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

<b>Objective:</b> To compare the long term efficacy of initiating therapy with metformin/pioglitazone/exenatide in new onset T2DM patients versus sequential addition of metformin followed by glipizide and insulin. <p><b>Research Design and</b> <b>Methods</b>: 318 drug naïve, new onset T2DM were randomized to receive for 3 years: (1) combination therapy with metformin/pioglitazone/ exenatide (Triple Therapy) or (2) sequential addition of metformin followed by glipizide and insulin (Conventional Therapy) to maintain HbA1c <6.5% (48 mmol/mol). Insulin sensitivity and beta cell function were measured at baseline and at 3 years. The primary outcome was the difference in HbA1c between the groups at 3 years. </p> <p><b>Results:</b> Baseline HbA1c was 9.0±0.2% and 8.9±0.2% in the Triple Therapy and Conventional Therapy groups. The decrease in HbA1c produced by Triple Therapy was greater at 6 months than Conventional Therapy (0.30%, 95% CI=0.21-0.39) (p=0.001), and the HbA1c reduction was maintained at 3 years in subjects receiving Triple Therapy compared to Conventional Therapy (6.4±0.1% and 6.9±0.1%, respectively) despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA1c between the two treatment groups at 3 years was 0.50% (95% CI=0.39-0.61, P<0.0001). </p> <p>Triple Therapy produced 3-fold increase in insulin sensitivity and 30-fold increase in beta cell function. In Conventional Therapy insulin sensitivity did not change and beta cell function increased by only 34% (both p<0.0001 versus Triple Therapy). </p> <p><b>Conclusion: </b> Triple Therapy with agents that improve insulin sensitivity and beta cell function in new onset T2DM patients produce greater, more durable HbA1c reduction, than agents that lower glucose without correcting the underlying metabolic defects. </p>