GLP-1 Therapies in 2026: Beyond Blood Sugar and the Scale

The glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) story keeps expanding. During the American Diabetes Association 2026 Scientific Sessions symposium, “GLP-1 Receptor Agonists: What’s New in 2026?,” 4 experts pushed well past the familiar conversation about weight loss and glycemic control and into terrain that is redefining how clinicians think about these agents entirely.

New oral and long-acting formulations are broadening patient access.¹ Emerging data on lean body mass, personalized nutrition, and joint disease are raising the clinical stakes.^2-4 Together, the data presented reveal a class of medications whose reach, and responsibilities, are still being mapped. Here is a closer look at each dimension of that expanding picture.

The Growing Focus on Muscle Preservation²

Losing weight with GLP-1 RAs typically means losing some muscle, too. But how much, and what to do about it, are questions that clinical practice is still catching up to answer.

Ian Neeland, MD, FAHA, FACC, director of cardiovascular prevention and codirector of the Center for Integrated and Novel Approaches in Vascular-Metabolic Disease for University Hospitals Harrington Heart & Vascular Institute, opened the symposium with a frank framing: as a rule of thumb, roughly 25% of total weight loss on any intervention, be it diet, pharmacotherapy, or surgery, comes from lean body mass loss. With newer, higher-dose GLP-1 compounds, the explained, that proportion can climb to 40% or more. Yet the picture is more nuanced than raw mass numbers suggest, he continued. Agents such as tirzepatide have demonstrated dose-dependent reductions in muscle fat infiltration by MRI, even as total lean mass declines.

The metabolic stakes are meaningful. “Each kilogram of muscle mass loss actually reduces resting energy expenditure by 13 kilocalories,” Neeland noted, “compared with fat mass, which contributes 4 kilocalories.” He underscored that preserving lean mass is not merely aesthetic but central to long-term metabolic health and weight maintenance.

Exercise and protein remain the cornerstone interventions. Neeland highlighted data from the S-LITE trial (NCT04122716), which demonstrated that combining liraglutide with supervised resistance and aerobic training not only produced superior weight loss but enabled patients to actually gain lean mass, an outcome not seen with pharmacotherapy alone.⁵ For protein targets, Neeland cited evidence supporting 1.2 to 1.6 g/kg/day as the effective range, with diminishing returns above that threshold.

Pharmacological strategies are advancing as well. The phase 2 BELIEVE trial (NCT05616013), which combined semaglutide with the myostatin inhibitor bimagrumab, reduced the lean mass fraction of total weight loss from roughly 21% to just 7%.⁶

Still, Neeland flagged a persistent gap: functional outcomes. “I have not seen great large-scale trials looking at function of muscle,” he said. “Furthermore, in the clinic, how we measure muscle function is also not really clear.”

New GLP-1 Formulations Expand Treatment Options¹

The landscape of GLP-1 RA therapy expanded markedly in 2026, with 4 new agents or formulations reaching or approaching approval, a development Donna H. Ryan, MD, called a turning point for both patient access and clinical decision-making. Ryan is professor emeritus at Pennington Biomedical Research Center and lead investigator on the SELECT Cardiovascular Outcomes Program, organized her presentation around 2 oral agents now available and 2 pipeline compounds poised to reshape treatment.

In the OASIS 4 trial (NCT05564117), oral semaglutide 25 mg produced mean weight loss of 13.6% to 16.6%,,⁷ with 36% achieving at least 15% reduction, results Ryan described as “very similar, frankly, to the oral semaglutide results.” The drug’s pharmacokinetic modeling, she explained, showed participants had exposure levels identical to the injectable formulation, suggesting comparable tolerability and efficacy. The second oral agent, orforglipron, the first small-molecule GLP-1 RA,⁸ achieved 7.5% to 11.2% weight loss across doses, she said, and carries a distinct metabolic profile, requiring dose adjustments when co-administered with cytochrome P450 3A4 inhibitors or inducers.

