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A Narrative Review Of Chronic Kidney Disease in Clinical Practice: Current Challenges And Future Perspectives Part 2

Apr 21, 2023

NOVEL/EMERGING TREATMENTS FOR CKD MANAGEMENT

Over the last 2 years, novel therapeutic approaches for CKD management have emerged, with particular attention on mineralocorticoid receptor antagonists (MRAs) and sodium–glucose co-transporter 2 (SGLT2) inhibitors. The clinical effectiveness of finer enone, a selective oral, non-steroidal MRA, has recently been demonstrated to lower the risks of CKD progression and cardiovascular events in diabetic kidney disease (DKD) [53]. Finerenone is under review for approval by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA).

According to relevant studies,cistanche is a traditional Chinese herb that has been used for centuries to treat various diseases. It has been scientifically proven to possess anti-inflammatory, anti-aging, and antioxidant properties. Studies have shown that cistanche is beneficial for patients suffering from kidney disease. The active ingredients of cistanche are known to reduce inflammation, improve kidney function and restore impaired kidney cells. Thus, integrating cistanche within a kidney disease treatment plan can offer great benefits to patients in managing their condition. Cistanche helps to reduce proteinuria, lowers BUN and creatinine levels, and decreases the risk of further kidney damage. In addition, cistanche also helps reduce cholesterol and triglyceride levels which can be dangerous to patients suffering from kidney disease.

Cistanche's antioxidant and anti-aging properties help to protect the kidneys from oxidation and damage caused by free radicals. This improves kidney health and reduces the risks of developing complications. Cistanche also helps to boost the immune system, which is essential in fighting off kidney infections and promoting kidney health. By combining traditional Chinese herbal medicine and modern Western medicine, those suffering from kidney disease can have a more comprehensive approach to treating the condition and improving their quality of life. Cistanche should be used as part of a treatment plan but is not to be used as an alternative to conventional medical treatments.

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Of these new and emerging therapies, SGTL2i offers the most clinical benefit with both cardiovascular and renal protective effects, independent of glucose-lowering. Clinical trials of SGTL2 in T2DM with and without CKD overall showed a 14–31% reduction in cardiovascular endpoints including hospitalization for HF and MACE and a 34–37% reduction in hard renal-specific clinical endpoints including a sustained reduction in eGFR, progression of albuminuria and progression to ESKD [54–58]. CREDENCE was a double-blind, multicentre, randomized trial in diabetic patients with albuminuric CKD (eGFR 30 to 90 mL/min per 1.73 m2 and ACR C 30 mg/mmol) [57]. In this trial, canagliflozin reduced the relative risk of the composite of ESKD, doubling serum creatinine and renal-related mortality by 34%, relative risk of ESKD by 34%, and risk of cardiovascular-related morbidity, including myocardial infarction and stroke, and mortality.

The SGTL2i dapagliflozin has proven its effectiveness in slowing CKD progression in addition to reducing cardiovascular risk in the early stages of CKD. The DECLARE-TIMI58 trial involved 17,160 diabetic patients with established atherosclerotic cardiovascular disease and early-stage CKD (mean eGFR was 85.2 mL/min per 1.73 m2) and were randomized to receive either dapagliflozin or placebo. Following a median follow-up of 4.2 years, there was a significant reduction in renal composite endpoints with dapagliflozin versus placebo, with a 46% reduction in the sustained decline of at least 40% eGFR to less than 60 mL/min per 1.73 m2 and a reduction in ESKD (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR \ 15 mL/min per 1.73 m2) or renal death.

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More recently, these cardiovascular and renal protective effects of SGTLT2i have also been demonstrated in a broad range of patients with more advanced stages of CKD (mean eGFR was 43.1 ± 12.4 mL/min per 1.73 m2 ) without diabetes [58, 59]. In the DAPA-CKD trial, many patients were without diabetes, including IgA nephropathy, ischemic/hypertension nephropathy, and glomerulonephritis [59]. Patients receiving dapagliflozin had a 39% relative risk reduction in the primary composite outcomes of a sustained decline in eGFR of at least 50%, ESKD, and renal- or cardiovascular-related mortality and a 31% relative risk reduction of all-cause mortality compared to placebo [58, 60]. Safety outcomes from clinical trials of dapagliflozin have also shown similar incidences of adverse events in both placebo and dapagliflozin arms [58, 61].

