Clinical pharmacokinetics · 2026
Metformin Pharmacogenetics in Heart Failure Patients with Reduced Ejection Fraction: Impact on Metformin and Growth Differentiation Factor-15 Plasma Levels.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Larsen Anders Hostrup, Stage Tore Bjerregaard, Christensen Mette Marie Hougaard, Feddersen Søren, Nielsen Flemming, Nørrelund Helene, Frøkiær Jørgen, Jessen Niels, Brøsen Kim, Wiggers Henrik
Аннотация
BACKGROUND: This study assessed plasma metformin trough steady-state concentrations and plasma growth differentiation factor-15 (GDF-15) in patients with heart failure with reduced ejection fraction (HFrEF), and evaluated the effect of genetic variations in OCT1, OCT2, MATE1, and MATE2-K on metformin trough levels and GDF-15 levels.
METHODS: The study population comprised 109 HFrEF patients with type 2 diabetes on stable metformin treatment (median 1700 mg, range 500-3000) in an open-label design. Patients were genotyped for seven selected variants in OCT1, OCT2, MATE1 and MATE2-K. Plasma metformin trough measurements (288 samples) were obtained in triplicates with a median 7-day interval (interquartile range, 6-10 days). Plasma GDF-15 concentrations were measured once per patient.
RESULTS: Mean dose-normalised metformin trough concentrations were 508 ng/L/g (range 68-3515) with substantial interpatient variation (intraclass correlation coefficient 0.79). Metformin trough levels were independent of genetic variants in OCT1 (p = 0.12), OCT2 (p = 0.10) and MATE1 (p = 0.95), after adjustment for estimated glomerular filtration rate (eGFR) and time since last tablet intake. MATE2-K was excluded due to insufficient variant frequency. Metformin dose correlated with trough concentrations (R2 = 0.36, p < 0.001), and metformin trough concentrations correlated with NT-proBNP levels (R2 = 0.31, p < 0.001) and with GDF-15 levels (R2 = 0.51, p < 0.001). GDF-15 levels were independent of genetic variants in OCT1, OCT2, and MATE1, after adjustment for eGFR and time since last tablet intake.
CONCLUSIONS: In HFrEF patients, transporter genetic variants in OCT1, OCT2, and MATE1 did not influence metformin trough steady-state concentrations or circulating GDF-15 levels. Metformin trough levels display large (50-fold) interpatient variability and a dose-dependent relationship.
CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov . Unique identifier: NCT02797340.
METHODS: The study population comprised 109 HFrEF patients with type 2 diabetes on stable metformin treatment (median 1700 mg, range 500-3000) in an open-label design. Patients were genotyped for seven selected variants in OCT1, OCT2, MATE1 and MATE2-K. Plasma metformin trough measurements (288 samples) were obtained in triplicates with a median 7-day interval (interquartile range, 6-10 days). Plasma GDF-15 concentrations were measured once per patient.
RESULTS: Mean dose-normalised metformin trough concentrations were 508 ng/L/g (range 68-3515) with substantial interpatient variation (intraclass correlation coefficient 0.79). Metformin trough levels were independent of genetic variants in OCT1 (p = 0.12), OCT2 (p = 0.10) and MATE1 (p = 0.95), after adjustment for estimated glomerular filtration rate (eGFR) and time since last tablet intake. MATE2-K was excluded due to insufficient variant frequency. Metformin dose correlated with trough concentrations (R2 = 0.36, p < 0.001), and metformin trough concentrations correlated with NT-proBNP levels (R2 = 0.31, p < 0.001) and with GDF-15 levels (R2 = 0.51, p < 0.001). GDF-15 levels were independent of genetic variants in OCT1, OCT2, and MATE1, after adjustment for eGFR and time since last tablet intake.
CONCLUSIONS: In HFrEF patients, transporter genetic variants in OCT1, OCT2, and MATE1 did not influence metformin trough steady-state concentrations or circulating GDF-15 levels. Metformin trough levels display large (50-fold) interpatient variability and a dose-dependent relationship.
CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov . Unique identifier: NCT02797340.