RESUMO
OBJECTIVE: The impact of CYP2C19 genotype on clopidogrel outcomes is one of the most well established pharmacogenetic interactions, supported by robust evidence and recommended by the Food and Drug Administration and clinical pharmacogenetics implementation consortium. However, there is a scarcity of large-scale real-world data on the extent of this pharmacogenetic effect, and clinical testing for the CYP2C19 genotype remains infrequent. This study utilizes the UK Biobank dataset, including 10 365 patients treated with clopidogrel, to offer the largest observational analysis of these pharmacogenetic effects to date. METHODS: Incorporating time-varying drug exposure and repeated clinical outcome, we adopted semiparametric frailty models to detect and quantify exposure-based effects of CYP2C19 (*2,*17) variants and nongenetic factors on the incidence risks of composite outcomes of death or recurrent hospitalizations due to major adverse cardiovascular events (MACE) or hemorrhage in the entire cohort of clopidogrel-treated patients. RESULTS: Out of the 10 365 clopidogrel-treated patients, 40% (4115) experienced 10 625 MACE events during an average follow-up of 9.23 years. Individuals who received clopidogrel (coverage >25%) with a CYP2C19*2 loss-of-function allele had a 9.4% higher incidence of MACE [incidence rate ratios (IRR), 1.094; 1.044-1.146], but a 15% lower incidence of hemorrhage (IRR, 0.849; 0.712-0.996). These effects were stronger with high clopidogrel exposure. Conversely, the gain-of-function CYP2C19*17 variant was associated with a 5.3% lower incidence of MACE (IRR, 0.947; 0.903-0.983). Notably, there was no evidence of *2 or *17 effects when clopidogrel exposure was low, confirming the presence of a drug-gene interaction. CONCLUSION: The impact of CYP2C19 on clinical outcomes in clopidogrel-treated patients is substantial, highlighting the importance of incorporating genotype-based prescribing into clinical practice, regardless of the reason for clopidogrel use or the duration of treatment. Moreover, the methodology introduced in this study can be applied to further real-world investigations of known drug-gene and drug-drug interactions and the discovery of novel interactions.
Assuntos
Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Humanos , Clopidogrel/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Farmacogenética , Citocromo P-450 CYP2C19/genética , Bancos de Espécimes Biológicos , Biobanco do Reino Unido , Hemorragia/induzido quimicamente , Genótipo , Resultado do Tratamento , Intervenção Coronária Percutânea/efeitos adversosRESUMO
CONTEXT: Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. OBJECTIVE: To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. METHODS: Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64â mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20â mg (SU), sitagliptin 100â mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3â mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. RESULTS: SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3â mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). CONCLUSION: Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.
Assuntos
Glicemia , Estudos Cross-Over , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Quimioterapia Combinada , Hipoglicemiantes , Células Secretoras de Insulina , Compostos de Sulfonilureia , Humanos , Masculino , Feminino , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Pessoa de Meia-Idade , Glicemia/efeitos dos fármacos , Glicemia/análise , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/uso terapêutico , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Idoso , Adulto , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/farmacologia , Fosfato de Sitagliptina/uso terapêutico , Metformina/administração & dosagem , Metformina/uso terapêutico , Gliclazida/administração & dosagem , Gliclazida/farmacologia , Gliclazida/uso terapêuticoRESUMO
Geyser eruption is one of the most popular signature attractions at the Yellowstone National Park. The interdependence of geyser eruptions and impacts of covariates are of interest to researchers in geyser studies. In this paper, we propose a parametric covariate-adjusted recurrent event model for estimating the eruption gap time. We describe a general bivariate recurrent event process, where a bivariate lognormal distribution and a Gumbel copula with different marginal distributions are used to model an interdependent dual-type event system. The maximum likelihood approach is used to estimate model parameters. The proposed method is applied to analyzing the Yellowstone geyser eruption data for a bivariate geyser system and offers a deeper understanding of the event occurrence mechanism of individual events as well as the system as a whole. A comprehensive simulation study is conducted to evaluate the performance of the proposed method.
Assuntos
Eczema/tratamento farmacológico , Eczema/radioterapia , Adulto , Feminino , Humanos , Masculino , Terapia PUVA , Fototerapia , Estudos RetrospectivosRESUMO
Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower-risk MDS in 82% of patients, with higher-risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub-analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub-types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease-risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia-free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease-modifying therapies are influenced by SES.