Metformin Pharmacogenetics in Heart Failure Patients with Reduced Ejection Fraction: Impact on Metformin and Growth Differentiation Factor-15 Plasma Levels

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. 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. 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. 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.