Treating to target in type 2 diabetes (4-T) study: 3-year results

Aims: Type 2 diabetes mellitus is a progressive condition in which glycated hemoglobin levels rise over time as beta-cell function declines. Maintenance of near-normal glycaemia reduces the risk of diabetic complications, but is difficult to achieve despite the use of multiple oral antidiabetic agents. As a result, oral therapy requires repeated escalation with the majority of patients requiring insulin in the longer term. There is, however, considerable uncertainty as to which insulin regimen should be used, Whether therapy should commence with the addition of a biphasic, a long-acting or a short-acting insulin preparation, or when a second insulin formulation should be introduced.

Methodology: The Treating to Target in Type 2 diabetes (4-T) was a 3-year, multicentre, open-label, randomized, controlled clinical trial of analogue insulins conducted in 58 UK and Irish centers. A total of 708 patients with type 2 diabetes, who had suboptimal glycemic control while receiving maximally tolerated doses of metformin and sulphonylurea therapy, were randomized to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulphonylurea therapy was replaced by a second type of insulin if hyperglycaemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycaemia, and weight gain.

Results: After 3 years the median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (insulin 6.9%)-based regimens (p=0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, p=0.006) or in the basal group (43.2%, p=0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (p=0.002). Median rates of hypoglycaemia/patient/year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (p<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups.

Conclusions: Patients who added a basal or prandial insulin-based regimen to oral therapy had better control glycated hemoglobin than patients who added a biphasic insulin-based regimen. Fewer hypoglycaemic episodes and less weight gain occurred in patients starting with basal insulin.