The RENAL LIFECYCLE Trial: A RCT to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe CKD

A Randomized Controlled Clinical Trial to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe Chronic Kidney Disease

Rationale:

Sodium glucose co transporter 2 (SGLT2) inhibitors are a relatively new class of agents, originally developed as oral antihyperglycemic drugs. SGLT2 inhibitors are clinically available since 2012 for the treatment of patients with diabetes mellitus type 2. Later, SGLT2 inhibitors appeared to have also specific reno- and cardioprotective effects. Remarkably, the trials that have been performed thus far excluded patients with an eGFR below 25 mL/min/1.73m2 at inclusion, prevalent dialysis patients, and kidney transplant recipients. This is unfortunate, because especially these patients are at high risk of reaching kidney failure requiring dialysis, cardiovascular complications and mortality, whereas there are only few proven effective therapies. There is emerging evidence from experimental studies and post hoc-analyses of randomized clinical trials that SGLT2 inhibitors may also be effective in preventing cardiovascular and mortality outcomes in these patients with severe CKD, including patients receiving dialysis or living with a kidney transplant. For instance, subgroup analysis of the DAPA-CKD trial comparing 624 patients with an eGFR<30 to the remainder of the trial population with better kidney function, demonstrated that the efficacy of the SGLT2 inhibitor dapagliflozin in reducing cardiovascular, heart failure and renal outcomes persisted in the population with impaired kidney function. Furthermore, in the DAPA-CKD trial patients continued to use dapagliflozin or placebo when dialysis was initiated. In the subgroup of patients who initiated dialysis, dapagliflozin was associated with a relative risk reduction for mortality of 21%. Finally, in kidney transplant recipients, SGLT2 inhibitors have been shown to be effective in lowering HbA1c, body weight, blood pressure and stabilize kidney function, and these agents were well tolerated and safe. Taken these findings together there is a sound rationale to study the long-term reno- and cardioprotective efficacy and safety of SGLT2 inhibitors in patients with severe CKD.

There are two cardiac sub-studies: the cardiac magnetic resonance imaging (MRI) sub-study and the echocardiography sub-study. The echocardiography sub-study is referred to as the "SGLT-2-inhibitors to Target Heart Failure in Peritoneal Dialysis" (STOP-HF-in-PD) study.

Study Overview

• Status: Enrolling by invitation
• Conditions: Heart Failure; Death; Kidney Disease, Chronic; Kidney Failure; Renal Transplant Failure
• Intervention / Treatment: Drug: Dapagliflozin 10 mg/day (oral); Drug: Placebo

Detailed Description

Objective:

To establish the reno- and cardioprotective efficacy and safety of dapagliflozin in patients with severe CKD

Study design:

Multicenter, randomized, controlled, double blinded, pragmatic, interventional trial

Study population:

• Patients with advanced CKD, i.e. an eGFR ≤25 mL/min*1.73m2
• Patients on dialysis (at least 3 months after start of dialysis)
• Patients with a kidney transplant and an eGFR ≤45 mL/min/1.73m2 (at least 6 months after transplantation)

Intervention:

Dapagliflozin 10 mg/day or matching placebo

Primary outcome measure:

Combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population

Study duration:

18 month recruitment phase, 30 month follow-up after enrollment of the last patient: Total study duration intended to last 48 months. It should be noted that the trial is event driven and will be terminated when 468 primary composite outcomes have occurred. The exact trial duration may therefore be shorter or longer than the intended 48 months.

Study visits:

Screening, baseline, week 2, month 3, month 6 and every 6 months thereafter. Information needed for the trial will be obtained as much as possible from visits taking place as part of routine clinical care.

Sample size:

Renal Lifecycle is designed as an endpoint driven trial and will finish when 468 primary study outcomes have occurred. The investigators have estimated a sample size of 1750-2000 patients.

Novel aspects:

A unique patient population with severe chronic kidney disease at very high risk of adverse outcomes for whom very few proven effective therapies exist. The initiation and efficacy of SGLT2 inhibitors, including dapagliflozin, has not been studied before in this population. However, SGLT2 inhibitors have the potential to be very effective and well tolerated which would imply a major advance in the pharmacotherapy of these patients.

When patients reach a renal endpoint, e.g. start or chronic dialysis or receiving a kidney transplantation, study medication will not be stopped as customary in many other trials in nephrology, but continued in the new phase of their "renal lifecycle", hence the name of the trial.

