Issue 178 Item 12 Genetics Predicts Treatment Response in Diabetes

Patients with diabetes and a certain genetic subtype of diabetes can be shown to be very sensitive for sulfonylurea.

Diabetic patients with hepatocyte nuclear factor-1a (HNF-1a) mutations are markedly sensitive to sulfonylurea therapy, according to the results of a randomized crossover trial published in The Lancet. The investigators suggest that defining the genetics has important implications for management.

"We have shown that the cause of diabetes determines the response to hypoglycemic drugs, with a genetic subtype of diabetes being very sensitive to the effects of sulfonylureas," senior author Andrew T. Hattersley, from Peninsula Medical School in Exeter, U.K., says in a news release. "This knowledge is crucial in deciding the best treatment for individual patients."

This study, which compared the glycemic response to the sulfonylurea gliclazide with the biguanide metformin in 36 patients with HNF-1a mutations or type 2 diabetes without a definable cause, was the first to determine whether different subtypes of diabetes have different responses to oral hypoglycemic agents.

At baseline, both groups were well matched for body mass index and blood glucose concentrations. However, the group with HNF-1a mutations had a 5.2-fold greater response to gliclazide than to metformin (P = .0007), whereas patients with type 2 diabetes responded similarly to both agents. Response to gliclazide in the HNF-1a patients was 3.9-fold greater than in the type 2 group (P = .002).

The authors note that the marked sulfonylurea sensitivity in HNF-1a diabetes is consistent with models of HNF-1a deficiency, which show that the beta-cell defect is upstream of the sulfonylurea receptor.

"The individualization of patients’ treatment is an important goal of the major work to define the genetic and environmental causes of diabetes," Dr. Hattersley says. Lancet. 2003;362:1275-1281