Abstract
Introduction
Persistent proteinuria despite control of overt disease activity remains an important marker of residual kidney risk in lupus nephritis (LN). Although sodium–glucose cotransporter 2 inhibitors improve kidney outcomes across broader chronic kidney disease populations, randomised evidence specifically in LN remains limited. The DAPA-LN trial will evaluate the efficacy and safety of adjunctive dapagliflozin in patients with biopsy-confirmed LN, clinically stable or low-activity disease and persistent proteinuria.
Methods and analysis
DAPA-LN is an investigator-initiated, multicentre, randomised, open-label, blinded-endpoint superiority trial conducted at seven hospitals in China. A total of 270 adults with biopsy-confirmed LN (class III or IV with or without class V involvement, or pure class V), persistent proteinuria defined as a urine protein-to-creatinine ratio >0.5 and ≤ 3.5 g/g, and an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 will be randomly assigned in a 1:1 ratio to receive dapagliflozin 10 mg once daily plus standard background therapy or standard background therapy alone. Background therapy will comprise stable maintenance immunosuppression and renin–angiotensin system inhibition with either an ACE inhibitor or an angiotensin receptor blocker as monotherapy. The primary efficacy endpoint will be renal response at week 52, defined by prespecified improvement in proteinuria together with preservation of kidney function. The primary safety endpoint will be the proportion experiencing at least one prespecified clinically significant adverse event of special interest through week 52. Secondary endpoints will assess proteinuria, kidney function, renal flare, immunosuppression intensification, disease activity, hospitalisation and safety outcomes. The primary efficacy analysis will follow the intention-to-treat principle and safety analyses will be descriptive. Exploratory follow-up will continue through week 104.
Trial registration number
ChiCTR2600131121.
Keywords: Lupus Nephritis; Clinical Trial; Lupus Erythematosus, Systemic
WHAT IS ALREADY KNOWN ON THIS TOPIC
Persistent proteinuria remains common among patients with clinically stable or low-activity lupus nephritis (LN) and is associated with an increased risk of adverse long-term kidney outcomes. Evidence supporting the use of sodium–glucose cotransporter 2 inhibitors in this population is derived largely from broader chronic kidney disease populations, with limited randomised evidence specifically in LN.
WHAT THIS STUDY ADDS
DAPA-LN is a seven-centre, parallel-group randomised trial evaluating dapagliflozin as an adjunct to stable maintenance immunosuppression and renin–angiotensin system inhibition in adults with biopsy-confirmed LN and persistent proteinuria. The primary efficacy endpoint is renal response at week 52, integrating prespecified improvement in proteinuria with preservation of kidney function; the primary safety endpoint comprises prespecified clinically significant adverse events of special interest.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The findings may provide evidence regarding the potential role of dapagliflozin as an adjunctive non-immunosuppressive strategy for addressing residual kidney risk in selected patients with clinically stable LN and persistent proteinuria, and may inform future clinical recommendations and the design of subsequent kidney-protection trials in LN.
Introduction
Lupus nephritis (LN) is one of the most serious manifestations of SLE and a major contributor to chronic kidney disease (CKD) progression, kidney failure and premature mortality.1 2 Contemporary management combines immunosuppression targeting immune-mediated kidney inflammation with supportive interventions aimed at reducing non-immune kidney injury, including blood pressure control, renin–angiotensin system (RAS) inhibition, dietary sodium restriction and management of cardiovascular and metabolic risk factors.2 3 Despite adequate control of overt disease activity, persistent proteinuria remains common during maintenance therapy and is associated with subsequent loss of kidney function and progression to kidney failure. Therefore, reducing proteinuria while preserving kidney function represents an important therapeutic goal in the long-term management of LN.2 4
In patients with clinically stable or low-activity LN, a major therapeutic challenge is to mitigate residual kidney injury without unnecessary escalation of immunosuppression.3 When persistent proteinuria reflects chronic structural damage or haemodynamic abnormalities rather than ongoing immune-mediated renal inflammation, further intensification of immunosuppression may provide limited additional benefit while increasing cumulative treatment-related toxicity.5 Accordingly, adjunctive non-immunosuppressive strategies targeting residual kidney risk represent an important unmet clinical need, although prospective evidence in this population remains limited.
Sodium–glucose cotransporter 2 (SGLT2) inhibitors represent biologically plausible candidates for this therapeutic approach. Large randomised trials have demonstrated that SGLT2 inhibitors reduce albuminuria and slow CKD progression in populations with and without diabetes mellitus.6 7 Their kidney effects are thought to involve multiple mechanisms, including restoration of tubuloglomerular feedback, reduction of intraglomerular pressure and attenuation of tubular metabolic stress.8 These mechanisms may remain relevant after immune-mediated renal inflammation has been controlled. However, patients with LN receiving immunosuppression were excluded from or minimally represented in pivotal SGLT2 inhibitor trials, limiting direct extrapolation of these findings to LN.6 7 9
Dapagliflozin was selected for evaluation because of its established efficacy across CKD populations and emerging evidence in SLE and LN. A phase I/II study in adults with SLE provided initial short-term safety data,10 and a small randomised crossover trial in inactive LN suggested that dapagliflozin added to stable background therapy may reduce residual proteinuria.9 However, these findings remain insufficient to support routine clinical use because of limited sample sizes, short follow-up durations and the absence of adequately powered parallel-group randomised trials evaluating prespecified renal outcomes.
The DAPA-LN trial was therefore designed to evaluate the efficacy and safety of adjunctive dapagliflozin in adults with biopsy-confirmed LN, clinically stable or low-activity disease, and persistent proteinuria despite stable maintenance immunosuppression and RAS inhibition with ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) monotherapy. The trial will evaluate renal response at week 52 as an intermediate measure of treatment response, integrating both improvement in proteinuria and preservation of kidney function during the randomised treatment period. By evaluating SGLT2 inhibition as an adjunct to established immunosuppressive and supportive care, this multicentre randomised trial may provide evidence regarding its potential role in the management of selected patients with LN.
