Beyond Glycemic Control: GLP-1 Receptor Agonists and Their Impact on Calcium Homeostasis in Real-World Patients

Abstract

Background/Objectives: The effect of glucagon-like peptide-1 receptor (GLP-1R) agonists on calcium homeostasis is poorly understood. This study aimed to investigate the association between GLP-1R agonist use and the risk of hypocalcemia and/or hypercalcemia, as well as other clinical outcomes. Methods: A retrospective cohort study used de-identified patient data from the TriNetX Global Collaborative Network, including 15,655 adult patients prescribed GLP-1R agonists and 15,655 propensity-matched controls. Outcomes included hypocalcemia, hypercalcemia, emergency visits, hospitalizations, cardiovascular events, and all-cause mortality. Results: GLP-1R agonist use was associated with a reduced risk of hypocalcemia (2.7% vs. 5.5%, RR 0.49, 95% CI: 0.44-0.55) but an increased risk of hypercalcemia (2.3% vs. 1.1%, RR 2.02, 95% CI: 1.69-2.42). The effect on hypocalcemia was most pronounced during the first six months of treatment. Among individual agents, tirzepatide showed the most pronounced effect, reducing hypocalcemia risk by 63% while increasing hypercalcemia risk by 85%. Semaglutide demonstrated similar effects, while dulaglutide and liraglutide showed modest effects. Furthermore, GLP-1R agonist use was associated with reduced risks of emergency visits (RR 0.57, 95% CI: 0.54-0.60), hospitalizations (RR 0.40, 95% CI: 0.36-0.44), cardiovascular events, and all-cause mortality (HR 0.27, 95% CI: 0.21-0.36). Conclusions: GLP-1R agonists exhibit a complex influence on calcium homeostasis, reducing hypocalcemia risk while increasing hypercalcemia risk. Beyond calcium regulation, these medications significantly reduce healthcare utilization, improve cardiovascular outcomes, and decrease mortality. Further research is needed to elucidate the mechanisms behind the differential effects of individual GLP-1R agonists, particularly tirzepatide, to optimize personalized treatment approaches and long-term safety.

Keywords: GLP-1R agonists; all-cause mortality; calcium homeostasis; cardiovascular events; healthcare utilization; long-term safety; obesity; personalized treatment; propensity-matched controls; type 2 diabetes.

Figure 1

Time-dependent analysis of hypocalcemia and hypercalcemia risks associated with GLP-1R agonist use. (A) Risk ratios for hypocalcemia at 0–6 months, 7–12 months, and 13–24 months after treatment initiation for each GLP-1R agonist. (B) Risk ratios for hypercalcemia at 0–6 months, 7–12 months, and 13–24 months after treatment initiation for each GLP-1R agonist. Error bars represent 95% confidence intervals. The dotted line (i.e., the control) indicates a risk ratio of 1 (no effect). Values below 1 indicate reduced risk, while above 1 indicate increased risk. Semaglutide (blue), liraglutide (red), dulaglutide (green), and tirzepatide (purple) are represented for each time interval. Asterisks (*) denote statistically significant differences (p < 0.05) compared to the control group.