Semaglutide can only be responsible for exercise intolerance and muscle wasting after all other causes have been carefully excluded

To the Editor,

We read with interest the article by Mohamad [1] about a 74-year-old man who had diabetes for 35 years and had undergone radical prostatectomy for non-metastatic prostate cancer 5 years previously. Two years later, he developed persistent fatigue and exercise intolerance, which was attributed to the semaglutide injection that he had been taking for 8 months. A reduction in semaglutide dose was considered responsible for partial recovery after 4 months of rehabilitation [1]. Although this study is noteworthy, several points require further consideration.

First, the diagnosis of myasthenia gravis was insufficiently documented [1]. As the patient exhibited bilateral ptosis and ophthalmoplegia on clinical examination, it is important to clarify whether myasthenia gravis was correctly diagnosed or if the patient’s symptoms had another cause. Therefore, we should know: (1) which myasthenia-associated antibodies were elevated (acetylcholine receptor, muscle-specific kinase, low-density lipoprotein receptor–related protein 4, and titin); (2) whether low-frequency or high-frequency repetitive nerve stimulation showed an abnormal decrement or incremental response; (3) whether single-fiber electromyography showed increased jitter or an increased number of blocks; and (4) whether Simpson test and Tensilon test were abnormal [2]. The most common differential diagnosis of ptosis and ophthalmoplegia is chronic progressive external ophthalmoplegia, a mitochondrial disease caused by point mutations in mitochondrial DNA (mtDNA) or nuclear DNA that secondarily cause single or multiple mtDNA deletions or mtDNA depletion [3]. Normal needle electromyography findings do not exclude mitochondrial myopathy. Furthermore, whether serum lactate levels were elevated at rest or during mild exercise remained unclear. Given the disease of the extraocular muscles, it is unclear why the patient did not receive treatment for myasthenia gravis, if this was considered the underlying cause.

Second, neuropathy has not been adequately ruled out as a cause of symptoms [1]. As the patient had diabetes for 35 years and had a hemoglobin A1c level of 8.4, it is probable that he developed diabetic neuropathy over time. Diabetic neuropathy can explain symptoms including, imbalance, instability, dizziness, and muscle wasting without muscle weakness [4].

A paraneoplastic syndrome (PNS) was not adequately ruled out as a cause of muscle wasting and fatigue. As the patient had a history of malignancy, it was important to rule out PNS manifesting in the central or peripheral nervous system. Since PNS-associated antibodies are elevated in nearly 50% of the patients, it is important to determine these antibodies in the serum or cerebrospinal fluid.

Furthermore, semaglutide is probably not the cause of muscle wasting or exercise intolerance. A strong reason against semaglutide as a cause of muscle wasting and exercise intolerance is that the symptoms began 2 years ago; however, semaglutide was only administered for 8 months. Furthermore, the patient also underwent 4 months of intensive rehabilitation; therefore, the increase in muscle strength and mass could be solely due to this systematic training and not related to the reduction in semaglutide injections.

In summary, patients with fatigue, exercise intolerance, and muscle wasting require a comprehensive and detailed examination to uncover their underlying causes. Drugs such as semaglutide should not be attributed to these symptoms until all possible causes have been carefully excluded.