Objective Exercise Outcomes During GLP-1 Based Therapy: Distinguishing Cardiorespiratory Fitness from Walking Capacity. A Narrative Review
DOI:
https://doi.org/10.12775/QS.2026.76.75671Keywords
glucagon-like peptide-1 receptor agonists, cardiorespiratory fitness, oxygen uptake, walking capacity, exercise trainingAbstract
Background. Glucagon-like peptide-1 (GLP-1) receptor agonists and related incretin-based therapies can produce substantial weight loss and metabolic benefits. Their effects on objective exercise outcomes are less clear because studies use non-interchangeable endpoints ranging from directly measured oxygen uptake (VO₂) to walking distance.
Objective. To summarize objective exercise outcomes during GLP-1-based therapy and separate directly measured cardiorespiratory fitness from changes observed with exercise training and from disease-specific walking capacity.
Methods. We searched PubMed and tracked relevant citations up to July 2026. Adult clinical studies reporting at least one objective exercise outcome were grouped by outcome domain.
Results. Ten clinical studies were included. In the 193-participant secondary analysis, liraglutide alone did not improve VO₂-derived fitness or physical-performance outcomes. Two smaller trials of exenatide or liraglutide without structured exercise were also neutral. VO₂ improved when structured exercise was included, but comparisons with matched exercise did not establish a clear additive drug effect. Walking outcomes improved most clearly in peripheral artery disease, whereas coronary artery disease and ischemia-focused endpoints were neutral. During substantial weight loss, body-mass-normalized VO₂ may rise partly because body mass in the denominator falls; absolute VO₂, VO₂ normalized to fat-free mass, workload, strength, and body composition therefore require separate interpretation.
Conclusions.The meaning of an objective exercise outcome depends on what was measured. Current evidence does not consistently show an independent improvement in directly measured cardiorespiratory fitness with pharmacotherapy alone. Structured exercise remains the best-supported context for improving aerobic fitness. Disease-specific gains in walking capacity should not be interpreted as generalized cardiorespiratory-fitness gains.
References
1. American Diabetes Association Professional Practice Committee for Diabetes. 8. Obesity and weight management for the prevention and treatment of diabetes: Standards of Care in Diabetes-2026. Diabetes Care 2026; 49(Suppl 1): S166–S182. https://doi.org/10.2337/dc26-S008.
2. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al.; SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022; 387: 205–216. https://doi.org/10.1056/NEJMoa2206038.
3. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al.; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015; 373: 11–22. https://doi.org/10.1056/NEJMoa1411892.
4. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al.; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989–1002. https://doi.org/10.1056/NEJMoa2032183.
5. American Thoracic Society; American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003; 167: 211–277. https://doi.org/10.1164/rccm.167.2.211.
6. Ross R, Blair SN, Arena R, Church TS, Despres JP, Franklin BA, et al. Importance of assessing cardiorespiratory fitness in clinical practice: A case for fitness as a clinical vital sign. Circulation 2016; 134: e653–e699. https://doi.org/10.1161/CIR.0000000000000461.
7. American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166: 111–117. https://doi.org/10.1164/ajrccm.166.1.at1102.
8. Caruso P, Maiorino MI, Longo M, Porcellini C, Matrone R, Digitale Selvaggio L, et al. Liraglutide for lower limb perfusion in people with type 2 diabetes and peripheral artery disease: The STARDUST randomized clinical trial. JAMA Netw Open 2024; 7: e241545. https://doi.org/10.1001/jamanetworkopen.2024.1545.
9. Chowdhary A, Thirunavukarasu S, Joseph T, Jex N, Kotha S, Giannoudi M, et al. Liraglutide improves myocardial perfusion and energetics and exercise tolerance in patients with type 2 diabetes. J Am Coll Cardiol 2024; 84: 540–557. https://doi.org/10.1016/j.jacc.2024.04.064.
10. Wägner AM, Miranda-Calderín G, Ugarte-Lopetegui MA, Marrero-Santiago H, Suárez-Castellano L, López-Madrazo MJ, et al. Effect of liraglutide on physical performance in type 2 diabetes: Results of a randomized, double-blind, controlled trial (LIPER2). Diabetes Metab 2019; 45: 268–275. https://doi.org/10.1016/j.diabet.2018.08.010.
11. Bonaca MP, Catarig AM, Houlind K, Ludvik B, Nordanstig J, Ramesh CK, et al.; STRIDE Trial Investigators. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): A phase 3b, double-blind, randomised, placebo-controlled trial. Lancet 2025; 405: 1580–1593. https://doi.org/10.1016/S0140-6736(25)00509-4.
12. Kumarathurai P, Anholm C, Nielsen OW, Kristiansen OP, Mølvig J, Madsbad S, et al. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes: A randomized double-blind placebo-controlled crossover study. Cardiovasc Diabetol 2016; 15: 105. https://doi.org/10.1186/s12933-016-0425-2.
13. Myat A, Redwood SR, Arri S, Gersh BJ, Bhatt DL, Marber MS. Liraglutide to improve coronary haemodynamics during exercise stress (LIONESS): A double-blind randomised placebo-controlled crossover trial. Diabetol Metab Syndr 2021; 13: 17. https://doi.org/10.1186/s13098-021-00635-6.
