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Contact your provider if you experience: Severe or persistent insomnia lasting more than 23 weeks despite implementing sleep hygiene measures Sleep disruption accompanied by other concerning symptoms such as chest pain, severe shortness of breath, palpitations, or excessive daytime fatigue affecting daily function Signs suggesting nocturnal hypoglycemia including nighttime sweating, nightmares, or morning headaches (overnight glucose monitoring may be recommended to confirm) Significant mood changes including new or worsening depression, anxiety, irritability, or thoughts of self-harm (particularly important for patients taking Zepbound, which carries a warning about suicidality) Symptoms suggesting sleep apnea such as loud snoring, witnessed breathing pauses, gasping during sleep, or excessive daytime sleepinessthese warrant evaluation even if you are losing weight Thyroid-related symptoms including neck mass, difficulty swallowing, or persistent hoarseness (related to the boxed warning for tirzepatide) Seek urgent medical attention for: Severe abdominal pain that prevents sleep, which could indicate pancreatitis or gallbladder disease Signs of dehydration from persistent vomiting or diarrhea, including decreased urination, dizziness, or confusion Symptoms of severe hypoglycemia, including confusion, inability to wake fully, or loss of consciousness Signs of allergic reaction such as facial/tongue swelling, difficulty breathing, severe rash, or hives Your healthcare provider can assess whether sleep disturbances are related to tirzepatide, require dose adjustment, or reflect an unrelated condition requiring separate treatment

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Acknowledgements This work was supported by project number 2020/39/B/NZ9/01894 from the National Science Centre (NCN), Poland and by the project number WZ/WB-II/2/2023 from the Ministry of Science and Higher Education.The authors are very grateful to Professor Shimshon Belkin, Dr Tal Elad, Dr Liat Moscovici and Dr Sharon Yagur-Kroll, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel for providing bacteria strains