Muscle Mass Changes With Incretin-Based Therapies for Weight Loss

Abstract

Purpose: This narrative review highlights the significance of lean body mass (LBM) and skeletal muscle mass (SMM), the health implications due to a reduction in LBM, how glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and GLP-1 RA/glucose-dependent insulinotropic polypeptides (GIPs) affect LBM, current strategies to preserve SMM, and other pipeline therapies for preserving SMM.

Summary: Obesity is a chronic condition associated with numerous complications, including metabolic, physical, and psychosocial issues. However, GLP-1 RA and GLP-1 RA/GIP safety data indicate an increase in muscle mass loss as patients lose body weight. Muscle loss due to muscle protein breakdown, associated with GLP-1 RAs and GLP-1 RA/GIPs, may negatively affect health outcomes, especially in individuals with sarcopenic obesity, which is age-related loss of muscle mass and function.

Conclusion: Current methods for preserving or enhancing muscle mass primarily involve nonpharmacological strategies, such as increasing protein intake and engaging in exercise. Ongoing studies are evaluating novel agents, such as growth hormones bimagrumab, trevogrumab, and garetosmab, to reduce the risk of sarcopenia in obese patients. Health care providers should be aware of the implications and effects of reduced LBM when prescribing GLP-1 RAs and GLP-1 RA/GIPs, especially to patients with prefrailty, to reduce the risk of sarcopenic obesity.

Introduction

Obesity is a chronic condition associated with numerous complications, including metabolic, physical, and psychosocial issues. Obesity is typically diagnosed using body mass index (BMI), calculated as weight (kg) divided by height² (m²). However, in some patients with higher muscle mass, BMI may be inaccurate. Therefore, other measures, such as waist circumference, waist to hip ratio, or waist to height ratio, can also be used. For adults, overweight is defined as a BMI of 25.0 to 29.9, and obesity is defined as a BMI of 30.0 or higher. The prevalence of obesity has been increasing in the United States. Between 2021 and 2023, approximately 40.3% of Americans were diagnosed with obesity, with no notable difference between the sexes.¹ Additionally, obesity is reaching pandemic proportions and is costly to the US health care system. It is estimated that approximately $173 billion per year is spent on obesity management.²

As a patient’s BMI rises, the risk of cardiovascular disease (CVD) also increases.³ Therefore, the FDA has approved several medications for weight loss, in addition to lifestyle modifications such as reduced-calorie eating patterns and increased physical activity, to improve cardiometabolic risk status. Criteria for obesity medications are a BMI of 30.0 or higher, or 27.0 or higher with 1 or more obesity-related conditions such as type 2 diabetes (T2D), hypertension, or dyslipidemia. Guidelines define a clinically significant goal of achieving 5% to 15% weight loss within 6 months.⁴ Oral medications such as phentermine (Adipex-P; Teva Pharmaceuticals), phentermine/topiramate (Qsymia; Vivus LLC), naltrexone/bupropion (Contrave; Currax Pharmaceuticals LLC), and orlistat (Xenical; H2-Pharma, LLC, and Alli; Haleon US Holdings) have been falling out of favor due to modest weight loss, lack of long-term benefits, and adverse effect (AE) profiles.⁴

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and GLP-1 RA/glucose-dependent insulinotropic polypeptides (GIPs) have become popular treatment options due to their efficacy, AE profiles, and long-term cardiovascular benefits, as demonstrated in data from the following pivotal phase 3 clinical trials: SCALE Obesity and Pre-diabetes (NCT01272219; liraglutide [Saxenda; Novo Nordisk]), STEP 1 (NCT03548935; semaglutide [Wegovy; Novo Nordisk]), and SURMOUNT-1 (NCT04184622; tirzepatide [Zepbound; Eli Lilly and Company]).^5-7 However, there is concern that GLP-1 RAs and GLP-1 RA/GIPs may be associated with muscle mass loss due to reduced overall body weight.

