Obesity is a growing threat to public health, increasing risks of numerous diseases and mortality, and impairing quality of life. There is a strong interest in developing obesity treatments based on glucagon-like peptide-1 (GLP-1) agonists, which have proved to limit morbidity and mortality in type 2 diabetes.
Figure 1. Milestones of GLP-1 mechanistic research and drug development. Source: Reference 1
Data on weight loss of GLP-1R agonists are being continuously refreshed along with the emergence of new iterations of the product. Novo Nordisk's semaglutide beats its counterpart liraglutide to become the next generation of weight loss innovation, and then Eli Lilly's GLP-1R/GIPR dual-target agonist tirzepatide achieves a 22.5% weight loss, surpassing semaglutide's weight loss history. Here, let's find out more about GLP-1RAs for weight loss and their future prospects.
Approved GLP-1 Agonists for Weight Loss
Currently, there are two GLP-1R agonists approved for the treatment of obesity, Saxenda (liraglutide) and Wegovy (semaglutide), both developed by Novo Nordisk and approved by the FDA in 2014 and 2021, respectively.
The emergence of GLP-1R as a popular target for weight loss is mainly attributed to its mechanistic features and the weight reduction efficacy shown by liraglutide and semaglutide.
Studies have shown that GLP-1R agonists not only promote insulin secretion and exert glucose-lowering effects but also effectively delay gastric emptying, reduce intestinal motility, activate neural pathways in the hypothalamus and appetite regulation areas, resulting in decreased appetite and reduced food intake, thus treating obesity.
Figure 2. The effects of GLP-1RAs on multiple human organizations, source: reference 
Data from Novo Nordisk's Phase III clinical trial showed that liraglutide 3.0 mg resulted in a 5% weight loss in approximately 62% of obese patients and a 10% weight loss in 34% of patients after a 56-week treatment period. This data supports the product's launch in 2014 as the first approved GLP-1 weight loss drug. In addition, liraglutide was expanded to adolescent obese patients aged 12 years and older in 2020. After the 56-week treatment period, BMI standard deviation scores (BMI SDS) decreased by a mean of 0.23 in the liraglutide group, with no change in the placebo group.
Figure 3. Liraglutide weight loss clinical trials
Semaglutide is another GLP-1 product developed by Novo Nordisk with a better weight loss effect than liraglutide. In a large Phase 3 clinical trial (STEP series), semaglutide demonstrated excellent weight loss and weight maintenance after weight loss. 18.2% average weight loss at week 68 was observed in patients in the STEP 4 trial, along with reduced blood glucose levels, improved lipid profile and significant improvements in overall quality of life and health status scores. In addition, a head-to-head trial of semaglutide and liraglutide was conducted in the STEP 8 trial, with a mean weight loss of 17.1% in the semaglutide group, which was significantly more effective than liraglutide (mean weight loss of 6.6%).
Figure 4. STEP series clinical trials of Semaglutide
Novo's two obesity products, Wegovy and Saxenda, have generated DKK 16.86bn (USD 2.5bn) in sales throughout 2022, doubling the preceding year's result of DKK 8.4bn (USD 1.2bn) – an increase of 101%. Novo Nordisk plans to achieve more than 25 billion DKK ($3.72 billion) in obesity sales by 2025.
Dual Agonists Under Investigation
Tirzepatide (Mounjaro®) was approved by the FDA on May 13, 2022 for the treatment of type 2 diabetes in adults, making it the first and only GIP/GLP-1 receptor agonist. Although tirzepatide is not currently marketed as a weight loss drug, it appears that it is only a matter of time from where we stand. The Phase III clinical SURMOUNT-1 (NCT04184622) for tirzepatide, is expected to be completed in the first half of 2024.
According to the results published in The New England Journal of Medicine (NEJM), participants taking tirzepatide achieved average weight reductions of 16.0% (35 lb. or 16 kg on 5 mg), 21.4% (49 lb. or 22 kg on 10 mg) and 22.5% (52 lb. or 24 kg on 15 mg), compared to placebo (2.4%, 5 lb. or 2 kg).
Figure 5. Tirzepatide Once Weekly for the Treatment of Obesity
AMG 133 is a novel bispecific glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist and glucagon-like peptide-1 (GLP-1) receptor agonist molecule. Amgen updated data from its Phase I study of the weight loss drug AMG133 at the 2022 American Heart Association Annual Scientific Sessions (AHA). At day 85 (approximately 12 weeks), patients in the low-dose group lost an average of 7.19 percent of their body weight and the high-dose group lost an average of 14.52 percent of their body weight, while the placebo group gained an average of 1.49 percent of their body weight. Amgen plans to advance AMG133 to Phase II clinical in early 2023.
Figure 6. AMG 133 Phase I results
Are GLP-1 Weight Loss Drugs the Next Blockbusters?
According to Citeline's Pharmaprojects analysis, the global market for weight loss drugs is expected to grow dramatically from $2.82 billion in 2022 to over $13 billion by 2029. However, compliant weight loss drugs are extremely scarce in the face of strong demand for weight loss. The FDA has only approved six weight loss drugs, including:
- ● Bupropion-naltrexone (Contrave)
- ● Liraglutide (Saxenda)
- ● Orlistat (Xenical, Alli)
- ● Phentermine-topiramate (Qsymia)
- ● Semaglutide (Wegovy)
- ● Setmelanotide (Imcivree)
Currently, the choice of weight loss drugs remains very limited and is divided into two main categories: pancreatic lipase inhibitors and appetite suppressants that act on the central nervous system.
Appetite suppressants are restricted due to the adverse neurological effects they can cause. The pancreatic lipase inhibitor orlistat loses weight by inhibiting pancreatic lipase activity, which in turn inhibits the breakdown and absorption of fat from food. However, it can cause steatorrhea, resulting in fat-soluble vitamin deficiency, and can even cause liver damage.
GLP-1 can act on the central GLP-1 receptors (especially the hypothalamus) and the central satiety center, causing a feeling of satiety and reducing food intake, thus achieving weight loss through appetite suppression. In contrast, the weight loss effect of GLP-1 drugs is more pronounced.
It is foreseeable that GLP-1 weight loss drugs with superior effects and safety will become the next blockbuster.
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 Gribble FM, Reimann F. Metabolic Messengers: glucagon-like peptide 1. Nat Metab. 2021;3(2):142-148. doi:10.1038/s42255-020-00327-x
 Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y, Zhang Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne). 2021 Aug 23;12:721135. doi: 10.3389/fendo.2021.721135. PMID: 34497589; PMCID: PMC8419463.
 A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1). Clinical Trials.gov. https://clinicaltrials.gov/ct2/show/NCT04184622
FDA Approves Semaglutide As An Powerful Weight-loss Drug
Evolution of GLP‐1 Receptor Agonists for Diabetes Treatment
FDA Approves Tirzepatide, A Potential Blockbuster Drug for Type 2 Diabetes
Anti-obesity Medications (AOMs): History And Progress