A higher-dose semaglutide formulation (7.2 mg) also drew attention, with the STEP UP trial (NCT05646706) showing mean weight loss of 20.7% compared with 17.5% at the standard 2.4-mg dose, offering a meaningful option for patients who plateau on current maintenance dosing.⁹

The most consequential development, Martin suggested, may be cagrilintide, a long-acting amylin analog coadministered with semaglutide. In the REDEFINE 1 trial (NCT05567796), the combination produced 22.7% mean weight loss, with 40% of patients exceeding 25%. Beyond weight, she said, the regimen drove a 17.5-cm reduction in waist circumference, a 65% drop in C-reactive protein, and meaningful reductions in hemoglobin A_1C, blood pressure, and triglycerides.

The disease-modification implications may be equally significant. Human amylin cosecreted with insulin can form fibrils that deposit in pancreatic islets, a proposed driver of diabetes progression also implicated in Alzheimer disease and diastolic dysfunction. “This is the next thing coming,” Martin said of the amylin pathway.

Can GLP-1 Drugs Change Osteoarthritis Care?³

Treating obesity improves osteoarthritis. That much, Sean Wharton, MD, PharmD, medical director of the Wharton Medical Clinic in Toronto, acknowledged, is not the hard question. The harder one is whether the benefits seen GLP-1 RAs stem from the mechanical unloading of joints as weight comes off or from something more: an anti-inflammatory, metabolic effect independent of weight loss altogether.

Wharton, an assistant professor at the University of Toronto and lead author of the 2020 Canadian Obesity Guidelines, grounded his presentation in a patient case before turning to trial data. Michael, a 45-year-old patient with a body mass index (BMI) of 35.9 and severe right hip osteoarthritis, was told by his orthopedic surgeon to lose weight before surgery could proceed. After starting a GLP-1 RA and achieving 13% weight loss, he underwent successful hip replacement and recovered well enough to play with his young son on a beach vacation in Cuba. “He cried in my office,” Wharton said. “He’s a big guy, and he’s 45. He’s as accountant. They don’t cry.”

Data from the STEP 9 trial (NCT05064735), in which semaglutide 2.4 mg was subcutaneously administered to patients with knee osteoarthritis and a mean BMI of 40.3, showed a 13.7% mean weight change and a 41.7-point reduction in Western Ontario and McMaster Universities Osteoarthritis Index pain scores in the treatment arm vs 27.5 points in the structured-care comparator group.¹⁰ Notably, use of pain medications including opioids declined significantly in the semaglutide arm, he noted.

Yet Wharton was candid about the study’s limits: no poststudy knee imaging, no synovial fluid analysis, no inflammatory biomarkers. Topline data from the TRIUMPH 4 trial (NCT05931367) of tirzepatide added a puzzling wrinkle. Roughly 23% weight loss produced similar pain score reductions to semaglutide’s 13%, raising the possibility that beyond a threshold of around 10% weight loss, additional reduction may not translate to proportionally greater joint benefit.

“We need to leave the door open for biological metabolic effects on top of the actual weight,” Wharton said, calling for MRI data, synovial biopsies, and biomarker analysis in future trials to untangle the mechanisms driving improvement.

How Nutrition Shapes Success on GLP-1 Therapy⁴

When a patient on semaglutide asks “Am I eating okay?,” the answer increasingly requires more than a standard dietary handout, expressed Patti Urbanski, MEd, RDN, LD, CDCES, FADCES, consultant in diabetes and nutrition services and member of the American Diabetes Association 2026 Nutrition Consensus Statement writing committee. With more than 30 years of experience, she built her presentation around a patient case and a practical framework for nutritional care in the GLP-1 RA era.

Her patient, Brad, a 61-year-old newspaper editor with hypertension, hyperlipidemia, and prediabetes, came in 6 weeks after starting semaglutide having lost 5.6 kg. His question was disarmingly simple. “My appetite and things have really, really changed and I’m thinking maybe I need to just check in, and I want your opinion of am I doing okay?” Urbanski used his case to walk through the full arc of nutritional management, from baseline screening to 6-month follow-up.