Methods
Study design and setting
The DAPA-LN trial is an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint superiority trial.11 A total of 270 adults with biopsy-confirmed LN and persistent proteinuria despite stable maintenance immunosuppression and RAS inhibition will be randomly assigned in a 1:1 ratio to receive dapagliflozin 10 mg once daily plus standard background therapy or standard background therapy alone. Participants and treating investigators will be aware of treatment allocation, whereas the primary efficacy endpoint, primary safety endpoint and other prespecified major renal and safety outcomes will be adjudicated by an independent endpoint adjudication committee blinded to treatment assignment.
The trial will be conducted at seven hospitals in China and coordinated by The Second Xiangya Hospital, Central South University. Participating centres are listed in online supplemental table S1. Recruitment is planned from January 2027 through January 2028. The randomised treatment period will continue through week 52, followed by exploratory extended follow-up through week 104 to characterise longer-term kidney trajectories and safety. Outcomes occurring after week 52 will not contribute to the primary efficacy or safety analyses. The overall trial design is presented in figure 1. The protocol was developed and is reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 statement.12
Figure 1. Overall design and planned participant flow of the DAPA-LN trial. Adults with biopsy-confirmed LN who meet the prespecified eligibility criteria will undergo screening and, if required, a 4–8-week prerandomisation RAS-inhibitor run-in period to establish stable ACEI or ARB monotherapy before eligibility is reconfirmed. Eligible participants will be randomly assigned in a 1:1 ratio to receive dapagliflozin 10 mg once daily plus standard background therapy or standard background therapy alone. The randomised treatment period will continue through week 52, followed by exploratory extended follow-up through week 104. ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; LN, lupus nephritis; RAS, renin–angiotensin system; UPCR, urine protein-to-creatinine ratio.
Eligibility criteria
Participants will be eligible if they meet all of the following criteria: (1) age 18–85 years; (2) fulfilment of either the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria or the 2012 Systemic Lupus International Collaborating Clinics classification criteria for SLE13 14; (3) biopsy-confirmed LN classified according to the International Society of Nephrology/Renal Pathology Society classification system as class III or IV, with or without class V involvement, or pure class V LN.15 16 For participants with more than one kidney biopsy, histological classification will be based on the most recent biopsy performed before randomisation; (4) an interval of at least 3 months between the initial biopsy-confirmed diagnosis of LN and randomisation; (5) clinically stable or low-activity LN, defined by a stable maintenance immunosuppressive regimen for at least 8 weeks, no rapidly progressive decline in kidney function and no indication for immediate induction therapy or rescue intensification of immunosuppression; (6) a prednisone-equivalent dose ≤20 mg/day at randomisation, with no change exceeding 5 mg/day during the preceding 4 weeks; (7) a urine protein-to-creatinine ratio (UPCR) >0.5 and ≤ 3.5 g/g on at least two measurements obtained 2–8 weeks apart; (8) an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2; (9) stable monotherapy with either an ACEI or an ARB for at least 4 weeks at the maximally tolerated or otherwise clinically appropriate dose; (10) systolic blood pressure ≥100 mm Hg and diastolic blood pressure ≥60 mm Hg without symptomatic hypotension; (11) serum potassium ≤5.5 mmol/L; (12) no use of an SGLT2 inhibitor during the preceding 12 weeks; and (13) provision of written informed consent.
Eligibility for clinically stable or low-activity LN will be determined by the investigator based on kidney function, proteinuria, urinary sediment, complement C3 and C4 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, extrarenal SLE activity and recent immunosuppressive treatment. Persistent proteinuria alone will not be considered sufficient evidence of active LN requiring induction therapy.
Exclusion criteria will be: (1) active LN requiring immediate induction therapy; (2) intravenous methylprednisolone pulse therapy, cyclophosphamide induction therapy, rescue intensification of immunosuppression for worsening LN or initiation of belimumab, rituximab, obinutuzumab or another biological agent within the preceding 12 weeks; (3) acute kidney injury within the preceding 4 weeks; (4) current maintenance dialysis or previous kidney transplantation; (5) type 1 diabetes mellitus; (6) a history of ketoacidosis, including euglycemic ketoacidosis; (7) known hypersensitivity to dapagliflozin or any component of the formulation, or any other contraindication to SGLT2 inhibitor therapy; (8) two or more episodes of urinary tract infection requiring antimicrobial therapy or two or more episodes of genital mycotic infection requiring antifungal therapy within the preceding 6 months; (9) severe infection at screening; (10) pregnancy, breastfeeding, planned pregnancy during the randomised treatment period or unwillingness of a woman of childbearing potential to use effective contraception during this period; (11) alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal, or total bilirubin >2 times the upper limit of normal; (12) active malignancy or malignancy diagnosed within the preceding 5 years; (13) concurrent participation in another interventional clinical trial; or (14) any other condition considered by the investigator to potentially compromise participant safety, protocol adherence or interpretation of trial results.
Participants who are not receiving stable ACEI or ARB monotherapy at screening will undergo a 4–8-week prerandomisation RAS-inhibition run-in period to establish a stable background antiproteinuric regimen before randomisation. During this period, an ACEI or ARB will be initiated or titrated to the maximally tolerated or otherwise clinically appropriate dose. Blood pressure, kidney function and serum potassium will be reassessed approximately 2 weeks after treatment initiation or any dose adjustment. The final ACEI or ARB regimen must remain unchanged for at least 4 weeks before randomisation, after which all eligibility criteria will be reassessed. Participants who cannot tolerate ACEI or ARB therapy or cannot achieve a stable regimen will not undergo randomisation. Combined ACEI and ARB therapy will not be permitted during the run-in period or after randomisation.
Randomisation, allocation concealment and endpoint adjudication
After eligibility confirmation and completion of baseline assessments, participants will be randomised in a 1:1 ratio through a secure centralised web-based randomisation system using permuted blocks of varying size, stratified by study centre. The computer-generated allocation sequence will be prepared by an independent statistician who will have no involvement in participant recruitment, treatment administration or outcome assessment. The allocation sequence and block sizes will remain inaccessible to investigators, study coordinators and other site personnel involved in participant enrolment. Treatment assignment will be released only after eligibility confirmation and entry of the required baseline information into the randomisation system, thereby ensuring allocation concealment.
