Breakthrough obesity treatments on the horizon, rivaling surgery’s success

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In a recently published study, Dr International Journal of ObesityResearchers discuss obesity pharmacotherapy pipeline.

Obesity is a chronic disease that affects approximately 650 million individuals worldwide. It increases the risk of various metabolic complications, including cardiovascular disease and type 2 diabetes (T2D). Lifestyle interventions form the core of obesity management. Still, mean weight loss (WL) is ≤ 10%, even with the most intensive interventions.

Moreover, weight maintenance is challenging because weight regain occurs over time. Although 5% to 10% WL is clinically beneficial, higher WL is required to improve or relieve complications of obesity. Furthermore, bariatric surgery can offer up to 30% WL and long-term weight maintenance; However, people may not opt ​​for bariatric surgery due to perceived postoperative risks.

Understanding the role of entero-pancreatic hormones has led to the development of glucagon-like peptide (GLP)-1 receptor agonists (RAs) for the treatment of obesity and T2D. Semaglutide is the latest GLP-1 RA approved for obesity, resulting in 15% to 17% mean WL. Nevertheless, a significant difference exists between WL achieved with obesity pharmacotherapy and bariatric surgery.

Further, current GLP-1 RAs for obesity are injectable, which some people may not consider. However, oral RAs are being developed to increase acceptance and adherence. In addition, a pipeline of pharmacotherapies based on entero-pancreatic hormones is being developed to augment or supplement GLP-1 RAs. In the current study, the authors discuss the obesity pharmacotherapy pipeline.

Study: What is the pipeline for future drugs for obesity?  Image credit: Suzanne Tucker / ShutterstockStudy: What is the pipeline for future drugs for obesity? Image credit: Suzanne Tucker / Shutterstock

GLP-1 RAs

Subcutaneous semaglutide (2.4 mg) and liraglutide (3 mg) have been approved for the management of obesity. A higher semaglutide dose (7.2 mg) is being evaluated in a phase 3 trial. Because people may be reluctant to use injectables, oral semaglutide has been introduced and approved for T2D, with a 14 mg dose improving hemoglobin A1c (HbA1c) levels and WL.

A phase 3 trial evaluated the efficacy and safety of a 50 mg oral dose of semaglutide in non-T2D obese subjects over 68 weeks. The trial revealed that semaglutide recipients achieved 17% WL while placebo subjects achieved <2% WL. In a different trial on T2D subjects, the 50 mg semaglutide dose resulted in approximately 10% WL compared with 5.4% WL with the 14 mg dose.

Danuglipron is a non-peptide, G protein-based, oral GLP-1 RA. A phase 2b study in obese subjects showed that 40 mg to 200 mg doses of danuglipron increased WL by more than 11% after 32 weeks. Orforglipron is another non-peptide, oral GLP-1 RA, being evaluated for the management of T2D and obesity.

In obese subjects, 36-week orforglipron treatment resulted in WL ≤ 14.7% and improvement in cardiometabolic risk factors. Similarly, among patients with T2D, approximately half of participants achieved 10% or greater WL after 26-weeks of orforglipron treatment in a phase 2 trial. Currently, several phase 3 trials of orforglipron and oral semaglutide are ongoing in different populations.

GLP-1 Glucagon like peptide-1, GIP glucose-dependent insulinotropic polypeptide, PYY Peptide YY, *Data mainly from animal studies.

GLP-1 Glucagon like peptide-1, GIP glucose-dependent insulinotropic polypeptide, PYY Peptide YY, *Data mainly from animal studies.

Entero-pancreatic hormones and their combinations for obesity management

Several entero-pancreatic hormones are currently being evaluated alone or in combination with GLP-1 RAs to enhance or complement the effects of GLP-1 agonism on weight and metabolism. Jejunal K-cells secrete glucose-dependent insulinotropic peptide (GIP) in response to food intake. GIP stimulates insulin secretion and increases lipogenesis, glucagon secretion and lipid buffering capacity.

Animal studies indicate an anorexigenic action of GIP receptor agonism. A phase 1 trial recently showed that repeated doses of long-acting GIP RA induced a modest WL in T2D subjects. Tirzepatide is a unimolecular subcutaneous dual (GIP and GLP-1) RA with comparable GIP receptor but lower GLP-1 receptor affinity.

A phase 3 study investigated the efficacy and safety of tergepeptide for obesity, and it is now approved for chronic weight management. Several trials are evaluating the efficacy and safety of tirzepatide in reducing cardiometabolic complications. Further, several injectable or oral GIP/GLP-1s are in the early stages of RA development.

Preliminary results from rodent studies indicate a synergistic role of dual glucagon and GLP-1 agonism in reducing food intake. As such, numerous glucagon/GLP-1 co-agonists have been developed. Despite the promising results of glucagon/GLP-1 co-agonism in experimental studies, the efficacy and tolerability of co-agonists in obese subjects is heterogeneous.

A triple agonist targeting glucagon, GIP, and GLP-1 may produce superior WL and glycemic control compared to a dual agonist. For example, retatrutide is a triple agonist and has been shown to improve WL and glucose profile in preclinical models compared to terzepatide through lower caloric intake and higher energy expenditure. A phase 2 study in non-T2D obese subjects reported dose-dependent WL after 48-week treatment with different doses of retatrutide.

Closing note

Taken together, a new era has begun for the treatment of obesity in which entero-pancreatic hormone combinations can achieve the WL efficacy of bariatric surgery. In addition to tirzepetide, a dual agonist approved for chronic management, various dual and triple agonists are being evaluated in phase 3 trials.

The multitude of obesity treatment options will enable therapies to be tailored based on individual preference, treatment response, and tolerability. Overall, obesity pharmacotherapies represent a rapidly growing field, and research on efficacy, safety, and cost-effectiveness will inform their place in therapeutic options for obesity and related complications.



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