Efficacy and Safety of Once-Weekly Dulaglutide Versus Insulin Glargine in Patients With Type 2 Diabetes on Metformin and Glimepiride (AWARD-2)

Abstract

OBJECTIVEThis study compared the efficacy and safety of once-weekly dulaglutide, a glucagonlike peptide-1 receptor agonist, with daily insulin glargine, both combined with maximally tolerated doses of metformin and glimepiride in patients with type 2 diabetes. The primary objective was noninferiority of dulaglutide 1.5 mg to glargine in the HbA 1c change from baseline at 52 weeks. RESEARCH DESIGN AND METHODSIn this 78-week, open-label study, 810 patients were randomized to dulaglutide 1.5 mg, dulaglutide 0.75 mg, or glargine. RESULTSThe baseline mean 6 SD HbA 1c was 8.1 6 1.0% (65.5 6 10.8 mmol/mol). The least squares mean 6 SE HbA 1c change from baseline to the primary end point was 21.08 6 0.06% (211.8 6 0.7 mmol/mol) for dulaglutide 1.5 mg, 20.76 6 0.06% (28.3 6 0.7 mmol/mol) for dulaglutide 0.75 mg, and 20.63 6 0.06% (26.9 6 0.7 mmol/mol) for glargine, with an end point mean 6 SD dose of 29 6 26 units (0.33 6 0.24 units/kg), and a fasting plasma glucose (mean 6 SD) of 118 6 23 mg/dL from self-monitored plasma glucose. Statistical criteria for superiority were met with dulaglutide 1.5 mg and for noninferiority with dulaglutide 0.75 mg. More patients on dulaglutide 1.5 mg achieved HbA 1c targets <7.0% (53 mmol/mol) versus glargine (P < 0.001). Body weight decreased with dulaglutide and increased with glargine. Total hypoglycemia rates were lower with dulaglutide; severe hypoglycemia was minimal. Increases in pancreatic enzymes were observed for dulaglutide. Incidence of nausea (15.4, 7.7, and 1.5%) and diarrhea (10.6, 9.2, and 5.7%) were more common with dulaglutide 1.5 mg and 0.75 mg than with glargine. CONCLUSIONSOnce-weekly dulaglutide 1.5 mg, compared with daily insulin glargine without forced titration, demonstrated greater HbA 1c reduction and weight loss, with a higher incidence of gastrointestinal adverse events and a lower risk of hypoglycemia.

Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers

“…Significantly more patients achieved an HbA1c target of <7.0% with dulaglutide 1.5 mg versus metformin, sitagliptin, exenatide BID, and insulin glargine (p < 0.05), with no difference observed in AWARD-6 versus liraglutide ( Figure 4 and Table 1). Similar results were observed at the final end point for the percentages of patients achieving HbA1c goal of <7.0% (Table 2) [26][27][28][29][30].…”

“…Across studies, dulaglutide 1.5 mg was superior, based on HbA1c change from baseline, to placebo in AWARD-1, AWARD-5, and AWARD-8 (Table 1; placebo data will not be discussed further in the context of this manuscript), and superior to the active comparators evaluated: metformin, sitagliptin, exenatide BID, and insulin glargine (the comparator in two separate studies), and noninferior to liraglutide at the primary end point. This effect was sustained in all studies through the final end point (Table 2) [26][27][28][29][30]32]. In four of the five Phase 3 studies that examined dulaglutide 0.75 mg-treated patients, at the primary end point, dulaglutide 0.75 mg was superior based on HbA1c change from baseline to placebo and the active comparators of metformin, sitagliptin, exenatide BID, and insulin glargine As previously indicated, specific HbA1c targets are associated with clinical outcomes and risks for diabetes-related comorbidities.…”

“…The range of HbA1c reduction from baseline to the primary end point with dulaglutide 1.5 mg was −0.78% to −1.64% and −0.71% to −1.59% for dulaglutide 0.75 mg, and −0.39% to −1.41% for active comparators ( Figure 3 and Table 1) in the seven studies included in this report [26][27][28][29][30][31][32][33]. Across studies, dulaglutide 1.5 mg was superior, based on HbA1c change from baseline, to placebo in AWARD-1, AWARD-5, and AWARD-8 (Table 1; placebo data will not be discussed further in the context of this manuscript), and superior to the active comparators evaluated: metformin, sitagliptin, exenatide BID, and insulin glargine (the comparator in two separate studies), and noninferior to liraglutide at the primary end point.…”

“…These Phase 3 studies were designed to assess efficacy, safety, and PROs in patients across different stages of the T2D treatment continuum from monotherapy (AWARD-3), in patients taking concomitant sulfonylurea (SU) (AWARD-8), metformin (AWARD-5 and AWARD-6), metformin and thiazolidinedione (TZD) (AWARD-1), metformin and SU (AWARD-2), or in combination with prandial insulin with or without metformin (AWARD-4) with a study duration of 24-104 weeks ( Figure 2) [26][27][28][29][30][31][32][33]. A diverse patient population representing the continuum of T2D progression was examined across the seven trials, with a mean baseline age of 54.1-59.4 years, a mean duration of diabetes of 2.6-12.7 years, mean HbA1c of 7.6-8.5%, mean weight of 85.5-96.0 kg, FBG of 154-177 mg/dL, and previous treatment ranging from antihyperglycemic medication naive to third-line therapy.…”

“…In four of the five Phase 3 studies that examined dulaglutide 0.75 mg-treated patients, at the primary end point, dulaglutide 0.75 mg was superior based on HbA1c change from baseline to placebo and the active comparators of metformin, sitagliptin, exenatide BID, and insulin glargine As previously indicated, specific HbA1c targets are associated with clinical outcomes and risks for diabetes-related comorbidities. In AWARD clinical trials, the ranges for percentages of patients reaching a target HbA1c of <7.0% were as follows: 53-78% for dulaglutide 1.5 mg, 37-69% for dulaglutide 0.75 mg, and 31-68% for patients treated with active comparators at the primary end point [26,27,29,32,33]. Significantly more patients achieved an HbA1c target of <7.0% with dulaglutide 1.5 mg versus metformin, sitagliptin, exenatide BID, and insulin glargine (p < 0.05), with no difference observed in AWARD-6 versus liraglutide ( Figure 4 and Table 1).…”