Metformin Pharmacogenetics in Heart Failure Patients with Reduced Ejection Fraction: Impact on Metformin and Growth Differentiation Factor-15 Plasma Levels
Abstract
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 2 = 0.31, p 2 = 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.…
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