Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series

Abstract

GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide) are effective for reducing body weight and fat mass, though lean soft tissue loss comprised 26%–40% of weight loss in recent trials. This case series describes three patients (two female, one male; body mass index: 32.9–51.9 kg m⁻²) who prioritized lean soft tissue preservation strategies during treatment with semaglutide or tirzepatide. Patients engaged in intentional exercise or structured physical activity 4–7 days·week⁻¹, including resistance training 3–5 days·week⁻¹. Typical protein intakes were 0.7–1.7 g·kg⁻¹·day⁻¹ relative to body mass and 1.6–2.3 g·kg⁻¹·day⁻¹ relative to fat-free mass. Changes in weight, fat mass, and lean soft tissue were: −33.0%, −53.4%, and −6.9% (case 1); −26.8%, −61.6%, and +2.5% (case 2); and −13.2%, −46.9%, and +5.8% (case 3). Accordingly, one patient lost 8.7% of weight as lean soft tissue, while two increased lean soft tissue. These findings highlight the potential for some individuals to preserve or even increase lean soft tissue during treatment with semaglutide or tirzepatide alongside supportive lifestyle strategies.

Introduction

Since the U.S. FDA approval of semaglutide (2021) and tirzepatide (2023) for chronic weight management, the use of incretin-based therapies for obesity treatment has accelerated rapidly. A 2024 poll indicated that ~12% of U.S. adults have used incretin-based drugs for weight loss, including ~6% who were currently being treated. ¹ The increased use of these therapies reflects their notable efficacy in clinical trials. In the STEP 1 trial, 2.4 mg·week⁻¹ of the glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide resulted in 15% mean weight loss over 68 weeks. ² Subsequently, 5–15 mg·week⁻¹ of tirzepatide—a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist (GLP-1/GIP RA)—led to mean weight loss of 15%–21% in 72 weeks in the SURMOUNT-1 trial. ³ While this degree of weight loss is meaningful, ⁴ much recent discussion has centered on the composition of weight loss, particularly the potential for disproportionate loss of various “lean” components, such as fat-free mass (FFM), lean soft tissue (LST), and skeletal muscle mass.^5–8 Both STEP 1 and SURMOUNT-1 trials included dual-energy X-ray absorptiometry (DXA) body composition assessments in a subset of participants.^2,9 DXA, as a molecular-level assessment, provides estimates of LST (i.e., total mass minus fat mass (FM) and bone mineral mass) or FFM (total mass minus FM); in contrast, organ/tissue-level techniques like magnetic resonance imaging and computed tomography are required to provide direct estimates of skeletal muscle mass.^7,10

In the STEP 1 trial, 95 participants treated with semaglutide in the DXA subset lost 6.9 kg (~13%) LST alongside 10.4 kg (~25%) FM, ² corresponding to ~40% of weight loss as LST. In the SURMOUNT-1 trial, 124 participants treated with tirzepatide in the DXA subset lost 5.6 kg (~11%) LST in comparison with 15.9 kg (~34%) FM, ⁹ corresponding to ~26% of weight loss as LST. While numerous factors influence the proportion of LST lost, 25% of weight loss as LST or FFM is often used as a general benchmark to evaluate if lean loss is relatively low or high, although this generalization has been critiqued. ¹¹ Among other factors, exercise and targeted nutritional intakes have been proposed to influence body composition outcomes during treatment with incretin-based medications, although these practices have been minimally examined in this context.^7,12,13 While controlled trials are needed to evaluate the extent to which targeted lifestyle changes can enhance body composition changes in patients being treated with modern obesity drugs, examining cases of free-living patients may also help inform the potential of such practices and illustrate individual changes that may be observed with lifestyle practices differing from those implemented in clinical trials to date. Accordingly, the purpose of this case series is to present detailed information concerning the DXA body composition changes observed in individuals who have implemented common best practices for maintenance of LST and skeletal muscle mass, such as structured resistance training and an emphasis on dietary protein intake.

