RESUMO
BACKGROUND: In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS: We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS: A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONS: In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).
Assuntos
Anticolesterolemiantes/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Inibidores de PCSK9 , RNA Interferente Pequeno/administração & dosagem , Idoso , Anticolesterolemiantes/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/sangue , RNA Interferente Pequeno/efeitos adversos , Fatores de Risco , Transaminases/sangueRESUMO
BACKGROUND: A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. METHODS: Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. RESULTS: We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. CONCLUSIONS: In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).
Assuntos
Autoanticorpos/sangue , Hiperlipoproteinemia Tipo I/imunologia , Lipase Lipoproteica/metabolismo , Receptores de Lipoproteínas/imunologia , Adulto , Autoanticorpos/fisiologia , Feminino , Humanos , Hiperlipoproteinemia Tipo I/sangue , Imunoensaio , Lipólise , Lipase Lipoproteica/sangue , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Transporte Proteico , Receptores de Lipoproteínas/metabolismoRESUMO
BACKGROUND: Familial hypercholesterolemia (FH) is the most frequent genetic disorder seen clinically and is characterized by increased LDL cholesterol (LDL-C) (>95th percentile), family history of increased LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) in the patient or in first-degree relatives, presence of tendinous xanthomas or premature corneal arcus, or presence of a pathogenic mutation in the LDLR, PCSK9, or APOB genes. A diagnosis of FH has important clinical implications with respect to lifelong risk of ASCVD and requirement for intensive pharmacological therapy. The concentration of baseline LDL-C (untreated) is essential for the diagnosis of FH but is often not available because the individual is already on statin therapy. METHODS: To validate a new algorithm to impute baseline LDL-C, we examined 1297 patients. The baseline LDL-C was compared with the imputed baseline obtained within 18 months of the initiation of therapy. We compared the percent reduction in LDL-C on treatment from baseline with the published percent reductions. RESULTS: After eliminating individuals with missing data, nonstandard doses of statins, or medications other than statins or ezetimibe, we provide data on 951 patients. The mean ± SE baseline LDL-C was 243.0 (2.2) mg/dL [6.28 (0.06) mmol/L], and the mean ± SE imputed baseline LDL-C was 244.2 (2.6) mg/dL [6.31 (0.07) mmol/L] (P = 0.48). There was no difference in response according to the patient's sex or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe. CONCLUSIONS: We provide a validated estimation of baseline LDL-C for patients with FH that may help clinicians in making a diagnosis.
Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Apolipoproteína B-100/genética , Criança , Estudos de Coortes , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Mutação , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Adulto JovemRESUMO
BACKGROUND: Hypercholesterolemia is a major risk factor for the late-onset form of Alzheimer disease (AD). Loss-of-function (LOF) mutations of PCSK9 and PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and have been associated with a reduced risk of cardiovascular disease. The aim of this study was to examine the effect of PCSK9 LOF variants on risk and age of onset of AD. METHODS: A total of 878 participants (410 controls and 468 AD cases) from the Quebec Founder Population were included in the study. RESULTS: Fifty-four (6.2%) participants carried the R46L mutation, whereas 226 (26.2%) participants carried the InsLEU mutation. There was no protective or no deleterious effect of carrying PCSK9 LOF mutations on AD prevalence nor on age of onset, even when stratified by apolipoprotein E epsilon 4 genotype or by gender. CONCLUSION: Our data indicate that carrying PCSK9 LOF mutations has a neutral effect on neurocognitive health and the prevalence of AD.
