Obesity has become a global health crisis, with an estimated 16% of the world’s adult population classified as obese. The search for effective treatments is more urgent than ever, as obesity significantly increases the risk of developing various health problems, including heart disease, stroke, type 2 diabetes, and certain types of cancer. The recent success of glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), has revolutionised the field of obesity treatment. These drugs mimic the natural gut hormone GLP-1’s effects to suppress appetite and regulate metabolism, leading to significant weight loss. However, these medications have limitations. They require weekly injections, frequently cause unpleasant side effects like nausea, vomiting, and diarrhoea, and may not be effective for an estimated 10–30% of people. Long-term concerns include the loss of muscle mass, the likelihood of weight regain after stopping therapy, and potential risks such as arthritis and pancreatitis. This has spurred a wave of research and development into new anti-obesity drugs that aim to address these limitations and offer more personalized treatment options.

GLP-1 agonists have also shown promise in reducing the risk of major adverse cardiovascular events, such as stroke and heart attack. This adds to their potential benefits in managing obesity and its related health complications.

Clinical Trial of Semaglutide and Bimagrumab

One promising avenue of research involves combining existing GLP-1 receptor agonists with experimental drugs designed to preserve muscle mass. A clinical trial, known as the BELIEVE Phase 2b study, is currently underway to test the combination of semaglutide and bimagrumab. Bimagrumab is a first-in-class, fully humanized monoclonal antibody developed by Versanis Bio, a clinical-stage biopharmaceutical company recently acquired by Eli Lilly. It targets activin type II receptors, which play a role in regulating muscle growth and fat storage. This trial aims to assess the efficacy and safety of bimagrumab in preserving or increasing muscle mass while promoting weight loss with semaglutide in non-diabetic patients with overweight or obesity.

To be eligible for the BELIEVE study, participants must have a body mass index (BMI) greater than or equal to 30, or greater than or equal to 27 with one or more obesity-related comorbidities. Key exclusion criteria include a history of hypersensitivity to monoclonal antibody drugs, treatment with any medication for obesity within 30 days before screening, and a diagnosis of diabetes requiring current use of any antidiabetic drug.

Pre-clinical studies have shown that blocking activin type II receptors with bimagrumab leads to increased lean mass and decreased fat mass in mice. In a Phase 2 study, bimagrumab produced a 22% reduction in fat mass and a 4.5% increase in lean mass in patients with type 2 diabetes and obesity. Notably, no weight regain was observed after stopping bimagrumab treatment, unlike the rebound effect often seen with GLP-1 therapies. This suggests that bimagrumab may offer long-term benefits in maintaining weight loss even after treatment cessation.

The ongoing clinical trial will provide valuable insights into the potential of combining semaglutide and bimagrumab to achieve superior fat loss while preserving muscle mass. This combination therapy could offer a more comprehensive weight management approach, addressing fat loss and muscle preservation.

Semaglutide and Bimagrumab: Mechanisms of Action

Semaglutide and bimagrumab work through distinct mechanisms to achieve their therapeutic effects. Semaglutide, a GLP-1 receptor agonist, mimics the action of GLP-1, a natural gut hormone crucial in regulating blood sugar and appetite. GLP-1 agonists work by

• Triggering insulin release from the pancreas
• Blocking glucagon secretion
• Slowing stomach emptying
• Increasing feelings of fullness

Semaglutide helps lower blood sugar levels, reduce appetite, and promote weight loss by mimicking these effects.

Bimagrumab, on the other hand, is a human monoclonal antibody directed against type II activin receptors (ActRII). Upon administration, bimagrumab binds to ActRII, which prevents binding the natural ligands, myostatin and activin, to activin receptors and blocks ActRII-mediated signalling. This increases protein synthesis, decreases protein degradation, stimulates skeletal muscle cell growth, and increases muscle function and strength10. Overstimulation of the ActRII-mediated signalling pathway is associated with muscle loss and weakness.

Other Anti-Obesity Drugs in Development

The success of semaglutide and tirzepatide has fueled a surge in the development of new anti-obesity drugs. These drugs target various biological pathways and aim to improve upon the limitations of existing therapies. Targeting multiple pathways simultaneously could allow for lower doses that achieve the same weight loss with fewer side effects. Some of the key areas of development include:

GLP-1 and GIP Receptor Agonists

Tirzepatide is a dual GLP-1 and GIP receptor agonist that has shown superior weight loss results compared to semaglutide in a large head-to-head trial by Eli Lilly. Participants who took tirzepatide lost an average of 20% of their body weight, outpacing the 14% reduction achieved with semaglutide. Tirzepatide is already available under the brand names Mounjaro and Zepbound.

There are two main strategies for modulating GIP activity: activation and blocking. While both approaches can lead to weight loss, they have different potential benefits and drawbacks. As seen with tirzepatide, GIP activation can further enhance energy metabolism and promote weight loss. However, some concerns blocking GIP signalling could adversely affect bone health, as GIP also plays a role in bone metabolism.

Amylin Analogues

Amylin is a hormone co-secreted with insulin that regulates blood sugar and appetite. CagriSema, a combination therapy developed by Novo Nordisk that pairs a long-acting analogue of amylin (cagrilintide) with semaglutide, has shown promising results in clinical trials. Participants in a 68-week, phase 3 trial lost an average of nearly 23% of their body weight.

Glucagon and GLP-1 Receptor Co-agonists

Glucagon is a hormone that raises blood sugar levels, while GLP-1 lowers them. Combining these two hormones in a single drug could offer a balanced approach to weight loss by increasing energy expenditure while maintaining blood sugar control. Survodutide, a glucagon and GLP-1 receptor co-agonist developed by Boehringer Ingelheim, is currently in clinical trials.

