Improving glycemic control in patients with type 2 diabetes mellitus (T2DM) is considered important in reducing microvascular complication rates and in potentially decreasing the risk of macrovascular disease. If glycemic control cannot be achieved or maintained with oral agents, consensus guidelines recommend adding insulin regimens. Unfortunately, evidence to suggest which insulin to add is limited and each insulin formulation has differing effects on glycemic control, weight gain, and hypoglycemic risk.1,2
Recently, the 3-year results from the Treating to Target in Type 2 Diabetes (4-T) study were reported.3 Of note, the results from the first phase of the study were published in 2007.4 Seven hundred and eight patients (235 in the biphasic group, 239 in the prandial group, and 234 in the basal group) with inadequate glycemic control (glycated hemoglobin levels [HgA1c] of 7-10%) on combination use of metformin and sulfonylurea were randomly assigned to one of three insulin regimens (twice daily biphasic insulin aspart [NovoMix 30], three-times-daily prandial insulin aspart [NovoRapid], or once or twice-daily basal insulin detemir [Levemir]) during the first year. Sulfonylurea therapy was replaced by a second type of insulin during the first year if patients had unacceptable levels of hyperglycemia (HgA1c > 10% or two consecutive HgA1c > 8% after at least 24 weeks of therapy) or if HgA1c > 6.5%. Midday prandial insulin was added to biphasic insulin; basal insulin at bedtime was added to the prandial insulin, and prandial insulin three times daily before meals was added to basal insulin. Patients were excluded if there was a history of thiazolidinedione therapy or triple oral antidiabetic therapy.
The primary 3-year outcome was the HgA1c level. Secondary outcomes included the proportion of patients with a HgA1c < 6.5%, the proportion of patients with a HgA1c < 6.5% but without hypoglycemic events of grade 2 or more (grade 1 defined as symptoms with a glucose > 56 mg/dL; grade 2 defined as hypoglycemic symptoms with a glucose < 56 mg/dL; grade 3 if assistance from a third party was required), number of patients requiring a second type of insulin, self-measured glucose readings, and weight gain.
For the primary outcome, the overall HgA1c value at three years did not differ significantly in the three insulin groups. At three years, the mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group. There were statistically significant fewer patients in the biphasic group (31.9%) that obtained a HgA1c < 6.5% than the prandial group (44.7%, p=0.006) or the basal group (43.2%, p=0.03). In patients with a baseline HgA1c < 8.5%, the patients in the biphasic group were less likely to obtain a HgA1c < 6.5% versus the patients in the prandial group (odds ratio, 0.48; p=0.007) or the basal group (odds ratio, 0.46; p=0.004). There were significant differences between the three groups with regards to replacing sulfonylurea therapy with a second type of insulin; 67.7% for the biphasic group, 73.6% for the prandial group, and 81.6% for the basal group (overall comparison; p=0.002). There were no significant differences demonstrated between the three groups in fasting blood glucose levels. Although weight gain was seen in patients in all three groups, the amount of weight gain was less in the basal group than the other two groups, which were similar to each other. While there were no significant differences in rates of hypoglycemia of grade 2 or more between the groups, the highest hypoglycemia rates were seen in the prandial group and lowest rates in the basal group.
Overall 130 patients (18.4%) did not complete the trial. There were no significant between-group differences. During the trial period 19 patients died (7 in the biphasic group, 9 in the prandial group, and 3 in the basal group; p=0.23); of these patients 14 died from cardiovascular disease (4 in the biphasic group, 9 in the prandial group, and 1 in the basal group; p=0.002).
The three year results of the 4-T study demonstrate the effectiveness of basal and prandial insulin regimens in reaching HgA1c goals in T2DM patients. However 68 to 82% of patients required an additional type of insulin to achieve a median HgA1c of 6.9%. The 4-T study used only insulin analogs produced from one company versus regular human insulin, which is considered first-line by consensus statements.5 Importantly, 18 to 32% of patients in the 4-T study continued to ...