Assuntos
Idade de Início , Doença de Alzheimer/genética , Técnicas de Genotipagem/métodos , Mutação , Pró-Proteína Convertase 9/genética , Doença de Alzheimer/patologia , LDL-Colesterol/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9/sangue , Fatores de RiscoRESUMO
Background: The role of plasma apolipoprotein (apo) C-I in cardiometabolic risk in humans is unclear. However, in vitro studies showed a dual role for apoC-I, both protective and harmful, depending on the carrier lipoprotein.Objective: We tested the hypothesis that triglyceride (TG)-rich lipoprotein (TRL) apoC-I, not total or HDL apoC-I, is associated with delayed postprandial plasma clearance of TRLs, independently of apoC-II, apoC-III, and apoE.Methods: This cross-sectional study examines the plasma clearance of a 13C-triolein-labeled high-fat meal (68% fat energy) in 20 postmenopausal overweight and obese women [body mass index (in kg/m2) ≥27; aged 45-74 y] as the increment change in area under the 6-h postprandial curves (iAUC6h) of TRL parameters. Lipoproteins were fractionated by fast-protein LC. Transferable apolipoproteins were measured by ELISA. TRL enrichment with apolipoproteins was calculated by dividing their TRL concentrations by TRL apoB. The effects of human apoC-I and apoC-III on the hydrolysis and storage of 3H-triolein-labeled TRLs were tested in 3T3-L1 adipocytes.Results: TRL apoC-I was positively associated with plasma apo B-48 and total and non-HDL TGs, cholesterol, and apoB (r = 0.52-0.97) and negatively with HDL cholesterol (r = -0.52) and LDL diameter (r = -0.91) (P < 0.05). Total and HDL apoC-I were correlated only with total (r = 0.62) and HDL (r = 0.75) cholesterol. Women with high fasting TRL enrichment with apoC-I (99-365 µmol apoC-I/µmol apoB), but not apoC-II, apoC-III, or apoE, had higher iAUC6h for TGs (+195%), 13C-TGs (+319%), and apo B-48 (+186%) than those with low enrichment (14-97 µmol apoC-I/µmol apoB). The 4-h postprandial increase in TRL apoC-I was associated with a 4-h increase in TRL TGs and iAUC6h for TGs, 13C-TGs, and apo B-48 (r = 0.74-0.86, P < 0.001), independently of 4-h changes in TRL apoB, apoC-II, apoC-III, or apoE. ApoC-I and apoC-III inhibited 3H-TRL clearance by adipocytes by >75% (P < 0.001).Conclusions: TRL enrichment with apoC-I is positively associated with postprandial hypertriglyceridemia and remnant accumulation in postmenopausal overweight and obese women, independently of apoC-II, apoC-III, or apoE, which may be due to inhibiting TRL clearance by adipocytes. Reducing TRL apoC-I may ameliorate delayed postprandial plasma clearance of TRLs and associated risks in humans.
Assuntos
Apolipoproteína C-I/sangue , Colesterol/sangue , Gorduras na Dieta/sangue , Hipertrigliceridemia/sangue , Obesidade/sangue , Período Pós-Prandial , Triglicerídeos/sangue , Células 3T3-L1 , Idoso , Animais , Apolipoproteína C-I/farmacologia , Apolipoproteínas/sangue , Área Sob a Curva , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Estudos Transversais , Dieta , Feminino , Humanos , Lipoproteínas/sangue , Camundongos , Pessoa de Meia-Idade , Sobrepeso , Pós-MenopausaRESUMO
OBJECTIVES: To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and statin efficacy, we measured in vivo HMGCR mRNA and lipid levels in French Canadian individuals affected by heterozygous familial hypercholesterolemia due to the deletion of more than 15 kb of the LDLR gene. RESULTS: Men and women carrying the AA genotype at rs3846662, and no APOE4 allele, had higher levels of total cholesterol (5.43 vs. 4.58 mmol/l, P<0.05) and LDL-cholesterol (5.20 vs. 4.39 mmol/l, P<0.05) at baseline. However, with regard to statin efficacy, the penetrance of the AA genotype was sex dependent. Indeed, the percentage reduction in LDL-cholesterol upon statin treatment was significantly decreased in women with the AA genotype compared with women without it (38.4 vs. 46.2%, P<0.05), whereas this was not observed in men. Although both men and women bearing the AA genotype showed a higher ratio of full-length HMGCR mRNA/total HMGCR mRNA compared with individuals without it (n=37, P<0.05), overall transcription of HMGCR was decreased and increased in men and women carrying this genotype, respectively (n=37, P<0.01 and P<0.05). Finally, in our familial hypercholesterolemia cohort, HMGCR alternative splicing explained between 22 and 55% of the variance in statin response. CONCLUSION: rs3846662 polymorphism and the alternative splicing of HMGCR mRNA significantly impact women's response to statin therapy.
