Can lithium and Ozempic (semaglutide) combine to cause hypercalcemia?

Lithium and Ozempic Combination: Hypercalcemia Risk

Lithium alone is a well-established cause of hypercalcemia through drug-induced hyperparathyroidism, but there is no evidence that Ozempic (semaglutide) contributes to or exacerbates lithium-induced hypercalcemia. The hypercalcemia risk in patients on lithium is independent of concurrent Ozempic use.

Lithium's Mechanism of Hypercalcemia

Lithium causes hypercalcemia through two distinct pathophysiological mechanisms:

• Acute effects: Lithium acts on the calcium-sensing receptor pathway and glycogen synthase kinase 3, creating a biochemical picture similar to familial hypocalciuric hypercalcaemia—this is potentially reversible 1
• Chronic effects: Long-term lithium therapy causes permanent parathyroid gland changes by either unmasking subclinical parathyroid adenomas or initiating multiglandular hyperparathyroidism, producing a biochemical picture identical to primary hyperparathyroidism 1, 2
• Lithium increases the calcium set-point in parathyroid glands for inhibition of PTH secretion, interfering with transmembrane signal transduction in the parathyroid cell 3

Clinical Significance and Prevalence

• Hypercalcemia and hyperparathyroidism are common consequences of lithium therapy, though often underrecognized 4
• Most patients develop mild, asymptomatic hypercalcemia 4
• Critical concern: Lithium-induced hypercalcemia increases the risk of cardiac arrhythmias, particularly bradycardia and conduction defects, requiring regular electrocardiographic monitoring 5

Ozempic's Role (or Lack Thereof)

The provided evidence contains no data linking semaglutide (Ozempic) to hypercalcemia or any interaction with lithium that would potentiate calcium dysregulation. Ozempic is not mentioned in any hypercalcemia guidelines or drug-related hypercalcemia reviews 6, 2.

Monitoring Algorithm for Lithium Patients

Regardless of Ozempic use, patients on lithium require:

• Baseline serum calcium and PTH levels before initiating lithium 4
• Periodic monitoring of calcium and PTH levels after lithium initiation 4, 3
• Regular electrocardiographic monitoring due to arrhythmia risk when hypercalcemia develops 5
• Measurement of ionized calcium (not just corrected calcium) for accurate diagnosis 6
• Assessment of lithium levels, as severe hypercalcemia may occur with toxic lithium concentrations 3

Management Approach When Hypercalcemia Develops

If hypercalcemia is detected in a patient on lithium (with or without Ozempic):

• Discontinue lithium if clinically feasible—this may normalize calcium and PTH levels in some patients 4
• Important caveat: After lithium discontinuation, hypercalcemia may persist and require parathyroidectomy in some cases, particularly with long-term therapy 4, 1
• For persistent hyperparathyroidism despite lithium discontinuation, parathyroidectomy is indicated 6, 5
• The decision to continue lithium in the presence of hypercalcemia must weigh psychiatric stability against metabolic complications 4, 3

Critical Pitfalls to Avoid

• Do not assume Ozempic contributes to hypercalcemia—attribute the calcium elevation to lithium's well-documented effects 4, 1, 2
• Do not delay calcium monitoring in lithium patients; early recognition improves outcomes 1
• Do not ignore mild hypercalcemia—the long-term consequences remain unknown, and cardiac complications can develop 4, 5
• Do not rely on corrected calcium alone; measure ionized calcium to avoid diagnostic errors 6