Sub studies:

Cardiac MRI sub-study The cardiac MRI sub-study will evaluate the effect of dapagliflozin on cardiac remodelling, as compared to placebo, measured with indexed left ventricular mass (LVMi), an intermediate cardiovascular outcome, in 250 participants across all three groups of the Renal Lifecycle Trial (i.e. advanced CKD, dialysis, kidney transplant recipients). This will provide robust evidence on the mechanisms under-pinning the cardioprotective effects of SGLT2 inhibitors in this high-risk patient population.

Primary outcome: Difference in LVMi after 12 months dapagliflozin compared to placebo.

Secondary outcomes: Differences between intervention groups in the following parameters at 12 months post-randomization: non-indexed LVM; indexed left atrial volume; non-indexed left atrial volume; indexed left and right ventricular end diastolic volume; indexed left and right ventricular end systolic volume; left and right ejection fraction.

Echocardiography sub-study (STOP-HF-in-PD) The echocardiography sub-study (STOP-HF-in-PD) will evaluate the effect of dapagliflozin on cardiac function, as compared to placebo, measured by left ventricular global longitudinal strain (LV-GLS), in 100 participants with kidney failure treated with peritoneal dialysis (PD). This will provide additional evidence on the mechanisms underlying the cardiac effects of SGLT2i in patients with kidney failure. Furthermore, the LV-GLS-data will be related to measured CKD- and PD-associated mediators of heart failure (measured in serum, urine and peritoneal effluent). This will aid to determine their relevance in patients with kidney failure, as well as to define if and to what extent SGLT2i affect these mediators in patients with kidney failure.

Primary outcome: Difference in LV-GLS after 6 months dapagliflozin compared to placebo.

Secondary and exploratory objectives: Differences between dapagliflozin compared to placebo after 6 and 12 months post-randomization for: LV-GLS; E/e'-ratio; left atrial volume index; left atrial strain; tricuspid velocity; left ventricular ejection fraction; LVMi; Physical functioning (6 minute walking test and KCCQ-12); 24h urine volume; residual kidney function; average daily ultrafiltration volume; peritoneal glucose exposure; peritoneal membrane characteristics.

Combined Cardiac Imaging Sub-studies A subset of participants enrolled in the echocardiography sub-study will also participate in the cardiac MRI sub-study, allowing for a combined evaluation of both imaging modalities. The aim is to evaluate the use of echocardiography and cardiac MRI as a tool to identify patients at highest risk for heart failure and those who may benefit from SGLT2i-induced cardio-protection.

Secondary outcomes: Association between change in LV-GLS and change in LVMi from baseline to 12-months across intervention groups; association between change in LV-GLS at 6 months and change in LVMi at 12 months across intervention groups.

Cognitive sub-study Patients with chronic kidney disease (CKD) are at a much higher risk for developing cognitive impairment compared with the general population and both lower glomerular filtration rate and the presence of albuminuria are associated with its development. SGLT-2 inhibitor use is associated with better preservation of cognitive function in patients with CKD including those on hemodialysis and after kidney transplantation compared to placebo.Patients will be requested to perform the symbol digit modalities test at the same time as the questionnaires, i.e. at baseline (visit 2), visit 5 and visit 6, once every year after visit 6 and at EoT/EET.The primary outcome of the cognition sub study is the change over time in the number of correct answers in the symbol digit modalities test within 90 seconds.

Kidney metabolism substudy The primary aim of this substudy is to evaluate the effect of dapagliflozin 10 mg compared to a placebo on energy metabolism assessed by changes in the renal mitochondrial oxidative phosphorylation capacity in kidney transplant recipients participating in the RENAL LIFECYCLE Trial at the 3-month Follow-up Visit. Further aims of this substudy are to evaluate the differences in metabolic substrate preferences by measuring ketone body or acylcarnitine substrate-driven mitochondrial respiration following the randomization to dapagliflozin or placebo.

Differences in mitochondrial architecture including mitochondrial quantity and morphology will be assessed using electron microscopy.