Assuntos
Processamento Alternativo , LDL-Colesterol/sangue , Hidroximetilglutaril-CoA Redutases/genética , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Canadá , LDL-Colesterol/efeitos dos fármacos , Feminino , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pessoa de Meia-Idade , Receptores de LDL/genética , Deleção de Sequência , Fatores SexuaisRESUMO
BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/metabolismo , Método Duplo-Cego , Esquema de Medicação , Feminino , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Serina Endopeptidases , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). METHODS AND RESULTS: In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; -57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; -51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). CONCLUSION: In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated. CLINICAL TRIAL REGISTRATION: Cinicaltrials.gov (identifiers: NCT01623115; NCT01709500).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do TratamentoRESUMO
PURPOSE: To demonstrate that OPTEASE and TRAPEASE filters can be removed after dwell times greater than 60 days. MATERIALS AND METHODS: A retrospective review was performed of patients who underwent an attempted removal of a TRAPEASE or OPTEASE filter with a greater than 60-day dwell time between 2009 and 2015 at a single institution. Eleven patients within that time span were identified, and 10 were included in the review. One patient was excluded from the study because the date of filter placement was unknown. RESULTS: All filters were successfully retrieved. The average dwell time for removed TRAPEASE filters was 1,273 days (range, 129-3,582 d), with a median of 492 days (n = 5). The average dwell time for OPTEASE filters was 977 days (range, 123-2,584 d), with a median of 661 days (n = 5). The average dwell time of all filters was 1,125 days (range, 123-3,582 d), with a median of 577 days (n = 10). All patients exhibited inferior vena cava (IVC) stenosis after filter retrieval. An IVC pseudoaneurysm was present following retrieval in one case and resolved. In one case, a fractured filter strut was left completely embedded in the caval wall. Two patients reported unilateral leg swelling on clinical follow-up, and the remainder reported no leg swelling or tightness. CONCLUSIONS: Initial experience suggests that TRAPEASE and OPTEASE filters can be removed after extended dwell times.
Assuntos
Remoção de Dispositivo/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/prevenção & controle , Filtros de Veia Cava/estatística & dados numéricos , District of Columbia/epidemiologia , Desenho de Equipamento , Análise de Falha de Equipamento , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipoprotein receptor. The aims of this cross-sectional cohort-study were to examine whether the PCSK9 R46L loss of function variant found in a cohort of familial hypercholesterolemia (FH) patients was associated with lower low density lipoprotein cholesterol, lower frequency of xanthomata, and cardiovascular risk. APPROACH AND RESULTS: We studied FH patients attending the IRCM (Institut de Recherches Cliniques de Montréal) Lipid Clinic and whose DNA genotyping was positive for a low density lipoprotein receptor mutation. The presence of the PCSK9 loss of function R46L missense variant was determined among a cohort of 582 FH patients by genotyping. Frequency of the R46L variant was 3%. Carriers had significantly lower low density lipoprotein cholesterol (11%, P=0.002), total cholesterol (9%, P=0.007), apolipoprotein B (10%, P=0.037), and non-high density lipoprotein (12%, P<0.001) concentrations compared with noncarriers. Furthermore, R46L carriers showed a decreased average number of xanthoma per individual compared with noncarriers (0.33 and 0.76, respectively; P<0.001). Importantly, the R46L genetic variant was associated with a significant 86% lower odd of presenting a cardiovascular event (odds ratio, 0.14; 95% confidence interval, 0.032-0.63; P=0.001). CONCLUSIONS: Even though the R46L variant was present in 3% of our FH population, carriers of this polymorphism showed attenuated effect of the low density lipoprotein receptor mutation on parameters, such as low density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non-high density lipoprotein. More importantly, this mutation is associated with a significant lower risk of cardiovascular disease compared with noncarriers. It is therefore likely that targeting PCSK9 in FH patients with novel anti-PCSK9 therapies will be useful in reducing cardiovascular risk in affected subjects.