14. Jensen SBK, Fiorenza M, Juhl CR, Sandsdal RM, Jensen E, Seier SS, et al. Physical fitness with exercise and GLP-1 receptor agonist treatment alone or combined after diet-induced weight loss: A secondary analysis of a randomized controlled trial in adults with obesity. Sports Med 2026; 56: 1785–1800. https://doi.org/10.1007/s40279-025-02386-0.
15. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease. Circulation 2017; 135: e726–e779. https://doi.org/10.1161/CIR.0000000000000471.
16. Gornik HL, Aronow HD, Goodney PP, Arya S, Packard Brewster L, Byrd L, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2024; 149: e1313–e1410. https://doi.org/10.1161/CIR.0000000000001251.
17. Ahmad E, Arsenyadis F, Almaqhawi A, Barker M, Jobanputra R, Sargeant JA, et al. Impact of novel glucose-lowering therapies on physical function in people with type 2 diabetes: A systematic review and meta-analysis of randomised placebo-controlled trials. Diabet Med 2023; 40: e15083. https://doi.org/10.1111/dme.15083.
18. Jobanputra R, Sargeant JA, Almaqhawi A, Ahmad E, Arsenyadis F, Webb DR, et al. The effects of weight-lowering pharmacotherapies on physical activity, function and fitness: A systematic review and meta-analysis of randomized controlled trials. Obes Rev 2023; 24: e13553. https://doi.org/10.1111/obr.13553.
19. Topolski K, Tłoczek W, Śliwa W, Twardowska D, Jelonek B, Tomczak B, et al. GLP-1 receptor agonists in recreational athletes: emerging weight-reduction strategy or potential health risk? A review of current evidence. Quality in Sport 2026; 55: 71600. https://doi.org/10.12775/QS.2026.55.71600.
20. Turczynowski K, Lichoń J, Kuna P, Turczynowski K, Kuna W, Pietrucha J, et al. Impact of GLP-1 receptor agonists on body composition and physical performance in patients with obesity: a comprehensive review of current research. Quality in Sport 2026; 51: 68929. https://doi.org/10.12775/QS.2026.51.68929.
21. Heymsfield SB, Brown J, Ramirez S, Prado CM, Tinsley GM, Gonzalez MC. Are lean body mass and fat-free mass the same or different body components? A critical perspective. Adv Nutr 2024; 15: 100335. https://doi.org/10.1016/j.advnut.2024.100335.
22. Lee J, Zhang X. Is there really a proportional relationship between VO₂max and body weight? A review article. PLoS One 2021; 16: e0261519. https://doi.org/10.1371/journal.pone.0261519.
23. Lolli L, Batterham AM, Weston KL, Atkinson G. Size exponents for scaling maximal oxygen uptake in over 6500 humans: a systematic review and meta-analysis. Sports Med 2017; 47: 1405–1419. https://doi.org/10.1007/s40279-016-0655-1.
24. Zhou N. Assessment of aerobic exercise capacity in obesity, which expression of oxygen uptake is the best? Sports Med Health Sci 2021; 3: 138–147. https://doi.org/10.1016/j.smhs.2021.01.001.
25. Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med 2021; 384: 1719–1730. https://doi.org/10.1056/NEJMoa2028198.
26. Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, et al.; American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee. Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010; 122: 191–225. https://doi.org/10.1161/CIR.0b013e3181e52e69.
27. Scalzo RL, Moreau KL, Ozemek C, Herlache L, McMillin S, Gilligan S, et al. Exenatide improves diastolic function and attenuates arterial stiffness but does not alter exercise capacity in individuals with type 2 diabetes. J Diabetes Complications 2017; 31: 449–455. https://doi.org/10.1016/j.jdiacomp.2016.10.003.
28. Mensberg P, Nyby S, Jørgensen PG, Storgaard H, Jensen MT, Sivertsen J, et al. Near-normalization of glycaemic control with glucagon-like peptide-1 receptor agonist treatment combined with exercise in patients with type 2 diabetes. Diabetes Obes Metab 2017; 19: 172–180. https://doi.org/10.1111/dom.12797.
29. Ingersen A, Schmücker M, Alexandersen C, Graungaard B, Thorngreen T, Borch J, et al. Effects of aerobic training and semaglutide treatment on pancreatic beta-cell secretory function in patients with type 2 diabetes. J Clin Endocrinol Metab 2023; 108: 2798–2811. https://doi.org/10.1210/clinem/dgad326.
30. Oliver CJ, Climstein M, Rosic N, Bosy-Westphal A, Tinsley G, Myers S. Fat-free mass: Friend or foe to metabolic health? J Cachexia Sarcopenia Muscle 2025; 16: e13714. https://doi.org/10.1002/jcsm.13714.
31. Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016; 39: 2065–2079. https://doi.org/10.2337/dc16-1728.
32. Rubino DM, Greenway FL, Khalid U, O'Neil PM, Rosenstock J, Sørrig R, et al. Effect of semaglutide on body composition in adults with overweight or obesity: exploratory analyses of the STEP 1 study. Diabetes Obes Metab 2022; 24: 93–106. https://doi.org/10.1111/dom.14524.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Julia Nowak, Jakub Grandos, Mateusz Łaszczych, Barbara Bralewska, Julia Wykrota, Mateusz Polak, Jakub Jonakowski, Kacper Kuczyński, Tomasz Nicpoń
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 48
Number of citations: 0