The clinical benefits and safety outcomes from these trials highlight the potential use of SGTL2i in reducing the cardiovascular burden and CKD progression in a broad range of CKD aetiologies at early and late stages where there is an unmet need. Currently, SGTL2i class drugs, including canagliflozin, dapagliflozin, and empagliflozin, are approved by the US FDA for the treatment of T2DM and, more recently, dapagliflozin and canagliflozin for CKD and DKD respectively [62, 63]. In addition, SGTL2i has been recommended for approval in the European Union (EU) by the Committee for Medicinal Products for Human Use (CHMP) of the EMA, for the treatment of CKD in adults with and without T2D [64]. Hence, there is now a need to raise awareness of the clinical applicability of these drugs in CKD to ensure full utilization and maximum benefits are met, for both patients and providers.

CONCLUSION

This narrative review has summarised some of the key challenges associated with CKD. Early stages of the disease are clinically silent which prevents early intervention to slow the progression of the disease and allows the progression of CKD and ESKD. At advanced stages of the disease, when clinical symptoms are present, patients with CKD are already at heightened risk of cardiovascular-related morbidity and mortality. Hence, advanced stages of CKD and ESKD are associated with poor outcomes and a signifificant clinical and economic burden.

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At present, there are no treatments to cure CKD; as such, strategies for CKD management have been developed to target the modifiable risk factors to reduce cardiovascular disease morbidity in patients with CKD and slow the progression of CKD to ESKD. However, despite available treatment options, the residual risk of adverse events and CKD progression remains; hence, an unmet need exists in CKD treatment. SGTL2i has the potential to fill this gap, with recent evidence from clinical trials showing a reduction in cardiovascular and renal adverse endpoints in a broad range of patients with CKD.

ACKNOWLEDGEMENTS

Funding. This manuscript was supported by a grant from AstraZeneca UK Ltd. in respect of medical writing and publication costs (the journal’s Rapid Service and Open Access Fees). AstraZeneca has not influenced the content of the publication and has reviewed this document for factual accuracy only.
Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions. All authors have been involved in the design of this review. Marc Evans, Ruth D. Lewis, and Angharad R. Morgan produced the primary manuscript. All authors have contributed to the drafting and revision of the manuscript and have approved the final version for publication. Marc Evans is responsible for the integrity of the work as a whole.
Disclosures. Marc Evans reports honoraria from AstraZeneca, Novo Nordisk, Takeda, and NAPP, and research support from Novo Nordisk outside the submitted work. Ruth D. Lewis and Angharad R Morgan are employees of Health Economics and Outcomes Research Ltd., Cardiff, UK who received fees from AstraZeneca for this study. Martin B. Whyte reports investigator-led research grants from Sanofi, Eli Lilly, and AstraZeneca and personal fees from AstraZeneca, Boehringer Ingelheim, and MSD outside the submitted work. Wasim Hanif reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from NAPP, and from MSD, outside the submitted work. Stephen C. Bain reports personal fees and others from Abbott, personal fees and others from AstraZeneca, personal fees and others from Boehringer Ingelheim, personal fees and others from Eli Lilly, personal fees and others from Merck Sharp & Dohme, personal fees and others from Novo Nordisk, personal fees and other from Sanofi-aventis, other from Cardiff University, other from Doctors.net, other from Elsevier, other from Onmedica, other from Omnia-Med, other from Medscape, other from All-Wales Medicines Strategy Group, other from National Institute for Health and Care Excellence (NICE) UK, and other from Glycosmedia, outside the submitted work. PAK reports personal fees for lecturing from AstraZeneca, Boehringer Ingelheim, NAPP, MundiPharma, and Novo Nordisk outside the submitted work. Sarah Davies has received an honorarium from AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk, Takeda, MSD, NAPP, Bayer, and Roche for attending and participating in educational events and advisory boards, outside the submitted work. Umesh Dashora reports personal fees from AstraZeneca, NAPP, Sanofifi, Boehringer Ingelheim, Lilly, and Novo Nordisk, outside the submitted work. Zaheer Yousef reports personal fees from AstraZeneca, personal fees from Lilly, personal fees from Boehringer Ingelheim, and personal fees from Novartis outside the submitted work. Dipesh C. Patel reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, non-financial support from NAPP, personal fees from Novo Nordisk, personal fees from MSD, personal fees, and non-financial support from Sanofi outside the submitted work. In addition, DCP is an executive committee member of the Association of British Clinical Diabetologists and a member of the CaReMe UK group. W. David Strain holds research grants from Bayer, Novo Nordisk, and Novartis and has received speaker honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, NAPP, Novartis, Novo Nordisk, and Takeda. WDS is supported by the NIHR Exeter Clinical Research Facility and the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula.

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Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any noncommercial use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

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For more info: david.deng@wecistanche.com  WhatApp:86 13632399501

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