Effects of Dapagliflozin in People without Diabetes and with Microalbuminuria

Sodium-glucose cotransporter 2 inhibitors slow progressive loss of kidney function in patients with type 2 diabetes across a wide range of eGFR and albuminuria. In the Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial, dapagliflozin reduced the risk of kidney failure by approximately 40% in participants with CKD, with consistent effects in those with and without type 2 diabetes (1). The majority of participants in the DAPA-CKD trial had severely increased (Kidney Disease Improving Global Outcomes [KDIGO] stage A3) albuminuria at baseline, with a median of 949 mg/g. Whether the kidney-protective benefits of dapagliflozin, as demonstrated in the DAPA-CKD trial, extend to participants without type 2 diabetes and with lower levels of albuminuria is unknown.

The DAPA-CKD trial was a double-blind, randomized trial of dapagliflozin 10 mg versus placebo, and it recruited 4304 adult participants with CKD. As previously reported, participants were eligible if they had an eGFR of 25–75 ml/min per 1.73 m² of body surface area and urinary albumin-creatinine ratio (UACR) between 200 and 5000 mg/g at the screening visit (2). In 1398 participants without type 2 diabetes, dapagliflozin reduced the risk of the composite kidney outcome (sustained ≥50% eGFR decline, kidney failure, or kidney death) by 49%, attenuated eGFR decline during chronic treatment by 1.29 (95% confidence interval [95% CI], 0.73 to 1.85) ml/min per 1.73 m² per year, and reduced UACR by 15% (95% CI, 6 to 23) relative to placebo (3,4). In this post hoc analysis, we assessed the annual rate of eGFR decline and UACR changes in participants without type 2 diabetes by baseline UACR, and we report results without adjustment for multiplicity.

Of all participants without type 2 diabetes, at baseline, 136 had KDIGO stage A2 albuminuria (microalbuminuria; UACR 30 to <300 mg/g, of whom 24 had UACR 30 to <200 mg/g at baseline), and 1262 had KDIGO stage A3 albuminuria (macroalbuminuria; UACR ≥300 mg/g). Baseline characteristics of participants with stages A2 and A3 albuminuria showed mean (SD) ages of 61 (15) and 56 (15) years, respectively; 49 of 136 (36%) and 411 of 1262 (33%) participants were women, respectively. Mean (SD) eGFRs were 42 (11) and 42 (12) ml/min per 1.73 m², respectively, and median UACRs were 245 (25th to 75th percentile, 207–266) and 955 (25th to 75th percentile, 557–1639) mg/g, respectively.

Dapagliflozin compared with placebo changed eGFR from baseline to week 2 with similar effects in participants without diabetes and with UACR <300 mg/g (−2.4 ml/min per 1.73 m²; 95% CI, −4.5 to −0.4) or ≥300 mg/g (−2.0 ml/min per 1.73 m²; 95% CI, −2.7 to −1.3; P for interaction =0.46). Thereafter, dapagliflozin compared with placebo led to a slower decline in the chronic eGFR slope in participants without diabetes with UACR <300 mg/g (between-group difference of 1.8 ml/min per 1.73 m² per year; 95% CI, 0.4 to 3.1) (Figure 1A) and in participants without diabetes with UACR ≥300 mg/g (between-group difference of 1.2 ml/min per 1.73 m² per year; 95% CI, 0.6 to 1.8; P for interaction =0.62) (Figure 1B). Corresponding percentage reductions in UACR were 16% (95% CI, −21 to 42) and 15% (95% CI, 5 to 23; P for interaction =0.36) (Figure 1C). Across the two UACR subgroups, there were no differences in the risk of adverse events leading to drug discontinuation (UACR <300 mg/g: dapagliflozin, two of 72 and placebo, one of 64; UACR ≥300 mg/g: dapagliflozin, 34 of 624 and placebo, 28 of 635) or serious adverse events (UACR <300 mg/g: dapagliflozin, 18 of 72 and placebo, 14 of 64; UACR ≥300 mg/g: dapagliflozin, 132 of 624 and placebo, 153 of 635). Incidences of the kidney composite end point among participants without type 2 diabetes and with UACR <300 mg/g, defined as sustained ≥50% eGFR decline, kidney failure, or death due to kidney failure, were infrequent during follow-up (one in the dapagliflozin group and three in the placebo group). To assess the robustness of our findings, we repeated the analysis and stratified the participants without type 2 diabetes by baseline UACR <600 or ≥600 mg/g, which approximates 1000-mg urinary protein excretion per 24 hours. In the subgroup of 489 participants with baseline UACR <600 mg/g, dapagliflozin compared with placebo led to a slower decline in the chronic eGFR slope (between-group difference of 0.8 ml/min per 1.73 m² per year; 95% CI, 0.0 to 1.6). In the subgroup with 909 participants without diabetes with UACR ≥600 mg/g, the between-group difference was 1.6 ml/min per 1.73 m² per year (95% CI, 0.9 to 2.3; P for interaction =0.26).

