Precise diabetic kidney disease phenotyping may improve therapeutic safety, efficacy
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SCOTTSDALE, Arizona — New therapies for diabetic kidney disease are emerging from clinical trials but focusing on more precise disease phenotyping might improve therapeutic safety and efficacy, according to a speaker at the Cardio Renal Metabolic Conference.
The presence of diabetic kidney disease is determined by the presence of albuminuria, low eGFR or both in patients with diabetes.
“DKD encompasses many phenotypes from glomerular lesions to tubulo-interstitial and vascular pathology,” Katherine R. Tuttle, MD, FASN, FACP, FNKF, executive director for research at Providence Health Care and professor of medicine in the nephrology division at the Institute of Translational Health Sciences at the University of Washington, said in her presentation. We’re going to have to treat these diseases quite differently if we really want to make the biggest impact on improving outcomes.”
That new approach, Tuttle said, “will take precision phenotyping to select patients for the proper therapy based on not only efficacy, but safety. I think this will include clinical criteria, traditional and new biomarkers and, importantly, tissue-based diagnostics.”
Like other nephrologists, Tuttle said she sees the value of sodium-glucose cotransporter (SGLT2) inhibitors, which can reduce the risk of myocardial infarction, stroke and cardiovascular disease death. Tuttle noted results from CREDENCE - the first trial in nephrology that was stopped early for overwhelming efficacy - showing a 30% reduction in hard outcome events for CKD. Glucagon-like peptide 1 (GLP-1) receptors are also promising therapies for patients with DKD, she said, as these also reduce the risk of major cardiovascular events but have a more predominant effect on atherosclerotic events.
The future of DKD treatment will need to be more intentional to improve outcomes because, even with these drugs, Tuttle said, there is still a high residual risk. The first large trial with a more precise approach to DKD was The Study of Diabetic Nephropathy with Atrasentan (SONAR), which evaluated the safety and efficacy of atrasentan, an endothelial receptor agonist. The study measured albuminuria reduction for responsiveness, with a less than 30% reduction considered non-responsive and greater than 30% reduction responsive.
Tuttle noted the trial ended early due to the end of sponsorship from AbbVie but resulted in heart and kidney disease hazard ratios of 0.65 and a 35% risk reduction. This suggested atrasentan may be a viable treatment for DKD, she said.
Tuttle, who is one of the investigators of the Kidney Precision Medicine Project, said the project ethically and safely obtains kidney biopsies from patients with CKD and diabetes, hypertensive kidney disease or acute kidney injury to create a reference kidney atlas. The goal of the project is to find disease subgroups to stratify patients and identify the cells, pathways and targets for novel therapies to create individualized treatments and improve the scientific knowledge of DKD, diabetic nephropathy and CKD.
“There’s going to be a limit to how many things we can pile on. We might not be able to keep adding and we’re going to have to, at some point, start deprescribing and pick the drug that’s going to work best,” Tuttle said. – by Erin T. Welsh
References:
Tuttle KR. New therapies for diabetic kidney disease from landmark clinical trials and beyond. Presented at: Cardio Renal Metabolic Conference, March 6-7, 2020; Scottsdale, Arizona.
Disclosure: Tuttle reports being a consultant for Eli Lilly and Company, Boehringer Ingelheim, Gilead, Astra Zeneca and Goldfinch Bio.
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