Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Patients assigned to orforglipron experienced significant reductions in HbA1c, and body weight compared to other groups.

2. The majority of treatment-related adverse events were mild-to-moderate in nature.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Glucagon-like peptide (GLP-1) receptor agonists are emerging as first-line therapies for the management of type 2 diabetes (T2D). Currently, semaglutide is the only orally administered GLP-1 agonist available. Orforglipron is a novel non-peptide GLP-1 agonist that may be superior to current therapy for T2D with pharmacokinetics that supports once-per-day dosing. This randomized controlled trial aimed to assess the safety and efficacy of orforglipron versus dulaglutide and placebo. The primary outcome of this study was mean change in glycated hemoglobin (HbA1c) from baseline to 26 weeks, while key secondary outcome included mean change in body weight. According to study results, oral orforglipron showed significant superiority versus placebo for mean reduction in HbA1c and body weight at 26 weeks. Although this study was well done, it was limited by a short follow-up, thus affecting the validity of the findings.

In-depth [randomized-controlled trial]:

Between Sept 15, 2021, and Sept 30, 2022, 569 patients were screened for eligibility across 45 centers in the USA, Hungary, Poland, and Slovakia. Included were patients ≥ 18 years with T2D, treated with or without metformin, with HbA1c 7.0-10.5% and BMI ≥ 23 kg/m2. Altogether, 383 patients (enrolled in placebo, dulaglutide 1.5 mg, and orforglipron 3 mg, 12 mg, 24 mg, 36 mg, and 45 mg) were included in the final analysis. The mean patient age was 58.9 years, mean HbA1c was 8.1%, mean BMI was 35.2 kg/m2, and the majority (59%) were men. The primary outcome of reduction in HbA1c at 26 weeks was -2.10% with orforglipron, -1.10% with dulaglutide, and -0.43% with placebo. Similarly, the secondary outcome of mean change in body weight was -10.1 kg with orforglipron (95% confidence interval [CI] -11.5 to -8.7), -3.9 kg with dulaglutide (95% CI -5.3 to -2.4), and -2.2 kg with placebo (95% CI -3.6 to -0.7). Overall, findings from this study suggest that orforglipron holds promise as an effective and convenient alternative for managing type 2 diabetes and obesity.

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