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New Research Papers Show Promise for Treatment of Patients With CKD

AUTHOR:
James Matera, DO
Practicing Nephrologist, Senior Vice President for Medical Affairs, and Chief Medical Officer
CentraState Medical Center
Freehold, New Jersey

CITATION:
Matera J. New research papers show promise for treatment of patients with CKD. Consultant360. Published online December 1, 2020.

 

In the last few months, 3 important studies were published regarding treatment options for patients with chronic kidney disease (CKD). Here’s my synopsis of each study and why it is important for everyday practice.

Hypoxia-Inducible Factor Stabilizers and CKD With Anemia1

A large proportion of patients with CKD and anemia still do not meet the hemoglobin (Hb) targets. The discovery of prolyl hydroxylase domain (PHD) enzymes as regulators of hypoxia-inducible factor (HIF)-dependent erythropoiesis has led to the development of novel therapeutic agents for renal anemia.

Roxadustat, the first small-molecule HIF-PHD inhibitor, has completed the phase 3 trial. There are currently more than 15 phase 3 clinical trials worldwide assessing the efficacy and safety of roxadustat in patients with CKD and anemia.

Administration of erythropoiesis-stimulating agents (ESAs) and iron supplementation are well-established and highly effective therapeutic approaches for renal anemia. However, safety concerns have always been a problem, including hypertension, hypercoagulability, and adverse cardiovascular effects, not among the least.

In current trials, roduxastat is clinically effective and well-tolerated, with results showing:

  • Increases in endogenous erythropoietin (EPO) levels within or near physiological range in a titratable manner by inducing HIF pathway activation transiently.
  • Improvements in iron metabolism by decreasing serum hepcidin and increasing intestinal iron absorption, which is beneficial to functional iron deficiency and absolute iron deficiency.

 

The erythropoietic response of roxadustat is independent of baseline inflammatory state of patients with CKD, which is an important factor in EPO resistance. Often times, patients’ inflammatory state predicts failure of ESAs.

Roxadustat is a promising approach against anemia in patients with CKD, which differs from those of conventional ESAs. Roxadustat corrects anemia among patients with CKD through multiple pathways:

  • Elevating EPO levels within physiological range.
  • Handling iron metabolism (particularly decreasing the hepcidin levels).

 

Adverse effects center around the nature that these agents regulate hundreds of genes and are a factor in several nonerythropeotic functions, including energy metabolism, angiogenesis, mitochondrial metabolism, cellular growth and differentiation, and inflammation.

Dapagliflozin in Patients With Chronic Kidney Disease (DAPA-CKD) Trial2

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are known to reduce heart failure hospitalization. The treatment effect size in the DAPA-CKD trial was large, with an approximate 50% risk reduction of this outcome and proportional risk reduction in primary and secondary prevention patients. This is important because it boosts the evidence that the benefit of SGLT-2 inhibitors on heart failure is independent of background atherosclerotic disease and is not mediated through prevention of atherosclerotic events.

The evidence shows that SGLT-2 inhibitors prevent a common, disabling, and deadly cardiovascular complication in patients with CKD, namely heart failure, in people without diabetes as well as without known cardiovascular disease.

The composite of cardiovascular death, myocardial infarction, or stroke was not reduced in DAPA-CKD, unlike CREDENCE (in which there was a higher percentage of baseline cardiovascular disease). However, there was another key difference between DAPA-CKD and CREDENCE:

  • Reduction in death from any cause in DAPA-CKD, which was not observed in CREDENCE.
  • This effect in DAPA-CKD was consistent in patients with and without a history of cardiovascular disease.  This is yet another benefit seen in the SGLT-2 class of agents.

 

A “cardiorenal” composite outcome was also studied in DAPA-CKD. Dapagliflozin led to an approximate 30% relative risk reduction in this outcome, and this effect was consistent in the primary and secondary prevention subgroups. Absolute risk reductions of 4% to 6% were also substantial, irrespective of history of cardiovascular disease.

The number needed to treat ranged from 24 in the primary prevention group to 24 in the secondary prevention group to prevent one patient experiencing a major fatal or nonfatal adverse renal or cardiovascular outcome, over a median of 2.3 years.

New Phosphate Binder (Tenapanor) Data from Kidney Week 20203

Phosphate binding is an important factor in reducing cardiovascular risk in patients with CKD and end-stage renal disease, but often pill burden, tolerability, and gastrointestinal effects limit full adherence with standard therapies.

A 52-week study was conducted, consisting of a 26-week, open-label, randomized treatment period with a 12-week placebo-controlled randomized withdrawal period, followed by a 14-week open label safety extension period.

Patients on maintenance dialysis with serum phosphorus (sP) levels at 6.0 mg/dL or more and less than 10.0 mg/dL and a 1.5 mg/dL increase in sP following washout were randomly assigned 3:1 to receive one tenapanor, 30 mg, tablet twice daily or sevelamer carbonate.

At end of the randomized treatment period, all patients in the tenapanor arm were again randomly assigned 1:1 to either tenapanor or placebo for the withdrawal period. The primary endpoint was the mean change in sP from the end of the treatment period to the end of the withdrawal period. Those results were compared between the tenapanor and placebo arms for the efficacy analysis set, defined as patients demonstrating a 1.2 mg/dL or more decrease in sP at the end of the treatment period.

The study achieved its primary endpoint, demonstrating a statistically significant difference in least squares mean sP change (-1.4 mg/dL, p < .0001) between tenapanor and placebo. For the efficacy analysis set (n=131), the mean sP decreased from 7.7 mg/dL at baseline to 5.1 mg/dL at the end of the 26-week tenapanor treatment period, with a mean reduction of 2.6 mg/dL.

During the 26-week treatment period, 77% of patients taking tenapanor in the intent-to-treat population (n=407) had a decrease in sP, with a mean reduction from baseline of 2.0 mg/dL. Tenapanor was generally well tolerated; the only adverse event, with an incidence rate of more than 5% during the treatment period, was loose stools/diarrhea (53.0%), the majority of which were mild to moderate and transient in nature. During the treatment period, 17.4% of patients taking tenapanor—compared with 23.4% of patients taking sevelamer—experienced a serious adverse event.

The trial results suggest that among patients on maintenance dialysis with hyperphosphatemia, one tablet of tenapanor twice daily is safe and efficacious as monotherapy.

References:

  1. Li ZL, Liu BC. Treatment of renal anemia with Roxadustat: advantages and achievement. Kidney Dis. 2020;6(2):65-73. https://doi.org/10.1159/000504850
  2. McMurray JJV, Wheeler DC, Stefánsson BV, et al; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on clinical outcomes in patients with chronic kidney disease, with and without cardiovascular disease. Circulation. Published online November 13, 2020. https://doi.org/10.1161/CIRCULATIONAHA.120.051675
  3. Chertow GM, Yang Y, Rosenbaum DP. Abstract PO0384: Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with CKD on dialysis. Paper presented at: American Society of Nephrology’s Kidney Week 2020; October 22-25, 2020; Virtual. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3450189