years to reduce CVD events in a secondary prevention setting. Approach and Results: From the CGPS (Copenhagen General Population Study; 2003-2015) of 58 527 individuals with measurements of Lp(a), 2527 aged 20 to 79 with a history of CVD were studied. The primary end point was major adverse cardiovascular event (MACE). We also studied 1115 individuals with CVD from the CCHS (Copenhagen City Heart Study; 1991-1994) and the CIHDS (Copenhagen Ischemic Heart Disease Study; 1991-1993). During a median follow-up of 5 years (range, 0-13), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1000 person-years were 29 (95% CI, 25-34) for individuals with Lp(a)<10 mg/dL, 35 (30-41) for 10 to 49 mg/dL, 42 (34-51) for 50 to 99 mg/dL, and 54 (42-70) for ≥100 mg/dL. Compared with individuals with Lp(a)<10 mg/dL (18 nmol/L), the multifactorially adjusted MACE incidence rate ratios were 1.28 (95% CI, 1.03-1.58) for 10 to 49 mg/dL (18-104 nmol/L), 1.44 (1.12-1.85) for 50 to 99 mg/dL (105-213 nmol/L), and 2.14 (1.57-2.92) for ≥100 mg/dL (214 nmol/L). Independent confirmation was obtained in individuals from the CCHS and CIHDS. To achieve 20% and 40% MACE risk reduction in secondary prevention, we estimated that plasma Lp(a) should be lowered by 50 mg/dL (95% CI, 27-138; 105 nmol/L [55-297]) and 99 mg/dL (95% CI, 54-273; 212 nmol/L [114-592]) for 5 years. CONCLUSIONS: High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population. This study suggests that Lp(a)-lowering by 50 mg/dL (105 nmol/L) short-term (ie, 5 years) may reduce CVD by 20% in a secondary prevention setting.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Hipolipemiantes/uso terapêutico , Lipoproteína(a)/sangue , Vigilância da População/métodos , Prevenção Secundária/métodos , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Lipoproteína(a)/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Adulto Jovem
13.
J Orthop Res ; 38(2): 297-310, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31471919

RESUMO

Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt-related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin-induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25-dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation-promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:297-310, 2020.


Assuntos
Tumor de Células Gigantes do Osso/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Sinvastatina/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Tumor de Células Gigantes do Osso/metabolismo , Humanos , Hipolipemiantes/farmacologia , Sinvastatina/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo
14.
Mayo Clin Proc ; 95(1): 77-89, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31630870

RESUMO

OBJECTIVE: To investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI). PATIENTS AND METHODS: The analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo. RESULTS: In ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.1%±12.4%), mild RI group (74.2%±12.3%), moderate RI group (79.8%±4.9%), and severe RI group (67.9%±16.4%) (P<.001 vs placebo in all groups). Low-density lipoprotein cholesterol levels were significantly reduced versus placebo: normal renal function, 57.6%±10.7%; mild RI, 35.1%±13.5%; moderate RI, 53.1%±21.3%; severe RI, 49.2%±26.6% (P<.001 for all). In ORION-1, PCSK9 level reductions at day 180 were 48.3% to 58.6% in the 300-mg single-dose groups and 67.3% to 73.0% in the 300-mg 2-dose groups (P<.001 vs placebo in all groups). The corresponding low-density lipoprotein cholesterol level reductions were 35.7% to 40.2% in the 300-mg single-dose groups and 50.9% to 58.0% in the 300 mg 2-dose groups (P<.001 vs placebo in all groups). In ORION-7, exposure to inclisiran was proportionally greater in individuals with increasing RI; inclisiran was undetectable in plasma 48 hours after administration in any group. CONCLUSION: The pharmacodynamic effects and safety profile of inclisiran were similar in study participants with normal and impaired renal function. Dose adjustments of inclisiran are not required in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT02597127 and NCT03159416.


