Issue 179 Item 10 Cause of Diabetes Affects Response to Treatment

Findings have important implications for patient management and selection of treatment. Individuals with maturity-onset diabetes of the young caused by heterozygous mutations in the hepatocyte nuclear factor HNF-1a gene have a greater response to sulphonylurea than do patients with type 2 diabetes according to the findings from a randomised crossover trial. Ewan R. Pearson, MA, of Peninsula Medical School, Exeter, United Kingdom, and colleagues compared the responses to the sulphonylurea gliclazide and the biguanide metformin in 18 patients with HNF-1a diabetes and another 18 patients with type 2 diabetes who were matched for body-mass index (BMI) and fasting plasma glucose.

Patients received 500 mg daily metformin for 1 week, increased to 500 mg twice daily for 1 week then to 1 g twice daily for 4 weeks or 40 mg daily gliclazide for 1 week, increased to 40 mg twice daily for 1 week then to 80 mg twice daily for 4 weeks. The groups had a 1-week wash out period before crossing over from one drug regimen to the other. Patients in the type 2 group had diabetes for a mean duration of 4.8 years and were a mean age of 66 years while those in the HNF-1a group had diabetes for a mean duration of 18.3 years and were a mean age of 44 years.

The researchers found that patients with HNF-1a diabetes had a 5.2-fold greater response to gliclazide than to metformin. Among this group the fasting plasma glucose reduction was 4.7 mmol/L for gliclazide compared with 0.9 mmol/L for metformin. Conversely, the patients with type 2 diabetes showed no difference in response to gliclazide and metformin.

When compared with the type 2 diabetes group, the HNF-1a group had a 3.9-fold greater response to gliclazide while the response to metformin was similar in the 2 groups.

Fructosamine assay testing in the patient groups during the last 2 to 3 weeks of taking each drug revealed that fructosamine was 136 micromol/L lower in the HNF-1a group while taking gliclazide compared with metformin. In the type 2 diabetes group the fructosamine was 23 micromol/L higher while on gliclazide compared with metformin. The investigators also noted that the HNF-1a group "had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes."

The researchers conclude, "the cause of diabetes affects the response to treatment." They suggest that these findings have important implications for patient management.
Lancet 2003;362:1275-81.