Obesity, as a “blue ocean” in the field of chronic diseases, is driving intense drug R&D activity. A recent review published in Pharmaceuticals focuses on the limitations of existing incretin-based weight-loss drugs, optimizations in next-generation formulations, multi-target peptides, novel non-incretin targets, muscle-preserving strategies, and comparisons of clinical pipelines, systematically reviewing progress in obesity drug R&D over the past five years (2022–2026) with the aim of addressing key challenges in current weight-loss medications, such as gastrointestinal side effects, lean muscle loss, weight regain after discontinuation, and poor adherence to injectable treatments.
Ultra-long-acting monthly injectable formulations
Natural incretin peptides have a half-life of less than 1 hour; existing weekly formulations rely on lipid modification to extend the half-life. New-generation monthly subcutaneous injection candidates currently in development:
- MariTide (maridebart cafraglutide)
A peptide-antibody conjugate developed by Amgen: dual mechanism of action combining GLP-1 agonism and GIP receptor antagonism; the half-life of the intact molecule is 14–16 days, with an overall half-life of 21–24 days, suitable for monthly administration. In a 52-week Phase II trial, the highest dose resulted in weight loss of 12.3%–16.2%; dose escalation reduced the incidence of nausea and vomiting from 24% to 2%–6%. However, controversy remains: tirupentide promotes weight loss by activating GIP, whereas MariTide blocks GIP; the differences in central and peripheral GIP receptor function between the two require verification through long-term safety studies. - PF-08653944 (Pfizer)
A once-monthly GLP-1 agonist; in a 28-week Phase II trial, it resulted in a 12.3% placebo-adjusted weight loss. The trial was extended to 64 weeks to assess long-term weight maintenance, and gastrointestinal adverse reactions were also observed.
Oral Semaglutide Tablets (Rybelsus/Wegovy Oral Tablets)
Core Technology: SNAC (Sugar-Nucleic Acid Complex) absorption enhancer, which creates a locally high-concentration environment in the stomach, resists degradation by stomach acid, and enables transcellular absorption through the gastric wall;
Approval Timeline: Approved for diabetes in 2019; approved for obesity in the U.S. in 2025;
Limitations: Must be taken on an empty stomach upon waking; patients must fast for 30 minutes after taking the medication, which limits convenience; a more patient-friendly oral formulation is still needed.
Non-peptide, oral GLP-1 small molecules (taken once daily, eliminating the need for peptide injections)
Challenging the conventional wisdom that “only peptides can activate GLP receptors”:
- Orforglipron (Eli Lilly, FDA-approved in 2026, brand name Foundayo)
A G protein-biased small-molecule agonist that does not activate the β-arrestin pathway; while its in vitro potency is weaker than that of native GLP-1, it requires occupancy of only 1.7% of receptors to produce a full in vivo weight-loss effect. Administered orally once daily, it demonstrates clear clinical weight loss. - Danuglipron (Pfizer, development discontinued)
A once-promising oral small molecule whose development was completely halted due to the risk of liver injury observed in clinical trials.
Single-Molecule Multi-Receptor Agonists
A single molecule simultaneously activates 2–3 types of incretin receptors, resulting in significantly greater weight loss compared to single GLP-1 agonists. This represents the mainstream development track in the current pipeline:
1. GLP-1+GIP dual agonists
Tirzepatide (already on the market as Zepbound): A GLP-1/GIP dual agonist that achieved a 20.9% weight loss at the maximum tolerated dose over 72 weeks, outperforming semaglutide’s 14.9%; Central GIP exerts dual effects of both promoting and suppressing appetite, while GIP in adipose tissue promotes fat storage but improves adipose inflammation; the mechanism remains controversial.
Domestic and overseas candidates in development: Hengrui’s Repepatide (Phase III, 23.6% weight loss at 36 weeks), Viking’s VK2735, Roche’s CT-388 (18.3% weight loss over 48 weeks).
