Effects of Fenofibrate Therapy in Diabetic Nephropathy

Summary

Diabetic nephropathy (DN) is a common cause of end-stage renal disease (ESRD) and accounts for nearly half of all new patients starting dialysis in Singapore, the country with the highest rates of DN in the Asia-Pacific region. Despite the scale of the problem, little progress has been made in our understanding of the pathogenesis of the disorder and no new therapies have been offered. The investigators have conducted a metabolomics study of human diabetic nephropathy that revealed evidence for alterations in mitochondrial fuel metabolism in patients with the disease, a finding also reported in other recent studies of human DN. Based on this finding the investigators believe that dysregulated mitochondrial fuel oxidation is a major driver of diabetic nephropathy. Fenofibrate is an agonist of peroxisome-proliferator activating receptor (ppar)-alpha that is approved for the treatment of hypercholesterolaemia and hypertriglyceridemia alone or combined in patients unresponsive to dietary and other non-drug therapeutic measures. Fenofibrate is also indicated for the reduction in the progression of diabetic retinopathy in patients with type 2 diabetes and existing diabetic retinopathy. Presently fenofibrate is not indicated for the treatment of diabetic nephropathy. The investigators hypothesize that treatment with fenofibrate, taken orally at 300mg per day or 100mg per day for 30 days will lead to significant changes in the circulating metabolomics patterns in patients with DN. The investigators propose to administer the drug for a period of 30 days and will perform a comprehensive analysis of the state of fuel metabolism in these patients before, and after the administration of fenofibrate using targeted metabolomics and other approaches. Fundal photography, Optical Coherence Tomography (OCT) and Optical Coherence Tomography Angiography (OCTA) will also be performed at baseline and post-treatment. A total of 300 subjects will be recruited from Singapore General Hospital (SGH) Diabetes and Metabolic Centre. Our goal is to discover key changes in fuel metabolism in DN patients receiving fenofibrate.

Timeline

Start

2019-03-08

Primary completion

2021-04-30

Completion

2021-04-30

Publications

• Background Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G; DAIS Investigators. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis. 2005 Mar;45(3):485-93. doi: 10.1053/j.ajkd.2004.11.004.
• Background Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61. doi: 10.1016/S0140-6736(05)67667-2.
• Background Liu JJ, Ghosh S, Kovalik JP, Ching J, Choi HW, Tavintharan S, Ong CN, Sum CF, Summers SA, Tai ES, Lim SC. Profiling of Plasma Metabolites Suggests Altered Mitochondrial Fuel Usage and Remodeling of Sphingolipid Metabolism in Individuals With Type 2 Diabetes and Kidney Disease. Kidney Int Rep. 2016 Dec 16;2(3):470-480. doi: 10.1016/j.ekir.2016.12.003. eCollection 2017 May.
• Teo CHY, Lin MT, Lee IXY, Koh SK, Zhou L, Goh DS, Choi H, Koh HWL, Lam AYR, Lim PS, Mehta JS, Kovalik JP, Coffman TM, Tan HC, Liu YC. Oral Peroxisome Proliferator-Activated Receptor-alpha Agonist Enhances Corneal Nerve Regeneration in Patients With Type 2 Diabetes. Diabetes. 2023 Jul 1;72(7):932-946. doi: 10.2337/db22-0611.

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