Assuntos
Doenças Cardiovasculares/etiologia , Hiperlipoproteinemia Tipo II/complicações , Lipoproteínas LDL/sangue , Mutação de Sentido Incorreto , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Adulto , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Estudos de Coortes , Estudos Transversais , Feminino , Frequência do Gene , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/sangue , Proteínas Mutantes/genética , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/sangue , Receptores de LDL/genética , Fatores de Risco , Serina Endopeptidases/sangue , Xantomatose/sangue , Xantomatose/etiologia , Xantomatose/genética , Adulto JovemRESUMO
PURPOSE: To measure the prevalence of diagnosed opioid abuse and prescription opioid use in a multistate managed care organization. METHODS: This retrospective claims data analysis reviewed the prevalence of diagnosed opioid abuse and the parallel prevalence of prescription opioid use in half-year intervals for commercial and Medicare members enrolled with Humana Inc., from January 1, 2008 to June 30, 2010. Diagnosis of opioid abuse was defined by ≥ 1 medical claim with any of the following ICD-9-CM codes: 304.0 ×, 304.7 ×, 305.5 ×, 965.0 ×, excluding 965.01, and opioid use was defined by ≥ 1 filled prescription for an opioid. The prevalence of opioid abuse was defined by the number of members with an opioid abuse diagnosis, divided by the number of members enrolled in each 6-month interval. RESULTS: The 6-month prevalence of diagnosed opioid abuse increased from 0.84 to 1.15 among commercial and from 3.17 to 6.35 among Medicare members, per 1,000. In contrast, there was no marked increase in prescription opioid use during the same time period (118.0 to 114.8 for commercial members, 240.6 to 256.9 for Medicare members, per 1,000). The prevalence of diagnosed opioid abuse was highest among members younger than 65 years for both genders in commercial (18- to 34-year-olds) and Medicare (35- to 54-year-olds) populations. CONCLUSIONS: Despite a stable rate of prescription opioid use among the observed population, the prevalence of diagnosed opioid abuse is increasing, particularly in the Medicare population.
Assuntos
Medicare/economia , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Analgésicos Opioides/economia , Bases de Dados Factuais , Humanos , Revisão da Utilização de Seguros/economia , Programas de Assistência Gerenciada , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/economia , Prevalência , Estudos Retrospectivos , Estados UnidosRESUMO
OBJECTIVE: Growth in the number of patients with pain conditions, and the subsequent rise in prescription opioid use for treatment, has been accompanied by an increase in diagnosed opioid abuse. Understanding what drives the incremental healthcare costs of members diagnosed with prescription opioid abuse may assist in developing better screening techniques for abuse. DESIGN: This retrospective analysis examined costs, resource use, and comorbidities 365 days pre- and postdiagnosis in prescription opioid users diagnosed with abuse (cases) vs. their matched nondiagnosed controls. Inclusion criteria for cases were diagnosis of opioid abuse (ICD-9-CM: 304.0x, 304.7x, 305.5x, 965.0x). Multivariate analysis used generalized linear modeling with log-transformed cost as dependent variable, controlling for comorbidities. RESULTS: Final sample sizes were 8,390 cases and 16,780 matched controls. Postindex abuse-related costs were $2,099 for commercial members, $539 for Medicare members aged < 65, and $170 for Medicare members aged ≥ 65. A higher percentage of cases had pain conditions (82.0% vs. 57.4% commercial, 95.9% vs. 87.5% Medicare members aged < 65, 92.9% vs. 82.4% Medicare members aged ≥ 65, P < 0.0001), and a higher numbers of cases had multiple opioid prescribers (3.7 vs. 1.4 commercial, 3.3 vs. 2.2 Medicare < 65, 2.2 vs. 1.6 Medicare ≥ 65, P < 0.0001) than controls preindex. Cases had higher rates of substance abuse and psychiatric diagnoses pre- and postindex (P < 0.0001, all comparisons). Adjusted costs were 28% higher for cases than for controls (P < 0.0001). CONCLUSION: Costs of members diagnosed with prescription opioid abuse are driven by higher pain and psychiatric comorbidities relative to nonabuse controls.
