The dose makes the medicine—and for many critical prescription medications, the dose is dependent on the patient’s body weight. Usually, this isn’t a problem; weight changes large enough to significantly affect dosage often occur gradually, over periods long enough for doctors to notice and adjust prescriptions. But in the age of new weight-loss drugs, that may no longer be the case.
In a cautionary tale published Monday in JAMA Internal Medicine, researchers from the University of Colorado reported the case of a man who lost nearly 30 percent of his body weight over a six-month period using a new weight-loss drug. He then presented to an emergency room with heart palpitations, excessive sweating, confusion, fever and hand tremors. Tests revealed that the man had atrial fibrillation, an irregular heart rhythm that can lead to heart failure and stroke if left untreated.
The 62-year-old had no history of atrial fibrillation, but he had previously been diagnosed with obesity, type 1 diabetes and hypothyroidism (a condition in which the thyroid gland does not produce enough thyroid hormone). For his hypothyroidism, he was taking levothyroxine, a synthetic thyroid hormone that is dosed by weight.
Six months before he went to the emergency room, a doctor prescribed the man tirzepatide (Zepbound), a gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) dual agonist used for chronic weight management. The plan was to start with a dose of 2.5 milligrams of tirzepatide and then increase the dose every four weeks to 10 milligrams, which the man reached in four months and continued taking for the next two months. The man was scheduled for a follow-up appointment to assess his progress, but he missed it.
When he started tirzepatide, the man weighed 132 kg (291 lbs) and was taking a daily dose of 200 micrograms of levothyroxine, approximately 1.5 micrograms/kg dose. At the end of the six months, the man weighed 93 kg (205 lbs). However, he was still taking the 200 micrograms of levothyroxine, which had now been increased to a dose of 2.15 micrograms/kg.
Dangerous dose
Doctors in the emergency department performed a blood test to measure the man's TSH, also known as thyrotropin or thyroid-stimulating hormone. TSH is inversely related to thyroid hormone levels; low TSH means too much thyroid hormone and high TSH means too little. For non-pregnant adults, a normal blood TSH level is between about 0.5 and 5.0 mIU/L. The man's TSH had dropped from 1.9 mIU/L before he started tirzepatide to 0.001 mIU/L when he went to the emergency department, indicating that he had too much thyroid hormone.
Doctors diagnosed the man with “thyrotoxicosis in the context of rapid weight loss due to tirzepatide.” The diagnosis explained his symptoms well. Previous studies have found that a low TSH triples the risk of atrial fibrillation.
The Colorado researchers presented the case as a teaching moment: In the age of weight-loss drugs, doctors should evaluate patients’ other prescriptions to see if they need to be adjusted to account for large weight changes, the researchers said. Many types of medications rely on weight-based dosages, including insulins, anticoagulants, anticonvulsants, antibiotics and antifungals, the researchers noted.
In an accompanying editorial, a group of researchers led by Tyrone Johnson of the University of California, San Francisco, called for “heightened vigilance” and noted that the man's illness could have been prevented. They also put the case in the context of current market conditions for the new weight-loss drugs, which include high out-of-pocket costs and supply shortages.
These factors may drive some patients to the direct-to-consumer market, compounding pharmacies, and counterfeit versions, all of which have “suboptimal prescribing” and inadequate clinical monitoring, to say the least. The case “highlights the potential dangers underlying undersupervised prescribing of GLP-1/GIP receptor agonists and reinforces the need for strong partnerships between patients and their clinicians during their use,” they write.