• Study Type: Interventional
• Enrollment (Estimated): 1750
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia
    • Box Hill Hospital (Eastern Health)
  • Australian Capital Teritory
    • Canberra, Australian Capital Teritory, Australia
      • Canberra Health Services
  • New South Wales
    • New Lambton Heights, New South Wales, Australia
      • John Hunter Hospital
    • Sydney, New South Wales, Australia
      • St George Hospital
    • Sydney, New South Wales, Australia
      • Concord Repatriation General Hospital
    • Sydney, New South Wales, Australia
      • Liverpool Hospital
    • Sydney, New South Wales, Australia
      • Prince of Wales Hospital
    • Sydney, New South Wales, Australia
      • Royal North Shore Hospital
    • Sydney, New South Wales, Australia
      • Royal Prince Alfred Hospital
    • Sydney, New South Wales, Australia
      • Westmead Hospital
    • Wollongong, New South Wales, Australia
      • Wollongong Hospital
  • Queensland
    • Birtinya, Queensland, Australia
      • Sunshine Coast Hospital and Health Services
    • Brisbane, Queensland, Australia
      • Royal Brisbane and Womens Hospital
    • Douglas, Queensland, Australia
      • Townsville University Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia
      • Western Health
    • Parkville, Victoria, Australia
      • Royal Melbourne Hospital
  • Western Australia
    • Perth, Western Australia, Australia
      • East Metro Health Services (Royal Perth Hospital and Armadale Health Services)
• Belgium
  • Antwerp, Belgium
    • UZ Antwerpen
  • Brussels, Belgium
    • UZ Brussel
  • Hasselt, Belgium
    • Jessa Ziekenhuis
  • Kortrijk, Belgium
    • AZ Groeninge
  • Leuven, Belgium
    • UZ Leuven
  • Ronse, Belgium
    • AZ Glorieux
• Germany
  • Berlin, Germany, 10117
    • Charité
  • Berlin, Germany, 12627
    • Praxis für Dialyse und Nierenkrankheiten
  • Düsseldorf, Germany, 40225
    • Universitätsklinikum Düsseldorf
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen
  • Halle, Germany, 06120
    • Universitätsklinikum Halle (Saale) Innere Medizin 2
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf
  • Hanover, Germany, 30625
    • Zentrum fuer Nieren-, Hochdruck- und Stoffwechselerkrankungen Hannover
  • Heidelberg, Germany, 69120
    • Nierenzentrum Heidelberg
  • Heilbronn, Germany, 74076
    • Dialysezentrum Heilbronn - Überörtliche Berufsausübungsgemeinschaft für Nephro und Dialyse (ÜBAG)
  • Jena, Germany, 07747
    • Universitätsklinikum JenaKlinik für Innere Medizin III
  • Mainz, Germany, 55131
    • Universitätsmedizin Mainz
  • Regensburg, Germany, 93053
    • Universitätsklinikum RegensburgAbteilung für Nephrologie
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen Medizinische Klinik IV
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm, Klinik für Innere Medizin I, Nephrologie
  • Villingen-Schwenningen, Germany, 678052
    • Nephrologisches Zentrum Villingen/Schwenningen
  • Wiesbaden, Germany, 2365191
    • Nierenzentrum Wiesbaden
  • Würzburg, Germany, 697080
    • Medizinische Klinik und Poliklinik I der Universitätsklinik WürzburgSchwerpunkt Nephrologie
• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Ziekenhuis
  • Alkmaar, Netherlands
    • Noordwest Ziekenhuisgroep Alkmaar
  • Amersfoort, Netherlands
    • Meander Medisch Centrum
  • Amstelveen, Netherlands
    • Niercentrum aan de Amstel
  • Amsterdam, Netherlands
    • Dialysecentrum Dianet (Amsterdam)
  • Delft, Netherlands
