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Variation in TCF7L2 influences therapeutic response to sulfonylureas: A GoDARTs study.

¹ Division of Medicine & Therapeutics, University of Dundee, UK
² Health Informatics Centre, University of Dundee, UK
³ Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, UK
⁴ Oxford Centre for Diabetes, Endocrinology & Metabolism, Oxford, UK
⁵ Institute of Biomedical Sciences, Peninsula Medical School, UK

Correspondence: e.pearson{at}chs.dundee.ac.uk

Objective.: There is considerable inter-individual variation in sulfonylurea response in type 2 diabetes (T2DM). TCF7L2 variants have been identified to be strongly associated with T2DM risk, probably due to decreased beta cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response.

Research Design & Methods.: The DARTS/MEMO collaboration database includes prescribing, biochemistry and clinical phenotype of all patients with diabetes within Tayside, Scotland from 1992. Of these, TCF7L2 genotype was determined in 4469 patients with T2DM recruited to GoDARTS between 1997 and July 2006. 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an HbA1c >7% within 3 to 12 months after treatment initiation. Covariates included TCF7L2 genotype, BMI, gender, age diagnosed, drug adherence and drug dose. HbA1c pre-treatment was available in a subset of patients (sulfonylurea n=579, metformin n=755).

Results.: Carriers of the risk allele were less likely to respond to sulfonylureas with an OR (95%CI) for failure of 1.95 (1.23-3.06), p=0.005, comparing rs12255372 T/T v G/G. Including the baseline HbA1c strengthened this association (OR 2.16 (1.21-3.86), p=0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either SNP, after adjustment for baseline HbA1c.

Conclusions.: TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.

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