Visual Abstract
Keywords: albuminuria, hospitalization, SGLT2, diabetic kidney disease
Abstract
Key Points
In this post hoc analysis of Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, canagliflozin reduced the risk of first and subsequent all-cause hospitalization by 14%.
Sodium-glucose cotransporter 2 inhibitor reduced the risk of hospitalization by 15%, with consistent effects irrespective of kidney function, albuminuria, and diabetes status.
Absolute reductions in hospitalizations with sodium-glucose cotransporter 2 inhibitor in patients with CKD are substantial, with major implications for individuals and health systems.
Background
Unplanned hospitalization, irrespective of cause, is a meaningful outcome for patients, caregivers, clinicians, and health systems. The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on all-cause hospitalization in patients with CKD have not been systematically evaluated.
Methods
We conducted a post hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial to evaluate the effect of canagliflozin on nonelective all-cause hospitalization using Cox proportional hazards models, with recurrent events analysis to assess effects on first and subsequent hospitalizations. We performed inverse variance weighted meta-analysis of three placebo-controlled SGLT2 inhibitor CKD-focused trials to assess the relative and absolute effects of SGLT2 inhibitors on first and subsequent all-cause hospitalizations overall and across clinically relevant subgroups. For analyses of cause-specific hospitalization, adverse events that were reported by investigators but not adjudicated were used.
Results
Over a median follow-up of 2.6 years, 3015 hospitalizations occurred among 1543 of 4401 (35%) participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Compared with placebo, canagliflozin reduced the risk of first all-cause hospitalization (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.80 to 0.98; P = 0.02) and first and subsequent hospitalizations (HR, 0.86; 95% CI, 0.76 to 0.96; P = 0.007). In a meta-analysis of three placebo-controlled SGLT2 inhibitor CKD-focused trials, SGLT2 inhibitors reduced the risk of first and subsequent hospitalizations from any cause by 15% (HR, 0.85; 95% CI, 0.78 to 0.95; P < 0.001), with consistent effects irrespective of diabetes, baseline kidney function, and albuminuria (all P interactions > 0.50). Reductions were driven by hospitalizations due to infection, cardiac, renal or urinary, and metabolism or nutritional disorders. We estimated that SGLT2 inhibition in CKD would prevent 36 (95% CI, 13 to 56) unplanned hospitalizations per 1000 patient-years of treatment, across a broad range of patients.
Conclusions
SGLT2 inhibitors reduce the risk of hospitalizations from any cause in patients with CKD, irrespective of diabetes status, kidney function, and degree of albuminuria.
Clinical Trial registry name and registration number:
Introduction
Unplanned hospitalization, irrespective of cause, is a critically meaningful outcome for clinicians, patients, and their caregivers and occurs frequently among patients with CKD.1 Rates of hospitalization are higher among patients with lower eGFR and more severe albuminuria, related both to complications of CKD (e.g., anemia and electrolyte abnormalities) and associated comorbidities (e.g., heart failure).2,3 Hospitalizations constitute a substantial portion of the health care–related costs of managing CKD and have enormous economic implications for health systems.4 Improving the health of patients with CKD and in turn reducing high rates of hospitalizations should be a priority for all stakeholders involved in health care delivery.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of kidney function decline and kidney failure, reduce the likelihood of cardiovascular events (particularly heart failure), and extend overall survival in patients with type 2 diabetes and those with CKD or heart failure, irrespective of diabetes.5 Completed SGLT2 inhibitor trials have demonstrated reductions in all-cause hospitalizations.6–9 However, the absolute effects across key clinical subgroups—including patients with varying levels of kidney function, albuminuria, and diabetes status—remain incompletely defined. These estimates are particularly important for informing patient-centered decision making and guiding clinicians and health care systems in evaluating the potential benefits of SGLT2 inhibitor therapy.
We conducted a post hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial to assess the effect of canagliflozin on first and total all-cause hospitalization in patients with CKD and type 2 diabetes. We then conducted a trial-level meta-analysis of three completed placebo-controlled SGLT2 inhibitor CKD-focused trials to better understand the relative and absolute effects of SGLT2 inhibitors on all-cause hospitalization in patients with CKD, overall and across clinically relevant subgroups.