Because the trial is open label, participants and treating investigators will be aware of treatment allocation. An independent endpoint adjudication committee, whose members will have no role in participant care or trial operations and will remain blinded to treatment assignment, will adjudicate renal response at week 52, potential primary safety endpoint events, renal flares, rescue intensification of immunosuppression and initiation of maintenance kidney replacement therapy. Adjudication will be based on standardised, de-identified source-document packages from which treatment assignment, study-drug names and other information that could reveal treatment allocation have been removed. All adjudication decisions will follow prespecified endpoint definitions and procedures described in an endpoint adjudication charter. Routine adverse events and serious adverse events that do not meet criteria for adjudicated endpoints will be recorded, assessed and reported by site investigators according to standardised safety-reporting procedures.
Interventions and concomitant therapy
During the 52-week randomised treatment period, all participants will receive protocol-defined standard background therapy consisting of stable maintenance immunosuppression, stable ACEI or ARB monotherapy and supportive care. Supportive care will include blood pressure management, dietary sodium restriction and management of cardiovascular and metabolic risk factors. Hydroxychloroquine will be recommended unless contraindicated or poorly tolerated.2 3
Participants assigned to the control group will continue standard background therapy alone. Participants assigned to the dapagliflozin group will receive dapagliflozin 10 mg orally once daily in addition to standard background therapy. Dapagliflozin exposure, adherence, temporary interruptions, permanent discontinuation and clinically relevant changes in background therapy will be recorded throughout the randomised treatment period.
The maintenance immunosuppressive regimen and ACEI or ARB dose will remain unchanged through week 52 unless modification is clinically necessary. Glucocorticoid tapering will be permitted when clinically appropriate and will follow the same treatment principles in both groups. Initiation or escalation of immunosuppression for worsening LN will be classified as rescue intensification according to prespecified criteria. Treatment changes attributable to extrarenal SLE activity, infection, drug toxicity or intolerance, or other conditions unrelated to LN will not be classified as rescue intensification but will be documented as changes in concomitant medications and therapies. Cumulative glucocorticoid exposure and all clinically relevant changes in immunosuppressive or RAS-inhibitor therapy will be recorded.
Dapagliflozin will be temporarily withheld in the event of acute kidney injury, clinically significant volume depletion or symptomatic hypotension, severe infection or other acute illness, major surgery or other procedures associated with prolonged fasting, or ketosis or suspected ketoacidosis. Treatment may be resumed only after the precipitating condition has resolved and relevant clinical and laboratory parameters have stabilised. Confirmed ketoacidosis, pregnancy or serious hypersensitivity attributable to dapagliflozin will require permanent discontinuation. Permanent discontinuation may also be considered when continued treatment is deemed clinically inappropriate because of unacceptable toxicity or other safety concerns.
Temporary interruption or permanent discontinuation of dapagliflozin will not constitute withdrawal from the trial. Participants who interrupt or discontinue dapagliflozin will remain in follow-up and continue scheduled efficacy and safety assessments unless they withdraw consent for further participation.
Initiation of dapagliflozin or any other SGLT2 inhibitor will not be permitted in the control group during the 52-week randomised treatment period. If initiation of an SGLT2 inhibitor is considered medically necessary, the treatment change will be recorded as a major protocol deviation. The participant will remain in follow-up, continue scheduled efficacy and safety assessments, and will be analysed according to the randomised treatment assignment in the primary intention-to-treat analysis.
The randomised treatment strategy will conclude after completion of the week 52 assessment. Thereafter, initiation, continuation or discontinuation of dapagliflozin or another SGLT2 inhibitor will be determined by treating clinicians. All SGLT2 inhibitor exposure, including treatment initiation, discontinuation and duration of use, will be recorded during the exploratory extended follow-up through week 104.
Endpoints
The primary efficacy endpoint will be renal response at week 52, defined by fulfilment of both of the following criteria: (1) UPCR ≤0.5 g/g or a ≥50% reduction from baseline with a final UPCR <1.0 g/g; and (2) an eGFR decline <20% from baseline. Renal response will be assessed at week 52 within a prespecified window of ±28 days. Participants who receive rescue intensification of immunosuppression for worsening LN, initiate maintenance kidney replacement therapy or die before week 52 will be classified as non-responders. Maintenance kidney replacement therapy will be defined as dialysis continued for at least 28 consecutive days or kidney transplantation.
The primary safety endpoint will be the proportion of participants experiencing at least one prespecified clinically significant adverse event of special interest (AESI) from randomisation through week 52. Prespecified events will include confirmed ketoacidosis, including euglycemic ketoacidosis; acute kidney injury meeting Kidney Disease: Improving Global Outcomes criteria;17 clinically significant volume depletion or symptomatic hypotension; urinary tract infection requiring antimicrobial therapy, including pyelonephritis and urosepsis; genital mycotic infection requiring antifungal therapy; and Fournier’s gangrene. Events will be included irrespective of investigator-assessed causal relationship to the assigned treatment. All potential primary safety endpoint events will undergo blinded independent adjudication according to prespecified operational definitions. The primary safety endpoint will be analysed descriptively and will not be included in the formal efficacy-testing hierarchy.
Secondary efficacy endpoints through week 52 will include: (1) relative change in UPCR from baseline; (2) the proportion of participants achieving a UPCR ≤0.5 g/g; (3) change in eGFR from baseline; (4) renal flare; (5) rescue intensification of immunosuppression for worsening LN; (6) change in the SLE Disease Activity Index 2000 (SLEDAI-2K) score from baseline18; and (7) the proportion of participants experiencing at least one all-cause hospitalisation, together with the proportions experiencing SLE-related or LN-related, infection-related and cardiovascular hospitalisations.
Secondary safety endpoints through week 52 will include the proportions of participants experiencing: (1) each individual component of the primary safety endpoint; (2) at least one AESI that also fulfils serious adverse event criteria; (3) at least one treatment-emergent adverse event; (4) at least one serious adverse event; (5) at least one adverse event considered by the investigator to be related to the assigned treatment; and (6) at least one serious adverse event considered by the investigator to be related to the assigned treatment. Among participants assigned to dapagliflozin, adverse events leading to temporary interruption or permanent discontinuation of dapagliflozin will also be summarised. Severe hypoglycaemia requiring assistance from another person will be assessed among participants receiving concomitant insulin or an insulin secretagogue.
