A recent review presented the safety, clinical implications, and challenges of obesity pharmacotherapies based on entero-pancreatic hormone- treatments.
This review is available in Nature’s International Journal of Obesity.
Study: What is the pipeline for future medications for obesity? Image Credit: winnond/Shutterstock.com
Obesity management strategies
Obesity is a complex, chronic, and increasingly common condition that elevates the risk of many diseases, such as metabolic-dysfunction associated steatotic liver disease (MASLD), type 2 diabetes (T2D), obstructive sleep apnoea (OSA), cardiovascular disease and osteoarthritis. Obesity occurs due to excess adiposity or abnormal accumulation of fat.
To manage obesity, several lifestyle interventions that are associated with diet and behavioral changes have been designed.
A common challenge in lifestyle-based interventions is prolonged weight maintenance. After significant weight loss, the main drivers of weight regain are increased appetite, which could be mediated via increased orexigenic and decreased anorexigenic signals, and a lower resting metabolic rate.
Bariatric surgery results in significant weight loss and supports long-term weight maintenance.
However, many people avoid this obesity management strategy due to the apparent post-operative complications. Besides surgery and lifestyle-based interventions, a pipeline of pharmacotherapies has been designed to manage obesity.
Existing pipeline of pharmacotherapies for obesity management
A large pipeline of entero-pancreatic hormone-based pharmacotherapies is currently under development for obesity treatment.
Since entero-pancreatic hormones, such as glucagon, amylin, and glucose-dependent insulinotropic polypeptide (GIP), play a crucial role in regulating appetite and glycaemic index, they are used to develop glucagon-like peptide-1 (GLP-1) receptor agonists (RA) effective against obesity and T2D.
Semaglutide is a GLP-1 RA drug that received approval in 2021 for obesity management. This drug promotes around 17% weight loss through a reduction in appetite.
A higher dose of subcutaneous semaglutide, i.e., 7.2 mg once weekly, is currently being assessed in a phase 3 trial for its capacity to alleviate obesity.
Tirzepatide is the first entero-pancreatic hormone composed of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RA.
Based on the findings of the SURPASS trial, this drug has received approval from the global regulatory bodies for the treatment of diabetes.
Orforglipron is a non-peptide GLP-1 RA, which is currently under assessment for managing obesity and T2D. In comparison to native GLP-1, orforglipron exhibited a different mechanism of action.
Notably, this drug is designed for oral administration, indicating its potential to reduce acceptance barriers. In addition to weight loss, orforglipron treatment also improved cardiometabolic risk factors.
Danuglipron is another non-peptide, G-protein-biased GLP-1 RA designed to support oral administration. Currently, this compound is being assessed in the phase 2b trial for its effectiveness in obesity management.
Besides these drugs, other non-entero-pancreatic hormone-based pharmacotherapies, including bimagrumab and growth differentiation factor 15 (GDF-15), are being assessed for safety and efficacy.
Overall, the combinations of GLP-1/glucagon RA promote a greater reduction of liver fat in people with MASLD.
This result could be due to a superior effect of glucagon on hepatic lipid oxidation. GLP-1 RA alone can lower epicardial fat, while 2.4 mg of semaglutide substantially reduces heart failure with preserved ejection fraction (HFpEF).
Current challenges and future outlooks
Even though the available pharmacotherapies for obesity are effective, they are not at par with the weight loss achieved through bariatric surgery.
In addition, heterogeneity in GLP-1 RA treatment responses was recorded. For instance, this treatment resulted in less weight loss in people with T2D than those without diabetes.
Since GLP-1 RA is an injectable treatment, many people with needle phobia avoid it. At present, oral GLP-1 RA is under development to improve the acceptance rate and inconveniences of the existing drug for obesity management.
The safety and efficacy of this drug in the diabetic and obese population are being assessed, along with their impact on cardiovascular conditions.
In the future, the cardioprotective effects of semaglutide, alone or in combination with other entero-pancreatic hormones, designed for obesity and T2D management must be assessed.
The cardiovascular safety of tirzepatide, in comparison to dulaglutide, is being evaluated in the SURPASS-CVOT trial. The 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 novel pharmacotherapeutic strategies for obesity management, including the risk of osteoporosis, fractures, and macro- and micronutrient deficiencies, must be assessed to understand their safety profile better.
In the next few years, many older molecules developed for obesity management will lose patents.
This will result in the development of many new formulations, which might positively impact medicine prices. More research is required to assess the cost-effectiveness and efficacy of novel compounds for long-term weight loss maintenance.
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