Research Progress of Peptide-based Weight Loss Drugs

Obesity has become a major global public health issue. It not only significantly increases the risk of metabolic diseases such as type 2 diabetes, cardiovascular diseases, and fatty liver disease but also imposes a heavy burden on public health care. Therefore, the research and development of safe and effective weight loss drugs have become a research focus in the global biopharmaceutical field. Due to their advantages of strong targeting, high safety, significant weight loss effect, and mild adverse reactions, peptide-based weight loss drugs have gradually replaced traditional weight loss drugs and become the mainstream direction of current research and development. In particular, peptide drugs targeting gastrointestinal hormones have achieved breakthrough development. Combined with the latest research results from 2025 to 2026, this article systematically reviews the research status, core categories, key technologies, existing problems, and future development trends of peptide-based weight loss drugs, providing a reference for subsequent research and clinical application in this field.

The core of peptide-based weight loss drug research and development relies on the body's metabolic regulation mechanism, among which the regulation of appetite and energy metabolism mediated by gastrointestinal hormones is the most critical pathway. Gastrointestinal hormones are a class of peptide substances secreted by endocrine cells in the gastrointestinal mucosa. They act on the central nervous system and peripheral tissues through autocrine, paracrine, or endocrine methods, participating in physiological processes such as appetite suppression, energy consumption, and nutrient absorption, and are highly related to the pathogenesis of obesity. The core gastrointestinal hormones closely related to weight loss mainly include glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and amylin. Natural gastrointestinal hormone peptides have defects such as short half-life (only a few minutes to a few hours) and low bioavailability, making them unable to be directly used as drugs. Therefore, the innovative application of peptide modification technologies (such as fatty acid acylation, double fatty acid chain modification, PEGylation, and amino acid substitution) has become a key support for promoting the development of peptide-based weight loss drugs, which can significantly optimize the pharmacokinetic properties of drugs, achieve long-acting administration, and improve efficacy.

At present, peptide-based weight loss drugs have formed a research and development pattern of multi-targets and multi-formulations. According to their targets and structural characteristics, they can be divided into three categories: single-target agonists, dual-target agonists, and multi-target agonists. The research progress and clinical application of each type of drug show differentiated advantages, which are as follows:

1. Single-target peptide-based weight loss drugs: As the earliest category to enter clinical application, they focus on a single gastrointestinal hormone target and achieve weight loss effect by specifically activating this target. At present, a mature product system has been formed and widely used in clinical practice. Among them, GLP-1 receptor agonists are the most representative drugs in this category. By simulating the physiological functions of natural GLP-1, they inhibit the hypothalamic appetite center, delay gastric emptying, increase energy consumption, and at the same time have a synergistic effect of improving blood glucose, making them the preferred drugs for the synergistic regulation of weight loss and hypoglycemia.

Approved GLP-1 receptor agonist weight loss drugs include liraglutide, semaglutide, benaglutide, mazdutide, etc. Among them, semaglutide has the most significant weight loss effect. Clinical studies have shown that oral semaglutide once a day for 68 weeks can reduce weight by 15.1%, and its long-acting preparation achieves once-weekly administration, which significantly improves patient medication compliance. In addition, amylin receptor agonists are a new direction in single-target research. By activating amylin receptors to regulate satiety signals and inhibit appetite, the representative drug cagrilintide has shown good weight loss effect in clinical studies, providing a new idea for single-target drug research and development. At present, the research focus of single-target drugs is concentrated on dosage form optimization and long-acting modification. At the same time, new single-target drugs such as enoglutide (a GLP-1R-preferred agonist) have entered the marketing application acceptance stage and are expected to be applied in clinical practice soon.

2. Dual-target peptide-based weight loss drugs: By activating two gastrointestinal hormone targets at the same time, they exert a synergistic weight loss effect, breaking through the weight loss ceiling of single-target drugs, and are a research hotspot in recent years. Such drugs mainly take GLP-1 receptor as the core, combined with targets such as GIP receptor, amylin receptor, and GCGR receptor, to achieve a "1+1>2" weight loss effect, while taking into account the comprehensive improvement of metabolic indicators, becoming a core breakthrough in weight loss drug research and development.