Adverse event categories will not be mutually exclusive. An AESI that fulfils serious adverse event criteria will be included in both categories. Detailed definitions and ascertainment procedures for safety outcomes are provided in online supplemental method 1.
Exploratory outcomes during extended follow-up through week 104 will include annualised eGFR slope; renal flare; rescue intensification of immunosuppression; cumulative glucocorticoid exposure; longitudinal changes in SLEDAI-2K score, complement C3 and C4 levels, and anti-dsDNA antibody levels; all-cause and cause-specific hospitalisations; initiation of maintenance kidney replacement therapy; all-cause mortality; and longer-term safety outcomes. Safety events occurring during weeks 52–104 will be summarised separately from those occurring during the 52-week randomised treatment period.
Renal flare will be defined according to prespecified increases in UPCR from the lowest postrandomisation value, together with an absolute proteinuria threshold, deterioration in eGFR, new or worsening active urinary sediment, or rescue intensification of immunosuppression attributable to worsening LN. Rescue intensification will comprise prespecified initiation or escalation of glucocorticoids, cyclophosphamide, mycophenolate, calcineurin inhibitors or biological therapy attributable to worsening LN. Treatment changes attributable to extrarenal SLE activity, infection, drug toxicity or intolerance, or other conditions unrelated to LN will not be classified as rescue intensification. Detailed definitions and adjudication criteria are provided in online supplemental method 2. A summary of study endpoints and their operational definitions is provided in table 1.
Table 1. Summary of study endpoints and operational definitions.
| Category | Endpoint | Definition/assessment method |
|---|---|---|
| Primary efficacy endpoint | Renal response at week 52 | Fulfilment of both criteria: (1) UPCR ≤0.5 g/g or a ≥50% reduction from baseline with a final UPCR <1.0 g/g; and (2) an eGFR decline of <20% from baseline. Participants who receive rescue intensification of immunosuppression for worsening LN, initiate maintenance kidney replacement therapy or die before week 52 will be classified as non-responders. Maintenance kidney replacement therapy is defined as dialysis maintained for at least 28 consecutive days or kidney transplantation. |
| Primary safety endpoint | Clinically significant adverse events of special interest through week 52 | Proportion of participants experiencing at least one prespecified clinically significant AESI occurring from randomisation through week 52. Events will be included irrespective of investigator-assessed causal relatedness to the assigned treatment and will undergo blinded independent adjudication. |
| Components of the primary safety endpoint | Confirmed ketoacidosis, including euglycemic ketoacidosis; acute kidney injury meeting KDIGO criteria; clinically significant volume depletion or symptomatic hypotension; urinary tract infection requiring antimicrobial therapy, including pyelonephritis or urosepsis; genital mycotic infection requiring antifungal therapy; and Fournier’s gangrene. | |
| Secondary efficacy endpoints | Relative change in proteinuria | Relative change in UPCR from baseline to week 52. The between-group effect will be estimated using a baseline-adjusted analysis of covariance model with log-transformed UPCR values and expressed as an adjusted geometric mean ratio, corresponding 95% CIs and relative percentage difference. |
| Proteinuria target | Proportion of participants achieving UPCR ≤0.5 g/g at week 52. | |
| Change in kidney function | Absolute change in eGFR from baseline to week 52. | |
| Renal flare | Committee-adjudicated renal flare defined according to prespecified changes in UPCR, eGFR, urinary sediment or rescue intensification of immunosuppression attributable to worsening LN. | |
| Rescue intensification of immunosuppression | Committee-adjudicated initiation or escalation of prespecified glucocorticoid, conventional immunosuppressive, calcineurin inhibitor or biological therapy because of worsening LN. | |
| Disease activity | Change in SLEDAI-2K score from baseline to week 52. | |
| Hospitalisation | Proportion of participants experiencing at least one all-cause hospitalisation and proportions experiencing SLE-related or LN-related, infection-related and cardiovascular hospitalisations through week 52. | |
| Secondary safety endpoints | Individual components of the primary safety endpoint | Proportion of participants experiencing each individual prespecified clinically significant AESI through week 52. |
| Serious adverse events of special interest | Proportion of participants experiencing at least one AESI that also fulfils the criteria for a serious adverse event. | |
| Treatment-emergent adverse events | Proportion of participants experiencing at least one adverse event that begins after randomisation or represents a clinically meaningful worsening of a pre-existing condition after randomisation. | |
| Any serious adverse event | Proportion of participants experiencing at least one serious adverse event from randomisation through week 52. | |
| Treatment-related adverse events | Proportion of participants experiencing at least one adverse event considered by the investigator to be related to the assigned treatment. | |
| Treatment-related serious adverse events | Proportion of participants experiencing at least one serious adverse event considered by the investigator to be related to the assigned treatment. | |
| Dapagliflozin interruption or discontinuation | Among participants assigned to dapagliflozin, the proportions experiencing an adverse event leading to temporary interruption and an adverse event leading to permanent discontinuation of dapagliflozin, reported separately. | |
| Severe hypoglycaemia | Among participants receiving insulin or an insulin secretagogue, proportion experiencing hypoglycaemia requiring assistance from another person. | |
| Exploratory endpoints through week 104 | Long-term kidney, disease-activity and safety outcomes | Annualised eGFR slope from baseline to week 104; renal flare; rescue intensification of immunosuppression; cumulative glucocorticoid exposure; longitudinal changes in SLEDAI-2K score, complement C3 and C4 levels and anti-dsDNA antibody levels; all-cause and cause-specific hospitalisation; initiation of maintenance kidney replacement therapy; all-cause mortality; and longer-term safety outcomes. |
Adverse event categories are not mutually exclusive. An AESI that fulfils serious adverse event criteria will be included in both categories. Temporary interruption or permanent discontinuation of dapagliflozin will be analysed as tolerability outcomes and will not, by itself, qualify an event for inclusion in the primary safety endpoint. The primary safety endpoint is prespecified but descriptive; the trial is powered for the primary efficacy endpoint and not for formal superiority, non-inferiority or equivalence testing of safety outcomes. Detailed safety definitions are provided in online supplemental method 1.