Figure 1.

Effects of dapagliflozin compared with placebo on the rate of change in eGFR and albuminuria in patients without type 2 diabetes and with stage A2 albuminuria. (A) Effects of dapagliflozin in reducing eGFR decline in patients without type 2 diabetes with stage A2 albuminuria. (B) Effects of dapagliflozin in reducing eGFR decline in patients without type 2 diabetes with stage A3 albuminuria. (C) Effects on albuminuria. 95% CI, 95% confidence interval; IQR, interquartile range; LS, least square; UACR, urinary albumin-creatinine ratio.

Dapagliflozin attenuated the decline in kidney function (week 2 to the end of the study) in participants without diabetes whether there was stage A2 or stage A3 albuminuria at baseline. These data suggest that the kidney-protective effects of dapagliflozin may extend to patients with CKD without type 2 diabetes and lower levels of albuminuria, as has been reported in patients with CKD with type 2 diabetes. Further data on the efficacy and safety of sodium-glucose cotransporter 2 inhibition in patients without diabetes with stages A1 and A2 albuminuria will be provided by the EMPA-Kidney trial, which finished in 2022 and enrolled 3570 participants without diabetes, of whom 1604 had UACR <300 mg/g (5).

Although the number of patients without diabetes and with stage A2 albuminuria enrolled in DAPA-CKD was relatively small, these data suggest that the benefits of dapagliflozin are extended to patients with CKD with and without diabetes and with lower levels of albuminuria. The safety and efficacy of dapagliflozin in patients with CKD due to conditions excluded from the DAPA-CKD trial (autosomal dominant polycystic kidney disease, type 1 diabetes, ANCA-associated vasculitis, and lupus nephritis) remain to be established.

