Semaglutide is an emerging pharmacological treatment for type 2 diabetic and weight loss. Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that improves the efficiency of incretin function by activating GLP-1 receptors; improving glucose metabolism; inducing weight loss; appetite and hunger suppression; decreasing energy intake; and controlling eating habits. However, there is limited evidence regarding the incidence of sarcopenia after semaglutide treatment. Sarcopenia is defined as the “age-related loss of muscle mass, low muscle strength, and/or low physical performance” [1]. Here, we report a case of fatigue secondary to sarcopenia caused by semaglutide treatment.

A 74-year-old Indian male patient with a 35-year history of diabetes mellitus and dyslipidemia presented to the Sports Medicine Clinic for evaluation of persistent fatigue since late 2022. Prior endocrine, neurological, and urological assessments were inconclusive, prompting referral for further investigation. He experienced noticeable fatigue for 2 years, which progressively worsened. He noticed that he could not replicate his physical regimen, having previously been capable of walking approximately 4 km for 60–90 minutes without requiring breaks or experiencing exhaustion. He experienced weariness after 1–2 km, necessitating a respite of 10–20 minutes before he could continue and complete a 4-km walk. He also observed that his walking speed diminished and that he experienced an imbalance. However, there were no records of falls resulting from instability. Throughout the exercise program, the patient refused any symptoms of hypoglycemia. He also refused to report any discomfort in the joints or muscles. This fatigue troubled him, as he was unable to engage in activities he cherished, as he did before. While performing household tasks, he was able to execute duties without experiencing fatigue. These symptoms did not exhibit diurnal fluctuations. He fell asleep at approximately 10 PM nightly, remained undisturbed throughout the night, and arose at approximately 6 AM, without early morning fatigue or feeling unrefreshed.

He was classified as New York Heart Association classification class I and denied any history of dyspnea, palpitations, dizziness, presyncope, ankle edema, orthopnea, or paroxysmal nocturnal dyspnea. There was no cold intolerance, constipation, or leg edema indicative of hypothyroidism. He exhibited no joint discomfort, joint swelling, joint deformity, rashes, mouth ulcers, or baldness indicative of systemic inflammation. He did not exhibit coffee ground vomiting, hematochezia, melena, or recent hemorrhage from the orifice. He was diagnosed with ocular myasthenia gravis, managed by a neurology and ophthalmology department, established in 2017 prior to the onset of fatigue. He was not initiated on medicine, steroids were not used, and he was issued with special medical glasses. He was on regular neurology team follow-up, his condition was stable, and a recent electromyogram did not indicate exacerbation of generalized myasthenia gravis, while a computed tomography scan of the chest revealed no sign of thymoma. He was investigated for cerebrovascular accidents; however, magnetic resonance brain showed no evidence of infarction or bleeding. The patient was screened for geriatric depression and was found to have a low risk of geriatric depression. He was diagnosed with localized prostate cancer in 2019 and underwent radical prostatectomy without postoperative chemotherapy or hormonal therapy. Recent surveillance using positron emission tomography revealed no distant metastasis. Further details revealed that he had a noticeable weight loss of 8 kg in the past 8 months after starting semaglutide. He was diagnosed with diabetes for 35 years, initially prescribed metformin 1 g twice a day, and a recent increase in his hemoglobin A1C (HbA1c) to 8.4, led to an upgrade treatment with injectable semaglutide 1 mg weekly for 6 months. This was due to the recent increase in body mass index (BMI), which the endocrinologist believed was the reason for the increase in his HbA1c, despite maintaining his physical activity. Thus, semaglutide was selected by an endocrinologist to manage the patient’s diabetes and reduce weight. However, it was switched to oral semaglutide (7 mg) because of severe fatigue and continued until first visit to the Sports Clinic in early 2024.

Clinical examination revealed a thin, built man with a height of 170 cm, weight of 60 kg, and BMI of 20.8 kg/m². He had a small muscle bulk of the upper and lower limbs, with normal tone, normal power, normal reflexes, and normal sensation of the upper and lower limbs. He had bilateral ptosis, ophthalmoplegia, and fatigue of the eyelids, but no fatigue in his voice or upper limbs. Cerebellar examination results were normal. Cardiovascular examination revealed the absence of pallor, blood pressure of 130/86 mm Hg, heart rate of 72 beats/min with a regular rhythm, and no signs of heart failure. He did not have hepatosplenomegaly or lymphadenopathy. He had a normal tracheal position and vesicular breathing sounds. His appendicular muscle mass was 6.78 kg/ m² (normal value, >7 kg/m²), with maximum hand grip strength of 20 kg over his right hand using JAMAR (normal value, >28 kg; Performance Health). His physical fitness assessments showed slow gaits (6 m walk test of 8 seconds) and reduced muscle endurance (5 times sit to stand of 14 seconds), and the 6-minute walk test was 530 m with a recovery heart rate at 1 minute of 102 beats per minute. According to the Asian Working Group for Sarcopenia (ASWG), sarcopenia is diagnosed in men when the appendicular muscle mass is <7 kg/m² and muscle strength using hand grip strength is <28 kg, or when muscle performance is reduced in either the gait speed test, 5 times sit to stand, or short physical battery performance [1]. With low appendicular muscle mass, muscle strength, and physical performance, these findings are consistent with severe sarcopenia based on the ASWG consensus [1].

