ABSTRACT
Background: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated.
Methods: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study.
Conclusion: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients.
ClinicalTrials.gov registry: NCT05558098
Keywords: Critical illness; Sodium-glucose transporter 2 inhibitors; Organ dysfunction; Critical care outcomes
RESUMO
Antecedentes: A doença crítica é um importante ônus permanente da assistência médica em todo o mundo e está associada a altas taxas de mortalidade. Os inibidores do cotransportador de sódio-glicose do tipo 2 têm demonstrado consistentemente benefícios nos desfechos cardiovasculares e renais. Os efeitos dos inibidores do cotransportador de sódio-glicose do tipo 2 em doenças agudas ainda não foram devidamente investigados.
Métodos: O DEFENDER é um estudo de iniciativa do investigador, multicêntrico, randomizado, aberto, desenhado para avaliar a eficácia e a segurança da dapagliflozina em 500 participantes adultos com disfunção orgânica aguda hospitalizados na unidade de terapia intensiva. Os participantes aptos serão randomizados 1:1 para receber 10mg de dapagliflozina e o tratamento padrão por até 14 dias ou apenas o tratamento padrão. O desfecho primário é um composto hierárquico de mortalidade hospitalar, início de terapia renal substitutiva e tempo de internação na unidade de terapia intensiva, até 28 dias. O monitoramento da segurança será rigoroso durante todo o estudo.
Conclusão: O DEFENDER é o primeiro estudo desenvolvido para investigar o uso de um inibidor do cotransportador de sódio-glicose do tipo 2 em pacientes de unidade de terapia intensiva geral com disfunção orgânica aguda. O estudo fornecerá informações relevantes sobre o uso de medicamentos dessa classe promissora em pacientes críticos.
Registro ClincalTrials.gov: NCT05558098
Descritores: Inibidores do transportador 2 de sódio-glicose; Disfunção orgânica; Protocolo de estudo clínico
INTRODUCTION
Critical illness is a major global challenge, with mortality rates after intensive care unit (ICU) admission reaching as high as 22%, according to international estimates.(1) Despite this alarming issue for health care systems, no specific therapy has yet been shown to improve outcomes in unselected patients with acute organ dysfunction in the ICU.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated a consistent reduction in cardiovascular and kidney outcomes in several randomized clinical trials (RCTs) across a range of clinical settings, including type 2 diabetes mellitus,(2) heart failure with reduced and preserved ejection fraction,(3-6) acute heart failure,(7) and chronic kidney disease.(8,9) Some of the postulated effects of this drug class(10) may also positively impact multiple deleterious pathways of acute illness and protect against organ injury and failure. Plausible mechanisms that may be involved-particularly in patients with sepsis(11)- include improved metabolic efficiency(12,13) and endothelial function,(14) inhibition of pro-inflammatory pathways(15) and sympathetic activity,(16) decreasing production of reactive oxygen species,(17) and increased erythropoietin production.(18) Experimental animal models of acute injury provide data that support the existence of an overlap between the effects of SGLT2 inhibitors and protection against organ dysfunction. Sodium-glucose cotransporter-2 inhibition prevented renal injury and reduced biomarkers of systemic inflammation(19) and pathological findings of lung injury(20) in lipopolysaccharide-induced inflammation models.
In humans, the DARE-19 trial(21) provided pivotal information to support the use of SGLT2 inhibitors in major acute illness; dapagliflozin numerically reduced the event rates of the coprimary prevention outcome (a composite of new or worsening organ dysfunction or death) in hospitalized COVID-19 patients when compared with placebo. Although the results of the trial failed to meet statistical significance for the efficacy outcome, the use of dapagliflozin was well tolerated, associated with a low rate of diabetic ketoacidosis, and did not lead to an increase in serious adverse events despite previous concerns.(22)
The DEFENDER study (“Estudo Clínico RanDomizado Avaliando a Eficácia da DapagliFlozina em Pacientes IntErNaDos em Estado CRítico”) was designed to assess the efficacy and safety of repurposing dapagliflozin for unselected critically ill patients with acute organ dysfunction.
METHODS
DEFENDER (ClinicalTrials.gov unique identifier NCT05558098) is an investigator-initiated trial coordinated and sponsored by the Academic Research Organization (ARO) of the Hospital Israelita Albert Einstein, funded through the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde (PROADI-SUS) from the Brazilian Ministry of Health.