Triple-Hormone Receptor Agonists

Retatrutide, a triple-hormone receptor agonist developed by Eli Lilly that targets GLP-1, GIP, and glucagon receptors, has shown impressive weight loss results in Phase 2 trials. This drug, dubbed “triple G,” delivered an average weight reduction of 24% after 48 weeks, setting a new benchmark for obesity treatments.

Alternative Delivery Methods for Anti-Obesity Drugs

Companies are also exploring alternative delivery methods to once-weekly injections, which can be challenging to incorporate into people’s routines and come with manufacturing challenges. Once-monthly injectables are in the works, but oral formulations of GLP-1 receptor agonists, such as orforglipron produced by Eli Lilly, could arrive first.

Another potential alternative is oral semaglutide. In a phase 3 study called OASIS 1, people taking oral semaglutide 50 mg once daily lost up to 15% of their initial body weight after about 15 months (68 weeks) of use. This is comparable to the weight loss benefits of Wegovy, the injectable version of semaglutide.

Potential Side Effects of Anti-Obesity Drugs

While anti-obesity drugs offer a promising approach to weight management, they can also cause side effects. Some of the common side effects of GLP-1 receptor agonists include nausea, vomiting, diarrhoea, and constipation. More serious side effects, such as pancreatitis and gallbladder problems, are rare but can occur.

Specific side effects associated with semaglutide include nausea, vomiting, diarrhoea, abdominal pain, constipation, heartburn, and burping. In rare cases, semaglutide can cause more serious side effects such as pancreatitis, kidney problems, and changes in vision.

Tirzepatide can cause similar side effects, including nausea, diarrhoea, decreased appetite, vomiting, constipation, and stomach pain. Serious side effects, such as pancreatitis, gallbladder problems, and low blood sugar, can also occur.

Another concern with GLP-1 and GIP drugs is the potential risk of pulmonary aspiration during anaesthesia. These drugs can cause delayed gastric emptying, which may increase the risk of residual gastric contents despite preoperative fasting. This can lead to aspiration, where food or liquid gets into the lungs during surgery.

The increased demand for GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists has led to temporary product shortages. This has resulted in the emergence of compounded formulations of these drugs, which produce entities that bypass regulatory measures. The American Diabetes Association recommends against using non-FDA-approved compounded GLP-1 and dual GIP/GLP-1 receptor agonist products due to concerns regarding their safety, quality, and effectiveness. The FDA has also issued an alert on dosing errors associated with compounded semaglutide injectable products, which have led to adverse events and hospitalisations in some cases.

It is important to note that the potential side effects of anti-obesity drugs vary depending on the specific medication and individual factors. Patients should discuss these medications’ possible risks and benefits with their healthcare provider to determine the most appropriate treatment option.

Alternative Treatments for Obesity: Bariatric Surgery

For some individuals, bariatric surgery may be an alternative treatment option for obesity. Bariatric surgery involves making changes to your digestive system to help you lose weight. It is typically considered for people with a BMI of 40 or higher or those with a BMI of 35 or higher who have obesity-related health problems.

There are several types of bariatric surgery, including

• Roux-en-Y gastric bypass: This procedure involves creating a small pouch at the top of the stomach and connecting it directly to the small intestine, bypassing most of the stomach and the first section of the small intestine
• Sleeve gastrectomy: This procedure involves removing about 80% of the stomach, leaving a long, tube-like pouch
• Biliopancreatic diversion with duodenal switch (BPD/DS): This is a two-part surgery that involves performing a sleeve gastrectomy and then connecting the end of the small intestine to the duodenum, bypassing most of the small intestine

Bariatric surgery can be very effective for long-term weight loss and can also improve or reverse obesity-related conditions such as diabetes, high cholesterol, and sleep apnoea. However, it is a major surgical procedure with potential risks and complications, such as bleeding, infection, and leaks in the gastrointestinal system. Patients should carefully consider the risks and benefits of bariatric surgery with their healthcare provider.

Emerging Applications of GLP-1 and GIP Drugs

While GLP-1 and GIP drugs are primarily known for their role in treating obesity and type 2 diabetes, research is exploring their potential applications in other disease areas. These include:

• Neurodegenerative diseases: Conditions such as Parkinson’s and Alzheimer’s disease involve protein misfolding and chronic inflammation. Studies have found that GLP-1 mimetics can cross the blood-brain barrier and have neuroprotective effects, including reducing oxidative stress and chronic inflammatory responses in the brain.
• Liver disease: GLP-1 and GIP receptor agonists have shown potential in improving liver health, particularly in individuals with nonalcoholic fatty liver disease (NAFLD).

These emerging applications highlight the versatility of GLP-1 and GIP drugs and their potential to address a wide range of health challenges beyond obesity and diabetes.

Conclusion

The field of anti-obesity drug development is rapidly evolving, with new therapies emerging that offer the potential for more effective and personalised weight management. While GLP-1 receptor agonists like semaglutide and tirzepatide have revolutionised the field, ongoing research is exploring new targets and combination therapies to address the limitations of existing medications. These advancements, such as the combination of semaglutide and bimagrumab, the development of triple-hormone receptor agonists like retratrutide, and the exploration of alternative delivery methods, hold promise for improving the lives of millions of people struggling with obesity and its related health complications.

However, it is crucial to acknowledge the potential side effects of these therapies, including gastrointestinal issues, pancreatitis, and the risk of pulmonary aspiration during anaesthesia. Patients should carefully consider the risks and benefits of these medications with their healthcare provider to determine the most appropriate treatment option.

Developing new anti-obesity drugs has significant implications for public health and the future of obesity management. These advancements offer hope for a more comprehensive and personalised approach to weight loss, potentially reducing the burden of obesity and its associated health problems.