Methods
Study Design
CREDENCE
CREDENCE (ClinicalTrials.gov no. NCT02065791) was a randomized, double-blind, placebo-controlled, event-driven trial evaluating the effects of canagliflozin on kidney, cardiovascular, and safety outcomes in 4401 participants with CKD, albuminuria, and type 2 diabetes (eGFR of 30 to <90 ml/min per 1.73 m2 and urinary albumin-to-creatinine ratio [UACR] of >300–5000 mg/g). The primary end point was a composite of sustained doubling of serum creatinine, kidney failure, or death due to cardiovascular disease (CVD) or kidney failure. Main findings from the trial have been published previously.10 All participants were required to be receiving maximum tolerated or labeled dose renin-angiotensin-system blockade for at least 4 weeks before randomization. Local institutional ethics committees approved the trial protocols at each site, and all participants provided written informed consent.
Dapagliflozin and Prevention of Adverse Outcomes in CKD
Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD; ClinicalTrials.gov number, NCT03036150) was a randomized, double-blind, placebo-controlled trial evaluating the effects of dapagliflozin on kidney, cardiovascular and safety outcomes in 4304 patients with CKD and albuminuria (eGFR of 25–75 ml/min per 1.73 m2 and UACR of 200–5000 mg/g) with or without type 2 diabetes.11 The primary endpoint was composite of ≥50% decline in eGFR, kidney failure, or death due to CVD or kidney failure. Local institutional ethics committees at each participating site approved the trial protocol and all trial participants provided written informed consent.
Study of Heart and Kidney Protection with Empagliflozin
Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY; ClinicalTrials.gov number, NCT03594110) was a randomized, double-blind, placebo-controlled trial, evaluating the effects of empagliflozin on kidney, cardiovascular, and safety outcomes in 6609 patients with CKD (eGFR 20 to <45 ml/min per 1.73 m2, or 45 to <90 ml/min per 1.73 m2 with UACR ≥200 mg/g).12 The primary end point was a composite of sustained ≥40% decline in eGFR, kidney failure, or death due to CVD or kidney failure. All-cause hospitalization was a prespecified secondary outcome. Regulatory authorities, as well as ethics committees in each region, approved the trial protocol, and all participants provided written informed consent.
Outcomes
In the post hoc analysis of CREDENCE, the primary outcome of interest was first hospitalization from any cause. Additional outcomes included first and subsequent all-cause hospitalization; first all-cause hospitalization or all-cause death; and first or subsequent all-cause hospitalization or all-cause death. Hospitalizations were ascertained from baseline to the end of the follow-up period using the adverse events database. For analyses of cause-specific hospitalization, we used hospitalization events as recorded in the adverse events database, classified according to Medical Dictionary for Regulatory Activities (MedDRA) system organ classes. These events were investigator reported, in other words, and not adjudicated by an independent committee. Each hospitalization could be attributed to more than one cause, and in such cases, we attributed the hospitalization to multiple categories based on the relevant MedDRA terms, and no priority was assigned to determine a primary cause.
In the meta-analysis of CREDENCE, DAPA-CKD, and EMPA-KIDNEY, we pooled treatment effects on first and subsequent all-cause hospitalization, since data for these outcomes were available across all three trials. All-cause hospitalization was a prespecified secondary end point in EMPA-KIDNEY; hospitalization for reasons other than components of the primary, kidney, or cardiovascular composite end points was not prespecified and evaluated post hoc using adverse event data in CREDENCE and DAPA-CKD.
Statistical Analyses
We performed analyses using the intention-to-treat principle that included all enrolled participants. We assessed the cumulative incidence of all-cause hospitalization outcomes using Kaplan-Meier plots and estimated the effects of canagliflozin versus placebo with Cox proportional hazards models to determine hazard ratios (HRs) and 95% confidence intervals (CIs). Cox models were stratified by eGFR categories at screening as prespecified in the primary trial analysis. To further examine the effect of canagliflozin on cause-specific hospitalizations, analyses were also performed according to the cause of hospitalization, classified using the MedDRA system organ classes.