AESI, adverse event of special interest; anti-dsDNA, anti-double-stranded DNA; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; LN, lupus nephritis; SLEDAI-2K, SLE Disease Activity Index 2000; UPCR, urine protein-to-creatinine ratio.
Follow-up and assessments
Participants will undergo assessments during screening and, where applicable, the prerandomisation RAS inhibition run-in period; at baseline and randomisation; and at weeks 4, 12, 24, 36 and 52 after randomisation. Exploratory extended follow-up assessments will be conducted at weeks 78 and 104, regardless of adherence to or discontinuation of the randomised treatment strategy, unless the participant withdraws consent for further follow-up.
The UPCR will be measured using a first-morning voided spot urine specimen. Serum creatinine and urinary protein and creatinine concentrations will be measured in accredited laboratories using standardised assays, and eGFR will be calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation.19 Whenever feasible, serial measurements for each participant will be performed in the same laboratory using the same assay platform. Baseline UPCR and eGFR will be defined using the first-morning UPCR and serum creatinine measurements obtained at the baseline visit before randomisation and initiation of assigned treatment. For participants who have not already met a prespecified non-response criterion, the primary efficacy endpoint will be assessed using UPCR and serum creatinine measurements obtained at the same week 52 visit within the prespecified ±28 day window. If either component is unavailable, missing data will be handled according to the prespecified statistical analysis plan.
Eligibility, baseline characteristics, treatment exposure and adherence, background and concomitant therapies, SLE and LN activity, kidney function, hospitalisation and safety outcomes will be assessed according to the schedule presented in table 2. Dapagliflozin exposure, adherence, temporary interruption and permanent discontinuation will be recorded throughout the 52-week randomised treatment period. Renal flares, rescue intensification of immunosuppression, hospitalisations, initiation of maintenance kidney replacement therapy, deaths and adverse events will be recorded continuously from randomisation through the relevant follow-up period. Initiation, continuation, discontinuation and duration of SGLT2 inhibitor therapy after week 52 will be recorded separately during extended follow-up.
Table 2. Schedule of study procedures and assessments.
| Study procedure or assessment | Screening and run-in | Baseline/randomisation | Week 4 | Week 12 | Week 24 | Week 36 | Week 52 | Week 78 | Week 104 |
|---|---|---|---|---|---|---|---|---|---|
| Written informed consent | √ | ||||||||
| Eligibility assessment and SLE classification | √ | √* | |||||||
| Kidney biopsy verification | √ | ||||||||
| RAS-inhibitor initiation or titration, if required | √ | ||||||||
| Blood pressure, kidney function and potassium reassessment during run-in | √ | ||||||||
| Randomisation, demographic characteristics and medical history | √ | ||||||||
| Physical examination and vital signs | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Pregnancy testing in women of childbearing potential | à | à | |||||||
| SLEDAI-2K | √ | √ | √ | √ | √ | √ | √ | √ | |
| First-morning UPCR | √‡ | √ | √ | √ | √ | √ | √ | √ | √ |
| Urinalysis and urinary sediment | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Kidney function and serum electrolytes | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Routine laboratory assessments | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Complement C3 and C4 and anti-dsDNA antibody levels | √ | √ | √ | √ | √ | √ | √ | √ | |
| Background and concomitant therapies | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Initiation of dapagliflozin | ä | ||||||||
| Study treatment exposure and adherence | √ | √ | √ | √ | √ | ||||
| SGLT2 inhibitor use | √ | √ | √ | √ | √ | √ | √ | √ | √ |
| Adverse events and serious adverse events¶ | √ | √ | √ | √ | √ | √ | √ | ||
| Prespecified adverse events of special interest¶ | √ | √ | √ | √ | √ | √ | √ | ||
| Study-drug interruption or discontinuation | √ | √ | √ | √ | √ | ||||
| Renal flare, rescue intensification of immunosuppression, hospitalisation and other major outcomes¶ | √ | √ | √ | √ | √ | √ | √ | ||
| Ketone and acid–base testing | As clinically indicated | As clinically indicated | As clinically indicated | As clinically indicated | As clinically indicated | As clinically indicated | As clinically indicated | As clinically indicated | As clinically indicated |
Eligibility will be reconfirmed immediately before randomisation.
Pregnancy testing will be repeated during follow-up whenever pregnancy is suspected or required by applicable institutional or regulatory procedures.
At least two qualifying UPCR measurements obtained 2–8 weeks apart will be required before randomisation.
Dapagliflozin will be initiated only in participants assigned to the dapagliflozin group.
Events will be collected continuously from randomisation through the relevant follow-up period and reviewed at each scheduled assessment.
anti-dsDNA, anti-double-stranded DNA; RAS, renin–angiotensin system; SGLT2, sodium–glucose cotransporter 2; SLEDAI-2K, SLE Disease Activity Index 2000; UPCR, urine protein-to-creatinine ratio.
Permitted visit windows will be ±7 days for week 4, ±14 days for weeks 12 and 24, ±21 days for week 36 and ±28 days for weeks 52, 78 and 104. When an in-person visit cannot be completed, clinical events, treatment changes, concomitant therapies and safety information may be collected remotely. Laboratory results obtained outside the participating study centre may be accepted only when prespecified requirements for specimen type, collection timing, assay methods, laboratory accreditation and source-document verification are fulfilled. Planned baseline variables are listed in online supplemental table S2.
Sample size calculation
Because no directly applicable estimate of the control-group response rate was available for the prespecified renal response endpoint in a comparable LN population, the trial steering committee and statistician prespecified an absolute between-group difference of 18 percentage points as the clinically meaningful effect size for sample-size determination. Response rates of 41% in the control group and 59% in the dapagliflozin group were assumed for sample-size estimation. These values were selected for planning purposes and should not be interpreted as predicted treatment-specific response rates.