Assuntos
Analgésicos Opioides/economia , Custos de Cuidados de Saúde , Medicare/economia , Transtornos Relacionados ao Uso de Opioides/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
Healthcare resource utilization (HCRU) and associated costs specific to pain are a growing concern, as increasing dollar amounts are spent on pain-related conditions. Understanding which pain conditions drive the highest utilization and cost burden to the healthcare system would enable providers and payers to better target conditions to manage pain adequately and efficiently. The current study focused on 36 noncancer chronic and 14 noncancer acute pain conditions and measured the HCRU and costs per member over 365 days. These conditions were ranked by per-member costs and total adjusted healthcare costs to determine the most expensive conditions to a national health plan. The top 5 conditions for the commercial line of business were back pain, osteoarthritis (OA), childbirth, injuries, and non-hip, non-spine fractures (adjusted annual total costs for the commercial members were $119 million, $98 million, $69 million, $61 million, and $48 million, respectively). The top 5 conditions for Medicare members were OA, back pain, hip fractures, injuries, and non-hip, non-spine fractures (adjusted annual costs for the Medicare members were $327 million, $218 million, $117 million, $82 million, and $67 million, respectively). The conditions ranked highest for both per-member and total healthcare costs were hip fractures, childbirth, and non-hip, non-spine fractures. Among these, hip fractures in the Medicare member population had the highest mean cost per member (adjusted per-member cost was $21,058). Further examination specific to how pain is managed in these high-cost conditions will enable providers and payers to develop strategies to improve patient outcomes through appropriate pain management.
Assuntos
Custos de Cuidados de Saúde , Seguro Saúde/economia , Manejo da Dor , Dor/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Dor nas Costas/economia , Dor Crônica/economia , Dor Crônica/etiologia , Feminino , Fraturas Ósseas/economia , Fraturas Ósseas/fisiopatologia , Fraturas do Quadril/economia , Fraturas do Quadril/fisiopatologia , Humanos , Revisão da Utilização de Seguros , Masculino , Medicare/economia , Pessoa de Meia-Idade , Osteoartrite/economia , Osteoartrite/fisiopatologia , Dor/etiologia , Manejo da Dor/economia , Parto , Estados Unidos , Ferimentos e Lesões/economia , Ferimentos e Lesões/fisiopatologiaRESUMO
INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death among prostate cancer (PC) patients. Androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone receptor (GnRH) agonist or antagonist is the standard treatment for advanced PC. Since 2010, the Food and Drug Administration has required labeling for GnRH agonists to include warnings about increased risk for diabetes and some CVDs. METHODS: In this observational, retrospective, real-world study, we evaluated time to a first cardiovascular (CV) event within 3 years postinitiation of ADT in PC patients while controlling for CVD history and risk factors. Data from a large administrative US claims dataset (2010-2019) were analyzed using Kaplan-Meier survival analysis to calculate the HR for time to first CV event and Cox regressions to identify factors associated with time to first CV event. RESULTS: Of 10,530 patients, 92% had no history of CVD, 8% had history of CVD, and 95% were exposed to a GnRH agonist during follow-up. Kaplan-Meier analysis indicated that patients with a baseline history of CVD had increased risk of CV events within 3 years of ADT initiation vs those without such history (HR, 3.20; 95% CI, 2.58-3.96; P < .0001). Among covariates associated with higher likelihood of CV event, baseline history of CVD yielded the highest HR (2.83; 95% CI, 2.40-3.32, P < .0001). CONCLUSIONS: PC patients with a history of CVD are at increased risk of a CV event within 3 years of ADT initiation compared with those with no history of CVD.
Assuntos
Doenças Cardiovasculares , Neoplasias da Próstata , Estados Unidos , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Androgênios/uso terapêutico , Estudos Retrospectivos , Incidência , Hormônio Liberador de Gonadotropina/agonistas , Doenças Cardiovasculares/induzido quimicamente , Fatores de RiscoRESUMO
BACKGROUND: Intermittent androgen deprivation therapy (iADT) alleviates some side effects of continuous (c) ADT in patients with prostate cancer (PC), but its relative impact on ADT-associated comorbidities is uncertain. We assessed real-world use of iADT and cADT and associated risk of cardiovascular and endocrine/metabolic events in patients with nonmetastatic (nm) PC. METHODS: This retrospective longitudinal cohort study included patients with nmPC initiating systemic ADT with gonadotropin-releasing hormone agonists (goserelin, histrelin, leuprolide, and triptorelin) or antagonists (degarelix) in the US Surveillance, Epidemiology and End Results-Medicare database (2010-2017), who had ≥ 36 months of continuous insurance coverage, unless death occurred, and did not receive chemotherapy or next-generation hormonal therapies during follow-up (through 2019). Risk of major adverse cardiovascular events (MACE [myocardial infarction, stroke, cardiomyopathy/heart failure, pulmonary embolism, ischemic heart disease, all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, and osteoporosis) were examined between cohorts. Inverse probability of treatment-weighted Cox regression models estimated adjusted hazard ratios (HRs) of the outcomes. RESULTS: Of 10,655 eligible patients, 2,095 (19.7%) received iADT and 8,560 (80.3%) cADT. Median follow-up was 43.9 and 48.4 months and median ADT duration (excluding iADT gaps) was 22.0 and 13.5 months for the iADT and cADT cohorts, respectively. Patients receiving cADT had a lower risk of MACE vs. iADT (HR 0.90; 95% confidence interval [CI] 0.83-0.96). No difference in risk of endocrine/metabolic events was observed (HR 0.97; 95% CI 0.92-1.03). Subgroup analysis found that the difference in MACE was maintained in patients with a history of cardiovascular disease (HR 0.90; 95% CI 0.83-0.98) and eliminated in patients without (HR 0.94; 95% CI 0.82-1.08). CONCLUSIONS: Patients with nmPC who received cADT had a lower risk of MACE and similar risk of endocrine/metabolic events vs. those who received iADT. Further research assessing both regimens is needed to inform treatment decisions.
