Does Semaglutide Make You Tired?

Fatigue as a Reported Side Effect of Semaglutide

The most frequently reported adverse effects of semaglutide in clinical trials are gastrointestinal, particularly nausea, vomiting, and diarrhea. Fatigue has not consistently ranked among the most common events in large phase 3 studies such as the SUSTAIN and STEP programs, yet it has been reported in both clinical research and post-marketing surveillance.

Case-based evidence suggests that fatigue can occur in specific circumstances. For example, muscle loss due to reduced caloric intake during treatment has been linked with decreased physical endurance and tiredness. In other cases, semaglutide-related thyroid or liver dysfunction has contributed to fatigue symptoms. Although these represent relatively rare outcomes, they illustrate potential pathways by which semaglutide may contribute to tiredness in some patients.

Biological Mechanisms That May Explain Fatigue

• Caloric Restriction and Muscle Mass Loss: Semaglutide promotes weight loss primarily by suppressing appetite, often leading to significant caloric restriction. While beneficial for obesity management, rapid reductions in calorie intake can also reduce lean muscle mass, particularly in older adults. Loss of muscle tissue contributes to weakness and diminished energy levels, which patients may perceive as fatigue.
• Endocrine Pathways: Rare reports describe semaglutide-induced alterations in thyroid hormone activity, including cases of subclinical hypothyroidism. Thyroid hormone imbalance is a well-established cause of fatigue, cognitive slowing, and reduced physical performance.
• Hepatic Effects: Although uncommon, drug-induced liver injury has been reported with semaglutide. The liver is essential to energy metabolism, and hepatic dysfunction can produce symptoms such as malaise, weakness, and persistent tiredness.
• Neurological and Psychiatric Pathways: Emerging evidence links semaglutide with mood-related side effects in isolated cases, including depression. Fatigue is a core symptom of depressive disorders and may therefore manifest as part of these psychiatric effects.

How Common Is Fatigue in Clinical Trials?

Large randomized controlled trials such as the STEP obesity program and the SUSTAIN diabetes program provide the strongest evidence for semaglutide’s safety profile. Across these studies, fatigue was reported but occurred at relatively low frequencies compared with gastrointestinal complaints. Importantly, when fatigue was observed, it was generally mild to moderate and tended to improve with continued therapy or dose adjustment.

In observational studies and pharmacovigilance data, fatigue appears more frequently than in controlled trials. This discrepancy may reflect differences in population monitoring, as real-world patients often have comorbidities such as thyroid dysfunction, depression, or chronic liver disease that increase susceptibility to fatigue.

Patients at Greater Risk

• Older adults, who may lose muscle mass more quickly when caloric intake decreases.
• Patients with pre-existing thyroid disease, who may be more vulnerable to subtle changes in hormone regulation.
• Individuals with hepatic or renal impairment, who are more susceptible to metabolic fatigue.
• Patients with psychiatric comorbidities, where fatigue may overlap with mood disturbances.

These groups warrant closer monitoring during treatment.

Clinical Guidance

For most patients, semaglutide is not associated with severe or persistent fatigue. When tiredness does occur, it is often mild and may be addressed by supportive strategies such as resistance exercise to maintain muscle mass, monitoring thyroid and liver function, and adjusting caloric intake to ensure adequate nutrition. Clinicians should also screen for depression in patients reporting persistent fatigue.

Discontinuation of semaglutide is rarely necessary, but may be appropriate if fatigue is severe, persistent, and clearly linked to therapy.