Using a two-sided test for two independent proportions based on the normal approximation without continuity correction, with a two-sided α level of 0.05, 80% power and 1:1 allocation, 118 participants per group were required before accounting for missing primary endpoint data. Allowing for up to 10% missing primary endpoint data and rounding upward to maintain equal allocation yielded a target sample size of 270 participants, with 135 participants assigned to each group.
The sample size was determined solely on the basis of the primary efficacy endpoint. The trial is not powered to formal superiority, non-inferiority or equivalence testing of the primary safety endpoint or individual safety events. Safety outcomes will therefore be analysed descriptively using event frequencies, effect estimates and corresponding CIs.
Statistical analysis
The primary efficacy analysis will follow the intention-to-treat principle and will include all randomised participants analysed according to their assigned treatment. A per-protocol analysis excluding participants with prespecified major protocol deviations will be performed as a sensitivity analysis. Safety analyses will include all randomised participants and will be conducted according to randomised treatment assignment. Supportive exposure-adjusted analyses based on person-time under safety observation and actual dapagliflozin exposure will be performed where appropriate.
Baseline characteristics will be summarised as means with SD or medians with IQRs, as appropriate, for continuous variables and as counts with percentages for categorical variables. Formal testing of baseline differences will not be performed.
The primary endpoint will be analysed using a covariate-adjusted logistic regression model including treatment group, study centre, log-transformed baseline UPCR, baseline eGFR and histological category as prespecified covariates. Histological category will be classified as proliferative LN (class III or IV with or without class V involvement) or pure class V LN. Study centre will be included as a fixed effect to account for centre-stratified randomisation.
Observed response proportions will be reported by treatment group. Adjusted response probabilities and the absolute between-group difference will be estimated by marginal standardisation and reported with corresponding 95% CIs. The adjusted OR and 95% CI will be reported as a complementary effect measure. The primary hypothesis will be tested using a two-sided α level of 0.05.
Participants meeting the prespecified non-response criteria will be classified accordingly. For participants who do not meet a prespecified non-response criterion but have missing week 52 UPCR or eGFR data, missing components will be handled using multiple imputation under a missing-at-random assumption, with the imputation model incorporating prespecified baseline characteristics and prognostic variables relevant to renal response. Non-responder imputation and tipping-point analyses will be performed as sensitivity analyses to assess robustness under alternative missing-data assumptions.
Continuous secondary endpoints at week 52 will be analysed using analysis of covariance adjusted for treatment group, study centre and the corresponding baseline value. Week 52 UPCR will be analysed on the logarithmic scale using analysis of covariance with treatment group, study centre and log-transformed baseline UPCR as covariates. Results will be back-transformed and reported as the adjusted geometric mean ratio and corresponding relative percentage difference with 95% CIs. Longitudinal outcomes will be evaluated using mixed-effects models for repeated measures incorporating treatment group, visit, the treatment-by-visit interaction, study centre, the corresponding baseline value and an appropriate covariance structure. Annualised eGFR slope through week 104 will be estimated using a linear mixed-effects model with time modelled as a continuous variable and a treatment-by-time interaction included to estimate the between-group difference in eGFR slope.
Binary secondary endpoints will be analysed using logistic regression adjusted for treatment group, study centre and the corresponding baseline measure where applicable. Time-to-event endpoints, including renal flare and rescue intensification of immunosuppression, will be analysed from randomisation to the first occurrence of the relevant event. Death occurring before the event of interest will be treated as a competing event. Cumulative incidence functions and cause-specific Cox proportional hazards models will be used, with Fine-Gray subdistribution hazard models performed as supportive analyses where event counts permit. Participants who remain alive and event free will be censored at the last available assessment or at the end of the prespecified analysis period. The proportional hazards assumption for the cause-specific Cox models will be evaluated using Schoenfeld residuals and complementary graphical methods before interpretation of the model estimates.
Prespecified exploratory subgroup analyses of the primary endpoint will be conducted according to histological category, baseline UPCR (<1.0 vs ≥1.0 g/g), baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), diabetes status and hypertension status. Treatment-effect heterogeneity will be assessed using treatment-by-subgroup interaction terms.
The primary safety endpoint will be analysed descriptively among all randomised participants according to randomised treatment assignment. The number and proportion of participants experiencing at least one prespecified clinically significant AESI will be reported by randomised treatment group with corresponding 95% CIs. The absolute between-group risk difference and its 95% CI will be reported as the principal descriptive effect estimate. The relative risk and its 95% CI will be provided as a supportive measure where estimable. Each component of the primary safety endpoint will be summarised separately.
Secondary safety endpoints will be summarised using participant counts and proportions. For recurrent events, total event counts and exposure-adjusted incidence rates will also be reported where appropriate. Serious adverse events and adverse events of special interest will be summarised by system organ class and preferred term. Adverse events and serious adverse events considered by the investigator to be related to the assigned treatment will be summarised separately and will not determine inclusion in the primary safety endpoint.
No formal hypothesis testing or adjustment for multiplicity is planned for safety endpoints. The trial is powered for the primary efficacy endpoint and is not powered to establish superiority, non-inferiority or equivalence with respect to safety. Missing safety data will not be imputed. No multiplicity adjustment is planned for secondary efficacy, safety, subgroup or exploratory analyses, which will be interpreted as supportive or hypothesis-generating. A detailed statistical analysis plan will be finalised before database lock and before any unblinded treatment comparisons are conducted.
Data management and quality control
Study data will be recorded in standardised electronic case report forms based on source documents and linked to unique study identification numbers. Directly identifiable information will not be included in the analysis dataset. Access to the electronic data capture system will be restricted to authorised study personnel through role-based permissions.
Automated validation rules and manual review procedures will be used to identify missing or out-of-range values, internal inconsistencies, protocol deviations, visit-window violations and discrepancies in treatment, endpoint and safety records. Data queries will be issued to the relevant study centre and resolved by authorised investigators with reference to the original source documents. All data entries, corrections and query resolutions will be retained in a time-stamped electronic audit trail.
