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

Abstract

<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>

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.…”

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test

“…For example, although first line therapy with metformin may provide acceptable metabolic control early in the course of the disease, it is often necessary to add one or more drugs to restore acceptable metabolic control 1,2,16,17 . Physicians have quite a number of options when selecting a second drug to prescribe for patients who are inadequately controlled on metformin monotherapy -including, DPP4 inhibitors, SGLT2 inhibitors, GLP1R agonists, sulfonylureas, and pioglitazone among others 1,2,17,18 .…”

Insulin secretion is a strong predictor for need of insulin therapy in patients with new‐onset diabetes and HbA1c of more than 10%: A post hoc analysis of the EDICT study

“…The study protocol was approved by the Institutional Review Board of University of Texas Health Science Center at San Antonio and informed written consent was obtained from all participants before enrolment. The study design 18 and primary outcome 19 have been published. Briefly, drug‐naïve, new‐onset (<2 years) T2D patients, age 18‐75 years, who otherwise were healthy, were recruited into the study.…”

“…15 Thus, including a TZD in glucose-lowering therapy, which is the only true insulin sensitizer available, will address both the major core defects of T2D, beta cell dysfunction and insulin resistance. 15 The Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study 18,19 compared the efficacy of two glucose-lowering therapeutic strategies in newly diagnosed T2D patients: (a) initiation of triple therapy with metformin plus pioglitazone plus GLP-1 RA at the time of diagnosis versus (b) initiation of therapy with metformin followed by sequential addition of sulphonylurea followed by basal insulin to maintain the HbA1c at less than 6.5%. Because there was no upper limit for HbA1c inclusion, 104 study participants had an initial HbA1c of more than 10% and all manifested weight loss in the preceding months.…”