The effects of canagliflozin versus placebo on first and subsequent hospitalizations (or death) were evaluated using recurrent event analysis primarily with the Andersen-Gill model. To assess the consistency of treatment effect estimates on first and subsequent hospitalizations across different time-to-event models, we conducted additional analyses using conditional risk set models from entry (Prentice, Williams, and Peterson Total Time) and from previous events (Prentice, Williams, and Peterson Gap Time and Wei, Lin, and Weissfeld models). For recurrent event analyses, the cumulative probability curves estimate the expected number of events per individual over time.
We assessed the effect of canagliflozin on all-cause hospitalizations across subgroups at baseline defined by age (younger than 65 years or 65 years or older), sex, history of CVD, heart failure, body mass index (<30 or ≥30 kg/m2), systolic BP (<140 or ≥140 mm Hg), glycated hemoglobin (<8% or ≥8%), eGFR (30 to <45, 45 to <60, or 60 to <90 ml/min per 1.73 m2), and UACR (≤300, >300 to ≤3000 or >3000 mg/g) by including treatment by subgroup interaction terms in the relevant models and with no correction of multiplicity.
Finally, we estimated the relative and absolute effect of SGLT2 inhibition on first and subsequent all-cause hospitalizations using data from CREDENCE, DAPA-CKD, and EMPA-KIDNEY. Treatment effects were pooled using inverse variance weighted meta-analysis overall and across three key subgroups: eGFR (<45 and ≥45 ml/min per 1.73 m2), UACR (<300 and ≥300 mg/g), and diabetes status. P values for heterogeneity across subgroups were obtained from the same model. To further examine the types of hospitalizations averted with SGLT2 inhibitors use, we also conducted a meta-analysis of effects on cause-specific hospitalization, as data for this outcome were available from all three trials.9,12 Since no heterogeneity was observed for the relative effect of SGLT2 inhibitors on first and subsequent all-cause hospitalizations across key subgroups, we estimated absolute effects, expressed as the number of events prevented per 1000 patient-years of treatment, by applying the overall relative risk reduction and 95% CIs to the mean event rate in the placebo arm, as previously performed by the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists Consortium.5
We conducted analyses using Stata, version 18, and R, version 4.3.1.
Results
Of 4401 participants enrolled in CREDENCE, during a median follow-up of 2.6 years, 734 and 809 participants experienced a hospitalization from any cause in the canagliflozin and placebo groups, respectively. Participants who were hospitalized during the trial were older, more likely to be men, have a history of CVD, and use insulin and diuretics (Supplemental Table 1). They also had longer duration of diabetes, lower eGFR, and higher body mass index, systolic BP, glycated hemoglobin, and UACR at baseline (Supplemental Table 1).
Canagliflozin reduced the risk of first all-cause hospitalization compared with placebo (155 versus 175 patients with an event per 1000 patient-years; HR, 0.88; 95% CI, 0.80 to 0.98; P = 0.02; Figure 1A). This effect was consistent across subgroups defined by baseline demographic or clinical characteristics (all P interactions > 0.32; Supplemental Table 2). A similar effect estimate was observed for the outcome of first hospitalization or death from any cause (HR, 0.89; 95% CI, 0.81 to 0.99; P = 0.02; Figure 1B).
Figure 1.
Canagliflozin reduced risk of hospitalization. Effects of canagliflozin versus placebo in CREDENCE on risk for (A) first hospitalization from any cause, (B) first hospitalization or death from any cause, (C) first and subsequent hospitalizations from any cause, and (D) first and subsequent hospitalizations or death from any cause. CI, confidence interval; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; HR, hazard ratio.
In the analysis of first and subsequent events, 3015 hospitalizations were recorded. Compared with placebo, canagliflozin reduced first and subsequent hospitalizations from any cause by 14% (242 versus 283 per 1000 patient-years; HR, 0.86; 95% CI, 0.76 to 0.96; P = 0.007; Figure 1C) as well as first and subsequent hospitalizations or death (HR, 0.86; 95% CI, 0.77 to 0.96; P = 0.006; Figure 1D). We estimated similar observed effects when alternative analytical methods were applied (Figure 2).
Figure 2.
Effect of canagliflozin versus placebo on first and subsequent hospitalizations in different recurrent events models in CREDENCE.
Reductions in all-cause hospitalization with canagliflozin were driven by fewer hospitalization due to infections and infestations (HR, 0.76; 95% CI, 0.64 to 0.90) and cardiac disorders (HR, 0.76; 95% CI, 0.63 to 0.93; Figure 3).
