New drugs help clinicians focus on cardiovascular, diabetes care in CKD
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In 1989, the FDA’s approval of Epogen – epoetin alfa manufactured by Amgen Inc. – offered patients with kidney disease an opportunity to break away from blood transfusions, the washout after dialysis and improve their quality of life.
Some 30 years later, FDA approvals of new drugs and others in the pipeline directed at patients with cardiovascular disease, diabetes and kidney disease – a triple threat that often proves lethal before the first dialysis treatment – are emulating the potential of epoetin alfa but on a broader therapeutic scale.
“This study is a game changer in the prevention and progression of cardiorenal disease in our patients,” Lance Sloan, MD, writes in this month’s First Word column about the recent FDA approval of the sodium-glucose cotransporter-2 (SGLT-2) inhibitor dapagliflozin (Farxiga, AstraZeneca) to slow kidney function decline in adults with proteinuric kidney disease with or without diabetes.
Source: Anna Burgner, MD, MEHP
“With this FDA approval, clinicians now have, for the first time, a proven treatment that can significantly alter the timeline to end-stage kidney disease and perhaps even prevent its occurrence,” Sloan writes.
Medicines in the SGLT-2 inhibitor class, which include dapagliflozin, canagliflozin (Invokana, Novo Nordisk) and empagliflozin (Jardiance, Boehringer Ingelheim/Lily), are tools now available to specialists and primary care physicians to reduce the risks that patients with diabetes face in the early stages of chronic kidney disease.
Advancing American Kidney Health
Of equal significance is the potential of many of these new treatments to help reach a goal set by CMS as part of the Advancing American Kidney Health initiative. The aim of the program is to reduce the number of new cases of end-stage kidney disease by 25% during the next 9 years. The Kidney Care Choices model, a new Medicare demonstration expected to launch in January 2022, will pay nephrologists to manage patients with CKD in stages 3-4 in an effort to slow progression of kidney disease.
That is a laudable goal, Anna Burgner, MD, MEHP, an assistant professor of medicine at Vanderbilt University School of Medicine and director of its inpatient dialysis program, told Nephrology News & Issues, but the new crop of approved drugs and those still in the pipeline, such as Bayer’s investigational drug finerenone for patients with CKD and type 2 diabetes, will be of help.
“Many of the patients that I see in stage 3 CKD with diabetic kidney disease will likely die of cardiac failure well before they go on dialysis,” Burgner said. “These new agents can prevent the cardiovascular damage that leads to high mortality. That will be a win for us in the long run as these drugs can lead to a longer life span for patients with CKD by protecting the heart and keeping diabetic complications under control.”
The key, Burgner said, is early intervention.
“By the time I see these patients in stage 3, most of them are already on an ACE inhibitor or angiotensin receptor blocker. We have made some good progress with SGLT-2 inhibitors as well, and both primary care physicians and endocrinologists have been receptive to using them,” she said.
SGLT-2 inhibitors also help lower the likelihood of hyperkalemia “and serve as a great diuretic,” Burgner said. “They may help to keep the kidneys functioning.”
Patients who already experience frequent urinary tract infections may see the frequency increase when using SGLT-2 inhibitors, Burgner said.
New agents
SGLT-2 inhibitors lead a long list of therapeutics that will likely change the approach for the treatment of kidney disease during the next few years. These include the following:
- Bardoxolone. Reata Pharmaceuticals announced on March 1 that it had submitted a new drug application (NDA) for bardoxolone methyl (bardoxolone) for treatment of CKD caused by Alport syndrome;
- Belimumab, voclosporin. Belimumab (Benlysta, GlaxoSmithKline) was approved by the FDA in December 2020 to treat lupus nephritis. The agency approved Lupkynis (voclosporin, Aurinia) 1 month later;
- Difelikefalin. The FDA accepted the NDA for priority review for difelikefalin (Korsuva, Cara Therapeutics), a kappa opioid receptor agonist for the treatment of moderate to severe pruritus in patients on hemodialysis;
- Finerenone. The FDA has granted priority review to an NDA for finerenone (Bayer) for the treatment of diabetic kidney disease. Data from the phase 3 FIGARO-DKD and FIDELIO-DKD studies have shown that finerenone significantly reduced the composite risk of time to first occurrence of cardiovascular death or non-fatal cardiovascular events compared with placebo in adults with CKD and type 2 diabetes;
“Finerenone not only slowed diabetic kidney disease progression but protected against the risk for CV events related to atherosclerosis, as well as heart failure, given no interaction with the prespecified endpoint,” George L. Bakris, MD, from the Comprehensive Hypertension Center at the University of Chicago Medicine, told Nephrology News & Issues. “We now have another agent in our arsenal to preserve kidney and cardiac function.”
Roxadustat, vadadustat and daprodustat. This class of hypoxia-inducible factor prolyl hydroxylase inhibitors from pharmaceutical companies FibroGen, Akebia Therapeutics and GlaxoSmithKline, respectively, have shown in clinical trials to not only match the effectiveness of current treatments for anemia in patients with kidney disease, but other medical benefits as well. All three have received approval for use in other countries but are awaiting review in the United States;
Tenapanor. In July, the FDA is expected to review this drug for approval. Tenapanor (Ibsrela, Ardelyx Inc.) offers the first alternative to phosphate binders to control high levels of phosphorus in patients with kidney disease; and
Viverimer. This orally administered polymer (TRC101, Tricida Inc.) in undergoing trials for the treatment of metabolic acidosis.
Practical issues
While the new drugs have great potential, clinicians told Nephrology News & Issues that tolerability and cost may limit use.
“Not all patients will be able to tolerate these drugs,” Burgner said, noting the increase in urinary tract infections among patients who use SGLT-2 inhibitors. In addition, questions remain as to whether Medicare will cover the cost.
“These drugs are expensive,” Jay B. Wish, MD, chief medical officer for dialysis at Indiana University Health in Indianapolis, told Nephrology News & Issues. “The payment in the Kidney Care Choices model is capitated with shared savings and quality incentives. Farxiga, for example, would add to the providers’ costs in that model so there is no guarantee it will be used to its full advantage.”
If the new drugs are available to all patients who can benefit, Burgner said there is hope.
“I think we are going to see a decrease in the number of people ending up on dialysis from diabetic kidney disease,” she said. “A 25% reduction in new cases of ESKD in 9 years sounds like a big number, but it may be achievable, particularly if we are working on early recognition of kidney disease and starting these medications early.
“With time, it could happen,” she said.
- References:
- https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-receives-fda-approval-ibsrelar-tenapanor-nhe3-sodium
- https://ir.auriniapharma.com/press-releases/detail/216/aurinia-presents-data-demonstrating-lupkynis
- www.clinicaltrialsarena.com/comment/reata-pharma-nda-bardoxolone-ckd-genetic-disease
- www.healio.com/news/endocrinology/20200710/finerenone-delays-diabetic-kidney-disease-progression-fideliodkd
- For more information:
- George L. Bakris, MD, is a professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine. He can be reached at gbakris@gmail.com.
- Anna Burgner, MD, MEHP, is an assistant professor of medicine at Vanderbilt University School of Medicine and director of its inpatient dialysis program, co-director of its nephrology clinical trials program, and director of its associate nephrology fellowship program. She is also an associate editor for Nephrology News & Issues. She can be reached at anna.burgner@vumc.org.
- Jay B. Wish, MD, is a professor of clinical medicine at Indiana University School of Medicine and chief medical officer for dialysis at Indiana University Health in Indianapolis. He is also a vice chair for Nephrology News & Issues. He can be reached at jwish@iu.edu.
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