Antineoplastic Agents Associated with Hypomagnesemia and Effect Modifiers for the Associations

Background: Hypomagnesemia (hypoMg) is common and associated with worse outcomes among patients with malignancy. In this study, we aimed toidentify anti-neoplastic agents associated with it and modifiable factors for the associations. Methods: In this retrospective cohort study, we enrolled patients receiving antineoplastic agents at Nagoya City University Hospital from 2018 to 2020. We employed mixed-effects logistic regression models to identify factors associated with hypoMg (Mg<1.8mg/dL) and effect modifiers for the associations. As a sensitivity analysis, missing data for dipstick proteinuria were multiply imputed and the data were analyzed by Poisson regression with frequency of laboratory measurements as an exposure variable. Results: A total of 2644 patients were included. The mean age was 63.8 (16.5) years and the mean eGFR was 71.9 (21.1) mL/min/1.73m2. Serum magnesium (Mg) was measured at least once in 1692 (64.0%) patients, of these, 718 (42.4%) developed hypoMg (15.5 events/100 patient-measurements). Cetuximab was most strongly associated with hypoMg (OR 4.36 [3.44-5.54]), followed by platinum drugs (2.20 [1.87-2.59]). Loop diuretics were negatively associated with hypoMg (0.76 [0.61-0.96]), while eGFR was not. Cetuximab was associated with hypoMg among non-users of vitamin D recptor activator (VDRA) (4.36 [3.44-5.54]) and non-users of bisphosphonates (4.70[3.65-6.04]) but not among users of these agents (p for interaction <0.001 and 0.003, respectively). In the sensitivity analyses, the effect modification by VDRA was consistent, while the effect modifications by bisphosphonates were not observed. Proteinuria was not associated with hypoMg and no effect modifications were seen by eGFR or proteinuria. Conclusion: HypoMg was common among those with malignancy, while only about two-thirds of patients had Mg measurements. Cetuximab was the agent most strongly associated with hypoMg, and cetuximab-induced hypoMg might be prevented by using vitamin D or bisphosphonates.