GLP-1R/GIPR dual agonists are the most mature research direction among dual-target drugs. Representative drugs include tirzepatide, HRS9531, BGM0504, CT-388, RAY1225, etc. Among them, tirzepatide has been approved for marketing. By synergistically activating GLP-1 and GIP receptors, it inhibits appetite and improves energy metabolism efficiency, and its weight loss effect is significantly better than that of single-target GLP-1 receptor agonists; new dual-target drugs such as HRS9531 have entered the pre-marketing preparation stage, and clinical data show excellent weight loss and metabolic improvement effects. In addition, GLP-1R/GCGR dual agonists (such as mazdutide) and GLP-1R/amylin receptor dual agonists (such as cagrisema) have also made important progress. Among them, mazdutide, as the world's first and only approved natural GCG/GLP-1 dual-target weight loss and hypoglycemic drug, its phase III clinical research results have been published in Nature. After 48 weeks, obese patients lost 14.84% of their weight, and at the same time, it can improve a number of cardiovascular and metabolic indicators; as a fixed-dose combination of semaglutide and cagrilintide, cagrisema achieved an average weight loss of 22.7% in the compliant population after 68 weeks in phase III clinical trials, which is significantly better than the effect of the two drugs used alone. The core advantage of dual-target drugs is that they take into account both weight loss effect and metabolic improvement. Some drugs can also achieve the dual effect of weight loss and muscle gain. For example, the combination of bimagrumab (activin type II receptor antagonist) and semaglutide can activate muscle growth while losing weight, solving the problem of muscle loss caused by traditional weight loss drugs.

3. Multi-target peptide-based weight loss drugs: Activating three or more gastrointestinal hormone-related targets at the same time to further strengthen the synergistic weight loss effect is an important direction for future weight loss drug research and development. At present, they have entered the clinical research stage and show great research and development potential. Such drugs take GLP-1R/GIPR/GCGR triple-target agonists as the core, and some drugs have broken through the four-target research and development to achieve more comprehensive metabolic regulation, providing a new treatment option for severely obese patients.

Representative drugs include retatrutide (GLP-1R/GIPR/GCGR triple-target), NA931 (GLP-1R/GIPR/GCGR/IGF1 four-target), etc. Among them, retatrutide achieved a weight loss of 24.2% in obese patients after 48 weeks in phase III clinical trials, which significantly surpassed the current dual-target drugs. By activating three targets at the same time, it inhibits appetite, increases energy consumption, and improves glucose and lipid metabolism. After 36 weeks, it can reduce HbA1c of type 2 diabetes patients by 2.02%; as a four-target agonist, NA931 can achieve a weight loss of 13.8% with once-daily oral administration for 13 weeks, with low gastrointestinal reactions and no muscle loss, solving the pain point of poor safety of multi-target drugs. In addition, AMG133, as an ultra-long-acting GIP antibody-conjugated GLP-1 drug, can reduce weight by 19.9% with once-monthly administration for 52 weeks. Although it has a significant weight loss effect, it has high gastrointestinal reactions and is still being optimized and improved. At present, the research focus of multi-target drugs is concentrated on optimizing target ratio, reducing adverse reactions, and achieving a balance between efficacy and safety.

The innovation of peptide modification technology and delivery system is the key support for promoting the development of peptide-based weight loss drugs towards long-acting and oral administration, and also a research hotspot in recent years. In terms of peptide modification technology, strategies such as fatty acid acylation and double fatty acid chain modification can significantly extend the half-life of drugs, realize long-acting administration, reduce the frequency of administration, and improve patient compliance. For example, bofan格鲁肽 (bofanlutide) was developed using fatty acid acylation strategy, with administration once every two weeks. After 30 weeks, it can reduce weight by 17.3%, and after 24 weeks, it can reduce HbA1c by 2.28% and comprehensively improve metabolism; zoviglutide (ZT002) achieves an ultra-long half-life through double fatty acid chain modification and active metabolites. As a monthly preparation with once-monthly administration, the first participant in the phase III clinical study of weight loss in China was dosed in January 2026. In its phase II trial, subjects who received 160mg once a month lost up to 13.8% of their weight at week 24, and the withdrawal rate due to gastrointestinal adverse events was almost zero; RAY1225, as an ultra-long-acting GLP-1RA/GIP RA, is administered once every two weeks, with a weight loss of 15.1% and a decrease of 2.2% in HbA1c after 24 weeks, and low gastrointestinal reactions.

