Higher-dose sitagliptin and the risk of congestive heart failure in older adults with CKD

Background and objectives Sitagliptin, a dipeptidylpeptidase-4 inhibitor, is commonlyprescribed to patientswith type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses.Wecompare the 1-year risk of death or hospitalizationwith congestive heart failure in patients with CKD newly prescribed sitagliptin at \u3c50 versus ≤50 mg/d. Design, setting, participants, & measurements This population-based cohort study included older adults (\u3e66 years) with type 2 diabetes and an eGFR\u3c45 ml/min per 1.73 m2 (but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control. Weighted hazard ratios were obtained using Cox proportional hazards regression, and 95%confidence intervalswere obtained using bootstrap variance estimators. Results Of 9215 patients, 6518 started sitagliptin at \u3e50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at \u3e50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, 20.12%; 95% confidence interval, 20.19 to 20.06) and a lower risk of allcause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98). Conclusions The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at \u3e50 versus ≤50 mg/d

Farmacogenética da varfarina : proposta de um algoritmo para a predição de dose

A varfarina é um medicamento da classe dos anticoagulantes orais cumarínicos muito utilizada na profilaxia de doenças tromboembólicas. Existe uma grande variação interindividual na resposta aos cumarínicos, uma vez que a farmacocinética e a farmacodinâmica do medicamento variam de acordo com fatores ambientais e genéticos. As enzimas CYP2C9, responsável pela maior parte da metabolização do fármaco, e VKORC1, alvo dos cumarínicos, estão diretamente envolvidas na farmacocinética e farmacodinâmica da varfarina, respectivamente. A enzima CYP4F2, envolvida na metabolização de vitamina K, atua de forma indireta na farmacodinâmica do medicamento. O fator II é um fator de coagulação dependente de carboxilação, sendo sua funcionalidade dependente da atuação da varfarina. Polimorfismos nestes genes estão relacionados com variação na resposta ao medicamento. Neste trabalho foi investigada a influência dos polimorfismos CYP2C9*2 e CYP2C9*3 no gene CYP2C9, -1639G>A, 1173C>T e 3730G>A no gene VKORC1, 1347C>T no gene CYP4F2 e 494C>T no gene F2 na dose/resposta de varfarina de forma independente, assim como foi elaborado um modelo incluindo fatores genéticos e não-genéticos capazes de predizer a dose de varfarina necessária a cada paciente. Para a realização das análises foram estudados 279 pacientes usuários de varfarina provenientes do Hospital de Clínicas de Porto Alegre com ascendência européia. Todos os SNPs dos genes CYP2C9, VKORC1, CYP4F2 e F2 foram identificados pelo sistema TaqMan de discriminação alélica através de PCR em tempo real. Os alelos CYP2C9*2 (PA, 1173C>T and 3730G>A in the VKORC1 gene, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene with warfarin dose/response independently. In addition, a model including genetic and nongenetic factors able to predict warfarin dose needed for each patient was developed. The analysis was performed with 279 patients of European ancestry from the Hospital de Clínicas de Porto Alegre taking warfarin. All SNPs from CYP2C9, VKORC1, CYP4F2 and F2 genes were identified by TaqMan system of allelic discrimination by real-time PCR. The CYP2C9*2 (P A (P T (P T in F2 gene are responsible for lower doses of anticoagulant. In contrast, the SNPs 1347C>T in the CYP4F2 gene and 3730G>A (P <0.001) in VKORC1 gene are responsible for higher doses of warfarin. P values regarding CYP4F2 and F2 polymorphisms refer to multivariate analysis after controlling for confounders, since in the univariate analysis these polymorphisms were not associated with warfarin dose. An algorithm considering these polymorphisms and some clinical variables was developed that explains 63.3% of the variation in warfarin dose. This algorithm included the following factors: body weight, age, use of anlodipine, amiodarone, carbamazepine, -blockers, loop diuretics and polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes. The average absolute difference between the predicted dose and observed dose was 6.9 mg/week and the correlation between the observed and predicted doses was rs=0.77. The model suggested is one with the higher coefficient of determination among those described in the literature, however, for a possible future clinical use it must be validated in an independent sample. More studies are warranted to find other factors that explain the 40% dose variation not explained so far