Proton pump inhibitor induced hypomagnesemia and mortality: mediation analyses in the Diabetes Care System cohort

Abstract Background: Chronic proton pump inhibitor (PPI) use and hypomagnesemia are common in people with type 2 diabetes (T2D), and both are associated with increased mortality and cardiovascular disease (CVD). Since PPI use can cause hypomagnesemia, we investigated if magnesium is a mediator of the association between PPI use and mortality and CVD in people with T2D. Methods: This study was performed in 4,037 participants of the Dutch prospective Diabetes Care System cohort. Serum magnesium was measured between 2008-2014 and PPI use was determined the year preceding magnesium measurement. The primary outcome was all-cause mortality with follow-up until 2020, and the secondary outcome was fatal and non-fatal CVD. We performed causal mediation analyses. Results: Mean serum magnesium was 0.80 mmol/l (SD 0.08) and 1,079 (26.7%) participants received PPI treatment. Median follow-up was 7.0 years [IQR 6.4-11.1], 711 (17.6%) participants died, and 608 (15.6%) had a cardiovascular event. PPI use was associated with a low serum magnesium level and an increased incidence of CVD and mortality. The association between PPI use and all-cause mortality was not mediated by magnesium (natural indirect effect (NIE): survival time ratio (STR) 0.99[95%CI 0.98;1.00] and magnesium was only a minor mediator in the association of PPI use and CVD (NIE: STR 0.98[95%CI 0.97;<1.00]. Conclusion: Serum magnesium was not a mediator of the association between PPI use and all-cause mortality. Magnesium explains only a minor part of the total effect of PPI use on CVD. Additional mediators of the association between PPI and adverse outcomes should be explored.