The clinical implications of type 2 diabetic renal disease and the use of fenofibrate as a novel therapy

Abstract

Diabetic renal disease is a serious complication and the FIELD study, a trial of the PPAR agonist fenofibrate in type 2 diabetes, provides an opportunity to address it. We found that eGFR and urinary albumin to creatinine ratio (ACR) are independent predictors of cardiovascular disease. Improvement in eGFR or ACR attenuates cardiovascular risk, reinforcing the importance of risk factor control. Therefore, we identified the predictors of impaired eGFR and elevated ACR. However, novel treatments are still needed. In FIELD, fenofibrate was shown to reduce albuminuria and slow eGFR loss while paradoxically increasing serum creatinine. Although the mechanism is poorly understood, this iatrogenic creatinine rise does not impair true GFR (directly measured by inulin clearance), is fully reversible and does not increase cardiovascular or renal risk. Consequently, fenofibrate’s benefit on eGFR is unmasked only when the artificial reduction in calculated GFR is removed on drug cessation. While the eGFR benefit is associated with baseline dyslipidaemia and the degree of triglyceride reduction, we found no predictors of ACR benefit, implying separate mechanisms. Using murine models of diabetes and PPAR deficiency, we demonstrated a beneficial non-PPAR mediated effect of fenofibrate on albuminuria, laying the foundation for further work in identifying novel therapeutic targets.