Cases

Patients of a virtual health clinic who had DXA body composition results spanning their obesity medication treatment with semaglutide or tirzepatide injections, along with records of nutrition and exercise habits during the same time period, were eligible for inclusion in the present case series. This study was reviewed and approved by the Texas Tech University Institutional Review Board (IRB2025-79; date of approval: March 4, 2025). All participants provided written informed consent to be included in the case series and HIPAA authorization. Each patient had DXA testing performed at local fee-for-service DXA centers, with all assessments conducted at the same center for each patient. At each facility, scans were performed using a General Electric (GE) DXA scanner. DXA reports were obtained from each patient, and relevant body composition variables were recorded for analysis, including body mass (BM), body mass index (BMI), LST, FM, and body fat percentage (BF%). Each patient also provided results of relevant laboratory testing and completed three standardized online questionnaires to obtain information about nutrition, dietary supplementation, and exercise practices during their obesity treatment. In addition to two custom-written questionnaires, the Muscle-Strengthening Exercise Questionnaire (MSEQ) ¹⁴ was used to collect more detailed information about participation in various resistance exercise modalities. The MSEQ-Long was administered, which consists of 20 items related to muscle-strengthening exercise participation and the use of weight machines, bodyweight exercises, resistance exercises, and holistic exercises. The MSEQ has been shown to exhibit high test-retest reliability for its primary content and moderate-to-high concurrent validity. ¹⁴ This case series was prepared using the CARE case report guidelines.

Case 1

Case 1 was a 42-year-old female with obesity who reported a multiracial/multiethnic background, specifically identification as Black, Latinx, and White. The patient had no maternal family history of obesity or cardiometabolic disease, and the paternal family history was unavailable. Approximately 5 years prior to the baseline DXA scan, the patient underwent a partial hysterectomy. Hormone replacement therapy was initiated approximately 1.5 years after the baseline DXA scan upon perimenopause diagnosis. The patient had a baseline BM of 141.4 kg, BMI of 51.9 kg m⁻², BF% of 56.4%, and LST of 58.5 kg. Treatment with tirzepatide was initiated at 2.5 mg·week⁻¹ for 12 weeks, with the baseline DXA scan completed <2 weeks after the start of medication. Thereafter, the patient was treated with 5.0 mg·week⁻¹ tirzepatide for 12 weeks, 7.5 mg·week⁻¹ for 8 weeks, 10 mg·week⁻¹ for 8 weeks, 12.5 mg·week⁻¹ for 31 weeks, and 15.0 mg·week⁻¹ for 17 weeks. The patient then transitioned to a maintenance period in which the dose of tirzepatide was progressively decreased to 5.0 mg·week⁻¹ before increasing back to 12.5 mg·week⁻¹ for 17 weeks prior to the final DXA assessment.

During treatment, the patient reported not following a specific nutrition program but attempting to emphasize protein and fiber intake, without prohibiting specific food items. The patient reported a typical energy intake of 1600–1800 kcal·day⁻¹ (range 1200–2200 kcal·day⁻¹), protein intake of 100–120 g·day⁻¹ (range: 80–140 g·day⁻¹), carbohydrate intake of 150–160 g·day⁻¹ (range: 75–200 g·day⁻¹), and fat intake of 55–65 g·day⁻¹ (range: 45–75 g·day⁻¹). The patient’s typical protein intake relative to BM was 0.7–1.3 g·kg−1·day⁻¹, and the typical intake relative to FFM was 1.6–2.1 g·kg−1·day⁻¹. The typical eating duration (i.e., duration from first to last energy consumption) was 12.0–13.5 h·day⁻¹, with an eating frequency of four intake events per day (three meals and one snack). Daily dietary supplementation included creatine monohydrate, a prenatal multivitamin/mineral, and a fiber supplement. Whey protein and magnesium citrate supplements were used as needed.