Assuntos
LDL-Colesterol/sangue , Doença da Artéria Coronariana , RNA Interferente Pequeno , Insuficiência Renal , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/efeitos adversos , Hipolipemiantes/farmacocinética , Testes de Função Renal/métodos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Insuficiência Renal/diagnóstico , Insuficiência Renal/fisiopatologia , Resultado do Tratamento
15.
J Agric Food Chem ; 68(1): 147-159, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31826616

RESUMO

This study was aimed at investigating the hypoglycemic and hypolipidemic effects of a polysaccharide (RTFP) isolated from Rosa roxburghii Tratt fruit on type-2 diabetic db/db mice. The results indicated that the oral administration of RTFP could significantly decrease the body weight, fat, and liver hypertrophy and the levels of fasting blood glucose, serum insulin, and serum lipids of the db/db mice. Histopathological observation showed that RTFP could effectively protect the pancreas, liver, and epididymal fat against damage and dysfunction. Real-time quantitative polymerase chain reaction analysis confirmed that the gene expression levels of peroxisome proliferator-activated receptors-γ (PPAR-γ), sterol regulatory element-binding protein-1 (SREBP-1c), acetyl-CoA carboxylase-1 (ACC-1), fatty acid synthase (FAS), and glucose-6-phosphatase (G6 Pase) were significantly down-regulated in the liver of db/db mice after treatment with RTFP. Moreover, RTFP treatment reversed gut dysbiosis by lowering the Firmicutes-to-Bacteroidetes ratio and enhancing the relative abundances of beneficial bacteria including Bacteroidaceae, Bacteroidaceae S24-7 group, and Lactobacillaceae. These findings suggest that RTFP can be used as a promising functional supplement for the prevention and treatment of type-2 diabetes mellitus.


Assuntos
Colo/microbiologia , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Extratos Vegetais/administração & dosagem , Polissacarídeos/administração & dosagem , Rosa/química , Animais , Colo/metabolismo , Modelos Animais de Doenças , Frutas/química , Microbioma Gastrointestinal , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/microbiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Triglicerídeos/metabolismo
16.
Curr Med Chem ; 27(2): 317-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-29865996

RESUMO

BACKGROUND: The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a transmembrane protein playing a crucial role in effective lipid homeostasis. Various therapeutic agents have been used in the management of dyslipidemias, however, the outcome of therapeutic target is debated. OBJECTIVE: The aim of this review is to summarize and fully understand the current concept regarding LDL-R and its molecular properties, metabolic pathway, factors affecting LDL-R activity and all available pharmacological interventions. Additionally, non-lipid related properties of LDL-R are also referred. METHODS: Literature from the PubMed database was extracted to identify papers between 1984 to 2017 regarding LDL-R and therapeutic agents on dyslipidemia management. RESULTS: We analyzed basic data regarding agents associated with LDL-R (Sterol Regulating Element-Binding Proteins - SREBPs, Protein ARH, IDOL, Thyroid Hormones, Haematologic Disorders, Protein convertase subtilisin kexintype 9 - PCSK-9, ApoC-III) as well as non-lipid related properties of LDL-R, while all relevant (common and novel) pharmacological interventions (statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and PCSK- 9) are also referred. CONCLUSION: LDL-R and its molecular properties are involved in lipid homeostasis, so potentially sets the therapeutic goals in cardiovascular patients, which is usually debated. Further research is needed in order to fully understand its properties, as well as to find the potential pharmacological interventions that could be beneficial in cholesterol homeostasis and various morbidities in order to reach the most appropriate therapeutic goal.


Assuntos
Lipoproteínas LDL/metabolismo , Colesterol , Dislipidemias , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipolipemiantes , Pró-Proteína Convertase 9
17.
J Manag Care Spec Pharm ; 26(1): 35-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31880222

RESUMO

INTRODUCTION: The Medicare 5-star quality rating system was designed to drive improvements in Medicare quality and to increase accountability among Medicare plans. Medicare star ratings provide significant bonuses for plans that improve medication adherence. Envolve's pharmacy division, Envolve Pharmacy Solutions, which provides services for Medicare Advantage Prescription Drug plans, developed an in-house medication therapy management (MTM) program to improve adherence rates and subsequent star ratings. As part of this program, Envolve invested in motivational interviewing (MI) as a means to improve adherence to antihypertensives, antihyperlipidemics, and antidiabetics but recognized the need for additional staff training to ensure pharmacist success with MI techniques. Thus, Envolve engaged a consultant to help train pharmacists and evaluate the program. This best practices article describes the implementation of an MI program and subsequent changes in patient adherence and star ratings. PROGRAM DESCRIPTION: A pharmacist-led, patient-centered adherence program incorporating MI for behavior change was developed and implemented at Envolve. The program used didactic learning, coaching and skills assessments, and a train-the-trainer (TtT) intervention. This approach resulted in improved adherence rates in all 3 therapeutic classes immediately. In addition, a quality improvement process was incorporated to evaluate the improvements in adherence with this new program over 24 months. OBSERVATIONS: Key findings of the program are as follows: (a) the program increased adherence rates 5-9 percentage points (chi-square tests for all plans and drug classes measured, P < 0.05) over 5 years and improved Medicare star ratings by 1-2 stars; (b) there is a need for support of pharmacy MTM managers to ensure continued success of the program; and (c) there is value in a TtT program for managers that allows them to provide continuous evaluation and feedback to staff for improvement. IMPLICATIONS: Each year, as the Medicare star ratings system matures and plans are held more accountable for improving adherence measures, high star ratings become more difficult to attain. This MI TtT program for pharmacists allows for rapid cycle change in response to these challenges. DISCLOSURES: Funding was provided by Envolve Pharmacy Solutions, which contracted with the University of California, San Francisco (UCSF), School of Pharmacy for the development and implementation of the motivational interviewing and train-the-trainer programs described in this best practices article. Spears, Erkens, and Misquitta are employees of Envolve Pharmacy Solutions. Stebbins and Cutler are faculty in the Department of Clinical Pharmacy at the UCSF School of Pharmacy, who were contracted through Envolve Pharmacy Solutions to provide consulting services for this best practice.


