In 2018, consolidating evidence for renoprotective benefits was seen with respect to sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists, which are currently being incorporated into clinical practice. The focus now turns to novel therapeutic targets to optimize renoprotection as diabetic kidney disease grows to epidemic proportions worldwide.
Key advances
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The CANVAS Program reported renal benefits of canagliflozin1; these findings build on evidence from the EMPA-REG OUTCOME trial7 for a renoprotective effect of sodium–glucose cotransporter 2 (SGLT2) inhibitors.
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The AWARD-7 trial reported renal benefits of dulaglutide2; these results add weight to previous findings of renoprotective effects of glucagon-like peptide 1 (GLP1) agonists.
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Targeting podocyte histone modification via promotion of H3K27me3 prevented glomerular cell dedifferentiation and loss of renal function in a mouse model of obesity and type 2 diabetes mellitus3.
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Inhibition of apoptosis signal-regulating kinase 1 (ASK1) prevented oxidative stress and fibrosis and was renoprotective in a mouse model; human trials of ASK1 inhibition in diabetic kidney disease are underway4.
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References
Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 6, 691–704 (2018).
Tuttle, K. R. et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 6, 605–617 (2018).
Majumder, S. et al. Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease. J. Clin. Invest. 128, 483–499 (2018).
Liles, J. T. et al. ASK1 contributes to fibrosis and dysfunction in models of kidney disease. J. Clin. Invest. 128, 4485–4500 (2018).
Thomas, M. C. & Cherney, D. Z. I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 61, 2098–2107 (2018).
Neal, B. et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 644–657 (2017).
Cherney, D. Z. I. et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 5, 610–621 (2017).
Drucker, D. J. & Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–1705 (2006).
Mann, J. F. E., Ørsted, D. D. & Buse, J. B. Liraglutide and renal outcomes in type 2 diabetes. N. Engl. J. Med. 377, 2197–2198 (2017).
Loomba, R. et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 67, 549–559 (2017).
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Cooper, M., Warren, A. A promising outlook for diabetic kidney disease. Nat Rev Nephrol 15, 68–70 (2019). https://doi.org/10.1038/s41581-018-0092-5
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DOI: https://doi.org/10.1038/s41581-018-0092-5
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