Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT.

Abstract

To compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin. Drug-naive patients (<i>N</i> = 318) with new-onset T2DM were randomly assigned to receive for 3 years either <i>1</i>) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or <i>2</i>) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA_1c at <6.5% (48 mmol/mol). Insulin sensitivity and β-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA_1c between the groups at 3 years. Baseline HbA_1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA_1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21-0.39]; <i>P</i> = 0.001), and the HbA_1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA_1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39-0.61; <i>P</i> < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in β-cell function. In conventional therapy, insulin sensitivity did not change and β-cell function increased by only 34% (both <i>P</i> < 0.0001 vs. triple therapy). Triple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA_1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.