The patient’s self-reported vocational physical activity was very light (defined as easy activity that does not noticeably increase breathing) and primarily consisted of sitting or standing desk work. During treatment, the patient reported performing intentional exercise or structured physical activity 5–6 days·week⁻¹, including walking, biking, jogging or running, and resistance training. The patient reported consistently walking throughout treatment, which then progressed to hiking, jogging, and trail races, with numerous 5000–10,000-km trail races completed. In addition, resistance training was completed throughout treatment, first as powerlifting-style training and later as kettlebell training. MSEQ responses indicated that the patient performed bodyweight exercises 3 days·week⁻¹, 30–45 min·session⁻¹, and at a subjective intensity rating of 7/10; and resistance exercise with free weights or bands 3 days·week⁻¹, 30–45 min·session⁻¹, and at an intensity rating of 7/10. These exercises targeted all major muscle groups (legs, hips, back, abdomen, chest, shoulders, and arms).

During the 115 weeks of treatment between the baseline DXA assessment and the last available scan, BM decreased by 33.0% to 94.7 kg, BMI to 34.7 kg m⁻², and BF% to 39.2%. FM decreased 53.4% to 37.1 kg, LST decreased 6.9% to 54.5 kg, and BMC decreased by 2.9% (Figure 1). Overall, 91.2% of weight loss was attributed to FM loss, 8.7% to LST loss, and 0.2% to BMC loss. During the treatment period, the patient’s total cholesterol decreased from 209 to 181 mg dL⁻¹, HDL cholesterol increased from 32 to 49 mg dL⁻¹, LDL cholesterol decreased from 154 to 123 mg dL⁻¹, and hemoglobin A1C decreased from 5.5% to 4.9%.

Figure 1.

Trajectory of body composition changes during treatment. Changes in body mass, fat mass, and lean soft tissue mass quantified by DXA are displayed for three patients. Each point indicates results from an individual DXA scan, and the weeks correspond to the duration since the baseline DXA assessment, which occurred near the beginning of treatment with semaglutide or tirzepatide.

DXA: dual-energy X-ray absorptiometry.

Case 2

Case 2 was a 42-year-old Caucasian premenopausal female with obesity (baseline BM of 96.2 kg, BMI of 42.8 kg m⁻², BF% of 45.4%, and LST of 49.4 kg). The patient reported a family history of obesity, with both parents exhibiting obesity in their early-to-mid 20’s with BM > ~150 kg, as well as suspected or confirmed hypertension, dyslipidemia, and prediabetes or type 2 diabetes in both parents. Treatment with 0.25 mg·week⁻¹ semaglutide for 4 weeks was initiated, during which the baseline DXA scan was performed. Thereafter, the patient was treated with 0.5 mg·week⁻¹ semaglutide for 8 weeks, 1.0 mg·week⁻¹ for 4 weeks, 1.7 mg·week⁻¹ for 8 weeks, and 2.4 mg·week⁻¹ for 18 weeks leading up to the final DXA assessment.

During treatment, the patient reported following an intuitive eating program with an emphasis on dietary protein (goal intake of 1.2–1.6 g·kg⁻¹·day⁻¹), fiber, and water consumption. The patient reported typically consuming 120 g·day⁻¹ protein (range 100–150 g·day⁻¹), without specific energy, carbohydrate, or fat intakes specified. The patient’s typical protein intake relative to BM was 1.2–1.7 g·kg−1·day⁻¹, and the typical intake relative to FFM was 2.2–2.3 g·kg−1·day⁻¹. The typical eating duration was 12.5 h·day⁻¹, with an eating frequency of four intake events per day. Daily dietary supplement consumption included 10 g·day⁻¹ fiber supplementation and 330 mg·day⁻¹ magnesium citrate, with an iron (65 mg) plus vitamin C (125 mg) supplement consumed 4 days week⁻¹ and a multivitamin/mineral consumed on the 3 days week⁻¹ without iron pus vitamin C supplementation.

