Meta-Analysis

. 2023 Dec 1;34(12):1965-1975.

doi: 10.1681/ASN.0000000000000248. Epub 2023 Oct 25.

Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials

Robert A Fletcher¹, Niels Jongs², Glenn M Chertow³, John J V McMurray⁴, Clare Arnott^{1

5

6}, Meg J Jardine^{1

7}, Kenneth W Mahaffey⁸, Vlado Perkovic^{1

9}, Patrick Rockenschaub^{10

11}, Peter Rossing^{12

13}, Ricardo Correa-Rotter¹⁴, Robert D Toto¹⁵, Muthiah Vaduganathan¹⁶, David C Wheeler^{1

17}, Hiddo J L Heerspink^{1

2}, Brendon L Neuen^{1

18}

Affiliations

¹ The George Institute for Global Health, UNSW, Sydney, New South Wales, Australia.
² Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Departments of Medicine, Epidemiology and Population Health, and Health Policy, Stanford University School of Medicine, Stanford, California.
⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
⁵ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
⁶ Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
⁷ NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia.
⁸ Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California.
⁹ Faculty of Medicine and Health, UNSW, Sydney, New South Wales, Australia.
¹⁰ Charité Lab for Artificial Intelligence in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹¹ QUEST Center for Transforming Biomedical Research, Berlin Institute of Health (BIH), Berlin, Germany.
¹² Complications Research, Steno Diabetes Center Copenhagen, Copenhagen, Denmark.
¹³ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁴ National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.
¹⁵ Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
¹⁶ Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
¹⁷ Department of Renal Medicine, University College London, London, United Kingdom.
¹⁸ Royal North Shore Hospital, Sydney, New South Wales, Australia.

PMID: 37876229
PMCID: PMC10703073
DOI: 10.1681/ASN.0000000000000248

Meta-Analysis

Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials

Robert A Fletcher et al. J Am Soc Nephrol. 2023.

. 2023 Dec 1;34(12):1965-1975.

doi: 10.1681/ASN.0000000000000248. Epub 2023 Oct 25.

Authors

Affiliations

¹ The George Institute for Global Health, UNSW, Sydney, New South Wales, Australia.
² Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Departments of Medicine, Epidemiology and Population Health, and Health Policy, Stanford University School of Medicine, Stanford, California.
⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
⁵ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
⁶ Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
⁷ NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia.
⁸ Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California.
⁹ Faculty of Medicine and Health, UNSW, Sydney, New South Wales, Australia.
¹⁰ Charité Lab for Artificial Intelligence in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹¹ QUEST Center for Transforming Biomedical Research, Berlin Institute of Health (BIH), Berlin, Germany.
¹² Complications Research, Steno Diabetes Center Copenhagen, Copenhagen, Denmark.
¹³ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁴ National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.
¹⁵ Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
¹⁶ Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
¹⁷ Department of Renal Medicine, University College London, London, United Kingdom.
¹⁸ Royal North Shore Hospital, Sydney, New South Wales, Australia.

PMID: 37876229
PMCID: PMC10703073
DOI: 10.1681/ASN.0000000000000248

Abstract

Significance statement: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD.

Background: Strategies to enable persistent use of renin-angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated.

Methods: We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups.

Results: During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials ( P -heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P -heterogeneity = 0.009).

Conclusions: In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade.

Clinical trial registry name and registration number: ClinicalTrials.gov, NCT02065791 and NCT03036150 .

Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_11_21_JASN0000000000000248.mp3.

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Conflict of interest statement

