The therapeutic landscape for obesity management is rapidly evolving. While GLP-1 receptor agonists and their multi-target counterparts—represented by semaglutide and tirzepatide (a dual GIP/GLP-1 agonist) - have achieved global dominance, the pipeline is advancing toward novel mechanisms offering potential for enhanced efficacy, tolerability, and convenience.
The following sections provide an overview of the most anticipated non-GLP-1 therapeutic candidates for obesity.
Multi-Target Incretin Agonists: Dual and Triple Agonists
To enhance metabolic outcomes and minimize adverse effects, emerging therapies target multiple receptors simultaneously. Dual and triple agonists—such as GLP-1/GIP or GLP-1/GIP/glucagon(GCGR) combinations—aim to leverage the synergistic benefits of incretin hormones.
Dual Agonists
Tirzepatide, currently the only marketed agent in this class, has already demonstrated superior weight-loss efficacy compared to Wegovy (semaglutide), a mono GLP-1 receptor agonist, achieving an 20.2% weight reduction vs. 13.7% over 72 weeks. [1]
Survodutide (BI 456906), licensed to Boehringer Ingelheim, is an investigational long-acting, glucagon/GLP-1 receptor dual agonist for once-weekly subcutaneous administration. In a recent phase 2 dose-finding trial, treatment with survodutide resulted in up to a mean 14.9% weight loss over 46 weeks in patients with a body mass index (BMI) ≥27 kg/m2 and without diabetes receiving 4.8 mg compared with 2.8% in the placebo group. [2]
AZD9550, a dual glucagon/GLP-1 receptor agonist, is now being developed in combination with AZD6234, a SARA, for the treatment of overweight and obesity and its associated co-morbidities. AZD-9550 is under Phase IIb trials, with data expected in the second half of 2026.
GLP-1/GIP/GCGR Triple Agonists
Retatrutide (LY3437943) is a first-in-class, investigational GLP-1/GIP/glucagon (GCGR) receptor triple agonist developed by Eli Lilly for treating obesity and type 2 diabetes. In the Phase 3 TRIUMPH-4 clinical trial, participants with obesity and knee osteoarthritis taking retatrutide 12 mg lost an average of 28.7% of their body weight at 68 weeks. This is double the percent body weight loss seen with Ozempic and Wegovy.[3] Beyond weight loss, retatrutide has demonstrated broad therapeutic potential, including the alleviation of knee osteoarthritis symptoms, resolution of fatty liver disease, and improvement of key cardiovascular biomarkers. Regulatory submission for retatrutide is expected in 2026.
Amylin Analogues
Amylin is a 37-amino acid peptide hormone co-secreted with insulin from pancreatic β-cells in response to nutrient intake, particularly during meals. Amylin has well-established physiological roles in glycemic regulation and energy balance control. It improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion.
In 2005, the U.S. FDA approved the first amylin analogue, pramlintide, as an adjunct to insulin therapy to improve glycemic control in patients with type 1 and type 2 diabetes.
These beneficial effects have led to the FDA-approved use of the amylin analog pramlintide in the treatment of diabetes mellitus. However, its clinical adoption was hindered by a heavy therapeutic burden, requiring multiple daily injections.
In recent years, a new generation of long-acting amylin analogs and multi-target agents has entered clinical pipelines, demonstrating transformative weight-loss potential.
CagriSema (Novo Nordisk)
CagriSema is a fixed-dose combination of the GLP-1 RA semaglutide and the long-acting amylin analog cagrilintide (2.4 mg). As the first-ever GLP-1/Amylin combination therapy, this once-weekly subcutaneous injection has shown exceptional efficacy in the REDEFINE 1 & 2 Phase III trials. In REDEFINE 1, participants lost an average of 20.4% of their body weight with CagriSema at week 68, compared to 3% with placebo. When accounting for full treatment adherence, weight loss with CagriSema resulted in greater weight loss of 22.7% at 68 weeks versus 2.3% in the placebo group. In REDEFINE 2, if all participants adhered to treatment, the estimated mean change in body weight from baseline to week 68 was 15.7% with CagriSema versus 3.1% with placebo. [4]
In early 2026, head-to-head data from the REDEFINE 4 trial showed that patients treated with CagriSema 2.4mg achieved a weight loss of 23.0% after 84 weeks compared to 25.5% with Zepbound 15mg, failing to meet the non-inferiority endpoint. [5] Nevertheless, CagriSema remains a highly anticipated alternative for patients who cannot tolerate GIP-based therapies or those requiring stronger satiety signals.