RESUMO
To assess the clinical impact of delayed testosterone recovery (TR) following the discontinuation of medical androgen deprivation therapy (ADT), a retrospective, longitudinal analysis was conducted in adult males with prostate cancer using the Optum® de-identified Electronic Health Record data set and Optum® Enriched Oncology Data (2010-2021). Of 3875 patients who initiated and discontinued ADT, 1553 received one or more testosterone-level tests within the 12 mo following discontinuation and were included in this study. These 1553 patients were categorized into two cohorts: 25% as TR (testosterone levels >280 ng/dl at any test within 12 mo following ADT discontinuation) and 75% as non-TR. At baseline, non-TR patients were older, had lower testosterone levels, and were more likely to have diabetes, hyperlipidemia, and hypertension, but less likely to have sexual dysfunction. After adjustment for baseline characteristics, the TR cohort had a lower risk of new-onset diabetes (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.27-0.79), trended toward a lower risk of new-onset depression (HR 0.58; 95% CI 0.33-1.02), and had a higher likelihood of seeking treatment for sexual dysfunction (HR 1.33; 95% CI 0.99-1.78) versus the non-TR cohort. These findings support monitoring testosterone levels after ADT discontinuation to manage potential long-term comorbidities in patients with prostate cancer. Patient summary: This real-world analysis of males with prostate cancer who were treated with medical androgen deprivation therapy (ADT) found that most patients did not have their testosterone level checked in the 12 mo after stopping ADT. Of those who did, 75% did not achieve normal testosterone levels (>280 ng/dl), and these patients were more likely to experience new-onset diabetes than those who achieved normal testosterone levels. These results suggest that to ensure effective clinical decision-making, physicians should check patients' testosterone levels after stopping ADT.
RESUMO
Delayed clearance of triglyceride-rich lipoprotein (TRL) by white adipose tissue (WAT) promotes hypertriglyceridemia and elevated apoB-lipoproteins, which are primarily in the form of LDL. This study examines whether LDL promotes delayed clearance of TRL by WAT. Following the ingestion of a (13)C-triolein-labeled high-fat meal, obese women with high plasma apoB (> median 0.93 g/l, N = 11, > 98% as IDL/LDL) had delayed clearance of postprandial (13)C-triglyceride and (13)C-NEFA over 6 h compared with controls. AUC6 h of plasma (13)C-triglyceride and (13)C-NEFA correlated with plasma apoB but not with LDL diameter or adipocyte area. There was no group difference in (13)C-triolein oxidation rate, which suggests lower (13)C-NEFA storage in peripheral tissue in women with high apoB. Ex vivo/in vitro plasma apoB correlated negatively with WAT (3)H-lipid following a 4 h incubation of women's WAT with synthetic (3)H-triolein-TRL. LDL-differentiated 3T3-L1 adipocytes had lower (3)H-TRL hydrolysis and (3)H-NEFA storage. Treatment of women's WAT with their own LDL decreased (3)H-TRL hydrolysis and (3)H-NEFA uptake. Finally, LDL, although not an LPL substrate, reduced LPL-mediated (3)H-TRL hydrolysis as did VLDL and HDL. Exposure to LDL decreases TRL clearance by human WAT ex vivo. This may promote production of apoB-lipoproteins and hypertriglyceridemia through a positive-feedback mechanism in vivo.