The patient’s self-reported vocational physical activity was very light and primarily consisted of sitting, with typical step counts of 3000 steps·day⁻¹ in the absence of intentional exercise. During treatment, the patient reported performing intentional exercise or structured physical activity 7 days·week⁻¹. Activities included walking, biking, jogging or running, and cross-training. The patient reported a goal of reaching 10,000–12,000 steps·day⁻¹, along with ⩾145 min·week⁻¹ of cycling classes and participation in a high-intensity functional training class 5 days·week⁻¹. MSEQ responses indicated that the patient performed bodyweight exercises 5 days·week⁻¹, 15 min·session⁻¹, and at an intensity rating of 7/10; and resistance exercise with free weights or bands 5 days·week⁻¹, 15 min·session⁻¹, and at an intensity rating of 8/10. These exercises targeted all major muscle groups (legs, hips, back, abdomen, chest, shoulders, and arms).

During the 39 weeks of treatment between the baseline and final DXA assessments, BM decreased 26.8% to 70.5 kg, BMI to 31.4 kg m⁻², and BF% to 23.8%. FM loss (−26.9 kg; 61.6%) exceeded weight loss (−25.8 kg) due to a concomitant increase in LST (+1.2 kg; 2.5%; Figure 1). BMC decreased by 0.1 kg (2.9%). DXA scan images from the four total assessments are displayed in Figure 2. Over a similar time period, the patient’s total cholesterol decreased from 193 to 162 mg dL⁻¹, HDL cholesterol increased from 63 to 68 mg dL⁻¹, and LDL cholesterol decreased from 116 to 81 mg dL⁻¹. Fasted blood glucose decreased from 97 to 81 mg dL⁻¹, with hemoglobin A1C remaining consistent at 4.8%–4.9%. Blood pressure decreased from 124/72 to 110/70 mmHg.

Figure 2.

DXA scan images. Images from DXA scans are displayed for case #2 at baseline (W0) and 10, 24, and 39 weeks later (W10, W24, and W39, respectively).

DXA: dual-energy X-ray absorptiometry.

Case 3

Case 3 was a 52-year-old Caucasian male with obesity (baseline body mass of 106.9 kg, BMI of 32.9 kg m⁻², BF% of 35.2%, and LST of 65.4 kg). The patient had a history of hyperlipidemia and was being treated with 10 mg of atorvastatin. The patient had a paternal history of obesity and type 2 diabetes but no family history of cardiovascular disease. The patient’s baseline DXA scan was performed <2 months prior to the start of medication use. The patient began treatment with semaglutide injections titrated to a dose of 2.4 mg·week⁻¹ over 12 weeks. Approximately 30 weeks after beginning treatment with semaglutide, the patient’s medication was changed to tirzepatide due to side effects (nausea and fatigue). Tirzepatide was titrated to a dose of 15 mg·week⁻¹ over 17 weeks and continued at 12.5–15 mg·week⁻¹ thereafter.

During treatment, the patient reported following a diet emphasizing lean animal proteins (primarily chicken and fish), fresh vegetables and fruits, and non-fat or low-fat dairy, with some intake of nuts and whole grains. The patient reported a typical energy intake of 2400 kcal·day⁻¹ (range 1200–3400 kg·day⁻¹), protein intake of 130 g·day⁻¹ (range: 50–180 g·day⁻¹), carbohydrate intake of 200 g·day⁻¹ (range: 100–300 g·day⁻¹), and fat intake of 40 g·day⁻¹ (range: 25–80 g·day⁻¹). The patient’s typical protein intake relative to BM was 1.2–1.4 g·kg−1·day⁻¹, and the typical intake relative to FFM was 1.8 g·kg−1·day⁻¹. The typical eating duration was 12.0 h·day⁻¹, with an eating frequency of 4–6 intake events per day. Daily dietary supplementation included creatine (5 g·day⁻¹), a multivitamin/mineral, and an omega-3 supplement.

