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The race to develop next-generation obesity therapeutics is accelerating the preclinical search for candidates that will counter the limitations of currently available drugs, including weight rebound, weight maintenance, and side effects.

Researchers presented four novel strategies in a session at the American Diabetes Association (ADA) 2026 Scientific Sessions. The approaches, now in preclinical trials, suggest the future of obesity treatment may involve novel receptor targets, molecules engineered specifically for metabolic durability and tolerance, and combination strategies.

Thioredoxin-Interacting Protein (TXNIP) Inhibitor Curbs Weight Rebound

Current research shows that about half of patients treated with GLP-1s stop the medication within a year, often because of side effects, cost, or the burden of injections. When they do, most regain the weight they lost.

TIX100, an oral TXNIP inhibitor recently approved by the FDA as an investigational drug for diabetes, was developed by TIXiMED, a University of Alabama at Birmingham (UAB) start-up. UAB researchers tested whether the drug could prevent post-GLP-1 discontinuation weight rebound.

For the study, male mice rendered obese through a high-fat diet received semaglutide for 2 weeks. During a 4-week period after discontinuing the drug, one group of mice was treated with oral TIX100, while another group was not.

Semaglutide led to more than 6 g of weight loss overall, but untreated mice gained nearly 8 g in the 4 weeks after stopping the drug. In contrast, mice receiving oral TIX100 maintained their weight loss despite continuing on the high-fat diet. Quantitative magnetic resonance showed that TIX100 reduced fat mass while preserving lean mass.

The findings suggest that TIX100 may represent a “novel, oral, muscle-sparing, non-GLP-1 approach for weight maintenance after GLP-1-induced weight loss, in addition to its promising antidiabetic properties,” the authors concluded.

Three co-authors declared having no conflicts of interest; one author reported being a founder and CSO/CMO of TIXiMED, Inc.

Long-Acting Therapeutic for Weight Maintenance

A team from PROTEINA Co., Ltd. in South Korea is also working on a maintenance therapeutic. Using protein engineering, they developed a long-acting, antibody-based glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist designed specifically for weight maintenance and extended dosing intervals.

Using their Single-molecule Protein Interaction Detection (SPID) platform with deep mutational scanning, the researchers identified a GIP receptor antagonist with 47-fold increased affinity for its target and a fivefold improvement in cellular potency compared with an earlier candidate. The lead candidate achieved a 47-day half-life and a 44% higher maximum plasma concentration, suggesting it could support longer dosing intervals.

In diet-induced obese mice, the engineered candidate produced 7.4% weight loss compared with 4.2% with the earlier candidate, despite comparable food intake.

Intraperitoneal glucose tolerance testing showed a 21.8% area under the curve reduction in glucose compared with vehicle, whereas the earlier candidate showed no meaningful effect. Histologic analysis revealed a 25.7% reduction in adipocyte size, normalized fat tissue morphology, reduced inguinal white adipose tissue and liver mass, and marked reduction in hepatic steatosis.

“The SPID-engineered [GIP receptor antagonist] provides durable metabolic control and supports its application as a long-acting maintenance therapy and a backbone for combination strategies,” the authors concluded.

All authors reported being employees of PROTEINA Co., Ltd.

Four-Target Agonist for Weight and Fat Loss

As dual and triple agonists have entered clinical use, researchers at Pep2Tango Therapeutics asked whether expanding the target panel further could improve outcomes. They developed a peptide tetra-agonist (PTT-A), a novel long-acting peptide targeting four receptors: GLP-1, GIP, amylin, and calcitonin. The study compared PTT-A with tirzepatide and cagrilintide plus semaglutide (CagriSema) in diet-induced obese rats.

Rats received PTT-A (at high and low doses), tirzepatide, or CagriSema for 21 days. Body composition was assessed by DEXA, MRI, carcass analysis, and metabolic parameters.

PTT-A produced dose-dependent reductions in cumulative food intake and body weight, driven by fat mass loss with preservation of lean mass. The higher PTT-A dose achieved a 19% reduction in body weight compared with the vehicle, while tirzepatide and CagriSema each achieved 12%.

PTT-A also reduced inguinal and epididymal fat by 36% and 50%, respectively, compared with 25% reductions from the dual and triple agonists. DEXA confirmed that high-dose PTT-A produced 84 g of total fat mass loss vs 60 g with tirzepatide or CagriSema.

Both tirzepatide and CagriSema showed significant skeletal muscle loss on carcass analysis and MRI, whereas PTT-A preserved muscle mass. PTT-A also showed superior improvements in glucose, insulin, and triglyceride levels.

“These findings support tetra-agonism as a promising therapeutic strategy for obesity and associated metabolic disorders and may offer durable clinical benefits with favorable safety profiles overall,” the authors concluded.

All co-authors reported receiving fees from Pep2Tango; one author reported being an employee, and another author reported having additional commercial relationships.

Dorzagliatin Plus Orforglipron: Synergy, Better Tolerance

While oral small-molecule GLP-1s such as orforglipron promote weight reduction, dose-dependent gastrointestinal adverse effects can limit adherence. Dorzagliatin, a first-in-class glucokinase activator, has been found to enhance glucose sensing and early-phase insulin secretion. Researchers from Hua Medicine in China evaluated whether combining these two oral agents could enhance glycemic control without compromising weight loss, potentially allowing for lower GLP-1 dosing to improve tolerability.

For the study, male transgenic mice expressing human GLP-1 receptors and rendered obese through a high-fat diet received vehicle, dorzagliatin, orforglipron, or combination therapy via oral gavage for 4 weeks. Researchers measured body weight, body composition, fasting glucose, oral glucose tolerance, and C-peptide levels.

Co-administration of dorzagliatin with orforglipron significantly improved glucose tolerance and glucose disposal compared with orforglipron alone. The combination also synergistically increased C-peptide secretion compared with monotherapies, indicating enhanced beta-cell responsiveness during glucose challenge.

Of note, the addition of dorzagliatin did not reduce orforglipron’s weight-lowering effect; the combination achieved 14%-20% reductions in total body weight depending on dose, with significant fat mass loss.

The combination of dorzagliatin and orforglipron also enhanced glycemic control beyond either agent alone, improving both basal and glucose-stimulated disposal while maintaining weight reduction.

“This dual-mechanism oral strategy may allow for optimized GLP-1 dosing, potentially reducing gastrointestinal side effects and improving treatment adherence in people with obesity-associated metabolic disorders,” the authors concluded.

Two co-authors reported being employees of Hua Medicine, and the other author declared having no conflicts of interest.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.