Spotlight on weight loss drugs
The American Society of Anesthesiologists released guidance on preoperative management of glucagon-like peptide-1 receptor agonists, and recent studies looked at the effects of semaglutide, retatrutide, and orforglipron on weight in patients with and without diabetes.
Recent publications offered guidance and data on existing and investigational weight loss drugs.
The American Society of Anesthesiologists (ASA) recently released guidance on preoperative management of glucagon-like peptide-1 (GLP-1) receptor agonists. For patients on a daily dose of a GLP-1 receptor agonist, they suggest clinicians consider holding it the day of the procedure. For patients on weekly dosing, the ASA suggests holding the drug a week prior. These suggestions apply irrespective of the indication (type 2 diabetes or weight loss), but if GLP-1 receptor agonists prescribed for diabetes are held for longer than the dosing schedule, clinicians should consider consulting an endocrinologist about bridging therapy, the ASA said.
A trial published by The Lancet on June 25 assessed the use of oral semaglutide for weight loss in patients without diabetes. The manufacturer-funded study randomized 667 patients with a body mass index (BMI) of at least 30 kg/m2 or 27 kg/m2 with complications other than diabetes to oral semaglutide or placebo, once per day for 68 weeks, plus lifestyle intervention. The estimated mean reduction in body weight was 15.1% with semaglutide versus 2.4% with placebo (P<0.0001). Weight loss of at least 5% was achieved by 85% of patients in the active group versus 26% on placebo. GI adverse events (mostly mild to moderate) were reported by 80% of participants on semaglutide and 46% of those on placebo.
Two pharma-funded phase 2 studies assessed retatrutide, an investigational single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors. One, published by The Lancet on June 26, included 281 U.S. patients with a BMI of 25 to 50 kg/m2 and type 2 diabetes treated with diet and exercise alone or with a stable dose of metformin. They were randomized to once-weekly injections of placebo, dulaglutide, or retatrutide at a variety of doses. At 36 weeks, HbA1c level reductions were significantly greater with retatrutide than placebo in all but the lowest-dose group and greater than with dulaglutide in the higher-dose groups. Body weight was also reduced at higher doses compared to dulaglutide. Mild to moderate GI adverse events occurred at similar rates with retatrutide and dulaglutide. “These results suggest that retatrutide is a promising therapeutic agent for the management of hyperglycaemia and obesity in the setting of type 2 diabetes, and support phase 3 clinical development,” concluded the study authors.
An accompanying editorial noted that more evidence of retatrutide's weight loss effects, including comparisons with higher dose GLP-1 receptor agonists and dual incretin agonists, is needed, as well as a better understanding of how weight loss is achieved by glucagon receptor agonism.
The other study, published by the New England Journal of Medicine (NEJM) on June 26, included 338 patients with a BMI of at least 30 kg/m2 or 27 kg/m2 with complications other than diabetes who were randomized to various doses of retatrutide or placebo. At 48 weeks, a weight reduction of 5% or more had occurred in 92% to 100% of patients on the different doses of retatrutide compared to 27% of those on placebo; weight loss of at least 15% occurred in 60% to 83% versus 2%, respectively. Weight reductions among the retatrutide patients were accompanied by improvements in cardiometabolic measures, noted the study authors, who said that longer-term data will be available from the phase 3 trial of the drug, which is currently underway.
Finally, another pharma-funded study, published by NEJM on June 23, reported phase 2 trial data on orforglipron, an investigational oral nonpeptide GLP-1 receptor agonist. The study randomized 272 participants with obesity or overweight plus complications other than diabetes to the drug or placebo. At 26 weeks, the mean decrease in weight ranged from 8.6% to 12.6% across the orforglipron groups versus 2.0% in the placebo group. At week 36, a reduction of at least 10% had occurred in 46% to 75% versus 9%, respectively. GI events led to discontinuation in 10% to 17% of active treatment participants. The study authors concluded that the efficacy of the trial drug appeared similar to that of the injectable GLP-1 receptor agonists that have already been approved for weight management.