Figure 3.
Effects of canagliflozin versus placebo on cause-specific hospitalizations in CREDENCE.
Characteristics of participants in the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials are presented in Table 1. In a meta-analysis of these three placebo-controlled SGLT2 inhibitor CKD-focused trials, SGLT2 inhibitors reduced first and subsequent hospitalizations by 15%, an effect that was consistent across trials (HR, 0.85; 95% CI, 0.78 to 0.95; P heterogeneity = 0.94; Figure 4). Effects were similarly consistent across eGFR, UACR, and diabetes subgroups defined at baseline (all P heterogeneity > 0.50). SGLT2 inhibitors reduced hospitalizations resulting from a broad range of causes (Figure 5), including infections and infestations (HR, 0.86; 95% CI, 0.77 to 0.95), cardiac disorders (HR, 0.80; 95% CI, 0.71 to 0.89), kidney and urinary disorders (HR, 0.77; 95% CI, 0.67 to 0.88), and metabolism and nutritional disorders (HR, 0.76; 95% CI, 0.64 to 0.91). These effects were consistent across all three sodium-glucose cotransporter 2 inhibitor trials (all P heterogeneity > 0.14), except for hospitalizations due to neoplasms, driven by an increase in risk in CREDENCE and reduction in DAPA-CKD, with no effect overall (overall HR, 0.92; 95% CI, 0.73 to 1.15; P heterogeneity = 0.004; Figure 5).
Table 1.
Baseline characteristics of the study participants in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, Dapagliflozin and Prevention of Adverse Outcomes in CKD, and Study of Heart and Kidney Protection with Empagliflozin
| Characteristic | CREDENCE (n=4401) | DAPA-CKD (n=4304) | EMPA-KIDNEY (n=6609) |
|---|---|---|---|
| Age, yr | 63.0±9.2 | 61.9±12.1 | 63.9±13.9 |
| Female sex, n (%) | 1494 (34) | 1425 (33) | 2192 (33) |
| Diabetes, n (%) | 4401 (100) | 2906 (68) | 3040 (46) |
| CVD, n (%) | 2220 (50) | 1610 (37) | 1765 (27) |
| Heart failure, n (%) | 652 (15) | 468 (11) | 658 (10) |
| eGFR, ml/min per 1.73 m2 | 56±18 | 43±12 | 37±15 |
| UACR, mg/g | 927 (463–1833) | 949 (477–1885) | 412 (94–1190) |
| Median follow-up, yr | 2.6 | 2.4 | 2.0 |
Values are mean±SD, median (interquartile range), or n (%). CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CVD, cardiovascular disease; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in CKD; EMPA-KIDNEY, Study of Heart and Kidney Protection with Empagliflozin; UACR, urinary albumin-to-creatinine ratio.
Figure 4.
Meta-analysis of the effects of SGLT2 inhibitors on first and subsequent all-cause hospitalizations overall and by baseline eGFR, UACR, and diabetes status in CREDENCE, DAPA-CKD, and EMPA-KIDNEY. DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in CKD; EMPA-KIDNEY, Study of Heart and Kidney Protection with Empagliflozin.
Figure 5.
Meta-analysis of the effects of SGLT2 inhibitors on cause-specific hospitalizations in CREDENCE, DAPA-CKD, and EMPA-KIDNEY.
Based on the pooled mean event rates in placebo arms, SGLT2 inhibition in CKD was estimated to prevent 36 (95% CI, 13 to 56) hospitalizations per 1000 patient-years of treatment (Figure 6). Absolute risk reductions were similar across baseline UACR subgroups but were numerically larger in persons with eGFR <45 ml/min per 1.73 m2 and those with diabetes due to the higher rates of hospitalization in these individuals (Figure 6).
Figure 6.
Absolute number of hospitalizations (first and subsequent) prevented with SGLT2 inhibitors per 1000 patient-years overall and by baseline eGFR, UACR, and diabetes status in CREDENCE, DAPA-CKD, and EMPA-KIDNEY.
