Durability of Early Combination Therapy Vs Conventional Therapy in New Onset T2dm

Hyperglycemia is the major risk factor for the development of diabetic microvascular complications. The ADA recommends lowering the A1c in T2DM individuals to levels (i.e. HbA1c <6.0-6.5%) 'as close to normal as possible while avoiding hypoglycemia'. The optimal pharmacologic therapy which achieves this goal never has been determined. We have demonstrated that starting newly diagnosed T2DM individuals on a combination of agents (metformin, pioglitazone, exenatide) which correct known pathophysiologic defects in T2DM (Triple Therapy) produces a greater decrease in HbA1c compared to stepwise addition of metformin, sulfonylurea and insulin (Conventional Therapy) and that the decrease in HbA1c was maintained for 36 months of follow-up. Subjects receiving Conventional Therapy experienced significant weight gain (3.7 kg) and a higher rate (7.4-fold increase) of hypoglycemic events compared to subjects receiving Triple Therapy who lost 3.1 kg of body weight. Moreover, Triple Therapy produced profound increases in insulin sensitivity and beta cell function compared to Conventional Therapy. In this grant, we propose to continue to follow-all currently active subjects for an additional 36 months to obtain information about the long term efficacy, durability, safety, and mechanism of action of Triple Therapy compared to Conventional Therapy. PUBLIC HEALTH RELEVANCE: In the currently ongoing Triple Therapy Study, we demonstrated that initiating therapy in newly diagnosed type 2 diabetic subjects with combination pioglitazone/metformin/exenatide therapy compared to the more conventionally recommended approach (start with metformin, then add a second oral agent [sulfonylurea], and then add to basal insulin) produces superior glycemic control. The difference in HbA1c between the two arms at 3 years was -0.75%, with 7-fold lower risk of hypoglycemia, mean weight loss as opposed to weight gain, decrease in blood pressure, and marked improvements in insulin sensitivity and beta cell function. The aim of the present grant proposal is to extend the follow-up to additional 3 years to examine the long term durability of the metabolic benefits of the combination therapy.