Background Following the identification of alleles that increase the risk of type 2 diabetes mellitus (T2DM), models have been developed to identify high-risk subjects. The authors hypothesise that these risk alleles affect the treatment response to oral antidiabetic drugs.
Purpose To investigate whether genetic risk factors for T2DM are associated with response to sulfonylurea (SU) treatment.
Materials and methods Patients starting treatment with SUs (tolbutamide, glibenclamide, glimepiride, gliclazide) with T2DM were recruited from 4 primary care centres. Data were retrieved from the electronic patient records. Primary end point was achieving stable SU dose defined as the 1st period of ≥270 consecutive days without dose adjustment, initiation of other SU, insulin or metformin. Secondary end points were stable dose of prescribed SU, and time to stable SU dose. 20 SNPs (Single nucleotide polymorphs)consistently associated with T2DM in 19 genes were selected: TCF7L2, KCNJ11, HHEX/IDE, SLC30A8, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, KCNQ1, PPARG, FTO, NOTCH2, WFS1, JAZF1, THADA, CDC123/CAMK1D, TSPAN8/LGR5, ADAMTS9, HNF-1β, MTNR1B. A genetic risk score per patient was calculated based on the number of risk alleles. The χ2-test was used to compare the primary end point between groups scoring differently for genetic risk.
Results The mean genetic risk score was 19.0 (95% CI 18.7-19.4) in our T2DM population (n=207). The genetic risk score was negatively associated with achievement of stable SU dose: 84.7% of the patients in the low risk group (n=59) achieved a stable dose versus 74.1% and 62.3% of the patients in the intermediate risk (n=81) and high risk group (n=62; p=0.004). No significant effect of the genetic risk score on the stable SU dose achieved during this study was found. Carriers of more than 17 T2DM risk alleles showed a marginally significant increased time to stable dose (hazard ratio: 0.81; 95% CI, 0.75-1.01, P=0.058).
Conclusion Patients with an increased genetic risk of T2DM are less responsive to SUs.
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