Disclosures

G.M. Chertow reports consultancy agreements with Akebia, Ardelyx, AstraZeneca, Cricket, DiaMedica, Gilead, Miromatrix, Reata, Sanifit, Unicycive, and Vertex; reports ownership interest in Ardelyx, CloudCath, Durect, DxNow, Eliaz Therapeutics, Outset, Physiowave, PuraCath, Renibus, and Unicycive; reports research funding from the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); serves on the board of directors for Satellite Healthcare; serves as a coeditor of Brenner & Rector's The Kidney (Elsevier); reports DSMB service for Angion, Bayer, Gilead, Mineralys, NIDDK, Palladio, and ReCor; has received fees from AstraZeneca for service on the DAPA-CKD trial steering committee; and has served on other trial steering committees for Akebia, AstraZeneca, Gilead, Sanifit, and Vertex. R. Correa-Rotter reports consultancy agreements with AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk; research funding from AstraZeneca, Baxter, GlaxoSmithKline, and Novo Nordisk; reports honoraria from AbbVie (honoraria for consultancy or speaker), Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Medtronic, and Sanofi; reports advisory or leadership roles for the Membership Steering Committee of DAPA-CKD for AstraZeneca, as the national leader of the ASCEND study for GSK, and as the national leader of the FLOW study for Novo Nordisk; serves on the editorial boards of American Journal of Kidney Diseases, Current Opinion in Nephrology and Hypertension, Nefrologia Latinoamericana, and Revista de Investigación Clinica; serves as an associate editor for Blood Purification and Frontiers in Nephrology; reports speakers bureau for Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Sanofi; serves as a member of the American Society of Nephrology, EDTA/ERA, the International Society of Nephrology, the Latin American Society of Nephrology and Hypertension, the Mexican Institute for Research in Nephrology, and the National Kidney Foundation; and has lectured for Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, and Takeda. H.J.L. Heerspink reports ongoing consultancy agreements with AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli Lilly, Gilead, GoldFinch, Janssen, Merck, Novo Nordisk, and Travere Pharmaceuticals; reports honoraria for lectures from AstraZeneca; reports research funding from AstraZeneca, Janssen research support (grant funding directed to the employer), and Novo Nordisk; reports lecture fees from AstraZeneca; reports speakers bureau for AstraZeneca; has received funding/honoraria and consulting fees to his institution for steering committee membership and/or advisory board participation from Abbvie, AstraZeneca (the DAPA-CKD study), Bayer, Chinook, CSL Pharma, Gilead, Janssen, Merck, and Travere Pharmaceuticals; and participated in advisory boards for Mitsubishi Tanabe and Mundipharma. A.M. Langkilde is an employee and stockholder of AstraZeneca. P. Rossing reports employment with Steno Diabetes Center Copenhagen; reports research funding from AstraZeneca, Bayer, and Novo Nordisk; reports honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk (all honoraria to the institution); reports advisory or leadership roles for Astellas, AstraZeneca, Bayer, Gilead, MSD, and Novo Nordisk (all honoraria to the institution); has received honoraria to Steno Diabetes Center Copenhagen for steering group membership and/or lectures and advice from AstraZeneca, Bayer, Eli Lilly, and Novo Nordisk; reports advisory board participation with Boehringer Ingelheim and Sanofi Aventis; and reports steering group participation with Gilead. C.D. Sjöström is an employee and stockholder of AstraZeneca. D.C. Wheeler reports consultancy agreements with Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Mundipharma, Napp, Tricida, Vifor Fesenius, and Zydus; reports honoraria from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelhiem, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Mundipharma, Napp, Pharmacosmos, Reata, and Vifor Fresenius; reports an advisory or leadership role for AstraZeneca; reports speakers bureau for Amgen, Astellas, AstraZeneca, Janssen, Merck Sharp and Dohme, Mundipharma, Napp, and Vifor Fresenius; and is an Honorary Professorial Fellow for The George Institute for Global Health. The remaining author has nothing to disclose.

Funding

This study was funded by AstraZeneca.

Author Contributions

G.M. Chertow, R. Correa-Rotter, H.J.L. Heerspink, A.M. Langkilde, P. Rossing, C.D. Sjöström, and D.C. Wheeler conceptualized the study; H.J.L. Heerspink and N. Jongs were responsible for data curation; G.M. Chertow, R. Correa-Rotter, H.J.L. Heerspink, N. Jongs, A.M. Langkilde, P. Rossing, C.D. Sjöström, and D.C. Wheeler were responsible for investigation; H.J.L. Heerspink and N. Jongs were responsible for formal analysis; H.J.L. Heerspink, N. Jongs, and D.C. Wheeler were responsible for methodology; H.J.L. Heerspink and D.C. Wheeler were responsible for funding acquisition; G.M. Chertow, R. Correa-Rotter, H.J.L. Heerspink, A.M. Langkilde, P. Rossing, C.D. Sjöström, and D.C. Wheeler provided supervision; H.J.L. Heerspink wrote the original draft; and G.M. Chertow, R. Correa-Rotter, N. Jongs, A.M. Langkilde, P. Rossing, C.D. Sjöström, and D.C. Wheeler reviewed and edited the manuscript.

Data Sharing Statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.