How GLP-1 Medications Work: History, Results, and Muscle Loss: Part 1

How GLP-1 Medications Work: History, Results, and the Muscle Question
Part 1 of a two-part series on weight management medications.

GLP-1 and related incretin-based medications have quickly moved quickly from niche diabetes drugs to some of the most talked-about tools in medicine ^{[1] [2]}.

These medications can meaningfully reduce the biological barriers that make losing weight so hard for many people. But the strongest and most consistent message across the research is that they work best as part of comprehensive care, not as a replacement for nutrition, physical activity, and long-term behavioral support ^{[1] [2] [3]}. This article looks at where these drugs came from, how they work in the body, their effectiveness in weight loss, and how much of that lost weight is fat versus lean (muscle and organ) tissue.

A Brief History of the Incretin Class

“GLP-1 medication” is a fairly new phrase in everyday conversation, but the science behind it is decades old. In the 1970s, researchers identified gut hormones, including glucagon-like peptide-1 (GLP-1), that help the body release insulin after eating. The first version of this hormone to be turned into a medicine was actually modeled on a protein found in the saliva of the Gila monster, a desert lizard whose venom happens to contain a long-lasting GLP-1 mimic. This led to the creation of “Exenatide” which was approved as a treatment for type 2 diabetes in 2005 ^[2].

From there, the class evolved quickly. Liraglutide, a once-daily injection, was approved for diabetes in 2010 and then specifically for chronic weight management in 2014. Semaglutide followed, approved for diabetes in 2017 and for weight management in 2021, followed by tirzepatide, a dual GLP-1/GIP medication, approved for diabetes in 2022 and weight management in 2023 ^[2]. Each generation was engineered to stay active in the body longer and to act on appetite more powerfully, which is a large part of why the newest agents can now produce weight loss in a range that used to be seen almost exclusively with bariatric surgery ^{[1] [2] [4] [3]}. As of September 2026, there are 13 FDA-approved medications currently on the market and nearly 200 active preclinical and clinical trials for new agents being tested.

How These Medications Actually Work

A common misconception is that these drugs “burn fat.” They don’t. Their core effect is to reduce energy intake by suppressing appetite and slowing gastric emptying, which helps many people eat less without the intense, constant hunger that often derails diet-only approaches [5] [6] [7]. Because body weight is shaped by biology as well as behavior, this matters most for people whose appetite regulation, weight regain tendency, or metabolic adaptation make lifestyle-only treatment unusually difficult ^[1].

How Well Do They Work? The Numbers

The results have been striking enough to change clinical practice. In the STEP 5 trial, adults treated with semaglutide 2.4 mg for two years lost an average of 15.2% of their body weight, compared with 2.6% on placebo ^[8]. In the SURMOUNT-1 trial, tirzepatide produced average weight loss of 15.0% to 20.9% depending on dose, versus about 3% with placebo ^[9]. And when the two drugs were compared head-to-head in the SURMOUNT-5 trial, tirzepatide outperformed semaglutide, with average weight loss of 20.2% versus 13.7% at 72 weeks ^[10].

Put another way, a substantial share of patients on these medications lose more than 20% of their starting body weight, a magnitude of change that, until recently, was mostly achievable through surgery. That is a genuine breakthrough, and it explains much of the enthusiasm surrounding this drug class ^{[1] [2] [4] [3]}.

The Part That Gets Less Attention: Fat Loss vs. Muscle Loss

Losing weight is not the same as losing only fat. Whenever someone is in a sustained calorie deficit, whether from diet, exercise, or medication, some of the weight lost comes from lean tissue: muscle, organ mass, and related structures. This is where the incretin medications deserve a closer look.

A recent systematic review and meta-analysis of randomized controlled trials found that, across semaglutide, tirzepatide, and liraglutide, roughly 25% to 39% of total weight lost was lean mass. That proportion is broadly similar to what is seen with lifestyle intervention alone. The most favorable body composition profile in that analysis, about 17.5% lean mass loss, was seen in the group combining lifestyle change with structured resistance training ^[11]. Other expert reviews describe a comparable range, generally citing that 20% to 40% of weight lost during incretin-based therapy can be fat-free mass ^{[3] [7]}.

Importantly, this does not mean the drugs are directly damaging muscle tissue. Current reviews argue that lean mass loss during GLP-1 treatment is largely driven by the size and speed of the energy deficit and by the body’s normal adaptive response to rapid weight loss, the same physiology that drives lean mass loss during aggressive dieting ^{[7] [12] [9]}. There is even some encouraging evidence that muscle quality can improve during treatment, through reductions in intramuscular fat and gains in insulin sensitivity, even as overall muscle mass declines ^{[7] [13] [14]}.