Discussion
In this post hoc analysis of CREDENCE and subsequent meta-analysis of three placebo-controlled SGLT2 inhibitor CKD-focused trials, we made three main observations. First, all-cause hospitalization rates among patients recruited into contemporary kidney-focused clinical trials are exceptionally high—at least three-fold higher than incidence rates of the primary composite end point in each individual trial. Second, SGLT2 inhibition reduces the risk of all-cause hospitalization, with consistent effects irrespective of kidney function, degree of albuminuria, and diabetes status. Finally, because of how frequently participants in these trials were hospitalized, these effects are projected to translate into substantial absolute reductions in hospitalizations, with meaningful consequences not only for patients and their loved ones but also for the health systems in which they receive care.
Data from over 25 million people in the CKD-Prognosis Consortium indicate that the risk of hospitalization for any cause is almost three times higher in persons with advanced CKD and severely increased albuminuria compared with those with normal or near normal kidney function and little or no albuminuria.13 Hospitalizations in patients with CKD tend to be driven by complex multiday admission involving multiple comorbidities, particularly heart failure.3,14 In particular, hospitalizations related to kidney failure invariably incur the highest costs in the United States and other health systems.4 These data underscore the economic effect of any intervention that can reduce hospitalizations in people with CKD.
Although all-cause hospitalization was evaluated post hoc in CREDENCE and DAPA-CKD, the consistency of effects on this outcome with the EMPA-KIDNEY data (where hospitalization was formally collected as a secondary end point) is a key finding that increases our confidence in the overall results.12 Our findings extend previous data from SGLT2 inhibitor trials in persons with type 2 diabetes at high cardiovascular risk and with heart failure, irrespective of ejection fraction, diabetes, and level of kidney function.6–9,15–17 The consistent relative risk reductions for hospitalization in CKD across subgroups defined by baseline kidney function, albuminuria, and diabetes status strongly suggest that benefits to individuals and health systems with respect to reducing hospitalizations are likely to be broad and widely generalizable.
The apparent reduction in infection-related hospitalizations with SGLT2 inhibitors is potentially noteworthy because after CVD, infection is the leading cause of death in patients with CKD.18,19 Indeed, in CREDENCE, infections were the most common reason for hospitalization overall, with higher incidence rates than hospitalizations for cardiovascular causes. The effect estimates on cause-specific hospitalizations are post hoc and thus should be interpreted with appropriate caution. Since these events were not adjudicated and no hierarchy was established for hospitalizations in which multiple causes were recorded, it is possible that these findings are biased by misclassification, or that the apparent reduction in infections is a by-product of fewer hospitalizations for other reasons, rather than a direct effect on the risk of infection. However, the reduction in infection-related hospitalizations observed in this analysis is consistent with data from the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 trial, which reported that dapagliflozin reduced infection-related hospitalizations in people with type 2 diabetes with or at high risk of atherosclerotic CVD.15 In the Evaluate Renal Function with Semaglutide Once Weekly trial, which evaluated the effect of semaglutide versus placebo in 3533 patients with CKD and type 2 diabetes, there were also fewer serious infection-related adverse events with semaglutide.20 Whether these findings reflect direct protective effects of these therapies on infection risk, the importance of preservation of kidney function and improvements in metabolism with respect to immune system function, or chance, requires further investigation. Although there were more hospitalizations related to neoplasms in the canagliflozin arm compared with placebo, this observation was based on few events, with no similar signal observed on analyses of cause-specific hospitalizations in other SGLT2 inhibitor trials,9,12 nor any suggestion of harm related to malignancies overall,21 suggesting this is likely to be a chance finding.
This study benefits from high-quality data collected in three large-scale international randomized trials conducted to a high standard. The large number of patients enrolled in the three trials allowed for the reliable assessment of effects on all-cause hospitalization overall and across clinically important subgroups. However, there are some limitations to consider when interpreting these data. CREDENCE was not powered to assess effects on cause-specific hospitalization, and thus, these findings should be interpreted as hypothesis generating due to the risk of chance findings due to multiple testing. Second, aside from EMPA-KIDNEY, hospitalizations were not a prespecified secondary end point but were captured as part of routine adverse event reporting during CREDENCE and DAPA-CKD. Although some events may have been missed, such errors would be expected to occur with no difference between the active and placebo groups, and therefore, the relative effect estimates should be relatively unaffected. In addition, such missingness means that absolute risk reductions may be underestimates for the full benefits.