2. GLP-1 + Glucagon (GCGR) Dual Agonists
Based on the endogenous oxymodulin (OXM), GCGRs increase energy expenditure, reduce hepatic fat, and improve metabolic and steatohepatitis (MASH), while simultaneously offsetting the risk of hypoglycemia associated with GLP-1-induced glucose lowering:
Mazdutide (Innovent / Eli Lilly, approved in China in 2025): 6 mg weekly for 48 weeks resulted in 14.01% weight loss;
Clinical pipeline: Survodutide (Boehringer Ingelheim, concurrently developing for obesity and MASH indications), Pemvidutide, Efinopegdutide (Merck / Hanmi, focusing on non-alcoholic fatty liver disease).
3. GLP-1+GIP+GCGR Triple Agonist
Retatrutide (Eli Lilly) Phase III landmark data: 28.7% weight loss over 68 weeks in patients with obesity and osteoarthritis; 16.8% weight loss over 40 weeks in patients with type 2 diabetes; the combination of three signaling pathways significantly increases energy expenditure, resulting in weight loss far exceeding that of dual agonists, though the incidence of adverse reactions such as nausea and diarrhea ranges from 17% to 26%. Additionally, Novo Nordisk’s UBT251 (Phase II clinical trial in China) achieved a maximum weight loss of 19.7% over 24 weeks.
4. General Patterns of Multi-Target Drugs
The more targets a drug has, the greater the weight loss, but gastrointestinal side effects also increase accordingly; monotherapy has a weight loss ceiling, leading to the development of combination therapy regimens (e.g., CagriSema, which achieved 20.4% weight loss in a Phase III trial, has been submitted to the FDA, and is expected to be approved by the end of 2026).
Addressing a Core Deficiency in GLP-1 Agents: A Combined Strategy for Lean Muscle Preservation
Treatment with semaglutide 2.4 mg for 7 months can result in a loss of approximately 3 kg of lean body mass (5% of body weight); the risk is extremely high among the elderly and individuals with sarcopenia. There are currently two well-established protective approaches:
1. Bimagrumab (ActRIIA/B-blocking antibody)
Administered via intravenous infusion every 12 weeks; as monotherapy, it resulted in a 9.7% weight loss over 48 weeks; when combined with semaglutide, weight loss reached 20.2%, and lean body mass loss decreased from 7.9% with monotherapy to just 2.6%. Phase II data were excellent, and the trial has advanced to Phase III.
2. Trevogrumab (anti-GDF8 myostatin) + Garetosmab (anti-activin A) dual-antibody combination
Simultaneously blocks two muscle degradation pathways, not only preventing muscle loss during weight loss but also increasing muscle mass; Phase II clinical trials continue to validate these findings.
New Non-Glucagon-Like Peptide Weight Loss Targets
A systematic compilation of 12 major categories of independent, novel receptors/signaling pathways, covering peptides, small molecules, antibodies, and siRNA nucleic acid therapeutics, categorized into clinical-stage (I/II/III) and preclinical targets.
1. Amylin Receptor Agonists
Mechanism of Action: Delay gastric emptying, inhibit glucagon, and reduce appetite; the benchmark drug is Cagrilintide, and the combination with semaglutide, CagriSema, is currently the leading combination therapy. Other pipeline candidates: Eli Lilly’s Eloralintide, Roche’s Petrelintide, and AstraZeneca’s AZD6234; Novo Nordisk’s Amycretin (a GLP-1 + amylin dual agonist; in a 36-week Phase II trial, it achieved a maximum weight loss of 24.3%).
2. MC4R (Melanocortin-4 Receptor)
A central satiety pathway; mutations lead to severe early-onset obesity. Setmelanotide has been approved for hereditary obesity and is currently being expanded to treat general obesity, with development of an oral formulation underway; it exhibits a synergistic weight-loss effect when used in combination with tirzopotide.
3. PYY (Y2 receptor)
A satiety peptide secreted by intestinal L cells; Novo’s PYY1875, in combination with semaglutide, showed limited weight loss gains in Phase II trials and poor gastrointestinal tolerability, leading to a pause in the pipeline.
