Genetic risk factors for type 2 diabetes mellitus and response to sulfonylurea treatment.

OBJECTIVE After the identification of type 2 diabetes mellitus (T2DM) risk alleles from genome-wide association studies, models have been developed to identify subjects at high risk to develop T2DM. We hypothesize that a panel of 20 repeatedly associated T2DM risk alleles influences response to sulfonylureas (SUs). METHODS Two hundred and seven incident SU (tolbutamide, glibenclamide, glimepiride, gliclazide) users with T2DM were recruited from four primary care centers. A genetic risk score per patient was calculated based on the number of risk-alleles. With this score, patients were categorized into three predefined genetic risk groups. The effect of the genetic risk group on the achievement of stable SU dose, prescribed stable SU dose, and time to stable SU dose was analyzed. RESULTS Carriers of more than 17 T2DM risk alleles had a 1.7-fold reduced likelihood to achieve stable SU dose (P=0.044). No significant effect of the number of T2DM risk alleles on prescribed dose was found. Carriers of more than 17 T2DM risk alleles showed a marginally significant increased time to stable dose (hazard ratio: 0.81; 95% confidence interval, 0.75-1.01, P=0.058). CONCLUSION T2DM risk alleles are associated with response to SUs in primary care T2DM patients. This suggests that individualization of T2DM treatment according to genetic profile may be an opportunity to improve clinical outcome.