1. In this randomized controlled trial, the triple-hormone-receptor agonist retatrutide was superior to placebo in reducing body weight among patients with obesity.
2. The most common adverse events were gastrointestinal symptoms and increased heart rate.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Obesity is an increasingly prevalent chronic disease that can be difficult to effectively manage. It is associated with significant cardiovascular morbidity and mortality. In addition to lifestyle modifications and previous pharmacotherapies, glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide and tirzepatide have proven highly effective by targeting the underlying neuroendocrine pathophysiology of obesity. Retatrutide is a novel triple-agonist of GLP-1, glucose-dependent insulinotropic polypeptide (PIP), and glucagon receptors. This study was a phase two trial to assess the efficacy and safety of retatrutide among patients with obesity. Compared to placebo, the weekly retatrutide injections resulted in significant weight reductions through 48 weeks, with between 60-82% of patients achieving a 15% weight reduction depending on the dosage. These reductions were accompanied by other metabolic parameters. Retatrutide also had an acceptable safety profile, with most adverse events being gastrointestinal and dose-dependent. The study was mainly limited by its lack of racial diversity and a small proportion of overweight patients with obesity-related conditions. Nonetheless, these results demonstrated the potential of retatrutide in treating obesity and improving metabolic measures.
In-Depth [randomized controlled trial]: The study was a double-blind placebo-controlled trial to assess retatrutide in treating patients with obesity. Patients between 18 and 75 years of age who either had a body mass index (BMI) of 30 to 50 or a BMI of 27 to 30 with at least one obesity-related condition were eligible for inclusion. Exclusion criteria included diabetes, candidacy for surgical obesity treatment, or other medications associated with significant weight changes. Overall, 338 patients were randomized 2:1:1:1:1:2:2 to receive either subcutaneous retatrutide (1mg throughout, 4mg from an initial 2mg dose, 4mg from 4mg initially, 8mg from 2mg initially, 8mg from 4mg initially, or 12mg from 2mg initially), or placebo once weekly for 48 weeks. The primary efficacy outcome was the percentage change in weight from baseline at 24 weeks. By 24 weeks, the least-squares mean percentage change in body weight was -7.2% in the 1mg retatrutide group, -12.9% in the combined 4mg group, -17.3% in the combined 8mg group, -17.5% in the combined 12mg group, and -1.6% in the placebo group. These dose-dependent weight reductions were sustained by 48 weeks, yielding -8.7% in the 1mg retatrutide group, -17.1% in the combined 4mg group, -22.8% in the combined 8mg group, -24.2% in the 12mg group, and -2.1% in placebo. Exploratory analyses also demonstrated dose-dependent improvements in metabolic measures such as waist circumference, blood pressure, fasting glucose, glycated hemoglobin, and insulin levels. The most common adverse events associated with retatrutide were gastrointestinal, such as nausea and vomiting, diarrhea, and dyspepsia. Adverse events of interest associated with retatrutide included one case of acute pancreatitis, serious gastrointestinal symptoms, and cardiac arrhythmias. In summary, these results demonstrated the efficacy and safety of retatrutide in reducing body weight among patients with obesity.
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