The study coordinating site is responsible for overseeing all trial operations (start-up activities, regulatory affairs, site management, data management, and scientific oversight). The steering committee (SC) comprises coordinating center members and academic leaders responsible for supervising the study’s progress, monitoring, and considering recommendations from the data monitoring and safety board (DSMB). SC members will also plan academic publications, draft and review the study manuscript, and present study results at scientific meetings. To ensure trial participants’ safety, the DMSB members are independent experts appointed to the committee, namely, Dr. Paul Young (chair), an intensivist and clinical researcher; Prof. Carol Hodgson, a physiotherapist specialist in intensive care and clinical trial; and Prof. Michael Bailey, a biostatistician.
The study is being conducted in accordance with Good Clinical Practice guidelines. Prior to study initiation or implementation of changes, the study protocol and all amendments will be approved by Ethical Committees at each participating site. Participants or their legal representatives will provide informed consent before enrollment. In cases where participants are initially deemed incapable of giving consent due to impairment in decision-making capacity, consent will be reobtained after the participant regains capacity during the study follow-up period (e.g., after recovery from delirium). The informed consent form (ICF) contains all requirements elements (Resolution 466, 2012) related to research with human subjects according to the Brazilian National Research Ethics Commission (Conep) and Good Clinical Practice guidelines. The study design is in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)(23) statement (Table 1S - Supplementary Material), and the trial registry contains all 24 items from the World Health Organization Trial Registration DataSet.
Study objective
The primary objective is to assess whether the use of dapagliflozin in patients with critical illness and acute organ dysfunction improves the hierarchical endpoint of hospital mortality, initiation of kidney replacement therapy (KRT) and hospital length of stay. The secondary objectives are to assess the effect of dapagliflozin on the individual components of the hierarchical endpoint (hospital mortality, initiation of KRT and hospital length of stay) and on patient-centered endpoints (hospitaland intensive care unit-free days and organ support-free days).
Study design and population
DEFENDER is an investigator-initiated, multicenter, randomized, open-label, phase 2/3 trial. Eligible participants will be 18 years of age or older, admitted to an ICU with an expected length of stay > 48 hours in the opinion of the attending physician, and with at least one organ dysfunction (hypotension, signs of acute kidney injury, and/or need for new use of a high-flow nasal catheter, noninvasive or invasive ventilation). Patients will be eligible within 24 hours after onset of organ dysfunction. Key exclusion criteria are age < 18 years, pregnancy, end-stage kidney disease on maintenance dialysis, planned ICU admission after elective surgery, use of dapagliflozin or of other SGLT2 inhibitors, total fasting, and type 1 diabetes mellitus or history of diabetic ketoacidosis. A full list of the inclusion and exclusion criteria is presented in table 1. Site investigators and personnel are encouraged to screen all ICU beds on a daily basis to identify potential participants.
Study procedures
Interventions
Eligible patients will be randomized 1:1 to dapagliflozin 10mg plus standard of care or standard care alone (Figure 1). Randomization is performed centrally through the Research Electronic Data Capture (REDCap) system,(24) stratified by study site with variable block sizes of 4, 8 and 12. A confidential randomization list was generated by the coordinating center. As an open-label study, no procedures to blind site staff, study personnel, or physicians involved in patient care will be conducted.
All study procedures will be performed by site staff. Patients in the intervention arm will receive dapagliflozin 10mg/day for 14 days (or until ICU discharge, whichever comes first). Patients in the control arm will receive a routine standard of care. Dapagliflozin will be started on the day of randomization, preferably in the morning without fasting, orally for all participants able to swallow pills. For participants who cannot take oral medications, dapagliflozin will be administered enterally (orogastric tube, oroenteral tube, gastrostomy, jejunostomy, as available) after maceration and dilution in water.
Dapagliflozin should only be withheld in the following situations:
-
- Requirement for absolute fasting and/or inability to access the enteral route for the drug.
-
- Occurrence of euglycemic diabetic ketoacidosis, defined by high anion gap metabolic acidosis and ketone bodies in the urine.
-
- More than one episode of severe hypoglycemia (≤ 50mg/dL) during drug use.
-
- Withdrawal of consent.
-
- Suspected allergic reaction to dapagliflozin as well as other idiosyncratic drug reactions, such as DRESS syndrome (drug rash with eosinophilia and systemic symptoms).
-
- Initiation of kidney replacement therapy.