Related Articles: 2026 FDA Drug Approvals: Blockbusters to Watch
Eloralintide (Eli Lilly)
Eloralintide (LY3841136) is a potent, once-weekly injectable, long-acting selective amylin receptor agonist currently under development for the treatment of obesity. In November 2025, Phase II data published in The Lancet showed that after 48 weeks of monotherapy, adults with obesity or overweight experienced mean body-weight reductions of 9.5% to 20.1%, significantly outperforming placebo, with good tolerability and manageable gastrointestinal adverse events. [6]
In early 2026, Lilly initiated the ENLIGHTEN-1 (NCT07321886) and ENLIGHTEN-2 (NCT07282600) pivotal trials. The program is also exploring eloralintide’s potential in obesity-related comorbidities, such as obstructive sleep apnea (OSA) and knee osteoarthritis. If successful, eloralintide will set the stage for a major dual-target rivalry against CagriSema.
Petrelintide / ZP-8396 (Zealand Pharma / Roche)
Petrelintide (ZP-8396) is a long-acting, highly selective amylin receptor agonist being jointly developed by Zealand Pharma and Roche under a strategic collaboration worth up to $5.3 billion.
On March 5, 2026, Phase II results revealed that petrelintide achieved a mean weight loss of 10.7% at week 42 in overweight and obese populations, significantly outperforming the placebo group (1.7%). [7] Based on these positive findings, Roche and Zealand are accelerating development both as a monotherapy and as a fixed-dose combination with Roche’s investigational GLP-1/GIP dual agonist (CT-388).
Small Interfering RNA (siRNA) Therapeutics
SiRNA is an emerging, next-generation therapeutic approach for obesity, designed to silence specific genes involved in fat maintenance, often with potential for infrequent, long-lasting dosing. At present, siRNA-based weight-loss programs targeting INHBE and ALK7 are in early-stage clinical development.
WVE-007 (Wave Life Sciences)
WVE-007 is an investigational INHBE GalNAc-siRNA using Wave’s proprietary SpiNA design. WVE-007 is designed to silence INHBE mRNA, an obesity target with strong evidence from human genetics.
Wave Life Sciences recently disclosed updated data from the first-in-human INLIGHT . At 6-month follow-up, a single 240 mg dose of WVE-007 (INHBE GalNAc-siRNA) continued to drive significant placebo-adjusted reductions in visceral fat (-14%; p<0.05) and total fat (-5%), stabilization of lean mass (+2%), and reductions in waist circumference (-3%) and body weight (-1%). [8]
ARO-INHBE and ARO-ALK7 (Arrowhead Pharmaceuticals)
On January 6, 2026, Arrowhead Pharmaceuticals released transformative interim Phase I/IIa data for its two flagship RNAi programs, ARO-INHBE and ARO-ALK7.