    • Reinier de Graaf Ziekenhuis
  • Deventer, Netherlands
    • Deventer Ziekenhuis
  • Eindhoven, Netherlands
    • Catharina Ziekenhuis Eindhoven
  • Eindhoven, Netherlands
    • Máxima Medisch Centrum
  • Groningen, Netherlands
    • Martini Ziekenhuis
  • Hilversum, Netherlands
    • Dialysecentrum Tergooi
  • Hoofddorp, Netherlands
    • Spaarne Gasthuis
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Leiden, Netherlands
    • Leiden UMC
  • Lelystad, Netherlands
    • St. Jansdal Ziekenhuis
  • Maastricht, Netherlands
    • Maastricht UMC+
  • Nieuwegein, Netherlands
    • St. Antonius Ziekenhuis
  • Nijmegen, Netherlands
    • Radboud UMC
  • Roosendaal, Netherlands
    • Bravis Ziekenhuis
  • Rotterdam, Netherlands
    • Franciscus Gasthuis en Vlietland
  • Uden, Netherlands
    • Bernhoven
  • Utrecht, Netherlands
    • UMC Utrecht
  • Utrecht, Netherlands
    • Diakonessenhuis Utrecht
  • Utrecht, Netherlands
    • Dialysecentrum Dianet (Utrecht)
  • Venlo, Netherlands
    • Viecuri Medisch Centrum
  • Zwolle, Netherlands
    • Isala Ziekenhuis
  • Drenthe
    • Assen, Drenthe, Netherlands
      • Wilhelmina Ziekenhuis Assen
  • Flevoland
    • Almere Stad, Flevoland, Netherlands
      • Flevoziekenhuis
  • Gelderland
    • Apeldoorn, Gelderland, Netherlands
      • Gelre Ziekenhuizen
  • Limburg
    • Roermond, Limburg, Netherlands
      • Laurentius Ziekenhuis
    • Sittard, Limburg, Netherlands
      • Zuyderland Medisch Centrum
  • North Brabant
    • Breda, North Brabant, Netherlands
      • Amphia Ziekenhuis
  • North Holland
    • Amsterdam, North Holland, Netherlands
      • Amsterdam UMC
    • Amsterdam, North Holland, Netherlands
      • OLVG
  • Overijssel
    • Almelo, Overijssel, Netherlands
      • Ziekenhuisgroep Twente
    • Hardenberg, Overijssel, Netherlands
      • Saxenburgh Medisch Centrum
  • Provincie Groningen
    • Groningen, Provincie Groningen, Netherlands
      • Dialyse Centrum Groningen
    • Groningen, Provincie Groningen, Netherlands
      • UMCG
  • South Holland
    • Dordrecht, South Holland, Netherlands
      • Albert Schweitzer Ziekenhuis
    • Leiderdorp, South Holland, Netherlands
      • Alrijne
    • Rotterdam, South Holland, Netherlands
      • Erasmus Medisch Centrum
    • Rotterdam, South Holland, Netherlands
      • Maasstad Ziekenhuis
    • The Hague, South Holland, Netherlands
      • Haaglanden Medisch Centrum
    • The Hague, South Holland, Netherlands
      • Hagaziekenhuis
  • Zeeland
    • Goes, Zeeland, Netherlands
      • Admiraal de Ruyter Ziekenhuis
• Singapore
  • Singapore, Singapore
    • National University Hospital
  • Singapore, Singapore
    • Changi General Hospital
  • Singapore, Singapore
    • Sengkang General Hospital
  • Singapore, Singapore
    • Singapore General Health
• Spain
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain
    • Hospital Universitari de Bellvitge
  • Barcelona, Spain
    • Vall d'Hebron University Hospital
  • Barcelona, Spain
    • Hospital Clinic Barcelona
  • Barcelona, Spain
    • Hospital Universitari Germans Trias i Pujol
  • Lleida, Spain
    • Hospital Arnau De Vilanova
  • Madrid, Spain
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain
    • Hospital Universitario Puerta de Hierro
  • Palma de Mallorca, Spain
    • Hospital Son Llatzer
  • Pamplona, Spain
    • Clinica Universidad de Navarra
  • Valencia, Spain
    • Hospital Clinico Universitario de Valencia
  • Valencia, Spain
    • Hospital Universitari Dr Peset