C. Arnott is supported by an NHMRC/MRFF Priority Fellowship and a NSW Health EMC Grant. G.M. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee, research grants from CSL Behring, NIAID, and NIDDK; he is on the board of directors for Satellite Healthcare, has received fees for advisory boards for Cricket, DiaMedica, and Reata. He holds stock options for Ardelyx, CloudCath, Durect, DxNow, Outset, Renibus, and Unicycive; has received fees from Akebia, Gilead, Sanifit, and Vertex for trial steering committees; and has received fees for DSMB service from Bayer, Gilead, Mineralys, Palladio and ReCor. G.M. Chertow also reports Consultancy: Akebia, Ardelyx, AstraZeneca, Calico, Gilead, Miromatrix, Reata, Sanifit, Unicycive, and Vertex; Ownership Interest: Eliaz Therapeutics, Physiowave, and PuraCath; Advisory or Leadership Role: Co-Editor, Brenner and Rector's The Kidney (Elsevier). R. Correa-Rotter has received consulting and/or speaker and/or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer, Chinook Therapeutics, GSK, Janssen, Novo Nordisk, and Sanofi. R. Correa-Rotter also reports Consultancy: Dimerix; Research Funding: Astra Zeneca, Baxter, GSK, and Novo Nordisk; Honoraria: Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Janssen, and Sanofi; Advisory or Leadership Role: Astra Zeneca, Bayer, GSK, Membership Steering Committee of DAPA-CKD, Membership Steering Committee FINEREAL, National Leader ASCEND study, National Leader FLOW study, Novo Nordisk, Editorial Board Nefrologia Latinoamericana, Revista de Investigación Clinica, American Journal of Kidney Diseases, Frontiers in Nephrology Associate Editor: Blood Purification Associate Editor; Speakers Bureau: Abbvie; and Other Interests or Relationships: Member of ASN, Member EDTA/ERA, Member of International Society of Nephrology, Member Latin American Society of Nephrology and Hypertension, Member Mexican Institute for Research in Nephrology, and Member of National Kidney Foundation. R.A. Fletcher is supported by a PhD studentship from the Health Data Research UK-The Alan Turing Institute Wellcome Trust Program in Health Data Science. This funding had no role in the production of this manuscript. R.A. Fletcher reports the following: Employer: The George Institute for Global Health and Sensyne Health PLC (employment ended August 2021). H.J.L. Heerspink is consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Merck, Novo Nordisk, ProKidney, Travere Therapeutics, and Vifor Fresenius. He has received research support from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk. H.J.L. Heerspink also reports Consultancy: Novartis; Honoraria: Lecture fees from AstraZeneca and Novo Nordisk; and Speakers Bureau: AstraZeneca. M.J. Jardine is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; is responsible for research projects that have received unrestricted funding from Amgen, Baxter, Eli Lilly, and Merck Sharpe Dohme; serves on a Steering Committee sponsored by CSL; has served on advisory boards sponsored by Akebia, Baxter, Boehringer Ingelheim, and Vifor; and has spoken at scientific meetings sponsored by Janssen; with any consultancy, honoraria, or travel support paid to her institution. M.J. Jardine also reports the following: Research Funding: CSL and Dimerix with all payments to institution; Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, MSD, Occuryx, and Vifor, and directs honoraria to clinical research programs; Advisory or Leadership Role: Chinook and Janssen, All honoraria directed to clinical research programs; and Speakers Bureau: Astra Zeneca, Boehringer Ingelheim, Janssen, and directs speaker fees to clinical research programs. N. Jongs reports travel grants from AstraZeneca. K.W. Mahaffey has received research support from Afferent, Amgen, Apple Inc., AstraZeneca, Cardiva Medical Inc., Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, National Institutes of Health, Novartis, Sanofi, St. Jude, and Tenax and has served as a consultant (speaker fees for continuing medical education events only) for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi Tanabe, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and University of California, San Francisco. J.J.V. McMurray has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; has received personal lecture fees from the Abbott, Corpus, Global Clinical Trial Partners (GCTP), Hikma, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Sun Pharmaceuticals. B.L. Neuen has received fees for advisory boards, steering committee roles, scientific presentations, and travel support from AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, Janssen, the Limbic, and Medscape, with all honoraria paid to his institution. B.L. Neuen also reports Consultancy: AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, and Janssen; Research Funding: Bayer; Honoraria: AstraZeneca, Bayer, Boehringer and Ingelheim, Cornerstone Medical Education, Janssen, the Limbic, and Medscape; Advisory or Leadership Role: AstraZeneca, Bayer, and Boehringer and Ingelheim; and Speakers Bureau: AstraZeneca and Boehringer and Ingelheim. V. Perkovic serves as a Board Director for St. Vincent's Health Australia, George Clinical and several Medical Research Institutes. He has received honoraria for Steering Committee roles, scientific presentations and/or advisory board attendance from Abbvie, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pfizer, Pharmalink, Reata, Relypsa, Roche, Sanofi, Servier, Travere, and Tricida. V. Perkovic