Intronic variants in OCT1 are associated with all-cause and cardiovascular mortality in metformin users with type 2 diabetes

Abstract

Purpose: Organic cation transporters (Octs) use cations like endogenous compounds, toxins, and drugs, such as metformin, as substrates. Therefore, these proteins determine the pharmacokinetics and-dynamics of metformin and thus its efficacy. Of note, metformin is today the most commonly used pharmaceutical in the treatment of type 2 diabetes (T2DM) with nevertheless a great variability in clinical response, which attributes to genetic var-iances. The aim of this study was to determine the influence of intronic OCT1 SNPs on prevalence of all-cause and cardiovascular death. Patients and Methods: Genotypes of 27 intronic SNPs in OCT1 were investigated in the LURIC study, a prospective cohort of 3316 participants scheduled for coronary angiography. We investigated whether these variants were associated with all-cause and cardiovascular death in 73 individuals with T2DM under metformin therapy, in individuals without diabetes, individuals with T2DM and individuals with T2DM without metformin therapy. Results: In a multivariate Cox regression analysis adjusted for classical cardiovascular risk factors, 4 intronic OCT1 SNPs were significantly associated with all-cause and cardiovascular mortality in individuals with T2DM on metformin therapy. Conclusion: According to their OCT1 genotype, some individuals with T2DM on metfor-min therapy might be prone to an increased risk of cardiovascular death.