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OBJECTIVE This study compared the efficacy and safety of once-weekly dulaglutide, a glucagon-like 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 HbA1c change from baseline at 52 weeks. RESEARCH DESIGN AND METHODS In this 78-week, open-label study, 810 patients were randomized to dulaglutide 1.5 mg, dulaglutide 0.75 mg, or glargine. RESULTS The baseline mean ± SD HbA1c was 8.1 ± 1.0% (65.5 ± 10.8 mmol/mol). The least squares mean ± SE HbA1c change from baseline to the primary end point was −1.08 ± 0.06% (−11.8 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, −0.76 ± 0.06% (−8.3 ± 0.7 mmol/mol) for dulaglutide 0.75 mg, and −0.63 ± 0.06% (−6.9 ± 0.7 mmol/mol) for glargine, with an end point mean ± SD dose of 29 ± 26 units (0.33 ± 0.24 units/kg), and a fasting plasma glucose (mean ± SD) of 118 ± 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 HbA1c targets CONCLUSIONS Once-weekly dulaglutide 1.5 mg, compared with daily insulin glargine without forced titration, demonstrated greater HbA1c reduction and weight loss, with a higher incidence of gastrointestinal adverse events and a lower risk of hypoglycemia.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.

OBJECTIVE Compare 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 A1c (HbA1c) at 26 weeks. RESEARCH DESIGN AND METHODS This 52-week double-blind study randomized patients to subcutaneous dulaglutide 1.5 mg, dulaglutide 0.75 mg, or metformin. Patients (N = 807) had HbA1c ≥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. RESULTS At 26 weeks, changes from baseline HbA1c (least squares [LS] mean ± SE) were: dulaglutide 1.5 mg, −0.78 ± 0.06% (−8.5 ± 0.70 mmol/mol); dulaglutide 0.75 mg, −0.71 ± 0.06% (−7.8 ± 0.70 mmol/mol); and metformin, −0.56 ± 0.06% (−6.1 ± 0.70 mmol/mol). Dulaglutide 1.5 and 0.75 mg were superior to metformin (LS mean difference): −0.22% (−2.4 mmol/mol) and −0.15% (−1.6 mmol/mol) (one-sided P < 0.025, both comparisons), respectively. Greater percentages reached HbA1c targets CONCLUSIONS Dulaglutide improves glycemic control and is well tolerated as monotherapy in patients with early stage type 2 diabetes.

This Phase 3, randomized, double-blind, parallel-arm, monotherapy study compared the efficacy and safety of 2 doses of dulaglutide (DU), a long-acting GLP-1-receptor agonist, to metformin (MET) in patients with early type 2 diabetes (mean 2.6 years) treated with diet and exercise alone or in combination with 1 oral antidiabetic medication (low dose for ≥ 3 months before screening).