The patient’s self-reported vocational physical activity was very light. The patient reported engaging in intentional exercise or structured physical activity 4–6 days·week⁻¹ during treatment, including participation in walking, biking, jogging or running, resistance training, sports, and cross-training. The participant reported a weekly goal of exercising 5–6 days·week⁻¹, with actual participation frequently being reduced to 3 days·week⁻¹ due to travel and work commitments. The patient reported running 5–7 miles·week⁻¹, across 2–3 sessions, and hiking or rucking once per week. In addition, the patient performed resistance training ~3 days·week⁻¹, which primarily consisted of basic powerlifting techniques. When traveling, the patient reported substituting other forms of exercise, such as high-intensity interval training classes. MSEQ responses indicated that the patient performed exercises using weight machines 3 days·week⁻¹, 45 min·session⁻¹, and at a subjective intensity rating of 7/10. These exercises primarily targeted the back and shoulders. The patient also reported participation in bodyweight exercises 2 days·week⁻¹, 5–10 min·session⁻¹, and at an intensity rating of 5/10, primarily employed as a warmup or as the final portion of a resistance exercise session. These bodyweight exercises targeted the legs, chest, and shoulders. The patient further reported performing resistance exercise with free weights or bands 3 days·week⁻¹, 45 min·session⁻¹, and at an intensity rating of 7/10. These exercises targeted the legs, back, chest, shoulders, and arms.

During the 139 weeks of treatment between the baseline and final DXA assessments, BM decreased by 13.2% to 92.8 kg, BMI to 28.5 kg m⁻², and BF% to 21.5%. FM loss (−17.6 kg; −46.9%) exceeded total weight loss (−14.1 kg) due to a simultaneous increase in LST (+3.8 kg; 5.8%; Figure 3). BMC decreased by 0.2 kg (4.8%). Over similar time intervals, the patient’s hemoglobin A1C decreased from 5.3% to 4.9%, fasting blood glucose decreased from 98 to 83 mg dL⁻¹, and LDL cholesterol decreased from 62 to 30 mg dL⁻¹. Blood pressure remained stable at 121/76 to 118/70 mmHg.

Figure 3.

Absolute and relative changes in body composition. Changes in BM, FM, and LST are displayed in absolute quantities (top row) and percent changes (bottom row). Changes were calculated from the first and last available dual-energy X-ray absorptiometry scans.

BM: body mass; FM: fat mass; LST: lean soft tissue.

Discussion

Body composition substudies of incretin-based therapies for weight management have indicated that, on average, approximately 26%–40% of weight loss is due to loss of LST when evaluated by DXA.^2,9 This has been observed in the context of 15%–21% weight loss over 68–72 weeks in the parent studies.^2,3 A recent network meta-analysis also reported that approximately 25% of weight loss was due to lean loss during treatment with various GLP-1RA and GLP-1/GIP RA drugs. ¹⁵ In the present case series, one patient lost 8.7% of weight as LST during treatment, while the other two patients increased LST by 2.5%–5.8% above baseline. Although one of the patients who increased LST lost a relatively smaller amount of weight (13.2% over 139 weeks), the other two patients achieved 33.0% weight loss over 115 weeks and 26.8% weight loss over 39 weeks, indicating favorable LST results despite substantial weight loss with incretin-based therapies.