Pharmacists are the most accessible health care professionals, so they need to understand the evidence on GLP-1 RAs, GLP-1 RA/GIP treatments, and muscle mass loss to provide proper counseling to patients.⁸ This narrative review highlights the significance of lean body mass (LBM) and skeletal muscle mass (SMM), the health implications due to a reduction in LBM, how GLP-1 RAs and GLP-1 RA/GIPs affect LBM, current strategies to preserve SMM, and other pipeline therapies for preserving SMM.

Significance of LBM and Impact of SMM Loss

Emphasize the importance of maintaining LBM to individuals who are taking weight loss medications. LBM, calculated as total body mass minus fat mass, represents the weight of all body tissues, including skeletal muscle, organs, and body fluids, but excluding fat. ⁹ LBM is measured and calculated using MRI, CT, dual-energy x-ray absorptiometry, air displacement plethysmography, and bioelectrical impedance analysis.^10,11 Due to the methods’ cost, accessibility, and accuracy, their applicability in real-world settings is limited. Although imaging tests are considered the gold standard, other more readily accessible methods of measurement include skinfold calipers and abdominal circumference.¹¹

SMM—a component in LBM that refers to voluntary muscles only—plays a significant role in insulin-stimulated glucose disposal, whole-body glucose turnover, improvements in insulin sensitivity, and reduction in insulin resistance.^12,13 Basal metabolic rate is associated with organ mass because organs, such as the heart, lungs, and liver, have high energy requirements. Therefore, maintaining LBM is associated with a decreased risk of CVD, prevention of T2D, improvements in physical function, and increased metabolism.⁹

SMM plays a key role in postprandial insulin-driven glucose uptake and glucose homeostasis. Increased insulin resistance in skeletal muscle significantly impairs glucose metabolism, leading to T2D. SMM increases glucose catabolism to help prevent β-cell and pancreas exhaustion. Increasing SMM by 10% correlates to an 11% reduction in insulin resistance and 12% decrease in the prevalence of prediabetes. SMM also plays a crucial role in regulating lipid metabolism by clearing free fatty acids, thereby decreasing lipid levels to prevent CVD.¹³

Muscle loss, which is associated with use of GLP-1 RAs and GLP-1 RA/GIPs due to muscle protein breakdown, may negatively affect health outcomes, especially in individuals with sarcopenic obesity. According to the European Society for Clinical Nutrition and Metabolism and the European Association for the Study of Obesity, sarcopenic obesity is defined as the coexistence of excess body fat and reduced muscle mass or function.¹³ Sarcopenic obesity is most prevalent among older individuals, and it accounts for approximately 43% of the adult population diagnosed with obesity.¹³ Although BMI has been widely used as an indicator for obesity, it has been shown to inadequately predict cardiometabolic risk in patients with sarcopenic obesity and mortality in older individuals. Therefore, it is recommended to use the fat-free mass index in these individuals.⁴ Individuals with sarcopenic obesity have an increased risk of developing cognitive dysfunction and a 38% higher risk of developing T2D.¹³

Investigators in a 2006 study determined that aging may lead to a 1% reduction in lean leg mass, corresponding to a 2.6% to 4.1% decline in strength.¹³ Muscle loss and sarcopenia may lead to muscle atrophy, mobility issues, loss of balance, increased risk of falls, and reduced quality of life. Study results showed that individuals with low SMM and obesity were likely to have liver dysfunction and increased 10-year CVD risk.¹³

In addition, weight cycling, the process of repeating weight loss and regain, is often common in patients who have stopped GLP-1 RA or GLP-1 RA/GIP therapy. Weight cycling is linked to increased fat mass and adipose tissue, decreased SMM, and an increased risk of sarcopenic obesity, thereby negatively impacting cardiometabolic health.¹³

Effect of GLP-1 RAs and GLP-1 RA/GIP on LBM

Weight-loss strategies, such as maintaining a calorie deficit, using pharmacological agents, or undergoing bariatric surgery, can result in varying changes in body composition.¹⁴ Although GLP-1 RAs and GLP-1 RA/GIPs have become more popular for weight loss, there are insufficient data evaluating changes in body composition due to therapy. Most studies examining the use of GLP-1 RAs and GLP-1 RA/GIP in obese populations with or without T2D consistently report reductions in LBM; however, these studies have limitations.