In terms of delivery systems, significant breakthroughs have been made in the research and development of oral dosage forms, effectively solving the problem of low oral bioavailability of peptide drugs. Through new excipients (such as SNAC) to promote the absorption of peptides in the stomach, oral peptide drugs such as oral semaglutide and ZT006 tablets have entered clinical application or clinical research stages. Among them, ZT006 tablets, as an oral peptide GLP-1 receptor agonist, are conducting phase II clinical research on weight loss. In addition, the research and development of oral small-molecule GLP-1 receptor agonists (such as orforglipron, HRS-7535, ASC30) is also accelerating. Among them, orforglipron can reduce weight by 12.4% with once-daily administration for 72 weeks in phase III clinical studies, with lower production costs and more convenient medication, becoming an important development direction of oral weight loss drugs; China's self-developed oral small-molecule GLP-1R agonist ASC30 also shows good research and development potential, helping China achieve a breakthrough in this field.

From the perspective of the global research and development pattern, significant achievements have been made in the research and development of peptide-based weight loss drugs. In particular, GLP-1 drugs have led the global upsurge in weight loss drug research and development, and China's research and development in this field has also achieved a key leap from "following" to "catching up/leading". In June 2025, Nature published a cover article pointing out that China is becoming an important innovative force in new drug research and development in this field. At present, a variety of GLP-1-based weight loss drugs have been approved for marketing in China, including benaglutide, liraglutide, tirzepatide, semaglutide, and mazdutide. At the same time, dozens of related drugs are under research and testing, covering multiple directions such as single-target, dual-target, multi-target, and oral dosage forms. Domestic enterprises have achieved remarkable innovative results in this field. For example, zoviglutide independently developed by Zhitai Biotech and mazdutide by Innovent Biologics both show excellent efficacy and safety; at the same time, many Chinese pharmaceutical companies have reached commercial cooperation with international pharmaceutical giants to jointly promote the research and development and market promotion of weight loss drugs, further enhancing China's international competitiveness in this field. In addition, China is actively advancing the research and development of GCGR/GLP-1R dual receptor agonists, covering multiple key stages such as preclinical, clinical application, phase I clinical, and phase II clinical, which is expected to bring more treatment options for patients in the future.

Although peptide-based weight loss drugs have made considerable progress and become an important means of obesity treatment, there are still some urgent problems to be solved: first, some drugs have gastrointestinal adverse reactions (such as nausea and vomiting), and the incidence of adverse reactions of multi-target drugs is higher. For example, the withdrawal rate of retatrutide's 12mg dose group due to adverse reactions is as high as 18.2%, and AMG133 also has high gastrointestinal reactions; second, most long-acting preparations are injection formulations, and patients' concerns about injection administration affect medication compliance. The efficacy of oral formulations still needs to be further improved, and the weight loss effect of oral drugs is generally lower than that of injections at present; third, the price of drugs is relatively high, and the annual cost of some multi-target injections exceeds 10,000 yuan, which limits their universality, especially the promotion and application in grass-roots areas is restricted; fourth, the long-term safety data of medication is insufficient, and the long-term effects of drugs on the cardiovascular system, liver and kidney functions, as well as weight rebound after drug withdrawal, still need long-term clinical follow-up studies; fifth, at present, no oral drugs have been approved for the treatment of obesity, and except for the United States, no drugs have been approved for the treatment of childhood obesity, so the applicable population still needs to be further expanded.

In the future, the research and development of peptide-based weight loss drugs will continue to move towards the direction of "oralization, long-acting, multi-target, and high safety", while focusing on differentiated innovation to break through existing technical bottlenecks. On the one hand, it will continue to optimize peptide modification technology and delivery systems, improve the bioavailability and efficacy of oral drugs, reduce adverse reactions, and at the same time promote the research and development of ultra-long-acting preparations, realizing the upgrade from "once a week" to "once every two weeks" and "once a month" to further improve patient medication compliance; on the other hand, it will further explore new targets, develop multi-target synergistic drugs, break through the existing weight loss ceiling, and at the same time expand the applicable population of drugs, such as children with obesity, to fill the gap in clinical treatment. In addition, through AI-assisted peptide sequence design, optimization of target ratio, and joint drug use research (such as combination of oral drugs and injections, combination of peptide drugs and other weight loss drugs), the weight loss effect will be further improved to meet the treatment needs of different obese populations; at the same time, domestic enterprises will continue to increase R&D investment, rely on independent technology platforms, promote the listing of more self-developed innovative drugs, reduce drug costs, and improve drug accessibility.

With the continuous in-depth research on peptide synthesis technology, drug delivery technology, and targets, peptide-based weight loss drugs will gradually overcome existing shortcomings and achieve comprehensive improvement in efficacy, safety, and convenience. They will not only provide more efficient and safe treatment options for the prevention and control of obesity and related metabolic diseases but also promote the rapid development of the global weight loss drug research and development industry, providing important support for the development of public health undertakings.