While future randomized controlled trials are needed to establish causation, the differences in lifestyle practices between the three patients included in the present case series and the participants in previous pharmaceutical trials are worth examining. In the STEP 1 trial, participants completed individualized counseling sessions to promote a 500 kcal·day⁻¹ energy deficit and completion of ⩾150 min·week⁻¹ physical activity. ² Similarly, in the SURMOUNT-1 study, participants received individualized lifestyle counseling with goals of achieving a 500 kcal·day⁻¹ energy deficit and increasing physical activity to ⩾150 min·week⁻¹ physical activity; however, it was explicitly noted that no specific strength training protocol was included.^3,9 All three patients in the present study reported participating in intentional exercise or structured physical activity 4–7 days·week⁻¹, including resistance training performed 3–5 days·week⁻¹. Exercise training of various types has been shown to reduce FFM loss during energy restriction. ¹⁶ Magnetic resonance imaging studies have also demonstrated the ability of both endurance and resistance exercise to preserve skeletal muscle tissue in adult females with obesity undergoing weight loss with energy deficits of approximately 1000 kcal·day⁻¹.^17,18 However, a study directly comparing different modalities of exercise found that exercise programs including resistance training may be particularly effective at reducing the loss of thigh skeletal muscle volume during weight loss. ¹⁹ Collectively, these studies support the implementation of structured exercise programs with resistance training components observed in all patients in the present report, although none of the aforementioned investigations included treatment with incretin-based therapies. In that regard, Lundgren et al. ²⁰ demonstrated that the addition of an exercise program to liraglutide treatment preserved FFM and potentiated FM loss following an initial low-calorie diet period, eliciting weight loss. In this trial, the exercise program was designated as “structured but flexible” and included recommendations to attend two weekly group sessions focused on interval-based cycling and circuit training and to perform two weekly individual sessions—primarily implemented as cycling, running, or brisk walking. A follow-up study also concluded that participation in the exercise program led to better maintenance of body weight and composition 1 year after the end of treatment. ²¹ While these studies demonstrate the potential of heterogeneous exercise participation to improve body composition changes during treatment, as well as maintenance of body weight and composition, trials comparing exercise programs in a more controlled manner may demonstrate the degree to which varying modalities and “doses” of exercise enhance outcomes during weight loss treatment with incretin-based therapies. As resistance training is considered the most potent nonpharmacological stimulus for attenuating muscle loss and inducing skeletal muscle growth, it may be worthy of particular focus in these trials.^7,22

In the present case series, all three patients reported an emphasis on dietary protein intake. Intakes relative to BM ranged from 0.7–1.7 g·kg⁻¹·day⁻¹ based on reported typical protein intakes and the range of body masses during treatment; due to the notable weight loss, estimated relative protein intakes were higher as treatment progressed. When expressed relative to FFM (i.e., LST plus bone mineral content), as has been recommended in the context of obesity, ²³ typical relative protein intakes were 1.6–2.3 g·kg−1·day⁻¹. While the recommended dietary allowance (RDA) for protein is 0.8 g·kg⁻¹·day⁻¹, expressed relative to BM, many have contended that higher protein intakes are warranted during weight management, with preservation of FFM and skeletal muscle being a commonly cited reason for this recommendation.^24–27 However, there are limitations to considering protein intakes relative to BM in the context of obesity and substantial weight loss, and expressing intakes relative to FFM may be preferable in this context. ²³ Future controlled trials should investigate the extent to which tailored dietary interventions, such as meeting specified protein intake targets or incorporating dietary supplementation, can influence body composition and health changes during weight management using GLP-1RA and GLP-1/GIP RA therapies.

Some limitations of the present work should be noted. First and foremost, this case series represents simple observation in a very small number of patients without a control group for comparison. The present study relied on self-reports for nutritional intake and physical activity information. As such, recall bias, social expectation bias, and related errors are possible. Additionally, while DXA scans were reviewed for validity by the investigators, scans were conducted at different fee-for-service facilities for each participant. However, within each participant, scans were performed at the same facility. While the detailed examples may be informative in clinical practice and for the design of future controlled trials, they are not generalizable to all patients.

Conclusion

The present case series demonstrates the potential for minimal LST loss, or even increases in LST, during treatment with semaglutide and tirzepatide. While future controlled trials are needed, it is hypothesized that consistent exercise participation and inclusion of resistance training may have contributed to the favorable body composition changes observed in the evaluated patients. In addition, dietary choices, such as an emphasis on adequate protein intake, may have supported adaptations elicited by the exercise program. The presented cases may be informative for clinicians seeking favorable body composition outcomes in patients being treated with GLP-1RA and GLP-1/GIP RA therapies, as well as for clinical researchers designing trials to examine the influence of targeted lifestyle interventions in conjunction with pharmacotherapy for chronic weight management.