Standard of care
Study sites and investigators will be expected to provide optimal management for critically ill patients according to Brazilian and international consensus and guidelines. This includes but is not limited to ventilation support (oxygen, noninvasive ventilation, mechanical ventilation, among others), hemodynamic support (vasopressors, inotropes), kidney replacement therapy (hemodialysis, hemofiltration, hemodiafiltration, among others), deep venous thromboembolism prophylaxis, delirium, sedation, and pain management. All participant care except for study medication will be solely determined by the local health care team.
Monitoring for adverse events
Study sites and investigators will receive specific recommendations on careful monitoring of blood glucose, acid‒base disorders, and renal function during the study to minimize SGLT2 inhibitor-related risks. Glycemic control is to be performed according to the institutional guidelines of each study site for all participants. The study protocol recommends that participants should be monitored at least every 6 hours for blood glucose levels using bedside blood glucose meters or venous/arterial samples until they recover from all organ dysfunctions. For unstable participants who require vasopressors or inotropes or are undergoing invasive mechanical ventilation, blood glucose levels should be monitored at least every 2 hours, but hourly monitoring is strongly recommended, with a target blood glucose level below 180mg/dL. Management of hyperglycemic episodes should preferably be done through an intravenous insulin pump for unstable or mechanically ventilated participants or through intermittent insulin (intravenous or subcutaneous) for other participants. The minimum daily carbohydrate intake for all participants was set at 100g of glucose, considering all infusions. Creatinine levels and blood gas analysis (pH, bicarbonate, anion gap, base excess) will be monitored daily during the first five days of study follow-up.
Study follow-up
Participants will be followed for 28 days or until hospital discharge, whichever is sooner. The intervention group will be assessed for adherence to the study drug daily from Days 1 to 14. For both the intervention and control groups, adherence to mandatory laboratory parameters (serum creatinine and blood gas analysis) will be assessed daily from Days 1 to 5.
Data collection and management
Trained research personnel from study sites will use the REDCap system to collect data. Data on eligibility criteria that are not met will be collected as screening logs. At randomization, demographic information, comorbidities, concomitant medications, reason for ICU admission, and illness severity will be collected. Daily data collection will include information on treatment adherence, blood gas analysis, and serum creatinine. Blood gas analysis forms will contain ranges of possible values for pH, bicarbonate, and base excess. Information regarding study outcomes will be collected on Day 28 or at hospital discharge. Serious adverse events and adverse events of special interest will be collected throughout the study.
To ensure data quality and confidentiality, investigators and study staff will receive training on data collection, including a dedicated training environment in the electronic data capture system that will register deidentified information about study participants. The coordinating center will check the data weekly, and study sites will receive a monthly report on data quality. On-site and remote monitoring will be conducted during the study. We plan to recruit 500 participants in at least 20 Brazilian ICUs.
Study outcomes
Primary outcome
The primary endpoint is a hierarchical composite of hospital mortality, initiation of KRT, and ICU length of stay up to 28 days after randomization, censored at hospital discharge. ICU length of stay is defined as the total number of calendar days (without fractions) in the ICU from randomization to hospital discharge.
Secondary outcomes
Secondary endpoints are hospital mortality, initiation of KRT, ICU-free days, hospital-free days, vasopressor-free days, mechanical ventilation-free days, and KRT-free days up to 28 days after randomization, censored at hospital discharge. To be deemed vasopressorand mechanical ventilation-free, a cutoff of 6 hours or less in an entire calendar day will be used.
Intensive care unit-free days, hospital-free days, vasopressor-free days, mechanical ventilation-free days, and KRT-free days endpoints are defined as the number of calendar days alive and free from each component, measured on an ordinal scale from 0 to 29, with higher values indicating a better outcome. A value of 0 will be assigned to participants who die prior to hospital discharge. Participants who are discharged prior to Day 28 will be assumed to be free of the endpoint through Day 28.
Safety outcomes
While meta-analyses of large placebo-controlled randomized trials of SGLT2 inhibitors found the use of this drug class to be generally safe, with a low occurrence of diabetic ketoacidosis (0.3%)(25) and no increased risk for acute kidney injury, hypoglycemia, or hypotension,(26) the DEFENDER study will be the first study involving evaluation of the use of an SGLT2 inhibitor in critically ill patients without COVID-19. Therefore, one of the key aspects of the study is to closely monitor for potential adverse events.
