The Relationship between Hypomagnesemia, Metformin Therapy and Cardiovascular Disease Complicating Type 2 Diabetes: The Fremantle Diabetes Study

Background: Low serum magnesium concentrations have been associated with cardiovascular disease risk and outcomes in some general population studies but there are no equivalent studies in diabetes. Metformin may have cardiovascular benefits beyond blood glucose lowering in type 2 diabetes but its association with hypomagnesemia appears paradoxical. The aim of this study was to examine relationships between metformin therapy, magnesium homoeostasis and cardiovascular disease in well-characterized type 2 patients from the community. Methods and Findings: We studied 940 non-insulin-treated patients (mean +/- SD age 63.4 +/- 11.6 years, 49.0% males) from the longitudinal observational Fremantle Diabetes Study Phase I (FDS1) who were followed for 12.3 +/- 5.3 years. Baseline serum magnesium was measured using stored sera. Multivariate methods were used to determine associates of prevalent and incident coronary heart disease (CHD) and cerebrovascular disease (CVD) as ascertained from self-report and linked morbidity/mortality databases. 19% of patients were hypomagnesemic (serum magnesium <0.70 mmol/L). Patients on metformin, alone or combined with a sulfonylurea, had lower serum magnesium concentrations than those on diet alone (P<0.05). There were no independent associations between serum magnesium or metformin therapy and either CHD or CVD at baseline. Incident CVD, but not CHD, was independently and inversely associated with serum magnesium (hazard ratio (95% CI) 0.28 (0.11-0.74); P=0.010), but metformin therapy was not a significant variable in these models. Conclusions: Since hypomagnesemia appears to be an independent risk factor for CVD complicating type 2 diabetes, the value of replacement therapy should be investigated further, especially in patients at high CVD risk.