There are important differences to note that make generalizability difficult, including among individual agents, classes of therapy, clinical diagnoses, concomitant use of other antiglycemic agents, baseline demographics, and body composition. Clinical trials exploring the effects of GLP-1 RAs and GLP-1 RA/GIPs for weight loss used different methods to measure or calculate LBM reduction, which can affect reported outcomes. A correlation between functional decline and reduced LBM cannot be established, as this was not evaluated in the studies.

There are more clinical trials involving semaglutide that demonstrate reductions in LBM than other GLP-1 RAs and GLP-1 RA/GIPs. In a 2021 study by Wilding et al, participants receiving semaglutide 2.4-mg subcutaneous (SC) injections once weekly, who were also adhering to a reduced-calorie diet and incorporating behavioral therapy and light-to-moderate exercise, experienced –5.26 kg of LBM compared with –1.83 kg in the control group and –8.36 kg of fat mass vs –1.37 kg in the control group (95% CI, –4.74 to –2.13).⁶ LBM and fat mass accounted for 39% and 61% of total weight reductions, respectively.⁶ Participants who received semaglutide 1 mg SC once weekly, along with a calorie deficit and physical and behavioral interventions, showed a 22% total weight reduction of LBM and 70% of fat mass. Results from 2 studies using oral semaglutide showed mild LBM reduction compared with fat mass reduction.¹⁴

In the LEAD trials, LBM reduction was dose dependent across all liraglutide arms. In the substudy, mean reductions of LBM from baseline (0.3, 0.8, and 1.5 kg) with liraglutide 0.6 mg, 1.2 mg, and 1.8 mg in combination with metformin were significantly different from the mean increase in LBM from baseline with glimepiride with metformin (0.6 mg: P = .0023; 1.2 and 1.8 mg: P < .0001). Conversely, 2 studies reported no changes or slight increases in LBM after 24 and 8 weeks of treatment, respectively.¹⁰

In SURMOUNT-1, tirzepatide SC reduced LBM by approximately 10.9% vs 2.6% for placebo (95% CI, –10.6 to –6.1).⁷ LBM accounted for 34.3% of the weight loss.¹² Investigators in a single study reported 0.1 kg (P = .684) and 0.2 kg (P = .498) losses of LBM and SMM, respectively, vs a 1.9-kg loss of mass (P = .043).^10,15 In another study comparing semaglutide 1 mg SC and tirzepatide SC with placebo, LBM decreased by approximately 15% or less across all groups.¹² The reduction in fat-free mass observed with tirzepatide relative to placebo (−1.5 kg; 95% CI, −2.3 to −0.7; P < .001) was greater than that observed with semaglutide relative to placebo (−0.8 kg; 95% CI, −1.5 to −0.1; P = .018).¹⁶

Loss of LBM and SMM may worsen cardiometabolic outcomes for patients receiving these medications for obesity, especially those who have concomitant sarcopenia. Further studies are needed to fully understand the effects on LBM, including long-term changes in body composition associated with the use of GLP-1 RAs and GLP-1 RA/GIPs. Nevertheless, providers should emphasize the importance of preserving LBM and encourage strategies to promote SMM while targeting fat loss.

Nonpharmacologic Therapies to Increase Muscle Mass

Lifestyle modifications (eg, exercise and increased protein intake) can help prevent and mitigate sarcopenic obesity, improve metabolic function, and preserve SMM. Although low-calorie diets may improve weight loss outcomes, caloric restrictions over prolonged periods, along with increased energy expenditure, may lead to reductions in LBM. Caloric deficits may decrease bone mineral content and density, leading to bone fragility, which is a concern especially in patients who have sarcopenic obesity, are older, or are postmenopausal.¹³ Therefore, health care providers should educate patients on increasing their protein intake.