Assuntos
Hipertrigliceridemia/sangue , Lipoproteínas LDL/sangue , Gordura Subcutânea/metabolismo , Triglicerídeos/sangue , Adulto , Apolipoproteínas B/sangue , Dieta Hiperlipídica , Feminino , Humanos , Hipertrigliceridemia/patologia , Lipoproteínas/sangue , Lipoproteínas/química , Lipoproteínas LDL/química , Lipoproteínas VLDL/sangue , Pessoa de Meia-Idade , Obesidade/sangue , Gordura Subcutânea/crescimento & desenvolvimento , Triglicerídeos/químicaRESUMO
BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease. METHODS AND RESULTS: This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (-28.0% [-34.0% to -22.1%] compared with 5.2% [-0.5% to 10.9%] increase with placebo; P<0.001). Mipomersen significantly reduced apolipoprotein B (-26.3%), total cholesterol (-19.4%), and lipoprotein(a) (-21.1%) compared with placebo (all P<0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo (P<0.001). CONCLUSIONS: Mipomersen is an effective therapy to further reduce apolipoprotein B-containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00706849.
Assuntos
Apolipoproteínas B/antagonistas & inibidores , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/epidemiologia , Heterozigoto , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/epidemiologia , Oligonucleotídeos/uso terapêutico , Alanina Transaminase/metabolismo , Anticolesterolemiantes/uso terapêutico , Bilirrubina/metabolismo , Comorbidade , Doença da Artéria Coronariana/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Injeções Subcutâneas , Fígado/metabolismo , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. METHODS: This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. FINDINGS: 77 patients were randomly assigned to study groups (15-16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. INTERPRETATION: REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. FUNDING: Sanofi US and Regeneron Pharmaceuticals Incorporated.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Azetidinas/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Análise de Variância , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Azetidinas/efeitos adversos , LDL-Colesterol/sangue , Método Duplo-Cego , Ezetimiba , Feminino , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Resultado do TratamentoRESUMO
PURPOSE: Multiparametric magnetic resonance imaging can be used to guide prostate biopsy by targeting biopsies to areas in the prostate at high risk for cancer. We compared the detection of clinically significant and insignificant cancer by transperineal magnetic resonance imaging targeted biopsy and transperineal template guided prostate biopsy. MATERIALS AND METHODS: A total of 182 men with a lesion suspicious for cancer on multiparametric magnetic resonance imaging underwent transperineal magnetic resonance imaging targeted biopsy using a cognitive registration technique, followed by systematic transperineal template guided prostate biopsy. The primary outcome was the detection rate of clinically significant prostate cancer. Clinical significance was defined using maximum cancer core length 4 mm or greater and/or Gleason grade 3 + 4 or greater (University College London definition 2). We secondarily evaluated other commonly used thresholds of clinically significant disease, including maximum cancer core length 6 mm or greater and/or Gleason grade 4 + 3 or greater, maximum cancer core length 3 mm or greater and/or Gleason grade 3 + 4 or greater, and maximum cancer core length 2 or greater mm and/or Gleason grade 3 + 4 or greater. Strategies were statistically compared with the McNemar test. RESULTS: Mean ± SD patient age was 63.3 ± 7.2 years. Median prostate specific antigen was 6.7 ng/ml (IQR 4.7-10.0). Clinically significant cancer was detected by magnetic resonance imaging targeted biopsy and template guided prostate biopsy in 103 (57%) and 113 of the 182 men (62%) (p = 0.174), and clinically insignificant cancer was detected in 17 (9.3%) and 31 (17.0%), respectively (p = 0.024). CONCLUSIONS: Prostate biopsy targeted to suspicious lesions on multiparametric magnetic resonance imaging has encouraging rates of detection of clinically significant cancer while also decreasing the detection rate of clinically insignificant cancer. This is achieved with fewer biopsy cores than for systematic template guided biopsy. Further prospective, multicenter, comparative trials of the performance of targeting strategies are needed to consider magnetic resonance imaging targeted biopsy an alternative to conventional systematic biopsy.