Before any dietary guidance, she emphasized the importance of a thorough, nonjudgmental baseline assessment, including screening for eating disorders, gastrointestinal conditions, renal insufficiency, sarcopenia, and social determinants of health that could undermine the best nutritional plan. “I can make the best nutrition recommendations in the world,” she said, “but if somebody has situations in their lifestyle and their socioeconomic status that are going to prevent them from being able to implement those changes, it certainly isn’t going to have an impact.”

Drawing from the 2025 obesity pillars nutrition and lifestyle consensus report,¹¹ Urbanski outlined specific targets: protein at 1.5 g/kg/day (aligning closely with Neeland’s 1.6 g/kg recommendation from earlier in the session), fiber at 25 to 30 g/day for women and 30 to 35 g/day for men, fat at 25 to 60 g/day on a lower-calorie diet, and a minimum of 2 liters of water daily. She framed all of these in food-first, real-world terms: smaller plates, meal replacement shakes kept at the office, and lean proteins and nonstarchy vegetables as anchors.

On the clinical side, she cited evidence that involving registered dietitian nutritionists can reduce GLP-1 RA discontinuation rates by as much as 5 to 10% in trials, and likely more in practice. Six months after his initial visit, Brad had lost 50 pounds, his BMI had dropped below 30, and his hemoglobin A_1C had improved from 6.1% to 5.5%.

References

1. Ryan DH. The latest in obesity pipeline: clinical trials of incretin-based therapies. Presented at: American Diabetes Association 2026 Scientific Sessions; June 5-8, 2026; New Orleans, LA.
2. Neeland I. Preserving lean body mass index while on GLP-1-based therapies. Presented at: American Diabetes Association 2026 Scientific Sessions; June 5-8, 2026; New Orleans, LA.
3. Wharton S. Treating osteoarthritis with obesity medications. Presented at: American Diabetes Association 2026 Scientific Sessions; June 5-8, 2026; New Orleans, LA.
4. Urbanski P. GLP-1 receptor agonists and optimal nutrition. Presented at: American Diabetes Association 2026 Scientific Sessions; June 5-8, 2026; New Orleans, LA.
5. Combined effects of GLP-1 analogue and exercise on maintenance of weight loss and health after very-low calorie diet (S-LITE). ClinicalTrials.gov. Updated November 2, 2020. Accessed June 9, 2026. https://clinicaltrials.gov/study/NCT04122716
6. Heymsfield SB, Aronne LJ, Montgomery P, et al. Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial. Nat Med. 2026;32(3):869-882. doi:10.1038/s41591-026-04204-0
7. Joszt L. FDA approves oral semaglutide as first GLP-1 pill for weight loss. AJMC^®. December 22, 2025. Accessed June 9, 2026. https://www.ajmc.com/view/fda-approves-oral-semaglutide-as-first-glp-1-pill-for-weight-loss
8. Hohmann E. FDA approves Lilly’s oral GLP-1 orforglipron for obesity. AJMC. April 1, 2026.Accessed June 9, 2026. https://www.ajmc.com/view/fda-approves-lilly-s-oral-glp-1-orforglipron-for-obesity
9. Wharton S, Freitas P, Hjelmesaeth J, et al. Efficacy and safety of semaglutide 7.2 mg in obesity: the STEP UP trial. Presented at: American Diabetes Association 2025 Scientific Sessions; June 20-23, 2025; Chicago, IL.
10. Research study looking at how well semaglutide works in people suffering from obesity and knee osteoarthritis. ClinicalTrials.gov. Updated November 17, 2025. Accessed June 9, 2026. https://clinicaltrials.gov/study/NCT05064735?tab=results
11. Mozaffarian D, Agarwal M, Aggarwal M, et al. Nutritional priorities to support GLP-1 therapy for obesity: a joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society. Am J Clin Nutr. 2025;122(1):344-367. doi:10.1016/j.ajcnut.2025.04.023