The weight-loss drug market is thriving. In 2024, two blockbuster medications—semaglutide (Wegovy) and tirzepatide (Zepbound)—raked in $8.45 billion (+86%) and $4.92 billion (+270%), respectively. This explosive growth is set to fuel even more innovation in obesity treatments. The focus for next-generation weight-loss drugs is to offer stronger results with fewer side effects than Wegovy and Zepbound. Recently, Nature published an in-depth report on the upcoming wave of next-generation weight-loss therapies.
New Weight-Loss Drugs in 2025
Figure 1. New Weight-Loss Drugs in 2025 [1]
Targeting Multiple Signaling Pathways
Tirzepatide
Unlike Wegovy, Zepbound (tirzepatide) activates not only the GLP-1 receptor but also the GIP receptor. By targeting multiple signaling pathways related to appetite and metabolism, it aims to enhance weight-loss effects. This dual-target mechanism is believed to be the key to Zepbound's superior weight-loss results. In a large head-to-head trial sponsored by Eli Lilly, participants taking tirzepatide lost an average of 20% of their body weight, surpassing the 14% weight loss seen with Novo Nordisk's semaglutide.
Targeting multiple signaling pathways is also a key development strategy for several weight-loss therapies currently in advanced clinical trials.
Retatrutide
Developed by Eli Lilly, Retatrutide is a triple-receptor agonist that activates not only the GLP-1 receptor but also the GIP and glucagon receptors.
Retatrutide has surpassed expectations in clinical trials, demonstrating superior results compared to tirzepatide and semaglutide. In a 48-week Phase 2 study on obesity, participants taking retatrutide at 8 mg and 12 mg doses experienced average weight reductions of 22.8% and 24.2%, respectively. Notably, participants continued to lose weight through the 48-week mark, with weight-loss curves showing no signs of plateauing. [2]
Figure 2. Retatrutide clinical trial result
Moreover, at week 48, liver fat decreased by 81.7% for those on the 8 mg dose of retatrutide, and by 86% for those on the 12 mg dose. Additionally, 89% of participants in the 8 mg group and 93% in the 12 mg group had reduced liver fat to below 5% by the end of the study.
MariTide
MariTide is an investigational peptide-antibody conjugate administered subcutaneously on a monthly or less frequent basis. Similar to tirzepatide, it works through a dual mechanism by targeting both the GLP-1 and GIP receptors. However, unlike tirzepatide, which activates the GIP receptor, MariTide blocks it.
In a Phase II clinical trial, MariTide achieved an average weight loss of around 20% at 52 weeks, without reaching a plateau, suggesting the potential for continued weight loss beyond the 52-week mark. [3] Unlike semaglutide or tirzepatide, which often lead to weight rebound after discontinuation, MariTide demonstrated a unique ability to maintain weight loss for several months following the final dose, aligning with patient expectations. Amgen is actively advancing Phase III trials for MariTide.
Figure 3. MariTide clinical trial result
CagriSema
CagriSema is a fixed-dose combination of a long-acting amylin analogue, cagrilintide 2.4 mg and semaglutide 2.4 mg. It targets both the incretin and GLP-1 signaling pathways. In the Phase 3 REDEFINE 1 trial, CagriSema resulted in a 22.7% weight loss at 68 weeks, outperforming the individual treatments of semaglutide and cagrilintide. [4] However, rapid weight loss may pose unpredictable risks for patients, and combination therapy still requires long-term exploration to fully assess its safety and effectiveness.
Figure 4. CagriSema clinical trial result
Making Medication More Convenient
The therapies mentioned above are peptide or protein-based treatments that require patients to inject once a week or once a month. To improve patient convenience and compliance, another focus in weight-loss therapy development is the creation of long-acting treatments that extend the interval between injections, or the development of oral small-molecule drugs to make medication more convenient.
Orforglipron
As an oral small-molecule candidate, Orforglipron has shown results similar to injectable GLP-1 treatments, helping obese patients lose around 10% of their body weight over 26 weeks, while also improving blood pressure and circulating fat molecule levels. Its major advantage is that it does not require injections like semaglutide, significantly improving patient compliance and offering attractive cost benefits to developers. However, due to the challenges in dosing oral medications, the development of Orforglipron has been slower compared to injectable treatments.
Eli Lilly's CEO, Dave Ricks, stated that the company expects to complete Phase III trials for Orforglipron by 2025, with the possibility of receiving U.S. regulatory approval in 2026.
Other Emerging Strategies
The discovery of new targets and the emergence of novel weight-loss drug development strategies have made obesity treatments more flexible. One such "game-changer" in the development of weight-loss drugs is Bimagrumab, a muscle-targeted therapy. Its mechanism involves targeting the activin type II receptors (ActRIIA and ActRIIB) to inhibit the activity of myostatin and other negative regulators of muscle growth. Initially developed as a candidate for age-related muscle loss and other conditions causing muscle wasting, Bimagrumab was discontinued by Novartis in 2017 due to lack of significant clinical improvement compared to the control group. However, researchers later recognized its potential in weight-loss therapy. Its mechanism allows it to effectively avoid the muscle loss side effect seen with drugs like semaglutide, promoting fat loss while increasing muscle mass, with no major safety concerns identified so far.
Conclusion
The next wave of weight-loss drugs will be introduced in the coming years, still resembling current treatments. However, new-generation obesity therapies will redefine the field over the next few decades, focusing on fat loss methods that preserve muscle, with anti-inflammatory and metabolic therapies becoming central themes. Convenience and efficacy will be key goals, and diverse mechanisms will create multiple approaches. The ongoing pursuit of innovation will drive the development of new weight-loss solutions.
References:
[1] Dozens of new obesity drugs are coming: these are the ones to watch. Retrieved February 27, 2025, from https://www.nature.com/articles/d41586-025-00404-9?linkId=12914818
[2] Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972
[3] https://www.amgen.com/newsroom/press-releases/2024/11/amgen-announces-robust-weight-loss-with-maritide-in-people-living-with-obesity-or-overweight-at-52-weeks-in-a-phase-2-study
[4] https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=915082
[5] Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023;389(10):877-888. doi:10.1056/NEJMoa2302392
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