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

Summary: Hypercalcemia is a prevalent electrolyte disturbance commonly associated with primary hyperparathyroidism, cancer, or medication adverse effects. Thiazide diuretics reduce urinary calcium excretion, increasing calcium reabsorption and hypercalcemia. Tirzepatide, a dual GIP and GLP-1 receptor agonist, is increasingly used for type 2 diabetes and obesity. While GIP/GLP-1 agonists typically have negligible effects on calcium homeostasis, the interaction between tirzepatide and thiazides remains unstudied. We report a 65-year-old female with obesity, hypertension, CKD3, and T2DM on chronic HCTZ who developed symptomatic hypercalcemia (corrected calcium: 4.58 mmol/L; normal range: 2.12-2.62 mmol/L), resulting in altered mental status days after initiating tirzepatide. PTH and vitamin D levels were low, and imaging ruled out malignancy. Discontinuation of tirzepatide/HCTZ, IV hydration, and calcitonin normalized her calcium by hospital day 4. This case highlights a potential association between HCTZ and tirzepatide in causing severe hypercalcemia. No prior reports link tirzepatide (or its combination with thiazides) to hypercalcemia. The mechanism likely involves thiazide-induced calcium reabsorption and tirzepatide's effects on bone turnover. As the use of tirzepatide and other GLP-1/GIP agonists becomes more prevalent, clinicians need to closely monitor calcium levels in thiazide-treated individuals, particularly those with CKD. Additional research is also needed to elucidate the drug's interaction with calcium metabolism. Learning points: Clinicians should be aware of the potential for severe hypercalcemia when tirzepatide is co-administered with chronic thiazide diuretics, particularly hydrochlorothiazide (HCTZ), in patients with pre-existing CKD. Tirzepatide, a dual GIP and GLP-1 receptor agonist, may influence calcium metabolism through mechanisms including increased osteoblastic activity and altered PTH regulation, especially in individuals with impaired renal clearance. Baseline and follow-up serum calcium monitoring is strongly recommended within 1-2 weeks of initiating tirzepatide in patients receiving thiazide diuretics or those with CKD. This case suggests a possible drug-drug interaction between tirzepatide and HCTZ leading to symptomatic hypercalcemia, highlighting the need for pharmacovigilance as newer agents are integrated into routine diabetes care. Severe hypercalcemia can present with nonspecific symptoms such as altered mental status, fatigue, constipation, and polyuria; clinicians should maintain a high index of suspicion in susceptible populations. Prompt cessation of the suspected offending agents, hydration, and short-term use of calcitonin can result in rapid and sustained normalization of calcium levels without the need for bisphosphonates.