Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add‐on therapy in subjects with new‐onset diabetes. Results from the E fficacy and D urability of I nitial C ombination T herapy for T ype 2 D iabetes ( EDICT ): a randomized trial

Aim To test our hypothesis that initiating therapy with a combination of agents known to improve insulin secretion and insulin sensitivity in subjects with new‐onset diabetes would produce greater, more durable reduction in glycated haemoglobin ( HbA1c ) levels, while avoiding hypoglycaemia and weight gain, compared with sequential addition of agents that lower plasma glucose but do not correct established pathophysiological abnormalities. Methods Drug‐naïve, recently diagnosed subjects with type 2 diabetes mellitus ( T2DM ) were randomized in an open‐fashion design in a single‐centre study to metformin/pioglitazone/exenatide (triple therapy; n = 106) or an escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin (conventional therapy; n = 115) to maintain HbA1c levels at <6.5% for 2 years. Results Participants receiving triple therapy experienced a significantly greater reduction in HbA1c level than those receiving conventional therapy (5.95 vs. 6.50%; p < 0.001). Despite lower HbA1c values, participants receiving triple therapy experienced a 7.5‐fold lower rate of hypoglycaemia compared with participants receiving conventional therapy. Participants receiving triple therapy experienced a mean weight loss of 1.2 kg versus a mean weight gain of 4.1 kg (p < 0.01) in those receiving conventional therapy. Conclusion The results of this exploratory study show that combination therapy with metformin/pioglitazone/exenatide in patients with newly diagnosed T2DM is more effective and results in fewer hypoglycaemic events than sequential add‐on therapy with metformin, sulfonylurea and then basal insulin.