In summary, SGLT2 inhibitors reduce the risk of hospitalizations from any cause, in patients with CKD, irrespective of diabetes, kidney function, and degree of albuminuria. These findings reinforce the role of SGLT2 inhibitors as foundational treatment to improve clinically meaningful outcomes for patients with CKD.
Supplementary Material
Acknowledgments
The authors thank all participants, investigators, and trial teams, for their participation in the included trials. The CREDENCE study was sponsored by Janssen Research and Development; DAPA-CKD was sponsored by AstraZeneca; and EMPA-KIDNEY was initiated, designed, conducted, analyzed, and reported by the University of Oxford and funded by Boehringer Ingelheim (the trial sponsor) and Eli Lilly. The funders were not involved in the design, analysis, reporting, or decision to submit this manuscript for publication. This analysis was supported by an unrestricted publication grant from Menarini, who were not involved in the design, analysis, writing of the manuscript, or decision to submit the manuscript for publication.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C345.
Author Contributions
Conceptualization: Brendon L. Neuen, Megumi Oshima.
Data curation: Niels Jongs, Brendon L. Neuen, Megumi Oshima.
Formal analysis: Luke Buizen, Niels Jongs, Megumi Oshima.
Investigation: Niels Jongs, Megumi Oshima.
Methodology: Brendon L. Neuen, Megumi Oshima.
Project administration: Brendon L. Neuen, Megumi Oshima.
Resources: Niels Jongs, Brendon L. Neuen.
Supervision: Clare Arnott, Glenn M. Chertow, Hiddo J.L. Heerspink, William G. Herrington, Meg J. Jardine, Adeera Levin, Kenneth W. Mahaffey, Brendon L. Neuen, Vlado Perkovic, Carol Pollock, David C. Wheeler.
Writing – original draft: Glenn M. Chertow, Brendon L. Neuen, Megumi Oshima.
Funding
B.L. Neuen: Menarini Group, National Health and Medical Research Council, and Ramaciotti Foundations.
Data Availability Statements
Original data created for the study are or will be available in a persistent repository upon publication. Clinical Trial Data. Other. Data from the CREDENCE trial is available in the public domain via the Yale University Open Data Access Project (http://yoda.yale.edu/). Details regarding data sharing for other trials can be found in the respective primary publications. https://yoda.yale.edu/.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/CJN/C346.
Supplemental Table 1. Baseline characteristics of the study participants with or without any hospitalization.
Supplemental Table 2. Effects of canagliflozin versus placebo on risk for first hospitalization from any cause by baseline patient characteristics.
References
- 1.Diwan V Hoy WE Wang Z, et al.; NHMRC CKD.CRE and the CKD.QLD Collaborative. Hospitalizations among adults with CKD in public renal specialty practices: a retrospective study from Queensland, Australia. Kidney Med. 2023;5(9):100700. doi: 10.1016/j.xkme.2023.100700 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Garcia Sanchez JJ James G Carrero JJ, et al. Health care resource utilization and related costs of patients with CKD from the United States: a report from the DISCOVER CKD retrospective cohort. Kidney Int Rep. 2023;8(4):785–795. doi: 10.1016/j.ekir.2023.01.037 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pollock C James G Garcia Sanchez JJ, et al. Healthcare resource utilisation and related costs of patients with CKD from the UK: a report from the DISCOVER CKD retrospective cohort. Clin Kidney J. 2022;15(11):2124–2134. doi: 10.1093/ckj/sfac168 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Tangri N Svensson MK Bodegard J, et al. Mortality, health care burden, and treatment of CKD: a multinational, observational study (OPTIMISE-CKD). Kidney360. 2024;5(3):352–362. doi: 10.34067/KID.0000000000000374 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400(10365):1788–1801. doi: 10.1016/S0140-6736(22)02074-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Feng KY Li J Ianus J, et al. Reasons for hospitalizations in patients with type 2 diabetes in the CANVAS programme: a secondary analysis. Diabetes Obes Metab. 2021;23(12):2707–2715. doi: 10.1111/dom.14525 [DOI] [PubMed] [Google Scholar]
