Background: Patients with diabetes mellitus (DM) are prone to develop vascular calcification and have a substantially increased cardiovascular risk. Since patients with DM display higher expression of phosphate transporters in vascular smooth muscle cells, these patients may be more susceptible to higher serum phosphate levels. We aimed to investigate the association between serum phosphate and all-cause mortality in a large, population-based cohort study, and studied effect modification by DM. 

Methods: We analysed the association between serum phosphate and all-cause mortality in the Dutch population-based Lifelines cohort using multivariable Cox regression, adjusted for age, gender, smoking, BMI, Hba1c, glucose, systolic BP, LDL cholesterol, cardiovascular history, eGFR and vitamin D supplement use. DM status was defined as self-reported DM, antidiabetic use, serum glucose and Hba1c. Effect modification was tested using multiplicative interaction terms. 

Results: We analysed 57,301 individuals (median[IQR] age 44[36-51] yrs, 41% male, 1921 with DM at baseline, serum phosphate 0.91±0.17 mmol/L, eGFR 96±15 mL/min/1.73 m2). After follow-up of 9.4[8.8-10.4] yrs, 1267 individuals died. A higher serum phosphate level (2nd serum phosphate tertile (range 0.86-0.98 mmol/L) vs 3rd tertile (range 0.98-1.83 mmol/L) was associated with an increased mortality risk (fully adjusted HR 1.18[95% CI 1.03-1.36], P=0.02). We found significant effect modification by DM status (Pinteraction=0.003). In patients with DM (141 events), the association between serum phosphate and mortality was stronger (fully adjusted HR 1.63[1.08-2.46], P=0.02) than in individuals free of DM at baseline (fully adjusted HR 1.13[0.97-1.32], P=0.11). Exclusion of patients with eGFR <60 mL/min/1.73 m2 yielded similar results. 

Conclusions: The association between high-normal serum phosphate levels and mortality was stronger in individuals with DM than those without. The susceptibility of patients with DM to phosphate sets the stage for follow-up studies with early phosphate-lowering interventions in DM.