also reports Consultancy: AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Travere, Tricida, and UptoDate; Ownership Interest: George Clinical; Research Funding: AstraZeneca, Bayer, Chinook, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Otsuka, Travere, and Tricida; Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Travere, Tricida, and UptoDate. P. Rockenschaub is supported by the Alexander von Humboldt Foundation. P. Rossing declares receiving consultancy and/or speaking fees (to his institution) from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Novo Nordisk, Sanofi, and Vifor Pharma, and research grants from AstraZeneca, Bayer, and Novo Nordisk. P. Rossing also reports Honoraria: Abbott, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk, all honoraria to institution; and Advisory or Leadership Role: AstraZeneca, Bayer, Gilead, and Novo Nordisk, all honoraria to institution. R.D. Toto reports grant support from NIH and is a consultant to and has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Otsuka, Reata, and Relypsa. M. Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, speaker engagements with AstraZeneca, Novartis, and Roche Diagnostics, and participates on clinical trial committees for studies sponsored by Bayer AG, Galmed, Impulse Dynamics, Novartis, and Occlutech. M. Vaduganathan also reports Consultancy: American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; Research Funding: Galmed, Impulse Dynamics, and Occlutech; and Speakers Bureau: AstraZeneca, Cytokinetics, Lexicon Pharmaceuticals, Novartis, and Roche Diagnostics. D.C. Wheeler has received honoraria and/or consultancy fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Medscape, Merck Sharp and Dohme, Mundipharma, Napp, Reata, Takeda, Tricida, Vifor Fresenius, and Zydus. D.C. Wheeler also reports Consultancy: Astellas, Eledon, Galderma, George Clinical, Pfizer, and ProKidney; Advisory Boards, Trial Committees and Consultancy; Honoraria: Astellas and Pharmacosmos; Advisory or Leadership Role: AstraZeneca; and Speakers Bureau: Amgen, Astellas, AstraZeneca, Janssen, Merck Sharp and Dohme, Mundipharma, Napp, and Vifor Fresenius. K. Mahaffey reports Consultancy: Amgen, Applied Therapeutics, Bayer, BMS, BridgeBio, CSL Behring, Elsevier, Fibrogen, Fosun Pharma, Johnson & Johnson, Lexicon, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, Theravance; Research Funding: AHA, Apple Inc, Bayer, California Institute Regenerative Medicine, Eidos, Ferring, Gilead, Google (Verily), Idorsia, Johnson & Johnson, Luitpold, Novartis, PAC-12, Precordior, Sanifit; and Honoraria: Inova, Intermountain Health, Medscape, Mount Sinai, CSL. J. McMurray reports Consultancy: Personal Consultancy fees: Alynylam Pharmaceuticals, Bayer, BMS, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp.; Data Safety Monitoring Board: George Clinical PTY Ltd.; Honoraria: Personal lecture fees: Abbott, Alkem Metabolics, AZ, Blue Ocean Scientific Solutions Ltd., BI, Canadian Medical and Surgical Knowledge, Emcure Pharma., Eris Lifesciences, European Academy of CME, Hikma Pharma., Imagica Health, Intas Pharma., J.B. Chemicals & Pharma.., Lupin Pharma., Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharma., The Corpus, Translation Research Group, Translational Medicine Academy.; Advisory or Leadership Role: employer, Glasgow University, has been paid for my participation in advisory boards organized by Novartis and AstraZeneca; and Other Interests or Relationships: Payments to my employer, Glasgow University, for my work on clinical trials, consulting and other activities: Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, Novartis; Director: Global Clinical Trial Partners Ltd (GCTP). C. Arnott reports Research Funding: Abbott Vascular; Honoraria: Amgen; Astra Zeneca, Novo Nordisk; and Advisory or Leadership Role: Novo Nordisk. R. Toto reports Consultancy: Amgen, Bayer, Astra-Zeneca, Boehringer-Ingelheim, Novartis, Novo Nordisk, CinCor, Calliditas, Otsuka, Medscape; Research Funding: NIH; Honoraria: Amgen, Bayer, Astra-Zeneca, Boehringer-Ingelheim, Novartis, Novo Nordisk, CinCor, Calliditas, Otsuka, Medscape; and Advisory or Leadership Role: Amgen, Bayer, Astra-Zeneca, Boehringer-Ingelheim, Novartis, Novo Nordisk, CinCor, Calliditas, Otsuka, Medscape.

Figures

**Figure 1**
**Cumulative incidence curves of incident temporary or permanent discontinuation of RAS blockade in CREDENCE and DAPA-CKD.** The insets show the same data on an expanded y axis. The competing risk of death was considered when estimating cumulative incidence functions. CI, confidence interval; CREDENCE, canagliflozin and renal events in diabetes with established nephropathy clinical evaluation; DAPA-CKD, dapagliflozin and prevention of adverse outcomes in CKD; RAS, renin–angiotensin system.

**Figure 2**
**Effects of SGLT2i on temporary or permanent discontinuation of RAS blockade.** SGLT2i, sodium–glucose cotransporter 2 inhibitor; HR, hazard ratio.

**Figure 3**
Effects of SGLT2i on temporary or permanent discontinuation of RAS blockade by baseline-defined participant subgroups.

See this image and copyright information in PMC

References

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Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials

Affiliations

Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials

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Abstract

Conflict of interest statement

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