What does the future hold for the development of obesity treatment drugs?

A recent review presents the safety, clinical implications, and challenges of obesity pharmacotherapy based on enteropancreatic hormone therapy.

This review is available at Nature's International Journal of Obesity.

study: What is the pipeline of future obesity drugs? Image credit: winnond/Shutterstock.com

Obesity management strategies

Obesity increases the risk of many diseases, including fatty liver disease associated with metabolic dysfunction (MASLD), type 2 diabetes (T2D), obstructive sleep apnea (OSA), cardiovascular disease, and osteoarthritis. It is a complex, chronic, and increasingly common condition. . Obesity is caused by excessive fat accumulation or abnormal accumulation of fat.

Several lifestyle interventions related to dietary and behavioral changes have been designed to manage obesity.

A common challenge in lifestyle-based interventions is long-term weight maintenance. A major factor in weight regain after significant weight loss is an increase in appetite, which may be mediated by increased orexigenic signals and decreased anorexigenic signals and a decreased resting metabolic rate.

Bariatric surgery results in significant weight loss and supports long-term weight maintenance.

However, many people avoid this obesity management strategy because of the obvious postoperative complications. In addition to surgery and lifestyle-based interventions, a pipeline of drug treatments is being designed to manage obesity.

Existing pipeline of pharmacotherapies for obesity management

A large pipeline of enteropancreatic hormone-based drug therapies for obesity treatment is currently under development.

Enteropancreatic hormones such as glucagon, amylin, and glucose-dependent insulinotropic polypeptide (GIP) play important roles in the regulation of appetite and glycemic index, and therefore the development of glucagon-like peptide 1 (GLP-1) receptors. will be used. An effective agonist (RA) against obesity and T2D.

Semaglutide is a GLP-1 RA treatment approved for obesity management in 2021. This drug promotes weight loss of approximately 17% by decreasing appetite.

The ability of a higher dose of subcutaneous semaglutide, 7.2 mg once weekly, to reduce obesity is currently being evaluated in a phase 3 trial.

Tirzepatide is the first enteropancreatic hormone composed of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RA.

Based on the results of the SURPASS trial, the drug has been approved by regulatory bodies worldwide for the treatment of diabetes.

Orforglipron is a non-peptide GLP-1 RA currently being evaluated for the management of obesity and T2D. Compared to native GLP-1, orforglyprone exhibited a different mechanism of action.

Of note, this drug is designed for oral administration and has been shown to have the potential to reduce acceptance barriers. In addition to weight loss, orforglipron treatment also improved cardiometabolic risk factors.

Danuglyprone is another non-peptide G protein-biased GLP-1 RA designed to support oral administration. This compound is currently being evaluated in a phase 2b trial for efficacy in obesity management.

In addition to these agents, other non-enteropancreatic hormone drug therapies, such as bimagrumab and growth differentiation factor 15 (GDF-15), are also being evaluated for safety and efficacy.

Overall, the GLP-1/glucagon RA combination promotes a significant reduction in liver fat in MASLD patients.

This result may be due to the superior effect of glucagon on hepatic lipid oxidation. Although GLP-1 RA alone can reduce epicardial fat, 2.4 mg of semaglutide maintains ejection fraction (HFpEF) and substantially reduces heart failure.

Current issues and future prospects

Although available drug treatments for obesity are effective, they cannot match the weight loss achieved by bariatric surgery.

Furthermore, heterogeneity in GLP-1 RA treatment response was noted. For example, with this treatment, T2D patients lost less weight than non-diabetic patients.

Because GLP-1 RA is an injectable treatment, many people with needle phobia avoid it. Oral GLP-1 RAs are currently being developed to improve the acceptance rate and inconvenience of existing obesity treatments.

safety and efficacy of Evaluation of this drug in diabetic and obese populations is being evaluated along with its effects on cardiovascular disease.

In the future, the cardioprotective effects of semaglutide designed for obesity and T2D management should be evaluated, either alone or in combination with other enteropancreatic hormones.

The cardiovascular safety of tirzepatide compared to dulaglutide was evaluated in the SURPASS-CVOT trial. SURMOUNT-MMO is being conducted to determine the impact of GLP-1/GIP RA on obesity management and cardiovascular safety.

The long-term complications of new drug therapy strategies for obesity management, including the risk of osteoporosis, bone fractures, and macro- and micronutrient deficiencies, need to be evaluated to better understand their safety profile.

In the coming years, many older molecules developed for obesity management will lose their patents.

This has led to the development of many new formulations, which may have a positive impact on drug prices. Further research is needed to evaluate the cost-effectiveness and effectiveness of novel compounds for long-term weight loss maintenance.