The RS7903146 Variant of TCF7L2 and the Risk for Sulfonylurea-Induced Hypoglycemia in Patients with Type 2 Diabetes

There is considerable interindividual variation in the hypoglycemic response to sulfonylureas (SU) in type 2 diabetes (T2D) patients. Typical risk factors for hypoglycemia in users of SU include advanced age, long duration of T2D, multimorbidity with particular renal impairment and polypharmacy. Moreover, a number of pharmacogenetic factors could be of critical importance for the risk of SU-induced hypoglycemia. The aim of the present study was to investigate the effects of the rs7903146 variant of TCF7L2 on risk for gliclazide-induced hypoglycemia in patients with T2D.

Methods:

A cohort study was conducted in 68 individuals (42 males) with newly diagnosed T2D, who had body mass index ≥18.5 and < 25 kg/m2. For all patients gliclazide in a dose of 30 mg/day was prescribed. If necessary, dose titration was carried out or other glucose-lowering therapy was prescribed for 3 months of observation. Adverse effects were based on self-report by individuals during clinical follow-up. Hypoglycemia was defined as a symptomatic event requiring treatment with high-sugar foods or drinks or with medications and was confirmed by a blood glucose measurement of < 3.9 mmol/l. The rs7903146 polymorphism was analyzed in the TCF7L2 gene by real-time polymerase chain reaction (RT-PCR). A p-value less than 0.05 was considered significant.

Results:

In T2D patients, mean age was 53.8±7.3 and mean HbA1c was 9.80±1.37%. According to RT-PCR results, 51.5% had the wild-type CC genotype, 45.6% had the heterozygous CT genotype, and 2.9% had the mutant TT genotype. The genotype distribution was in accordance with the Hardy-Weinberg equilibrium (p > 0.05). All participants were divided into two groups: wild genotype carriers (n=35) and the minor T allele carriers (n=33). All baseline demographics and laboratory investigations were comparable with p-value >0.05. There was a significant decrease in HbA1C levels after 3 months of gliclazide treatment in newly diagnosed T2D patients both with or without the risk T allele (p < 0,001). However, hypoglycemic events were significantly more in patients harbouring the risk T allele of the rs7903146 polymorphism compared with wild-type homozygotes: 30.3% vs. 8.6% respectively (p=0.043). Carriers of the risk T allele had increased odds of SU-induced hypoglycemia (OR 4.64; 95% CI: 1.15-18.76; p=0.031).

Discussion/Conclusion:

The present study revealed that the rs7903146 SNP of the TCF7L2 gene was associated with higher risk for hypoglycemia in T2D patients treated with gliclazide. Further, pharmacogenomics and functional investigations should be conducted in a bigger cohort to confirm the effects of this genetic variant on SU therapy and provide more powerful evidence for its use as a predictor of anti-diabetic treatment response.