The dose makes the medicine—and for many critical prescription drugs, the dose depends on a patient's body weight. Usually, this is not a problem; weight changes large enough to significantly affect dosages often occur gradually, over periods long enough for doctors to notice and adjust prescriptions. But, in the era of new weight loss drugs, that may no longer be the case.
In a cautionary tale published Monday in JAMA Internal Medicine, researchers at the University of Colorado reported the case of a man who lost nearly 30 percent of his body weight in a six-month period using a new weight loss drug. Then, he showed up at an emergency department with heart palpitations, excessive sweating, confusion, fever, and hand tremors. Tests indicated the man had atrial fibrillation, an irregular heart rhythm that can lead to heart failure and stroke without treatment.
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 took levothyroxine, a synthetic thyroid hormone that is dosed by weight.
Six months before he went to the emergency department, 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 2.5-milligram dose of tirzepatide and then increase the dose every four weeks to get to 10 mg, which the man reached in four months and kept taking for the next two months. The man was supposed to have a follow-up appointment to assess his progress, but he missed it.
At the time he started tirzepatide, the man weighed 132 kg (291 lbs) and was taking a daily 200-microgram dose of levothyroxine, about 1.5 microgram/kg dosage. By the end of the six months, the man weighed 93 kg (205 lbs). But, he was still taking the 200-microgram dose of levothyroxine—which had now increased to a 2.15 microgram/kg dose.
Dangerous dose
Doctors at the emergency department did a blood test of the man's TSH, aka thyroid-stimulating hormone or thyrotropin. TSH is inversely related to the level of thyroid hormone; Low TSH means an excess amount of thyroid hormone and high TSH means too little. For adults who aren't pregnant, a normal TSH level in the blood is between about 0.5 to 5.0 mIU/L. The man's TSH had fallen from 1.9 mIU/L before he started the tirzepatide to 0.001 mIU/L when he went to the emergency department, indicating he had excess thyroid hormone.
Doctors diagnosed the man with "thyrotoxicosis in the context of rapid weight loss from tirzepatide." The diagnosis explained his symptoms well. Earlier studies found that low TSH raises the risk of atrial fibrillation by threefold.
The Colorado researchers presented the case as a teachable moment: In the era of weight loss drugs, doctors need to assess patients' other prescriptions to see if they need to be adjusted to account for big changes in weight, the researchers say. Many types of medications depend on weight-based dosages, including insulins, anticoagulants, anticonvulsants, antibiotics, and antifungals, the researchers note.
In an accompanying editorial, a group of researchers led by Tyrone Johnson, of the University of California, San Francisco, called for "heightened vigilance," noting that the man's illness could have been prevented. They also put the case in context of the current market conditions for the new weight loss medicines, which include high out-of-pocket costs and supply shortages.
These factors can drive some patients to the direct-to-consumer market, compounding pharmacies, and counterfeit versions, which all 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 affirms the need for strong partnerships between patients and their clinicians during their use," they write.