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

Abstract

OBJECTIVE 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. RESEARCH DESIGN AND METHODS Drug-naive patients (N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA1c 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 HbA1c between the groups at 3 years. RESULTS Baseline HbA1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21–0.39]; P = 0.001), and the HbA1c 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 HbA1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39–0.61; P < 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 P < 0.0001 vs. triple therapy). CONCLUSIONS Triple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.

Early Glycosylated Hemoglobin Target Achievement Predicts Clinical Outcomes in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

“…Previous studies provided evidence that longterm durable glycemic control can decrease the incidence of diabetic complications [ 5 ]. Although previous studies have suggested the potential benefit of early intensive glucose-lowering therapy, most of the current practice guidelines recommend serial escalation of diabetic medications in patients with newly diagnosed diabetes unless those patients are severely hyperglycemic [ 6 , 7 ]. The optimal duration to target glycosylated hemoglobin (HbA1c) achievement and its potential benefits in a clinical setting are poorly understood.…”

Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT)

“…The 3-year HbA1c results were previously reported. 18,19 OGTT-derived indices of insulin sensitivity and insulin secretion were calculated from plasma glucose, insulin, and C-peptide concentrations during OGTT, as previously described. 20,21 The Matsuda Index and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were used to quantitate insulin sensitivity.…”

“…The EDICT study is an ongoing single‐centre (Texas Diabetes Institute), randomized controlled trial (NCT01107717) designed to compare two therapeutic approaches for the management of patients with new‐onset T2D: (1) initial combination therapy with medications (metformin/pioglitazone/exenatide) that correct core metabolic defects present in T2D (triple therapy) versus (2) stepwise addition of medications that lower plasma glucose without correcting underlying pathophysiological abnormalities (conventional therapy). Interim analysis of the study results focusing on glycaemic control, physiological measurements of beta cell function, and insulin sensitivity have previously been reported 18,19 . The initial study protocol was designed for 3 years of follow‐up and was extended to 6 years of follow‐up.…”

“…Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have also been shown to reduce steatosis 14‐16 and improve liver histology, 15‐17 but they do not have a major effect in decreasing fibrosis 17 . EDICT (Efficacy and Durability of Initial Combination Therapy) was a 3‐year study designed to compare the efficacy of triple (pioglitazone/exenatide/metformin) versus conventional (metformin/sulphonylurea/insulin) therapy on glycaemic control in newly diagnosed T2D patients 18,19 . EDICT was subsequently extended to 6 years.…”

Long-term effectiveness and safety of quadruple combination therapy with empagliflozin versus dapagliflozin in patients with type 2 diabetes: 3-year prospective observational study

“…Even though injectable forms of antidiabetic drugs, such as insulin or glucagon-like peptide-1 receptor agonist (GLP-1RA), are highly effective, but not all patients and even physicians are willing to initiate or maintain their use due to underlying psychological barriers [2,3,4]. More recently, there are increasing reports that administration of a combination therapy of oral antidiabetic drugs (OADs) with distinct modes of action at an earlier stage of T2D development may have more benefit than a drug regimen that sequentially escalates dosing with one or more drugs [6,7]. However, the type and number of oral or injectable drugs that can be effectively used to treat T2D remains to be fully described, especially with the broad spectrum of patients and their specific clinical needs.…”