Efficacy and Safety of Dulaglutide Monotherapy Versus Metformin in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-3)

Abstract

OBJECTIVECompare the efficacy and safety of monotherapy with dulaglutide, a once-weekly GLP-1 receptor agonist, to metformin-treated patients with type 2 diabetes. The primary objective compared dulaglutide 1.5 mg and metformin on change from baseline glycosylated hemoglobin A 1c (HbA 1c ) at 26 weeks. RESEARCH DESIGN AND METHODSThis 52-week double-blind study randomized patients to subcutaneous dulaglutide 1.5 mg, dulaglutide 0.75 mg, or metformin. Patients (N = 807) had HbA 1c ‡6.5% ( ‡48 mmol/mol) and £9.5% (£80 mmol/mol) with diet and exercise alone or low-dose oral antihyperglycemic medication (OAM) monotherapy; OAMs were discontinued at beginning of lead-in period. RESULTSAt 26 weeks, changes from baseline HbA 1c (least squares [LS] mean 6 SE) were: dulaglutide 1.5 mg, 20.78 6 0.06% (28.5 6 0.70 mmol/mol); dulaglutide 0.75 mg, 20.71 6 0.06% (27.8 6 0.70 mmol/mol); and metformin, 20.56 6 0.06% (26.1 6 0.70 mmol/mol). Dulaglutide 1.5 and 0.75 mg were superior to metformin (LS mean difference): 20.22% (22.4 mmol/mol) and 20.15% (21.6 mmol/mol) (one-sided P < 0.025, both comparisons), respectively. Greater percentages reached HbA 1c targets <7.0% (<53 mmol/mol) and £6.5% (£48 mmol/mol) with dulaglutide 1.5 and 0.75 mg compared with metformin (P < 0.05, all comparisons). No severe hypoglycemia was reported. Compared with metformin, decrease in weight was similar with dulaglutide 1.5 mg and smaller with dulaglutide 0.75 mg. Over 52 weeks, nausea, diarrhea, and vomiting were the most common adverse events; incidences were similar between dulaglutide and metformin. CONCLUSIONSDulaglutide improves glycemic control and is well tolerated as monotherapy in patients with early stage type 2 diabetes.Muscle and liver insulin resistance and b-cell failure represent the core pathophysiologic defects in type 2 diabetes. In addition, there is increasing evidence that the gastrointestinal (GI) tract plays an essential role in the development of carbohydrate intolerance of type 2 diabetes (1). The incretin concept suggests that ingested glucose results in a considerably larger and more sustained insulin secretion compared with glucose administered intravenously due to the release of two intestinal-derived

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

“…The HbA1c reduction observed at 26 weeks in the present study in Japanese patients with type 2 diabetes is consistent with the upper range of reductions seen in the global AWARD studies for dulaglutide (0.75 or 1.5 mg) 11, 12, 13, 14. It has been previously reported that GLP‐1 receptor agonists exert greater HbA1c‐lowering effects in Asian compared with non‐Asian people, and it has been suggested that differences in BMI between the ethnicities may be a contributing factor in the observed differential effects 19.…”

“…The safety profile of dulaglutide in this study (Table 2) was similar to that seen in previous GLP‐1 receptor agonist studies 11, 12, 13, 14, 17, 18. The most‐frequently reported adverse event was nasopharyngitis, reported by 12–13% of patients in the active treatment groups.…”

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

“…The improvement in FBG was sustained through the longest study duration of 104 weeks in AWARD-5 [31]. In AWARD-3 study (monotherapy vs. metformin), treatment with dulaglutide also resulted in significant reductions in postprandial glucose (PPG) from baseline after 2 weeks and this reduction lasted through the study [28]. Consistent with the early reduction in FBG and PPG, dulaglutide was shown to reduce HbA1c in patients with T2D as early as 4 weeks [28,30,31,33] after the start of treatment, and the reduction was shown to be sustained through 104 weeks [31].…”

“…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.…”