PHARMACOGENETICS OF METFORMIN

Introduction: Genetic polymorphisms in metformin transporters and their impact at the steady state metformin plasma concentrations is evaluated in a large well characterized type 2 diabetes cohort given by South Danish Diabetes Study. SNPs in PMAT, OCT1-2 and MATE 1-2 have been linked to reduced pharmacodynaminc response and large interindividual pharmacokinetic variation. Materials/Patients: South Danish Diabetes Study was designed as a 2 x 2 x 2 factorial prospective, randomized, double-blinded, placebo-controlled, multi-centre study comprising 386 in 8 parallel groups. It was initialized to investigate the optimal pharmacological combination of metformin, rosiglitazon and insulin Asp/NPH in a cohort of type 2 diabetics. One hundred and eighty-six patients were allocated to metformin, and repeated measurements of steady state concentrations were collected. The final results will be adjusted for gender, age, BMI, duration of disease, metformin dose, co-medication, smoking, creatinine clearance, HbA1c-pretreatment and polymorphisms in PMAT, OCT 1-2 and MATE 1-2. Results: The preliminary unadjusted result
for 456 repeated measurements of metformin confirm the large inter-individual variation in steady state metformin concentration:769 ± 649ng/ml (SD), range: 9.7 to 4133ng/ml. In the cohort 369 samples could be genotyped. In the renal transporter OCT2, the A270S genotype frequencies were determined: heterozygous 19%, homozygous 0.5% and wild-type 80.5%, which corresponds well with the databases at NCBI. Conclusion: The preliminary results strengthen the thesis that Danish type 2 diabetics have the same allele frequencies in transporter SNP as healthy Caucasian, and it indeed underscores the enormous interindividual variation in metformin steady state concentration.