Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials.

The present systematic review aimed to synthesize available data from recently published randomized trials (RCTs) investigating the efficacy and safety of the novel, orally administered, small-molecule glucagon-like peptide 1 receptor agonists (GLP-1RAs) orforglipron and danuglipron for the treatment of type 2 diabetes mellitus (T2DM), obesity or both. Literature search was performed through Medline (via PubMed), Cochrane Library and Scopus until August 16, 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with random effects meta-analysis. Totally, 1037 patients among seven RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB2). Novel GLP-1RAs led to significant reduction in HbA1c in patients with T2DM compared to controls (MD = −1.03 %; 95 % CI = [−1.29, −0.77]; P < 0.001). A significantly greater weight reduction was also noted both in patients with T2DM or obesity compared to controls (MD = −3.26 kg; 95 % CI = [−4.79, −1.72]; P < 0.001 and MD = −7.52 kg; 95 % CI = [−14.63, −0.41]; P = 0.038, respectively; P for subgroup differences = 0.25). Regarding safety, novel GLP-1RAs showed a neutral effect on the odds of severe hypoglycemia or serious adverse events (OR = 0.34; 95 % CI = [0.09, 1.31]; P = 0.11 and OR = 0.95; 95 % CI = [0.39, 2.34]; P = 0.91, respectively) and significantly higher odds of gastrointestinal, treatment-emergent adverse events (OR = 2.57; 95 % CI = [1.49, 4.42]; P < 0.001) and adverse events leading to discontinuation (OR = 2.89; 95 % CI = [1.22, 6.87]; P = 0.016). Preliminary evidence supports that orforglipron and danuglipron are efficient in glycemic control and weight reduction in T2DM, obesity or both. More longitudinal research is warranted in order to provide deeper insights into their efficacy, safety and tolerability before their potential incorporation in the pharmacological arsenal against T2DM or obesity. What is the key question? • Are the novel, GLP-1RAs orforglipron and danuglipron effective and safe in patients with T2DM and/or obesity? What are the new findings? • The novel GLP-1RAs demonstrated a significant reduction in HbA1c in patients with T2DM compared to controls. • A significantly greater weight reduction was also noted both in patients with T2DM and obesity compared to controls. How might this impact on clinical practice in the foreseeable future? • Orforglipron and danuglipron are effective for glycemic control and weight reduction in patients with T2DM, obesity or both. [ABSTRACT FROM AUTHOR]