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with advanced CKD i.e. an eGFR ≤25 mL/min/1.73m2
• Dialysis patients (at least 3 months after start of dialysis)
• Transplant patients with an eGFR ≤45 mL/min/1.73m2 (at least 6 months after transplantation)

In addition, to be eligible all subjects must meet all criteria below

• Age >18 years
• Willing to sign informed consent
• Pre-dialysis patients with eGFR ≤25 mL/min/1.73m2 have to be on a stable dose (no changes in dose or type of drug) of ACEis or ARBs for at least 4 weeks prior to the screening visit to be eligible to proceed to the randomization visit unless there is documented evidence that the patient does not tolerate an ACEi or ARB. These subjects will maintain their stable doses of ACEis or ARBs throughout the trial (when possible and tolerated by the patient). ACEi or ARBs are not required for patients on maintenance dialysis or kidney transplant recipients.

Exclusion Criteria:

• Mentally incapacitated subjects (i.e. not able to sign informed consent)
• Diagnosis of type 1 diabetes mellitus
• Concurrent treatment with SGLT2 inhibitor
• History of ≥2 urinary tract / genital infections during the last six months
• Life expectancy <6 months in the opinion of the treating physician.
• Scheduled start of dialysis within 3 months or kidney transplantation within 6 months
• patients treated for a renal indication during the last 6 months with a course of systemic immunosuppressive agents or intensification of treatment with systemic immunosuppressive agents, such as patients with a kidney transplant and acute rejection or patients with GPA (Morbus Wegener) and a recent flare.
• Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin.
• History of severe hypersensitivity or known severe hepatic impairment (Child-Pugh class C)
• History of severe noncompliance to medical regimens or unwillingness to comply with the study protocol.
• Pregnancy or breastfeeding
• Presence of other transplanted organ besides a kidney transplant
• Severe lactose intolerance
• Autosomal Dominant Polycystic Kidney Disease (ADPKD) treated with tolvaptan

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; Dapagliflozin 10 mg/day (oral)	Drug: Dapagliflozin 10 mg/day (oral); Patients take 10 mg dapagliflozin or matching placebo once daily in the morning; Other Names: Forxiga
Placebo Comparator: Placebo; Placebo 10 mg/day (oral)	Drug: Placebo; Patients take 10 mg dapagliflozin or matching placebo once daily in the morning

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of partipants with all-cause mortality, kidney failure, and hospitalization for heart failure	To determine whether dapagliflozin is superior to placebo in reducing the incidence of the primary composite endpoint Combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population	Total study duration intended to last 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants to reach all-cause mortality	To determine if dapagliflozin is superior to placebo in reducing the incidence of all-cause mortality	Total study duration intended to last 48 months
Incidence of hospitalization for heart failure	Incidence of hospitalization for heart failureTo determine if dapagliflozin is superior to placebo in reducing the incidence of heart failure	Total study duration intended to last 48 months
Incidence of kidney failure (chronic dialysis, kidney transplantation or mortality due to kidney failure)	To determine if dapagliflozin is superior to placebo in reducing the incidence of kidney failure	Total study duration intended to last 48 months
incidence of the composite outcome (kidney failure, hospitalization for heart failure, and all-cause mortality) in subgroups	To determine whether dapagliflozin is superior to placebo in reducing the incidence of the composite outcome in subgroups subgroups: advanced CKD i.e. an eGFR ≤30 mL/min/1.73m2, dialysis patients and transplant patients	Total study duration intended to last 48 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
measuring Quality of life with the EQ-5D questionnaire	To determine whether dapagliflozin is superior to placebo in comparing the Quality of Life for all subgroups based on the EQ-5D questionnaire	Total study duration intended to last 48 months
measuring Quality of life with the SF12 questionnaire	To determine whether dapagliflozin is superior to placebo in comparing the Quality of Life for all subgroups based onthe SF12 questionnaire	Total study duration intended to last 48 months
Cost-effectiveness of SGLT2-inhibition using the Quality of Life-data derived from the EQ-5D and SF-12 questionnaires	cost-effectiveness of SGLT2-inhibition in the overall study population as well as in the three subpopulations	Total study duration intended to last 48 months
incidence of de-novo type 2 diabetes in patients without diabetes	To determine whether dapagliflozin is superior to placebo in reducing the incidence of de-novo type 2 diabetes	Total study duration intended to last 48 months
Change in the eGFR slope	To determine whether dapagliflozin is superior to placebo in reducing the eGFR slope eGFR slope; for the dialysis subgroup slope residual kidney function will be calculated using the average of 24hr urinary creatinine and urea clearance values over time	Total study duration intended to last 48 months
incidence of diuresis <200 ml/24hr in the dialysis subgroup	To determine whether dapagliflozin is superior to placebo in the incidence of diuresis <200 ml/24hr in the dialysis subgroup for this purpose 24hr urine samples will be collected ≥2 times per year	Total study duration intended to last 48 months
incidence of the composite outcome (kidney failure, hospitalization for heart failure, and all-cause mortality) in subgroups with and without type 2 diabetes separately	To determine if dapagliflozin is superior to placebo in reducing the incidence of kidney failure with and without type 2 diabetes separately	Total study duration intended to last 48 months

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: AstraZeneca; Dutch Kidney Foundation
• Investigators: Principal Investigator: Ron Gansevoort, University Medical Center Groningen