Before participant enrolment, investigators and research personnel at all centres will receive standardised training in eligibility assessment, randomisation, study interventions, follow-up procedures, endpoint definitions, safety reporting and electronic data entry. The coordinating centre and designated study monitors will oversee trial conduct and data quality, with particular attention to informed consent, eligibility, treatment allocation, adherence to the assigned treatment strategy, completeness of week 52 endpoint assessments, serious adverse event reporting and documentation of rescue intensification of immunosuppression.
Before database lock, predefined checks will be completed for data completeness, logical consistency, eligibility, protocol deviations, concomitant treatment, study-treatment exposure, adverse events and endpoint data. The database will be locked only after completion of data cleaning, query resolution, medical review, reconciliation of safety and endpoint records and blinded endpoint adjudication. Detailed data management and quality-control procedures are provided in online supplemental method 3.
Safety oversight and interim analysis
An independent data and safety monitoring board, comprising clinicians with relevant expertise and a statistician with no other role in trial conduct, will review unblinded safety data during the randomised treatment period. The first scheduled review will be conducted after approximately 50 participants have completed 12 weeks of follow-up, with subsequent reviews conducted approximately every 6 months. Additional ad hoc reviews may be convened in response to an unexpected serious safety concern.
The board will review treatment-emergent adverse events, serious adverse events, adverse events of special interest, deaths, treatment interruptions and discontinuations, clinically relevant laboratory abnormalities and emerging patterns of toxicity by randomised treatment group. On the basis of the totality of the available safety data, the board may recommend continuation of the trial without modification, modification of the protocol or safety-monitoring procedures, temporary suspension of recruitment or study treatment, or early termination of the trial. The board’s membership, review schedule, access to unblinded data, decision-making procedures and reporting responsibilities will be specified in a dedicated charter.
No formal interim efficacy analysis is planned, and no efficacy-based stopping boundary will be applied. Accordingly, no adjustment of the type I error rate will be required for interim efficacy testing. Safety monitoring will not be used to make formal claims of superiority, non-inferiority or equivalence with respect to safety.
Trial registration
The trial was prospectively registered with the Chinese Clinical Trial Registry on 28 August 2026 (ChiCTR2600131121).
Patient and public involvement
Patients and members of the public were not involved in the design, conduct, reporting or dissemination planning of the trial.
Trial status and dissemination
The current protocol is V.3.0, dated 30 July 2026. Study initiation activities from September to December 2026 will include site initiation, investigator training, implementation of centralised randomisation and electronic data capture systems, and establishment of study-drug management procedures. Participant recruitment is planned from January 2027 to January 2028. Completion of the week 52 follow-up and the primary efficacy and safety analyses is anticipated by March 2029, with exploratory extended follow-up through week 104 expected to be completed by March 2030. At the time of manuscript preparation, participant recruitment has not commenced.
Study findings will be submitted for publication in peer-reviewed journals and presented at national and international scientific conferences, regardless of the direction or statistical significance of the results. The primary publication will report the prespecified week 52 efficacy and safety analyses, whereas findings from the week 104 extended follow-up may be reported separately if appropriate. No participant-identifiable information will be included in any publication or scientific presentation.
Discussion
Current management of LN combines suppression of immune-mediated kidney inflammation with long-term strategies aimed at reducing residual kidney injury.2 3 RAS inhibition remains the principal antiproteinuric intervention for patients with persistent proteinuria.2 Recent Kidney Disease: Improving Global Outcomes guidance and contemporary expert reviews have acknowledged a potential role for SGLT2 inhibitors in selected patients with clinically stable LN, while emphasising appropriate patient selection and caution among those receiving intensive immunosuppression or at increased risk of infection.2 20 However, these recommendations are based largely on evidence extrapolated from broader CKD populations rather than direct evidence from patients with LN.6 7 Therefore, SGLT2 inhibition has not yet been established as an evidence-based LN-specific therapeutic strategy, particularly in patients with controlled inflammatory activity but persistent proteinuria despite maintenance immunosuppression and RAS inhibition.
Direct evidence regarding dapagliflozin in SLE and LN remains limited. A phase I/II study involving 38 adults with SLE, including 17 with LN, provided preliminary short-term safety data but did not demonstrate significant improvements in proteinuria or disease activity.10 A subsequent randomised crossover trial suggested that dapagliflozin added to stable maintenance immunosuppression and RAS inhibition may reduce residual proteinuria among patients with inactive LN.9 However, only 30 participants were randomised, and 21 were included in the final analysis. The small sample size, short treatment duration and crossover design limited the evaluation of sustained renal response, preservation of kidney function and longer-term safety. An ongoing single-centre randomised trial is evaluating dapagliflozin in patients with quiescent LN and CKD, but its population, treatment duration and primary endpoint differ from those of DAPA-LN (ClinicalTrials.gov identifier NCT06155604). Available evidence therefore supports further evaluation but remains insufficient to guide routine clinical use.
The rationale for SGLT2 inhibition in clinically stable LN is complementary to, rather than substitutive for, immunosuppression. Restoration of tubuloglomerular feedback and reduction of intraglomerular pressure may reduce proteinuria and kidney stress after overt immune-mediated activity has been controlled.8 Additional effects on tubular workload, hypoxia, oxidative stress and podocyte function have been proposed, although their clinical relevance in LN remains uncertain.21 These potential benefits must be considered alongside risks including volume depletion, symptomatic hypotension, an early haemodynamic decline in eGFR, urinary tract and genital mycotic infections, and ketoacidosis.22 These risks may be particularly relevant in patients receiving maintenance immunosuppression. The DAPA-LN protocol therefore incorporates targeted eligibility criteria, prespecified treatment-interruption procedures, blinded adjudication of clinically significant adverse events of special interest and independent safety oversight.
The DAPA-LN trial was designed to address the unmet need for non-immunosuppressive strategies targeting residual kidney risk after stabilisation of immune-mediated LN. Although prevention of kidney failure and sustained eGFR decline remain the ultimate goals of kidney-protective strategies, these long-term outcomes generally require prolonged follow-up and larger sample sizes to demonstrate treatment effects. In patients with LN, persistent proteinuria after control of immune-mediated activity represents an important marker of residual kidney risk and remains a clinically meaningful therapeutic target. Therefore, DAPA-LN focuses on adults with established LN-associated kidney involvement and residual proteinuric risk, characterised by biopsy-confirmed LN, persistent proteinuria and stable background therapy consisting of maintenance immunosuppression and ACEI or ARB monotherapy(online supplemental file 2).