Still, unmonitored lean mass loss is a real concern, particularly for older adults, people who are already frail, and those with sarcopenia or metabolic dysfunction-associated liver disease, for whom even modest muscle loss can affect strength, mobility, and independence ^{[14] [12] [10] [15]}.

What This Means for You

The evidence supports incretin medications as a powerful tool for reducing the biological obstacles to weight loss ^{[9] [10] [8]}. However, because roughly a quarter to nearly 40% of the weight lost can come from lean tissue, medication alone is not the recommended approach for most people. Protecting muscle, function, and long-term metabolic health requires pairing these drugs with adequate nutrient intake and structured exercise ^{[3] [11] [7]}. As with any medical decision, we must consider the human as more than simply the condition being treated. Consider how weight management medication may provide an important opportunity for someone to overcome barriers that have made weight loss and physical activity difficult for years. Reducing body weight can lessen joint pain and physical limitations, while improving dietary control can help people regain confidence and establish healthier eating behaviors. In this context, weight management medications are not an “easy way out,” but rather a tool that can help level the playing field and give individuals the capacity to take greater control of their health.

Part 2 of this series will focus on why exercise and dietary structure matter so much during GLP-1 treatment, what a hybrid approach looks like in practice, and the physical activity recommendations for anyone trying to lose weight and keep it off. Decisions about starting, continuing, or stopping any weight management medication should always be made with a licensed clinician, particularly for people with diabetes, liver disease, frailty, or other obesity-related conditions ^{[2] [1]}.

References

1. 1. 1. Celletti F, Farrar J, De Regil LD. World Health Organization Guideline on the Use and Indications of Glucagon-Like Peptide-1 Therapies for the Treatment of Obesity in Adults. JAMA. 2025. doi:10.1001/jama.2025.24288
      2. Bloomgarden Z. An Update on GLP-1 Receptor Agonists. Journal of Diabetes. 2025;17(8):e70147. doi:10.1111/1753-0407.70147
      3. 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. Obesity (Silver Spring, Md.). 2025;33:1475–1503. doi:10.1002/oby.24336
      4. Sancho-Haro E, Muñoz-López M, Baz-Valle E, et al. Optimizing Weight Loss in the GLP-1 Era: Preserving Muscle Mass, Function and Metabolic Health Through Precision Nutrition and Resistance Training. Pharmaceuticals. 2026;19. doi:10.3390/ph19060897
      5. Codella R, Senesi P, Luzi L. GLP-1 agonists and exercise: the future of lifestyle prioritization. Frontiers in Clinical Diabetes and Healthcare. 2025;6. doi:10.3389/fcdhc.2025.1720794
      6. De Girolamo G, Sangineto M, Di Gioia G, Bianco R, Ciarnelli M, Serviddio G. Muscle health in the modern era of incretin-based therapies. European Journal of Clinical Investigation. 2025;56. doi:10.1111/eci.70155
      7. Szafraniec A, Korzeniowska A, Chmiela M, Jonderko L. Muscle Mass Preservation as a Therapeutic Challenge in GLP-1 Receptor Agonist Therapy. Quality in Sport. 2026. doi:10.12775/qs.2026.56.72375
      8. Garvey WT, Batterham RL, Bhatta M, et al; STEP 5 Study Group. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nature Medicine. 2022;28(10):2083–2091. doi:10.1038/s41591-022-02026-4
      9. Jastreboff AM, Aronne LJ, Ahmad NN, et al; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. 2022;387(3):205–216. doi:10.1056/NEJMoa2206038
      10. Aronne LJ, Horn DB, le Roux CW, et al; SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine. 2025;393(1):26–36. doi:10.1056/NEJMoa2416394
      11. Eisa N, Barood O. Lean Mass Changes With Incretin Therapy Versus Lifestyle Intervention: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Diabetes, Obesity and Metabolism. 2026;28:4818–4827. doi:10.1111/dom.70666
      12. Linge J, Birkenfeld AL, Neeland I. Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss? Circulation. 2024;150:1288–1298. doi:10.1161/circulationaha.124.067676
      13. Iorra F, Jayakar T, Yee M, Thursz M, Schaan B, Manousou P. Effects of GLP-1 Receptor Agonists on Muscle Mass, Strength, and Quality in MASLD: A Systematic Review. Liver International. 2026;46. doi:10.1111/liv.70643
      14. Sievenpiper J, Ard J, Blüher M, et al. Nutritional and lifestyle supportive care recommendations for management of obesity with GLP-1-based therapies: An expert consensus statement using a modified Delphi approach. Obesity Pillars. 2025;17. doi:10.1016/j.obpill.2025.100228
      15. Izquierdo M, Merchant R, Morley JE, et al. International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines. The Journal of Nutrition, Health & Aging. 2021;25:824–853. doi:10.1007/s12603-021-1665-8