All serious adverse events will be promptly reported by the study sites. Additionally, we will collect information on adverse events of special interest, including liver transaminase elevation (greater than three times above the reference range), skin lesions, hypoglycemia, urinary tract infection, bloodstream infection, and diabetic ketoacidosis, irrespective of their severity and causality assessment. Participants will receive dapagliflozin in a strictly monitored environment, which enables the timely identification and management of potential adverse events. Acid‒base disorders and kidney function will be monitored during the first five days of study follow-up.
Statistical considerations
Planned Statistical Analysis
The primary outcome analysis will be conducted using the unmatched win ratio (WR) method(27) as proposed by Pocock et al.,(28) with the hierarchical composite primary outcome of (1) hospital mortality, (2) initiation of KRT, and (3) ICU length of stay-LOS (in days). The win ratio will be assessed by comparing every possible pair of participants from the intervention and control groups in a pairwise descending fashion. A structural framework using nodes in a decision tree will be used for each level of comparison, with labels of “win” or “loss” assigned if one participant has a better outcome than the other or a “tie” otherwise. Hospital mortality will be the primary level of comparison, and reflecting the higher importance of this outcome, pairwise comparisons in which both participants die will be determined as an early “tie.” If both participants survive, they proceed to the second level of the hierarchy for a comparison of the initiation of KRT. If both participants do not require KRT, or if both require it, the pair is then moved to the third level to compare the ICU LOS. For the ICU LOS outcome, the pair with the shorter duration of stay is considered the “winner.” The structural framework for the three pairwise comparisons according to the hierarchy of the composite primary outcome is shown in figure 2.
The WR is calculated as the ratio of the total number of “wins” between the intervention and control groups, and a WR > 1.0 indicates a better outcome in the intervention group. The 95% confidence intervals (95%CI) for the WR will be calculated by bootstrapping based on 10,000 samples, and 95%CI not including the unit (1.0) will be considered statistically significant.
Secondary binary outcomes will be analyzed using a Bayesian hierarchical logistic regression model. The model will include the study group as a predictor and will be adjusted for study site, age, clinical suspicion of sepsis, use of vasopressors, and mechanical ventilation at randomization. A neutral prior of moderate strength(29) and normal distribution, centered at an odds ratio (OR) of 1.0 and a standard deviation of 0.35, corresponding to a 95% probability that the effect (OR) is within the 0.5 - 2.0 range, will be used. Superiority of the dapagliflozin group over the control group will be determined if the posterior distribution of the adjusted odds ratio (aOR) being less than 1.0 [Pr (aOR < 1.0)] is more than 95%. The results will be presented as the posterior distribution of the aOR (in log scale), a 95% credible interval, and the probability of the aOR being less than 1.0.
Intensive care unit-free days, hospital-free days, vasopressor-free days, mechanical ventilation-free days, and KRT-free days will also be analyzed using a Bayesian hierarchical ordinal model, using the same covariates from the binary outcomes model. Frequentist analysis exploratory analysis for secondary outcomes will also be performed, and no p values will be presented. Binary outcomes will be analyzed thorough a logistic regression model, with the same covariates as the Bayesian models, and data will be presented as aOR, crude OR, and corresponding 95%CI. Treatment differences in free day outcomes will be calculated using the Hodges‒Lehmann method and presented as the difference in days and 95%CI.
All primary, secondary and safety analyses will follow the intention-to-treat principle. A sensitivity safety analysis will also be conducted in all participants who received at least one dose of dapagliflozin (safety population). Full details of all planned analyses are provided in version 1.0 of the Statistical Analysis Plan (Supplementary Material). All analyses will be performed using R software (R Project for Statistical Computing).
Subgroup analysis
For the primary and secondary outcomes, the following relevant subgroup analyses were planned: clinical suspicion of sepsis at randomization (yes/no), diabetes mellitus (yes/no), serum creatinine at enrollment (< 1.5mg/dL, 1.5 - 3.0mg/dL, and > 3.0mg/dL), cardiovascular reason for ICU admission (yes/no), and age (< 65 and ≥ 65 years). Stratified WR analysis will be performed for each subgroup stratum. The 95%CIs will be calculated by bootstrapping 10,000 samples for each analysis, and 95%CIs not including the unit (WR = 1.0) will be considered statistically significant. We will also perform additional analysis for the secondary outcomes within each subgroup using the same Bayesian models and exploratory frequentist analysis.
