Aim: Increased cardiovascular incidents and a high risk for microvascular complications are associated with type 2 diabetes. Worldwide, metformin is the most commonly prescribed antidiabetic drug. Polymorphisms in the Oct1 gene can alter the function or activity of organic cation transporter 1 (Oct1), thus changing metformin efficacy (Oct1 acting as its main transporter) as well as influencing the actions of Oct1 physiological substrates. In the past, polymorphisms in Oct1 were associated with cardiovascular risk factors, thus they might contribute to cardiovascular risk development.
We investigated, whether the Oct1 polymorphism rs3777392 is associated with increased risk for cardiovascular death in a cohort of patients with and without type 2 diabetes (T2DM) on various therapies.
Methods: Data from the LURIC study (n=3316), a prospective cohort study of Caucasians scheduled for coronary angiography were analysed. We identified 1820 non-diabetics, 1220 T2DM patients, including 73 metformin users (Met), 154 sulfonylurea users (SF) and 967 T2DM individuals without medication. Cardiovascular mortality was assessed in all groups according to Oct1 rs3777392 genotypes using Cox proportional hazard models and associations with cardiovascular biomarkers were investigated.
Results: Cardiovascular mortality risk for each minor allele copy was HR 2.08 (95% CI: 1.01, 4.28) only in metformin users. Variants of rs3777392 were associated with BMI, baseline insulin values and triglyceride levels in all T2DM patients (P=0.016, P=0.048 and P=0.007, respectively), patients without medication (P=0.006, P=0.041, P=0.008, respectively) and non-diabetics (P=0.021, P=0.074, P=0.125, respectively) but not in the Met and SF groups.
Conclusion: In our study, the minor allele of rs3777392 in the Oct1 gene was associated with an increased cardiovascular mortality risk in T2DM patients on metformin therapy, which might be due to loss of association with cardiovascular parameters. Besides very positive effects in the majority of metformin users, some individuals may profit from a pre-treatment genotyping and careful monitoring.
20 - 23 May 2017
European Society of Endocrinology