Increasing protein intake will increase satiety, decrease fat mass, improve body composition, and prevent sarcopenia.¹⁴ The US Department of Agriculture Dietary Reference Intake for protein is 0.8 to 2.0 g/kg/day depending on age, sex, and physical activity.¹⁷ However, for inpatients with obesity, a higher protein intake of 60 to 75 g/day and up to more than 1.5 g/kg/day may be necessary, especially for patients in the setting of caloric restriction and other weight loss therapies.¹⁸ For patients taking GLP-1 RAs and GLP-1 RA/GIPs, meal-replacement products higher in calories, such as shakes, bars, and other formulated products, can be used to reach protein goals and preserve SMM to prevent sarcopenic obesity.¹⁸

A combination of mindful exercises, such as aerobic, endurance, mobility, balance, and resistance exercises, not only improves cardiovascular health and maintains glucose regulation but also preserves muscle mass during weight loss. For patients with obesity, the Obesity Medicine Association (OMA) recommends a physical activity goal of 150 to 300 minutes or more of moderate aerobic activity per week, or 75 to 150 minutes or more of vigorous aerobic activity per week, with resistance training or muscle strengthening at least 2 times a week.¹⁷ These strategies promote weight reduction and prevent weight cycling. Resistance strength training targets large muscle groups (eg, using free weights, machines, resistance bands, and other weight-lifting techniques) to increase LBM percentage, especially during negative caloric balances.¹⁷

In a study comparing the effects of moderate to vigorous exercise, liraglutide 3 mg SC once daily, and a combination of exercise and liraglutide, the combination group reduced body weight by almost 8% while maintaining total LBM.¹⁹ Comparatively, other strategies for weight loss often result in higher reductions in LBM. For example, 20% to 50% and 30% to 47% of LBM may be lost after bariatric surgery and GLP-1 RA treatment, respectively.¹⁹

Pharmacological Treatments to Increase Muscle Mass

Currently, recombinant growth hormone (GH) is among the most commonly used pharmacological agents to increase muscle mass. Recombinant GH increases the release of insulin-like growth factor 1, which promotes bone and tissue growth.²⁰ A meta-analysis by Mekala et al focused on the effects of recombinant GH on body composition in obesity, which included fat mass, percentage of body fat, LBM, and visceral adipose area and lipid profile. Overall, the authors found reduced visceral adiposity, increased LBM, and improved lipid profiles, without affecting weight loss.²¹

An open, prospective, randomized, controlled study examined the role of GH treatment in preventing LBM loss during the early postoperative period after bariatric surgery.²² All female participants who underwent laparoscopic-adjustable silicone gastric banding had GH deficiency. One treatment group received a standardized diet and exercise program plus recombinant GH, whereas the other group received only a standardized diet and exercise program. After 6 months of GH treatment in combination with diet and exercise, the authors found a reduction in loss of LBM and SMM.²²

However, GH’s role as an adjunct to GLP-1 RA or GLP-1 RA/GIP therapy is theorized and lacks strong clinical evidence. Some drawbacks to using GH are cost and AEs such as arthralgia, myalgia, peripheral edema, insulin resistance, and T2D.¹² It is unclear whether long-term use of GH in patients without GH deficiency is safe and effective. More evidence is needed to clarify the role of pharmacologic treatments; therefore, pharmacists should recommend evidence-based nonpharmacologic treatments to preserve lean body mass.

Emerging and Investigational

Pipeline pharmacological agents, such as bimagrumab (Eli Lilly and Company), trevogrumab (Regeneron Pharmaceuticals), and garetosmab (Regeneron Pharmaceuticals), antagonize these targets and may increase SMM. These monoclonal antibodies are used in conjunction with incretin receptor agonists or alone to help prevent LBM loss. The myostatin-activin pathway regulates skeletal muscle growth, and the signaling proteins activin A and myostatin are negative regulators of muscle mass and growth.¹²

Trevogrumab works by antagonizing myostatin, a protein that inhibits muscle growth. Garetosmab is an inhibitor of activin A. Early trials of trevogrumab and garetosmab, combined with semaglutide, in primates showed fat mass loss and increased LBM.⁹ Trevogrumab and garetosmab are being investigated in a phase 2 clinical trial evaluating their safety and efficacy in combination with semaglutide in adult patients with obesity for weight loss and fat loss.²³