Publications and helpful links

General Publications

• Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14.
• Chertow GM, Vart P, Jongs N, Toto RD, Gorriz JL, Hou FF, McMurray JJV, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Langkilde AM, Wheeler DC, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease. J Am Soc Nephrol. 2021 Sep;32(9):2352-2361. doi: 10.1681/ASN.2021020167. Epub 2021 Jul 16.
• Chewcharat A, Prasitlumkum N, Thongprayoon C, Bathini T, Medaura J, Vallabhajosyula S, Cheungpasitporn W. Efficacy and Safety of SGLT-2 Inhibitors for Treatment of Diabetes Mellitus among Kidney Transplant Patients: A Systematic Review and Meta-Analysis. Med Sci (Basel). 2020 Nov 17;8(4):47. doi: 10.3390/medsci8040047.
• Heerspink HJL, Jongs N, Chertow GM, Langkilde AM, McMurray JJV, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Wheeler DC, Greene T; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):743-754. doi: 10.1016/S2213-8587(21)00242-4. Epub 2021 Oct 4.
• Garcia-Cosio Carmena MD, Farrero M, Blasco Peiro MT, Crespo M, Delgado Jimenez J, Diaz Molina B, Fernandez Rivera C, Garrido Bravo IP, Lopez Jimenez V, Melilli E, Mirabet Perez S, Perez Tamajon ML, Rangel Sousa D, Rodrigo E, Cruzado JM, Hernandez Marrero D; Spanish Society of Transplantation, the Spanish Society of Nephrology, and the Spanish Society of Cardiology (SET-SEC-SEN). Management of Kidney Disease in Heart Transplant Patients: A National Delphi Survey-based Consensus Expert Paper. Transplantation. 2025 Sep 1;109(9):e431-e445. doi: 10.1097/TP.0000000000005302. Epub 2025 Feb 7.
• Gill M, Leung M, Luo CY, Cheung C, Beauchesne A, Chang D, Lan J, Johnston O. Erythrocytosis and thrombotic events in kidney transplant recipients prescribed a sodium glucose cotransport-2 inhibitor. Clin Transplant. 2023 Aug;37(8):e15013. doi: 10.1111/ctr.15013. Epub 2023 May 11.
• Bakker WM, Heerspink HJL, Berger SP, Wanner C, Badve SV, Arnott C, Abrahams AC, van den Born JC, van Faassen TC, Gaillard CAJM, Gelens MACJ, Gorris JL, Hemmelder MH, Jakulj L, van Kruijsdijk RCM, Kuypers DRJ, van der Meer P, van der Net JB, Nijmeijer HH, Vervloet MG, de Vries APJ, Walsh M, Wang AY, Gansevoort RT; Renal Lifecycle Trial Investigators. Rationale and design of the Renal Lifecycle trial assessing the effect of dapagliflozin on cardiorenal outcomes in severe chronic kidney disease. Nephrol Dial Transplant. 2025 Aug 29;40(9):1746-1755. doi: 10.1093/ndt/gfaf046.
• Karsten M, Badve SV, Gansevoort RT, Berger SP, Heerspink HJL, Abrahams AC, Billot L, Bon RHACM, Gelens MACJ, Guinness D, Hamilton-Craig C, van Heerebeek L, Hemmelder MH, Houston L, Kozor R, Kuypers DRJ, Monaghan H, Neal B, Neuen BL, Otton J, Perkovic V, Rajwani A, Wang AY, Vervloet MG, Arnott C, Jakulj L; Renal Lifecycle Trial Cardiac Imaging Sub-studies Investigators. Cardiac impact of dapagliflozin in advanced chronic kidney disease: rationale and design of the Renal Lifecycle Trial cardiac imaging sub-studies. Clin Kidney J. 2025 Dec 2;19(1):sfaf376. doi: 10.1093/ckj/sfaf376. eCollection 2026 Jan.

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2022
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: April 22, 2022
• First Submitted That Met QC Criteria: May 9, 2022
• First Posted (Actual): May 16, 2022

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Dapagliflozin; dialysis; kidney transplant; advanced CKD; all-cause mortality; kidney failure; hospitalization for heart failure
• Additional Relevant MeSH Terms: Urogenital Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Chronic Disease; Disease Attributes; Pathological Conditions, Signs and Symptoms; Heart Failure; Renal Insufficiency; Renal Insufficiency, Chronic; Death; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; dapagliflozin
• Other Study ID Numbers: 202100617; 2021-005446-15 (EudraCT Number); 2023-508389-13-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No