ARO-INHBE is designed to reduce the hepatic expression of the INHBE gene and its secreted gene product, Activin E. In patients with obesity and type 2 diabetes (T2DM), ARO-INHBE in combination with tirzepatide achieved a 9.4% reduction in body weight at week 16, approximately doubling the effect observed with tirzepatide alone (4.8%). ARO-INHBE also produced substantial improvements in adiposity, including reductions of 23.2% in visceral fat, 15.4% in total fat, and 76.7% in liver fat. As a monotherapy, ARO-INHBE achieved a mean visceral fat reduction of 9.9% at week 16 following a single dose, and a placebo-adjusted reduction of 15.6% at week 24 with two doses. Notably, single-dose treatment was also associated with a 3.6% increase in lean muscle mass. [9]
ARO-ALK7 is designed to silence expression of the ACVR1C gene in adipocytes, thereby reducing production of activin receptor-like kinase 7 (ALK7), a key receptor involved in pathways regulating energy homeostasis in adipose tissue. It is the first RNAi therapeutic to demonstrate targeted knockdown of an adipocyte-expressed gene in humans, achieving a mean reduction of 88% in ALK7 mRNA, with a maximum reduction of 94%. As a monotherapy, ARO-ALK7 delivered a placebo-adjusted 14.1% reduction in visceral fat as early as week 8 following a single dose. [9]
ActRII (Activin Type II Receptor)
The Activin type II receptor (ActRII) is expressed in both adipose and muscle tissues, serving as a critical regulator of body composition. In adipocytes, activin signaling via ActRII facilitates lipid storage; consequently, inhibiting this pathway promotes lipid metabolism. In myocytes, ActRII-mediated signaling pathways suppress muscle growth and drive atrophy. By blocking these signals in skeletal muscle, researchers can arrest muscle wasting and promote hypertrophy, allowing patients with obesity to improve their metabolic profile by increasing lean mass while simultaneously shedding fat.
Bimagrumab (Eli Lilly)
Bimagrumab is an investigational antibody targeting ActRII, intended to reduce total body and visceral fat mass and promote muscle growth.
On 2 March 2026, Lilly presented updated clinical data on bimagrumab in combination with semaglutide (Wegovy, Novo Nordisk). At week 72, the high-dose combination (bimagrumab 30.0 mg/kg plus semaglutide 2.4 mg) achieved 24.2 kg weight loss (22.1% reduction), compared with 16.5 kg (15.7%) for semaglutide 2.4 mg alone and 12.0 kg (10.8%) for bimagrumab 30 mg/kg alone. Importantly, 92% of weight loss in the high-dose combination group was from fat mass, compared with 76% for semaglutide alone. Semaglutide 2.4 mg resulted in 7.4% lean mass loss, whereas bimagrumab 30 mg/kg produced a 2.5% increase in lean mass, and high-dose combination preserved lean mass with only 2.9% reduction. [10]
Conclusion
In summary, the research and development landscape for obesity therapeutics has fundamentally moved beyond the era of monotherapy dominance. We are now witnessing the dawn of a new epoch in precision medicine—one characterized by multi-mechanistic synergy and multidimensional therapeutic complementarity.
References:
[1] https://investor.lilly.com/news-releases/news-release-details/zepbound-tirzepatide-showed-superior-weight-loss-over-wegovy
[2]le Roux CW, Steen O, Lucas KJ, Startseva E, Unseld A, Hennige AM. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol. 2024 Mar;12(3):162-173. doi: 10.1016/S2213-8587(23)00356-X. Epub 2024 Feb 5. Erratum in: Lancet Diabetes Endocrinol. 2026 Feb;14(2):e2. doi: 10.1016/S2213-8587(25)00399-7. PMID: 38330987.
[3] https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial
[4] https://www.novonordisk.ca/content/dam/nncorp/ca/en/press-releases/2025/redefine-canadian-press-release-english.pdf CagriSema 2.4 mg / 2.4 mg demonstrated 22.7% mean weight reduction in adults with overweight or obesity in REDEFINE 1, published in NEJM
[5] https://www.ddw-online.com/head-to-head-obesity-trial-disappointment-for-novo-nordisk-40644-202602/ Head-to-head obesity trial disappointment for Novo Nordisk
[6] https://lilly.gcs-web.com/news-releases/news-release-details/lillys-selective-amylin-agonist-eloralintide-demonstrated
[7] https://www.roche.com/media/releases/med-cor-2026-03-05
[8] https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-interim-phase-1-data
[9] https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-announces-interim-clinical-data-rnai
[10] Heymsfield, S.B., Aronne, L.J., Montgomery, P. et al. Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial. Nat Med 32, 869–882 (2026). https://doi.org/10.1038/s41591-026-04204-0