Assuntos
Liderança , Medicare Part C/normas , Adesão à Medicação , Entrevista Motivacional , Assistência Centrada no Paciente/normas , Farmacêuticos/normas , Papel Profissional , Melhoria de Qualidade/normas , Indicadores de Qualidade em Assistência à Saúde/normas , Anti-Hipertensivos/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Fatores de Tempo , Estados Unidos
18.
J Ethnopharmacol ; 247: 112273, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31586692

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Luohanguo (LHG), a traditional Chinese medicine, could clear heat, moisten the lung, soothe the throat, restore the voice, and lubricate intestine and open the bowels. LHG has been utilized for the treatment of sore throats and hyperglycemia in folk medicine as a homology of medicine and food. The hypoglycemic pharmacology of LHG has attracted considerable attention, and mogrosides have been considered to be active ingredients against diabetes mellitus. We have found that these mogrosides could be metabolized into their secondary glycosides containing 1-3 glucose residues in type 2 diabetes mellitus (T2DM) rats in previous studies. These metabolites may be the antidiabetic components of LHG in vivo. Thus far, no reports have been found on reducing blood glucose of mogrosides containing 1-3 glucose residues. AIMS OF THE STUDY: The aim of this study was to confirm that mogrosides containing 1-3 glucose residues were the active components of LHG for antidiabetic effects and to understand their potential mechanisms of action. MATERIALS AND METHODS: First, the special fraction of mogrosides containing 1-3 glucose residues was separated from a 50% ethanol extract of LHG, and the chemical components were identified by ultra-performance liquid chromatography (UPLC) and named low-polar Siraitia grosvenorii glycosides (L-SGgly). Second, the antidiabetic effects of L-SGgly were evaluated by HFD/STZ-induced (high-fat diet and streptozocin) obese T2DM rats by indexing fasting blood glucose (FBG), fasting insulin (FINS), and insulin resistance, and then compared with other fractions in the separation process. The changes in serum lipid levels were also detected. Finally, possible mechanisms of antidiabetic activity of L-SGgly were identified as increasing GLP-1 levels and activating liver AMPK in T2DM rats. RESULTS: The chemical analysis of L-SGgly showed that they contain 11-oxomogroside V, mogroside V, mogroside III, mogroside IIE, mogroside IIIA1, mogroside IIA1, and mogroside IA1, respectively. The total content of the mogrosides in L-SGgly was 54.4%, including 15.7% mogroside IIA1 and 12.6% mogroside IA1. L-SGgly showed excellent effects on obese T2DM rats compared with the other fractions of LHG extract, including significantly reducing the levels of FBG (p < 0.001) and modifying insulin resistance (p < 0.05). Meanwhile, they could significantly decrease the content of triglyceride (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and free fatty acid (p < 0.001) and increase the content of high-density lipoprotein cholesterol (p < 0.001) in serum of T2DM rats. Moreover, L-SGgly can significantly increase (p < 0.01) GLP-1 levels and decrease (p < 0.01) IL-6 levels in T2DM rat serum. AMPK-activating activity in T2DM rats was also upregulated by L-SGgly, but no statistical significance was shown. CONCLUSION: L-SGgly, fractions separated from LHG extract, were verified to have obvious anti-hyperglycemic and anti-hyperlipidemic effects on T2DM rats. Furthermore, L-SGgly regulated insulin secretion in T2DM rats by increasing GLP-1 levels. These findings provide an explanation for the antidiabetic role of LHG.