Supplement 1 shows the extensive blood investigations performed to rule out the cause of fatigue. Figure 1 shows the pre-and post-intervention results of the body impedance analysis. Echocardiography revealed an ejection fraction of 62%, with mild diastolic dysfunction. We performed cardiopulmonary exercise testing to rule out respiratory and cardiovascular causes of fatigue. Figure 2 shows the cardiopulmonary exercise testing analysis, which revealed a low VO2 peak with a normal anaerobic threshold.

After ruling out all causes of fatigue, we postulated that the fatigue was caused by sarcopenia secondary to weight loss, most likely induced by semaglutide. His semaglutide dose was reduced to 3 mg while maintaining the metformin dose, as his diabetic control was good and his HbA1c is 6.1. We tailored exercise prescriptions to improve muscle mass and strength. Table 1 shows the tailored exercise prescriptions. After 4 months of rehabilitation, his appendicular muscle mass improved to 8.75 kg/m², with improved hand grip strength of 26 kg and improved walking speed (5 seconds in 6 meters).

The patient provided written informed consent for the publication of research details and clinical images.

Semaglutide is an effective antidiabetic drug associated with significant weight loss. However, evidence regarding the incidence of sarcopenia after semaglutide use is limited. Diabetes with sarcopenia, an increased risk of mortality, and the preservation of skeletal muscle mass protect patients with type 2 diabetes mellitus from an increased mortality risk [2]. Park et al. [3] found that older adults with type 2 diabetes have reduced muscle quality and strength by up to 30%. Improved glycemic control, reduced cardiovascular risk factors, and complications from diabetes.

GLP‐1 analogs, which involve glucoregulatory actions, help with weight loss by reducing energy, suppressing appetite, and promoting early satiety [4]. A network meta-analysis of randomized controlled trials found that semaglutide, dapagliflozin, and canagliflozin had significant weight loss effects, with pronounced muscle loss due to a decrease in fat-free mass [5]. It has been postulated that a reduction in energy intake leads to a loss of fat mass and fat-free mass. Therefore, it is important to highlight the complications of sarcopenia following semaglutide treatment.

To prevent sarcopenia, it is not advisable to discontinue antidiabetic medication because it could lead to dysglycemia and poorly controlled diabetes. Instead, we recommend nutritional and exercise interventions after initiating semaglutide treatment to prevent or treat semaglutide-induced sarcopenia. Adequate amounts of protein can help prevent sarcopenia. The recommended dietary allowance (RDA) of protein for healthy population is 0.8 g/kg/d, but to prevent sarcopenia, RDA of protein increase to 1.14 g/kg/d [6]. Additional supplements, such as vitamin D (800 IU/d), calcium (1,000 mg/d), and the essential amino acid leucine, help improve muscle function and prevent sarcopenia [7]. Physical activity is the most effective preventive strategy. In cooperation with aerobics, resistance, and proprioceptive training is an integral part of the prescription to prevent sarcopenia. Lowload aerobic exercises such as walking, brisk walking, static cycling with resistance, and swimming can improve cardiovascular fitness and prevent sarcopenia. However, careful attention should be paid to the risk of hypoglycemia and complications of diabetes such as cardiovascular diseases. Pre-participation health screening is recommended for this population. Low-intensity exercise was started and progressed gradually in terms of intensity and duration, aiming for a minimum of 150 min/wk of moderate-intensity exercise. Resistance training consists of two components: muscle strength and endurance. Muscle strength is the ability of a muscle or muscle group to exert force, whereas muscle endurance is the ability of a muscle to produce repetitive forces. In the initial prescription phase, the aim is to train the major muscles (shoulder, chest, gluteal, quadriceps, and core) to improve muscle endurance. For muscle endurance training, we recommend using low loads (<50% of 1-repetition maximum [1RM]) with high repetitions (15‒25 repetitions). We focused on functional training such as sit-to-stand, wall push-ups, shoulder presses, lunges, and step exercises. After improving the muscle endurance, we increased the number of training challenges by focusing on muscle strength exercises. For muscle strength, we used high loads (60%‒80% 1RM), low repetition (8‒12 repetitions), and controlled motion. It is important that exercise prescriptions are tailored to individual basics and have a low risk of injury. Proprioceptive training, such as tandem balance, single-leg balance, yoga, and tai chi, helps neuromuscular training.

Semaglutide induces sarcopenia. Thus, prevention strategies, including nutritional intervention and safe exercise prescriptions, should be emphasized in patients with type 2 diabetes who have started on semaglutide.

Supplementary materials can be found via https://doi.org/10.4082/kjfm.25.0008.

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