Bimagrumab specifically blocks the activin type II receptor (ActRII); ActRII blockade induces skeletal muscle hypertrophy and reduces fat mass. In a study evaluating its effectiveness in obese and T2D populations, researchers found that those in the bimagrumab group experienced a net weight loss of 6.5% after 48 weeks, an increase in lean mass by 3.6%, and a decrease in fat mass by 20.5%, with no difference in food intake.⁹ Bimagrumab is being investigated in a phase 2b clinical trial evaluating it as monotherapy and in combination with semaglutide for the treatment of obesity in nondiabetic adults with overweight or obesity.²⁴ There is more to be discovered with future clinical trials when it comes to preserving LBM and SMM in the setting of weight loss.

Role of the Pharmacist and Conclusion

Given the lack of clinical evidence surrounding pharmacological treatments to help preserve or enhance muscle mass, pharmacists should recommend lifestyle modifications such as increasing protein intake and exercising. This is especially true for older individuals for whom sarcopenic obesity is of great concern. Overall, it is important for the pharmacist to be aware of the negative health outcomes that can potentially come with GLP-1 RA or GLP-1 RA/GIP use.

For many patients, reductions in LBM and SMM associated with GLP-1 RAs and GLP-1 RA/GIP use are associated with improvements in cardiometabolic health and quality of life.

Current methods for preserving or enhancing muscle mass are mostly nonpharmacological and include increasing protein intake and engaging in exercise. This narrative review highlights the differences between SMM and LBM to clarify how each approach measures and contextualizes data from studies examining muscle mass loss associated with GLP-1 RA and GLP-1 RA/GIP use. Guidelines emphasize resistance, strength training, and aerobic exercise, in addition to aGLP-1 RA or aGLP-1 RA/GIP, to promote SMM preservation. Further studies are needed to evaluate the health outcomes of SMM loss and reductions in LBM during weight loss therapy, especially when pharmacologic agents are used. There are ongoing studies for novel agents such as GH, bimagrumab, trevogrumab, and garetosmab that may reduce the risk of sarcopenia in the setting of obesity.

Health care providers should be aware of the implications and effects of reduced LBM when prescribing GLP-1 RAs or GLP-1 RA/GIPs to patients—especially in those with pre-frailty—to help reduce the risk of sarcopenic obesity. Health care providers should emphasize strategies to prevent LBM reductions and increase SMM in adults receiving pharmacotherapy for weight loss. More long-term clinical trials are needed to fully understand the long-term effects of GLP-1 RAs and GLP-1 RA/GIPs on musculoskeletal health and changes in body composition. Future studies should assess the efficacy and safety of strategies to preserve LBM when using GLP-1 RAs or GLP-1 RA/GIPs for weight loss management, as well as the effects of emerging pharmacological treatments on LBM preservation.

REFERENCES

1. Emmerich SD, Fryar CD, Stierman B, Ogden CL. Obesity and severe obesity prevalence in adults: United States, August 2021–August 2023.CDC. Updated September 24, 2024. Accessed April 3, 2025. https://www.cdc.gov/nchs/products/databriefs/db508.htm

2. About obesity. CDC. January 23, 2024. Accessed April 3, 2025. https://www.cdc.gov/obesity/php/about/index.html

3. Valenzuela PL, Carrera-Bastos P, Castillo-García A, Lieberman DE, Santos-Lozano A, Lucia A. Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol. 2023;20(7):475-494. doi:10.1038/s41569-023-00847-5

4. Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22(suppl 3):1-203. doi:10.4158/EP161365.GL

5. Pi-Sunyer X, Astrup A, Fujioka K, 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(1):11-22. doi:10.1056/NEJMoa1411892

6. Wilding J, Batterham RL, Calanna S, et al; STEP 1 Study Group.Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183

7. Jastreboff AM, Aronne LJ, Ahmad NN, et al; SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387(3):205-216. doi:10.1056/NEJMoa2206038