Assuntos
Cucurbitaceae/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Obesidade/tratamento farmacológico , Triterpenos/farmacologia , Administração Oral , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Fracionamento Químico , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicosídeos/análise , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Humanos , Hipoglicemiantes/análise , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/análise , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/uso terapêutico , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Obesidade/sangue , Obesidade/etiologia , Ratos , Estreptozocina/toxicidade , Triterpenos/análise , Triterpenos/isolamento & purificação , Triterpenos/uso terapêutico
19.
J Sci Food Agric ; 100(5): 2007-2017, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31849068

RESUMO

BACKGROUND: Previous studies have shown that Lactobacillus plantarum LIP-1 (hereafter LIP-1) has an obvious hypolipidemic effect, and microencapsulated probiotics can ensure the strains live through the gastrointestinal tract. Although there has been much research on both preparation and assessment methods for probiotics microcapsules, most assessments were made in vitro and few were validated in vivo. In this study, the protective effect of microencapsulation and the possible hypolipidemic mechanisms of probiotic LIP-1 were evaluated in rats. Treatments included rats fed on a normal diet, a high-fat diet, and a high-fat diet with an intragastric supplement of either non-microencapsulated LIP-1 cells (NME LIP-1) or microencapsulated LIP-1 (ME LIP-1). Lipid metabolism indicators were measured during the experiment and following euthanasia. RESULTS: Microencapsulation increased survival and colonization of LIP-1 in the colon. ME LIP-1 was superior to NME LIP-1 in reducing cholesterol. The mechanisms behind the hypolipidemic effect exerted by LIP-1 are possibly due to promoting the excretion of cholesterol, improving antioxygenic potentials, enhancing recovery from the injury in the liver, cardiovascular intima and intestinal mucosa, promoting the generation of short-chain fatty acids, and improving lipid metabolism. CONCLUSIONS: This study confirms that microencapsulation provides effective protection of LIP-1 in the digestive system and the role of LIP-1 in the prevention and cure of hyperlipidaemia, providing theoretical support for probiotics to enter clinical applications. © 2019 Society of Chemical Industry.


Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Lactobacillus plantarum/metabolismo , Probióticos/administração & dosagem , Animais , Cápsulas/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Humanos , Hiperlipidemias/metabolismo , Lactobacillus plantarum/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar
20.
Life Sci ; 242: 117182, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31863770

RESUMO

AIMS: The present study was designed to compare the effects of a low-fat diet (LF), calorie restriction (CR), quercetin (Que) and exercise (Ex) on hepatic steatosis in a high-fat (HF) diet-induced obesity prone (OP) model in the perspective of microRNA (miR)-dependent thyroid hormone (TH) synthesis and action. MAIN METHODS: Male C57BL/6J mice were administered a HF diet for 10 weeks to induce OP phenotype and then divided into 5 groups, HF diet (OP-HF), LF diet (OP-LF), 70% CR (OP-CR), 0.05% Que (OP-Que) and a treadmill exercise regimen (OP-Ex); one additional group fed LF diet served as control (LF). 7 weeks later, serum indexes, metabolic alterations, redox status and histological appearance in the thyroid and liver, and TH related miRs with their targets expressions were determined. KEY FINDINGS: No significance on T3 levels was observed among the six groups. LF, CR, Que and Ex significantly ameliorated HF-induced hepatic steatosis to varying degrees, inhibited T4 production via differentially elevating miR-339, miR-383 and miR-146b to decrease NIS expression and regulating miR-200a/Nrf2 to maintain redox status in the thyroid. Furthermore, these four interventions differentially and significantly decreased miR-383 and miR-146b to elevate TRb and DIO1 expression, and subsequent TH responsive lipid metabolism genes regulation. Among them, the effects of CR on hepatic steatosis were the most prominent. SIGNIFICANCE: Our data indicated that amelioration of hepatic steatosis by LF, CR, Que and Ex resulted in many shared, but also many differential changes in the miR-dependent TH production and action.


Assuntos
Dieta com Restrição de Gorduras , Fígado Gorduroso/terapia , MicroRNAs/fisiologia , Obesidade/complicações , Condicionamento Físico Animal , Hormônios Tireóideos/metabolismo , Animais , Restrição Calórica , Fígado Gorduroso/dietoterapia , Fígado Gorduroso/etiologia , Hipolipemiantes/uso terapêutico , Lipídeos/análise , Fígado/química , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Estresse Oxidativo , Quercetina/uso terapêutico
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