Zepbound® and fatigue

The fatigue row in three sets of product information

The US table pools SURMOUNT-1, in adults without diabetes, and SURMOUNT-2, in adults with type 2 diabetes, both 72 weeks long; it lists reactions reported by at least 2% on Zepbound® and more often than on placebo. ^[1] Canada prints the same trials with patient counts and a 1% cut-off. ^[3] In the EU, tirzepatide is authorised as Mounjaro®, whose product information groups fatigue, asthenia, malaise and lethargy under one entry. ^[4]

What the row does and does not tell you

The rate edges up by about one point per maintenance dose, and more than nine in ten people on each dose did not report it. ^[1] The two sleep apnea trials, with 467 adults, appear only as a statement that their reactions resembled the weight trials, so there is no separate fatigue figure for people treated for sleep apnea. ^[1][3]

There is also no timing. The label says most nausea, vomiting and diarrhea came during dose escalation and then decreased, but it makes no such statement about fatigue, gives it no severity grade and no stopping rate of its own. ^[1]

Words matter here. MedlinePlus separates fatigue, a lack of energy and motivation, from drowsiness, the need to sleep. ^[8] The Medication Guide lists both drowsiness and weakness among signs of low blood sugar, ^[2] so noticing which one you feel is a useful first step.

Sleep apnea: the other side of the question

Zepbound® also carries a sleep apnea approval: adults with obesity whose obstructive sleep apnea is moderate or severe. ^[1] In Studies 5 and 6, average Epworth Sleepiness Scale scores at the start were 10.5 and 10, and most participants had severe sleep apnea (63.1% and 68.2%). ^[1] After 52 weeks, remission or mild sleep apnea without symptoms, a definition that includes an Epworth score of 10 or less, was reached by 42.2% and 50.2% on Zepbound® against 15.9% and 14.3% on placebo. ^[1] Both the US and Canadian documents report improvement in sleep-related impairment on a standard questionnaire compared with placebo. ^[1][3]

A post hoc analysis of the same trials, written by Lilly authors with one academic co-author, grouped people by how they felt at the start. In the first study, those who described themselves as fatigued gained more on a vitality score than those who did not (8.5 versus 1.0 points above placebo), and sleepy participants improved more on sleep-related impairment. ^[5] These are average changes in symptom questionnaires over a year, separate from the fatigue side-effect row, and they do not predict how any one person will feel.

Canada adds a practical point: Zepbound® does not replace a positive airway pressure machine for people who need one, and decisions about starting, continuing or changing it belong to your healthcare professional. ^[3]

Routes to tiredness the documents describe

• Fluid loss (label-supported). The label warns that fluid lost through nausea, vomiting and diarrhea can end in dehydration and kidney injury. ^[1] Canada’s patient information lists dark yellow, strong-smelling urine, extreme thirst and feeling dizzy as signs to act on at once, ^[3] and MedlinePlus counts listlessness among signs of severe dehydration. ^[10]
• Low blood sugar (label-supported). In SURMOUNT-2, readings below 54 mg/dL occurred in 4.2% on Zepbound® against 1.3% on placebo, rising to 10.3% with a sulfonylurea; insulin also adds risk. ^[1] Weakness and drowsiness are on the Medication Guide’s list of signs, ^[2] and MedlinePlus lists tiredness or weakness. ^[9]
• Eating too little (label-supported in Canada). The Canadian monograph warns that malnutrition, sometimes severe, has been reported, and its patient table describes weight loss with weakness, feeling faint, fatigue, dry skin, irritability and trouble paying attention. ^[3] In SURMOUNT-1 to -4, adverse events pointing to malnutrition were rare (0.03% to 0.06%), and 0.53% stopped for reasons possibly related to nutrition, mainly reaching a desired weight or feeling they had lost too much. ^[7]
• Proposed but not measured: tirzepatide decreases calorie intake, likely through appetite. ^[1] Lower intake could plausibly lower energy, but no Zepbound® study has charted fatigue against food intake or dose steps.
• A single case: a woman in her early 30s with obesity and no diabetes developed persistent vomiting, upper abdominal pain and fatigue six days after her first tirzepatide injection; tests showed ketoacidosis with mildly low blood sugar, and she recovered within 48 hours after intensive care. ^[6] One case cannot show how often this happens or prove cause, but it shows why fatigue with vomiting that will not stop needs attention.

Causes that have nothing to do with the injection

MedlinePlus notes that fatigue is common and usually not due to a serious disease, but should be checked if enough sleep, good nutrition and a low-stress setting do not relieve it. ^[8] Its list of causes includes iron deficiency with or without anaemia, depression or grief, insomnia, obstructive sleep apnea and narcolepsy, an overactive or underactive thyroid, alcohol or drug use, long-lasting infections including COVID-19, autoimmune conditions, diabetes, heart failure and kidney or liver disease. ^[8]

Several medicines can add to it: sedatives, some antidepressants, antihistamines for allergies, sleeping pills, steroids, water pills and blood pressure medicines. ^[8] Fatigue lasting at least six months that rest does not relieve can point to chronic fatigue syndrome, which is diagnosed only after other causes are ruled out. ^[8]

What the sources suggest

To cut the risk of dehydration, the Zepbound® Medication Guide tells you to keep drinking fluids, and, if you use insulin or a sulfonylurea, to talk about low blood sugar and how to handle it before starting. ^[2] Canada adds that low blood sugar can affect concentration, so avoid driving or using machines when you have its signs. ^[3] MedlinePlus offers general steps for fatigue:

• Sleep enough each night, eat a balanced diet and drink water through the day. ^[8]
• Exercise regularly, try relaxation such as yoga or meditation, and keep a workable schedule. ^[8]
• Ask your provider whether a vitamin might help instead of starting one on your own. ^[8]
• Avoid alcohol and nicotine; MedlinePlus is clear that stimulants, caffeine included, are not a treatment for fatigue and may leave you worse once stopped, and that sedatives usually add to it. ^[8]
• Do not stop or change any medicine without talking to your provider first. ^[8]

Zepbound® and Mounjaro® are registered trademarks of Eli Lilly and Company. PepLabo is not affiliated with or endorsed by Eli Lilly and Company.

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