8. ManolakisPG, SkeltonJB. Pharmacists’ contributions to primary care in the United States collaborating to address unmet patient care needs—the emerging role for pharmacists to address the shortage of primary care providers. Am J Pharm Educ. 2010;74(10):S7. doi:10.5688/aj7410s7

9. Neeland IJ, Linge J, Birkenfeld AL. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024;26(suppl 4):16-27. doi:10.1111/dom.15728

10. Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans. Endocrinol Metab (Seoul). 2019;34(3):247-262. doi:10.3803/EnM.2019.34.3.247

11. Duren DL, Sherwood RJ, Czerwinski SA, et al. Body composition methods: comparisons and interpretation. J Diabetes Sci Technol. 2008;2(6):1139-1146. doi:10.1177/193229680800200623

12. Linge J, Birkenfeld AL, Neeland IJ. Muscle mass and glucagon-like peptide-1 receptor agonists: adaptive or maladaptive response to weight loss? Circulation. 2024;150(16):1288-1298. doi:10.1161/CIRCULATIONAHA.124.067676

13. Stefanakis K, Kokkorakis M, Mantzoros CS. The impact of weight loss on fat-free mass, muscle, bone, and hematopoiesis health: implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation. Metabolism. 2024;161:156057. doi:10.1016/j.metabol.2024.156057

14. Bikou A, Dermiki-Gkana F, Penteris M, Constantinides TK, Kontogiorgis C. A systematic review of the effect of semaglutide on lean mass: insights from clinical trials. Expert Opin Pharmacother. 2024;25(5):611-619. doi:10.1080/14656566.2024.2343092

15. SekoY, SumidaY, TanakaS, et al. Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res. 2017;47(11):1206-1211. doi:10.1111/hepr.12837

16. HeiseT, DeVries JH, Urva S, et al. Tirzepatide reduces appetite, energy intake, and fat mass in people with type 2 diabetes. Diabetes Care. 2023;46(5):998-100. doi:10.2337/dc22-1710

17. Alexander L, Christensen SM, Richardson L, et al. Nutrition and physical activity: an Obesity Medicine Association (OMA) clinical practice s statement 2022. Obes Pillars. 2022;1:100005. doi:10.1016/j.obpill.2021.100005

18. Almandoz JP, Wadden TA, Tewksbury C, et al. Nutritional considerations with antiobesity medications. Obesity (Silver Spring). 2024;32(9):1613-1631. doi:10.1002/oby.24067

19. Sandsdal RM, Juhl CR, Jensen SBK, et al. Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial. Cardiovasc Diabetol. 2023;22(1):41. doi:10.1186/s12933-023-01765-z

20. Locatelli V, Bianchi VE. Effect of GH/IGF-1 on bone metabolism and osteoporosis. Int J Endocrinol. 2014;2014:235060. doi:10.1155/2014/235060

21. Mekala KC, Tritos NA. Effects of recombinant human growth hormone therapy in obesity in adults: a meta-analysis. J Clin Endocrinol Metab. 2009;94(1):130-137. doi:10.1210/jc.2008-1357

22. Savastano S, Di Somma C, Angrisani L, et al. Growth hormone treatment prevents loss of lean mass after bariatric surgery in morbidly obese patients: results of a pilot, open, prospective, randomized,controlled study. J Clin Endocrinol Metab. 2009;94(3):817-826. doi:10.1210/jc.2008-1476

23. A study to test if trevogrumab or trevogrumab with garetosmab when taken with semaglutide is safe and how well they work in adult patients with obesity for weight loss, fat loss, and lean mass preservation. Regeneron. Accessed April 22, 2025. https://clinicaltrials.regeneron.com/clinical-trials/a0MPr0000005iU3MAI/nct06299098

24. Safety and efficacy of bimagrumab and semaglutide in adults who are overweight or obese. ClinicalTrials.gov. Updated July 18, 2025. Accessed April 30, 2025. https://clinicaltrials.gov/study/NCT05616013