The trial will enrol 270 adults with LN who have clinically stable or low-activity disease but persistent proteinuria despite optimised maintenance immunosuppression and RAS inhibition. Standardisation of background therapy, including establishment of a stable RAS inhibition regimen through a prerandomisation run-in period when required, is intended to minimise the influence of concurrent changes in conventional antiproteinuric therapy on outcome assessment. The primary efficacy endpoint, renal response at week 52, integrates improvement in proteinuria with preservation of kidney function rather than evaluating proteinuria reduction alone. This approach reflects contemporary principles of LN management, in which achieving proteinuria reduction while maintaining kidney function represents an important indicator of treatment response during the randomised treatment period.
Exploratory follow-up through week 104 will further evaluate longer-term kidney trajectories, including eGFR slope, renal flare, major kidney outcomes and longer-term safety after SGLT2 inhibition in LN. The trial incorporates several methodological strengths, including a multicentre randomised controlled design, centralised randomisation, independent blinded endpoint adjudication, standardised first-morning UPCR measurements, uniform background RAS inhibition and prespecified statistical procedures. These design features are intended to minimise potential bias related to treatment allocation, background therapy changes and outcome assessment, thereby strengthening internal validity and improving the interpretability of the trial findings.
The findings of DAPA-LN may clarify whether adjunctive dapagliflozin provides additional renal benefit without unacceptable safety concerns in selected patients with stable LN and persistent proteinuria. If adjunctive dapagliflozin improves renal response without an unacceptable safety burden, these findings would support further evaluation of non-immunosuppressive kidney-protective strategies as adjuncts to long-term LN management. Such an approach would complement, rather than replace, immunosuppressive treatment. Conversely, a neutral or unfavourable result would help define the limitations of extrapolating the benefits of SGLT2 inhibitors from broader CKD populations to LN. In either circumstance, DAPA-LN will provide evidence relevant to future clinical recommendations and the design of subsequent kidney-protection trials in LN.
Limitations
Several limitations should be considered. First, the open-label design may introduce potential bias related to treatment adherence, concomitant management and reporting of subjective or non-serious adverse events. Centralised randomisation, standardised follow-up procedures, objective kidney measurements and blinded adjudication of the primary efficacy endpoint and potential primary safety endpoint events will reduce, although not completely eliminate, this bias. Second, eligibility will be based on clinical stability or low disease activity without a protocol-mandated repeat kidney biopsy assessment. Therefore, persistent proteinuria may reflect heterogeneous contributions from chronic structural damage, podocyte dysfunction, haemodynamic abnormalities and residual histological activity, potentially contributing to variability in treatment response. Third, the trial is powered for the primary efficacy endpoint of renal response at week 52 rather than for kidney failure, sustained major eGFR decline, mortality or formal hypothesis testing of the primary safety endpoint. Safety analyses will therefore be descriptive, and the sample size will not allow precise estimation of uncommon events such as ketoacidosis or Fournier’s gangrene. Because the primary safety endpoint comprises clinically heterogeneous events, each component will also be reported separately. Fourth, SGLT2 inhibitor use after week 52 will be determined by treating clinicians rather than assigned by the trial protocol, limiting causal interpretation of outcomes during extended follow-up. Therefore, outcomes assessed through week 104 will be interpreted as exploratory. Finally, recruitment from participating hospitals in China and the requirement for biopsy-confirmed LN, eGFR ≥30 mL/min/1.73 m2, stable maintenance immunosuppression and ACEI or ARB monotherapy may limit generalisability to patients with active disease requiring induction therapy, advanced kidney dysfunction, unavailable biopsy information or intolerance to RAS inhibition.
Conclusion
The DAPA-LN trial will evaluate the efficacy and safety of adjunctive dapagliflozin in adults with biopsy-confirmed LN, clinically stable or low-activity disease, and persistent proteinuria despite stable maintenance immunosuppression and RAS inhibition. The trial will generate randomised evidence regarding the efficacy and safety of SGLT2 inhibition as an adjunctive, non-immunosuppressive strategy for addressing residual kidney risk in selected patients with LN and may inform future research directions and clinical recommendations for the long-term management of this population.
Supplementary material
Acknowledgements
The authors thank the investigators and research staff at all participating DAPA-LN centres for their contributions to protocol development and trial preparation. The graphical abstract was created with BioRender (Agreement number: DD2A90WVI6).
Footnotes
Funding: This work was supported by the Scientific Research Program of FuRong Laboratory (No. 2025PT5001), the Chinese Society of Cardiology Foundation (No. CSCF2024B02), the National Natural Science Foundation of China (Nos. 82070356 and 81770337), the Young Backbone Talent Project of Health High-level Talents under the Furong Plan of Hunan Province (No. 20241226079), the Hunan Provincial Young Backbone Teacher Project for Ordinary Universities (No. 206030802), the Hunan Provincial Natural Science Foundation of China (No. 2021JJ30033), the Key Project of Hunan Provincial Science and Technology Innovation (No. 2024JK2119) and the Clinical Medical Technology Innovation Guidance Project of Hunan Science and Technology Agency (No. 2021SK53519).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Ethics approval: The study protocol was approved by the Clinical Research Ethics Committee of The Second Xiangya Hospital, Central South University (approval number: LYEC2026-0204) and the required ethics approvals were obtained from all participating centres. The trial will be conducted in accordance with the Declaration of Helsinki and applicable ethical and regulatory requirements. Written informed consent will be obtained from all participants before any trial-specific procedures are performed. Findings will be disseminated through peer-reviewed journals.
Data availability free text: No participant data are currently available because recruitment has not commenced. After publication of the primary trial findings, de-identified participant-level data and relevant study documents may be made available from the corresponding author upon reasonable request, subject to approval by the trial steering committee and compliance with applicable ethical, institutional and regulatory requirements.
Data availability statement
No data are available.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
No data are available.