4. CRHR2 Corticotropin-Releasing Hormone Receptor 2 (Muscle Protection Target)
UCN2 is a selective agonist of CRHR2; Hanmi’s HM17321 (Phase I ongoing): In a fed monkey model, weight loss was accompanied by an 8% increase in lean body mass, achieving “fat loss with muscle gain” and perfectly overcoming the muscle loss drawback associated with GLP-1.
5. CCK1 Cholecystokinin Receptor
Peripheral vagus nerve-mediated satiety; early-stage NN9056 was terminated due to pancreatic toxicity in non-human primates; currently developing a GLP-1/CCK1 dual agonist prodrug, which demonstrates synergistic glucose-lowering and weight-loss effects in preclinical studies and also improves cognitive function in Alzheimer’s disease.
6. FGF21 Fibroblast Growth Factor 21
Key target: Improves hepatic steatosis and treats MASH; offers moderate weight loss (only 2–3 kg as monotherapy); representative drugs include Efruxifermin and Pegozafermin (both in Phase III trials for fatty liver disease); derivative GLP-1/FGF21 dual agonists are being developed for metabolic fatty liver disease.
7. GDF15 (GFRAL receptor)
Inhibits appetite centrally and increases muscle energy expenditure; monomeric GDF15 agonists (Eli Lilly’s LY3463251, Novartis’ MBL949) show only minimal weight loss in humans; however, QL1005 (a GLP-1/GDF15 fusion protein) demonstrates superior weight loss compared to semaglutide in preclinical studies while also improving liver fibrosis; currently in preclinical development.
8. Ghrelin Receptor Antagonists
The endogenous LEAP2 is a natural ghrelin antagonist; Phase I human infusions reduced ad libitum food intake by 12%; a long-acting, lipid-encapsulated LEAP2 prodrug is under development and can be used alone or in combination with GLP.
9. A3 Adenosine Receptor (Namodenoson, a small molecule)
Downregulates liver inflammation and increases adiponectin; Phase II fatty liver trials showed only mild weight loss, with a focus on liver disease indications.
10. GRK-biased β2-adrenergic receptor agonist (Compound 15)
Selective muscle glucose uptake; reverses GLP-induced muscle atrophy; demonstrated safety in Phase I; intended for combined use in weight loss and muscle protection.
11. siRNA Therapeutic: ARO-INHBE
Silences the INH gene in the liver, reducing visceral fat storage; Phase I/IIa clinical trials ongoing; a novel gene-regulatory pathway for weight loss.
12. Early-stage preclinical targets (pre-research phase)
Glutamate scaffold protein inhibition, GPR75/GPR45, neurokinin NK2, irisin, mitochondria-targeted drugs, artemether, etc. Effective only in animal models; have not yet entered human trials.
Conclusion
Intestin-1 receptor agonists have revolutionized the weight-loss market; however, five major challenges—gastrointestinal side effects, lean muscle loss, injection adherence, weight regain upon discontinuation, and a weight-loss ceiling—remain unresolved, creating an urgent need for drugs with entirely new mechanisms of action. In response to these challenges, three major R&D innovations have emerged for intestin-1 receptor agonists: formulation improvements, multi-target single-molecule approaches, and combination therapy strategies. At the same time, weight-loss drugs are no longer limited to obesity and type 2 diabetes; new indications such as metabolic-associated steatohepatitis (MASH), osteoarthritis, cardiovascular disease, chronic kidney disease, substance addiction, and cognitive protection in Alzheimer’s disease are being developed concurrently. In the future, precision obesity pharmacology will be developed based on genomic and AI-driven personalized metabolic profiling; next-generation drugs will combine four key advantages—potent weight loss, low gastrointestinal toxicity, muscle preservation, and improvement of fatty liver—to reduce the global burden of obesity-related chronic diseases.
References: Lee, S.; Song, H.; Kwon, Y. A Lineup for Next Anti-Obesity Medicines: Beyond Incretin-Based Pharmacotherapy. Pharmaceuticals 2026, 19, 1047.