Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY

Abstract

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that combination therapy with metformin plus rosiglitazone provided superior durability of glycemic control compared with metformin alone, with significantly lower treatment failure rates (38.6 vs. 51.7%), and metformin plus lifestyle was intermediate. Herein we describe the temporal changes in measures of β-cell function and insulin sensitivity over a 4-year period among the three treatments.

Research design and methods: TODAY participants (699) were tested periodically with an oral glucose tolerance test to determine insulin sensitivity (1/fasting insulin [1/IF]), insulinogenic index (ΔI(30)/ΔG(30)) or C-peptide index (ΔC(30)/ΔG(30)), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]).

Results: During the first 6 months, metformin plus rosiglitazone exhibited a significantly greater improvement in insulin sensitivity and oDI versus metformin alone and versus metformin plus lifestyle; these improvements were sustained over 48 months of TODAY. Irrespective of treatment, those who failed to maintain glycemic control had significantly lower β-cell function (~50%), higher fasting glucose concentration, and higher HbA1c at randomization compared with those who did not fail.

Conclusions: The beneficial change in insulin sensitivity and the resultant lower burden on β-cell function achieved in the first 6 months with metformin plus rosiglitazone appear to be responsible for its superior glycemic durability over metformin alone and metformin plus lifestyle. However, initial β-cell reserve and HbA1c at randomization are independent predictors of glycemic durability. Therefore, efforts to preserve β-cell function before significant loss occurs and to reduce HbA1c may be beneficial in the treatment of youth with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00081328.

Figure 1

Baseline adjusted geometric mean ± SE asymmetric limits (obtained as exp[mean ± SE of log values]) of OGTT-derived measures of insulin sensitivity (1/I_F) (A), insulinogenic index (△I₃₀/△G₃₀) (B), and oDI ([1/I_F] × [△C₃₀/△G₃₀]) (C) in the three treatment groups over 48 months of follow-up in TODAY, analyzed using log-transformed values. The P value refers to the overall effect of treatment group assignment in the longitudinal models for the various parameters under question within the groups.

Figure 2

Baseline adjusted geometric mean ± SE asymmetric limits (obtained as exp[mean ± SE of log values]) of OGTT-derived measures by treatment failure with the three treatment groups combined, analyzed using log-transformed values. A: Insulin sensitivity (1/I_F). B: Insulinogenic index (△I₃₀/△G₃₀). C: oDI ([1/I_F] × [△C₃₀/△G₃₀]). The P value refers to the overall effect of failed vs. not failed group assignment in the longitudinal models for the various parameters under question within the two groups.