A potential association between tirzepatide and hypercalcemia in the setting of chronic hydrochlorothiazide use

Hypercalcemia is a common electrolyte disturbance, often associated with primary hyperparathyroidism, malignancy, and medication effects (1). Thiazide diuretics, including hydrochlorothiazide (HCTZ), have long been recognized as contributors to hypercalcemia by reducing urinary calcium excretion (2). Other common causes of hypercalcemia such as granulomatous diseases (e.g., sarcoidosis), vitamin A toxicity, lithium use, and multiple myeloma were clinically excluded based on imaging, medication review, and absence of clinical features suggestive of these etiologies. Meanwhile, tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is an emerging therapeutic option for type 2 diabetes and obesity (3). While GLP-1 receptor agonists have been associated with minor calcium homeostasis disturbances (6), the interplay between tirzepatide and chronic thiazide use remains unknown. Here, we present a case in which a single dose of tirzepatide in a patient on chronic HCTZ therapy precipitated profound symptomatic hypercalcemia.

A 65-year-old obese female with a medical history of hypertension (HTN), hyperlipidemia (HLD), hypothyroidism, chronic kidney disease 3 (CKD3), and diabetes mellitus type 2 (T2DM) presented to the emergency room (ER) with generalized weakness and altered mental status (AMS). She also experienced fatigue, mild constipation, and polyuria, consistent with hypercalcemia. These symptoms began 3 days after receiving her first-ever dose of tirzepatide (2.5 mg subcutaneously). Of note, the patient had been taking Losartan/HCTZ 100/25 mg daily for her hypertension for several years. She was not taking any calcium, vitamin D, over-the-counter supplements, or other medications associated with hypercalcemia. Before tirzepatide initiation, labs showed baseline corrected calcium of 2.30 mmol/L (normal: 2.12–2.62 mmol/L), parathyroid hormone (PTH) 4.76 pmol/L (normal: 1.05–6.89 pmol/L), 25-OH vitamin D 85 nmol/L (normal: >50 nmol/L), and serum creatinine 106 μmol/L (normal: 53–115 μmol/L). The patient was found by her mother on the floor, confused and minimally responsive. Emergency Medical Services (EMS) was called, and on arrival, EMS found the patient severely dehydrated. She received resuscitation fluid before being transported to the ER. Initial vital signs included respiratory rate of 20 breaths/min, pulse of 104 beats/min, temperature of 97.8°F (36.6°C), blood pressure of 220/93 mmHg, and oxygen saturation of 96%. Initial laboratory workup is presented in Tables 1 and 2.

On examination, the patient appeared lethargic but was responsive and coherent, with no focal neurological deficits, thyromegaly or lymphadenopathy. Cardiovascular, pulmonary, abdominal, and neurological exams were unremarkable. ECG showed normal sinus rhythm without QTc prolongation or arrhythmias.

Imaging was performed to rule out malignancy, metastatic disease, and other structural causes of altered mental status or hypercalcemia. CT of the chest, abdomen, pelvis, and MRI of the brain showed no acute abnormalities. The management strategy was directed by the current treatment guidelines, which included immediate cessation of tirzepatide and HCTZ and aggressive intravenous fluid hydration. Blood pressure was controlled with IV hydralazine and labetalol as needed and calcitonin injections were administered as an adjunct to aid in lowering the very high serum calcium level. Calcitonin was chosen due to its rapid onset of action, typically within minutes, compared to bisphosphonates, which require 48–72 h to take effect. Given the patient's rapid clinical and biochemical improvement following calcitonin administration, discontinuation of the suspected offending agents, and aggressive intravenous hydration, we opted to avoid additional medications, favoring a more conservative approach once therapeutic goals were being met. The patient's calcium level was measured daily and it normalized by day 4 of admission, and her blood pressure was managed with the addition of amlodipine.

Repeat labs at outpatient follow-up 3 weeks later showed sustained normocalcemia (corrected calcium: 2.45 mmol/L).

This article showcases a 65-year-old obese lady with a history of chronic kidney disease stage 3 (CKD3), type 2 diabetes mellitus (T2DM), and hypertension on HCTZ for several years, who developed severe hypercalcemia and altered mental status a few days following initiation of the first dose of tirzepatide. The timing of the onset of the events above suggests a possible synergistic effect of HCTZ and tirzepatide on calcium homeostasis, particularly in the setting of CKD. We considered dehydration as one of the causes of this patient's hypercalcemia; however, it is very rare for dehydration alone to cause hypercalcemia with corrected calcium above 3.00 mmol/L. Thus, this article investigates other factors contributing to the severe hypercalcemia, including HCTZ use, tirzepatide use, and her history of chronic kidney disease. We also ruled out other causes of severe hypercalcemia as documented in our workup – including hypercalcemia of malignancy, primary hyperparathyroidism, granulomatous diseases, and thyrotoxicosis – which could typically present with corrected calcium levels above 3.50 mmol/L.

This case highlights a potential synergistic relationship between HCTZ and tirzepatide in causing severe hypercalcemia in a patient with CKD stage 3. An extensive literature review did not reveal any previous documentation of tirzepatide, or a combination of tirzepatide and HCTZ, as a cause of severe hypercalcemia. Since a single case report cannot establish causality, it is worth investigating further the effect of tirzepatide on calcium homeostasis, as well as the drug-drug interaction relationship between tirzepatide and HCTZ. Given the temporal relationship observed, further research is warranted to explore the potential effects of tirzepatide on calcium metabolism, particularly in the context of concurrent thiazide diuretic use. Furthermore, given the increasing use and high demand for tirzepatide and other GLP-1 agonists, further investigations and a better understanding of its effect on calcium homeostasis are warranted. Second, there should be close monitoring of calcium levels in patients starting GIP and GLP-1 agonists, especially in patient populations such as CKD patients or patients on HCTZ who are already susceptible to hypercalcemia.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

There was no other external source of funding for this report. This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare-affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Written informed consent has been obtained from the patient for the publication of anonymized clinical data.

SNM conceived the idea of reporting this case and obtained the patient's detailed history, and observed the clinical course of the patient. She was also present during the consent discussion alongside BN. SNM drafted the initial manuscript and led the revisions. BN was involved in the patient's clinical care and collaborated in the consent process. He contributed significantly to the manuscript's critical revisions and literature verification. VV supervised the case management and approved the reporting of the case. All authors reviewed and approved the final version of the manuscript.

This research activity was determined to be exempt or excluded from the HCA Healthcare Graduate Medical Education Institutional Review Board oversight in accordance with current regulations and institutional policy.