- 7.Kaku K Wanner C Anker SD, et al. The effect of empagliflozin on the total burden of cardiovascular and hospitalization events in the Asian and non-Asian populations of the EMPA-REG OUTCOME trial of patients with type 2 diabetes and cardiovascular disease. Diabetes Obes Metab. 2022;24(4):662–674. doi: 10.1111/dom.14626 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Szarek M Bhatt DL Steg PG, et al.; SOLOIST-WHF committees and investigators. Effect of sotagliflozin on total hospitalizations in patients with type 2 diabetes and worsening heart failure: a randomized trial. Ann Intern Med. 2021;174(8):1065–1072. doi: 10.7326/M21-0651 [DOI] [PubMed] [Google Scholar]
- 9.Schechter M Jongs N Chertow GM, et al. Effects of dapagliflozin on hospitalizations in patients with chronic kidney disease: a post hoc analysis of DAPA-CKD. Ann Intern Med. 2023;176(1):59–66. doi: 10.7326/M22-2115 [DOI] [PubMed] [Google Scholar]
- 10.Perkovic V Jardine MJ Neal B, et al.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295–2306. doi: 10.1056/NEJMoa1811744 [DOI] [PubMed] [Google Scholar]
- 11.Heerspink HJL Stefansson BV Correa-Rotter R, et al.; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–1446. doi: 10.1056/NEJMoa2024816 [DOI] [PubMed] [Google Scholar]
- 12.Herrington WG Staplin N Wanner C, et al.; The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117–127. doi: 10.1056/NEJMoa2204233 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Grams ME Coresh J Matsushita K, et al.; Writing Group for the CKD Prognosis Consortium. Estimated glomerular filtration rate, albuminuria, and adverse outcomes: an individual-participant data meta-analysis. JAMA. 2023;330(13):1266–1277. doi: 10.1001/jama.2023.17002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Sullivan MK Jani BD McConnachie A, et al. Hospitalisation events in people with chronic kidney disease as a component of multimorbidity: parallel cohort studies in research and routine care settings. BMC Med. 2021;19(1):278. doi: 10.1186/s12916-021-02147-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Schechter M Wiviott SD Raz I, et al. Effects of dapagliflozin on hospitalisations in people with type 2 diabetes: post-hoc analyses of the DECLARE-TIMI 58 trial. Lancet Diabetes Endocrinol. 2023;11(4):233–241. doi: 10.1016/S2213-8587(23)00009-8 [DOI] [PubMed] [Google Scholar]
- 16.Wanner C Inzucchi SE Zinman B, et al.; EMPA-REG OUTCOME Investigators. Consistent effects of empagliflozin on cardiovascular and kidney outcomes irrespective of diabetic kidney disease categories: insights from the EMPA-REG OUTCOME trial. Diabetes Obes Metab. 2020;22(12):2335–2347. doi: 10.1111/dom.14158 [DOI] [PubMed] [Google Scholar]
- 17.Mayne KJ Sardell RJ Staplin N, et al.; EMPA-KIDNEY Collaborative Group. Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial. Clin J Am Soc Nephrol. 2024;19(9):1119–1129. doi: 10.2215/CJN.0000000000000498 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Mix TC St peter WL Ebben J, et al. Hospitalization during advancing chronic kidney disease. Am J Kidney Dis. 2003;42(5):972–981. doi: 10.1016/j.ajkd.2003.06.001 [DOI] [PubMed] [Google Scholar]
- 19.Iwagami M, Caplin B, Smeeth L, Tomlinson LA, Nitsch D. Chronic kidney disease and cause-specific hospitalisation: a matched cohort study using primary and secondary care patient data. Br J Gen Pract. 2018;68(673):e512–e523. doi: 10.3399/bjgp18X697973 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Perkovic V Tuttle KR Rossing P, et al.; FLOW Trial Committees and Investigators. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391:109–121. doi: 10.1056/NEJMoa2403347 [DOI] [PubMed] [Google Scholar]
- 21.Spiazzi BF Naibo RA Wayerbacher LF, et al. Sodium-glucose cotransporter-2 inhibitors and cancer outcomes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2023;198:110621. doi: 10.1016/j.diabres.2023.110621 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Original data created for the study are or will be available in a persistent repository upon publication. Clinical Trial Data. Other. Data from the CREDENCE trial is available in the public domain via the Yale University Open Data Access Project (http://yoda.yale.edu/). Details regarding data sharing for other trials can be found in the respective primary publications. https://yoda.yale.edu/.