Matthijs L. Becker

Genetic Variation in the Multidrug and Toxin Extrusion 1 Transporter Protein Influences the Glucose-Lowering Effect of Metformin in Patients With Diabetes: A Preliminary Study

OBJECTIVE— Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin. RESEARCH DESIGN AND METHODS— We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Associations between 12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed. RESULTS— One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 G>A SNP was significantly associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669, the A1C reduction was 0.30% (95% CI −0.51 to −0.10; P = 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045. CONCLUSIONS— The rs2289669 G>A SNP is associated with a reduction in A1C level, consistent with a reduction in MATE1 transporter activity. These results suggest that the transporter MATE1, encoded by SLC47A1, may have an important role in the pharmacokinetics of metformin, although replication is necessary.

Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus.

The organic cation transporter 1, encoded by the SLC22A1 gene, is responsible for the uptake of the anti-hyperglycaemic drug, metformin, in the hepatocyte. We assessed whether a genetic variation in the SLC22A1 gene is associated with the glucose-lowering effect of metformin. Incident metformin users in the Rotterdam Study, whose HbA1c measurements were available, were identified. Associations between 11 tagging single nucleotide polymorphisms in the SLC22A1 gene and change in the HbA1c level were analyzed. A total of 102 incident metformin users were included in this study sample. Except for the rs622342 A>C polymorphism, no significant differences in metformin response were observed. For each minor C allele at rs622342, the reduction in HbA1c levels was 0.28% less (95% CI 0.09–0.47, P=0.005). After Bonferroni correction, the P-value was 0.050. To conclude, genetic variation at rs622342 in the SLC22A1 gene was associated with the glucose-lowering effect of metformin in patients with diabetes mellitus.

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response.

Objective Metformin is transported into the hepatocyte by organic cation transporter 1 (OCT1) and out of the hepatocyte by multidrug and toxin extrusion 1 (MATE1). Recently, we discovered that polymorphisms rs622342 A>C in the SLC22A1 gene, coding for OCT1, and rs2289669 G>A in the SLC47A1 gene, coding for MATE1, are associated with the degree of glucose lowering by metformin. In this study, we assessed whether there exists an interaction between these two polymorphisms. Methods We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Multiplicative interaction between the polymorphisms and change in HbA1c levels was analyzed in 98 incident metformin users. Results In incident metformin users with the OCT1 rs622342 AA genotype, genetic variation at the MATE1 rs2289669 polymorphism was not associated with change in HbA1c levels [−0.10; 95% confidence interval (CI): −0.35 to 0.14; P=0.39]. In users with the OCT1 rs622342 AC genotype, there was a tendency between rs2289669 polymorphisms and change in HbA1c (−0.31; 95% CI: −0.65 to 0.03; P=0.070) and in users with the OCT1 rs622342 CC genotype there was a significant association with change in HbA1c levels (−0.68; 95% CI: −1.06 to −0.30; P=0.005). The multiplicative interaction between these two genotypes was statistically significant (−0.52; 95% CI: −0.94 to −0.11; P=0.015). Conclusion The effect of the MATE1 rs2289669 polymorphism on the glucose lowering effect of metformin is larger in incident users with the OCT1 rs622342 CC genotype than in incident users with the AA genotype. The effect in incident users with the OCT1 rs622342 AC genotype is in between.

Cytochrome P450 2C9 *2 and *3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus.

Sulfonylurea hypoglycemics are mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme. The CYP2C9*2 and *3 polymorphisms encode proteins with less enzymatic activity and are correlated with elevated serum levels of sulfonylurea, as demonstrated in healthy volunteers. In this study, the effect of these variants is described for patients with diabetes mellitus treated with sulfonylurea. Associations between CYP2C9 polymorphisms, prescribed doses of sulfonylurea, and change in glucose levels after the start of sulfonylurea therapy were assessed in all patients with incident diabetes mellitus starting on sulfonylurea therapy in the Rotterdam Study, a population‐based cohort study of 7,983 elderly people. In CYP2C9*3 allele carriers using tolbutamide, the prescribed dose was lower compared to patients with the wild‐type CYP2C9 genotype. No differences in the prescribed dose were found in tolbutamide users with the CYP2C9*1/*2 or CYP2C9*2/*2 genotype compared to wild‐type patients or in patients using other sulfonylurea. In CYP2C9*3 allele carriers, the mean decrease in fasting serum glucose levels after the start of tolbutamide therapy was larger than in patients with the wild‐type genotype, although not statistically significant. Patients with diabetes mellitus who are carriers of a CYP2C9*3 allele require lower doses of tolbutamide to regulate their serum glucose levels compared to patients with the wild‐type genotype.

Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in The Rotterdam Study.

Objectives CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the HMG-CoA reductase inhibitor simvastatin. The objective of this study was to investigate whether a new CYP3A4 functional single nucleotide polymorphism (SNP) in intron 6 (CYP3A4*22) modifies the effect of simvastatin on total cholesterol (TOTc) or LDL cholesterol (LDLc) reduction in a population-based cohort study. Methods In a total of 80 incident simvastatin users, the association between the CYP3A4 intron 6 C>T SNP (rs35599367) and reduction in cholesterol levels was analyzed using linear regression analysis and adjusting for potential confounding factors. Results The CYP3A4*22 allele was associated with a trend towards a stronger simvastatin lipid-lowering response, as reflected by the greater reduction in both TOTc and LDLc levels when compared with homozygous wild type. We observed that the CYP3A4*22 allele carriers had an increased reduction in TOTc and LDLc: −0.25 mmol/l (95% confidence interval [CI95%]=[−0.52; 0.01], P=0.058) and −0.29 mmol/l (CI95%=[−0.58; 0.01], P=0.054) when compared with homozygous CC. When we adjusted the model for potential confounding factors, the corresponding reduction in TOTc was −0.31 mmol/l (CI95%=[−0.59;−0.04], P=0.028) and for LDLc −0.34 mmol/l (CI95%=[−0.66; −0.02], P=0.034) greater for CYP3A4*22 allele carriers when compared with homozygotes wild type. Conclusion The CYP3A4*22 intron 6 SNP T-variant allele was associated with reduced CYP3A4 activity, resulting in a better lipid lowering response to simvastatin, when data were adjusted for confounding factors. This observation is a step towards the clarification of the reasons of interindividual variability in statins response and may potentially lead to improved tailoring of simvastatin therapy.

Increasing Exposure to Drug-Drug Interactions Between 1992 and 2005 in People Aged ≥55 Years

AbstractBackground: Drug-drug interactions (DDIs) are responsible for a variety of adverse reactions, particularly in an elderly population. Objective: To assess the frequency and potential clinical relevance of DDIs in a population aged ≥55 years. Methods: Exposure to DDIs was assessed in 7842 people participating in the Rotterdam Study, a population-based cohort study. These people were followed between 1 January 1992 and 1 July 2005. The DDI list of the Royal Dutch Association for the Advancement of Pharmacy, in which DDIs are categorized by potential clinical relevance and quality of evidence, was used. Simultaneous use of interacting drug combinations was calculated on the basis of drug dispensing data from community pharmacies. Results: The incidence of a first dispensing of DDIs in the study period was 10.5 per 100 person-years and 2.7 per 100 person-years for potentially life-threatening DDIs. The prevalence of DDIs in people aged ≥70 years increased from 10.5% in 1992 to 19.2% in 2005. Ten DDIs comprised two-thirds of the total exposure time to DDIs. The prevalence of potentially life-threatening DDIs in people aged ≥70 years increased from 1.5% to 2.9%. This increase was most likely caused by an increase in use of spironolactone combined with renin-angiotensin-aldosterone system inhibitors. Conclusion: A large number of people in the Netherlands aged ≥55 years are exposed to DDIs and this number has increased sharply between 1992 and 2005. Healthcare professionals should pay special attention to the potential risks of DDIs in these people, particularly if spironolactone is involved.

OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users

Substrates for the Organic Cation Transporter 1, encoded by the SLC22A1 gene, are metformin, amantadine, pramipexole, and, possibly, levodopa. Recently, we identified that the rs622342 A > C polymorphism is associated with the HbA1c lowering effect in metformin users. In the Rotterdam Study, we associated this polymorphism with higher prescribed doses of all anti-Parkinsonian drugs. Between the first and fifth prescriptions for levodopa, for each minor rs622342 C allele, the prescribed doses were 0.34 defined daily dose higher (95% CI 0.064, 0.62; p = 0.017). The mortality ratio after start of levodopa therapy was 1.47 times higher (95% CI 1.01, 2.13; p = 0.045).

Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy

Simvastatin and atorvastatin are metabolized by the CYP3A4 enzyme and transported by the ABCB1 transporter. We studied whether the polymorphism CYP3A4*1B and the polymorphisms C1236T, G2677A/T and C3435T in the ABCB1 gene were associated with a decrease of the prescribed dose or a switch to another cholesterol lowering drug during simvastatin and atorvastatin therapy. These events may indicate that statin plasma levels were too high and resulted in an adverse drug reaction or a too strong reduction in cholesterol level.

Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea.

Objective The single nucleotide polymorphism rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene is associated with QTc prolongation, through an effect on the intracellular Ca2+ levels. As sulfonylurea stimulate insulin secretion by an increased influx of Ca2+, we hypothesized that this polymorphism is associated with the glucose-lowering effect and mortality risk in sulfonylurea users. Methods Associations between the NOS1AP polymorphism, prescribed doses, and mortality rates in sulfonylurea, metformin, and insulin users were assessed in the Rotterdam Study, a population-based cohort study of 7983 elderly people. Results We identified 619 participants who were prescribed oral antidiabetic drugs during follow-up. In glibenclamide users carrying the TG genotype, the prescribed doses were higher compared with the glibenclamide users carrying the TT genotype [0.38 defined daily dose units, 95% confidence interval (CI) 0.14–0.63]. Glibenclamide users with the TG or GG genotype had an increased mortality risk compared with glibenclamide users with the TT genotype [hazard ratio (HR) 2.80, 95% CI: 1.09–7.22]. Tolbutamide users with the TG or GG genotype (HR: 0.30, 95% CI: 0.14–0.63) and glimepiride users with the TG or GG genotype (HR: 0.18, 95% CI: 0.04–0.74) had a decreased mortality risk compared with tolbutamide and glimepiride users with the TT genotype. Conclusion In participants with the TG or GG genotype at rs10494366 in the NOS1AP gene, glibenclamide is less effective in reducing glucose levels and mortality rates were higher compared with glibenclamide users with the TT genotype. In tolbutamide and glimepiride users, the TG and GG genotype were associated with a reduced mortality rate.

The SLCO1B1 c.521T>C polymorphism is associated with dose decrease or switching during statin therapy in the Rotterdam Study.

Objective The SLCO1B1 c.521T>C polymorphism is associated with statin plasma levels and simvastatin-induced adverse drug reactions. We studied whether the c.521T>C polymorphism is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy, because these events are indicators of adverse drug reactions. Materials and methods We identified 1939 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations were studied using Cox proportional hazards analysis. Meta-analysis was performed with data from the Utrecht Cardiovascular Pharmacogenetics study. Results Simvastatin users with the c.521 CC genotype had a significantly higher risk of a dose decrease or switch than users with the TT genotype [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.05–2.88]. Female sex, age below 70 years, and low starting dose were risk factors. In atorvastatin users with starting dose of more than 20 mg, the risk of a dose decrease or switch was higher in users carrying a C allele than in users with the TT genotype (HR 3.26, 95% CI 1.47–7.25). In the meta-analysis the association in simvastatin users remained, with a significantly higher risk of a dose decrease or switch in simvastatin users with two minor alleles (HR 1.69, 95% CI 1.05–2.73). For atorvastatin users no significant association was found. Conclusion In simvastatin users in the Rotterdam Study, we demonstrated an association between the c.521T>C polymorphism and dose decrease or switching, as indicators of adverse drug reactions, and provided risk factors for this association. For atorvastatin, an association was found in users with a starting dose of more than 20 mg.