Power and sample size
We estimated that a sample size of 500 participants would provide at least 85% power to detect a win ratio and corresponding 95%CI above 1. This calculation was made based on the following assumptions: (1) a 2% absolute reduction in hospital mortality from 30 to 28% with dapagliflozin; (2) a 3% absolute reduction in initiation of KRT from 10 to 7% with dapagliflozin; and (3) a mean reduction in ICU LOS of 0.5 days with dapagliflozin. The estimation was obtained after performing 10,000 simulations in samples of 500 participants using these assumptions and 95% confidence intervals obtained by bootstrapping. Figure 3 displays the results of the obtained lower boundaries of the 95% confidence intervals of the win ratio values from these simulations.
Lower boundary of the win ratios 95% confidence intervals obtained through 10,000 simulations on samples of 500 patients.
Interim analysis and Data and Safety Monitoring Board
The DSMB regularly reviews unblinded patient-level data during the study to ensure participant safety. The first safety analysis occurred on March 27, 2023, after 100 participants were enrolled. An interim analysis will occur when half of the sample size (n = 250) has been enrolled and followed for at least 14 days. For this specific analysis, trial recruitment will be halted for four weeks and will resume only after the DSMB deliberation. Another safety analysis is planned to occur after 375 participants are enrolled. The sole purpose of the interim analysis is to assess safety, and the trial will not be halted for benefit or futility. The frequency of safety interim analysis might be changed if deemed appropriate by the DSMB members.
At the interim analysis, the DSMB will use a Bayesian framework (simple logistic regression) to assess the posterior probability distribution for harm (OR > 1.0) for hospital mortality and initiation of KRT. If this probability is greater than 80%, the DSMB will recommend stopping the trial. Harm will also be assessed in two key subgroups: participants with hypotension or acute kidney injury at randomization. If the probability of harm is greater than 80% for either subgroup, the DSMB will recommend excluding them from the trial.
Additional interim analyses may be convened at the discretion of any DSMB member if new scientific data or concerns arise during the study, especially regarding the ongoing SGLT2i arms of the ACTIV-4A (NCT04505774) and RECOVERY (NCT04381936) platform trials. Based on the interpretation and quality of the data, the number of events, and other factors, the DSMB may recommend modifications to the protocol (e.g., changes to inclusion/exclusion criteria), suspension, or termination of the trial, and advise the Steering Committee. However, all final decisions regarding trial conduct will be at the discretion of the Steering Committee.
Current status
The first participant was randomized in November/2022, and there are currently 14 active and 13 enrolling sites. The list of active and enrolling sites is updated on a monthly basis and can be accessed publicly on the study clinicaltrials.gov webpage.
DISCUSSION
DEFENDER will be the first study to test the hypothesis that SGLT2 inhibitors can reduce organ dysfunction and mortality of critical illness from different etiologies. This approach is different from that of several other randomized clinical trials that failed to demonstrate improved outcomes in ICU patients, such as the use of vitamin C(30-32) and statins for sepsis,(33) probiotics for ventilator-associated pneumonia,(34) among others.(35)
Sodium-glucose cotransporter-2 inhibitors have been used in more than 45,000 participants in over 13 large-scale trials, and the evidence overwhelmingly suggests that the cardiovascular and kidney benefits outweigh the low risk of serious harm.(25) It is biologically plausible that the effects of drugs in this class may positively impact pathways of organ dysfunction during acute critical illness.(36) Furthermore, the initiation of SGLT2 inhibitors in hospitalized patients with acute heart failure during placebo-controlled randomized clinical trials was safe and did not increase the risk of hypotension, hypoglycemia, or acute kidney injury.(26)
Given that this is the first time that SGLT2 inhibitors will be used in general ICU patients, we have implemented a series of safety measures to minimize potential risks and preventable harm for current and future study participants that will permit a comprehensive understanding of the risk/benefit profile of dapagliflozin in critically ill patients. In conclusion, DEFENDER presents a new approach to evaluate the potential of SGLT2 inhibitors in reducing organ dysfunction and mortality in critically ill patients and will provide valuable information for future trials in this population.
-
Responsible editor: Felipe Dal-Pizzol
-
Funding: This trial is funded by the Brazilian Ministry of Health through the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde (PROADI-SUS). The funder approved the protocol but is not otherwise involved in the execution, data collection, statistical analysis, or any other aspect of the present trial.
REFERENCES
- 1 Crawford AM, Shiferaw AA, Ntambwe P, Milan AO, Khalid K, Rubio R, et al. Global critical care: a call to action. Crit Care. 2023;27(1):28.
- 2 McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZ, Dagogo-Jack S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148-58.
- 3 McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, B `é lohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CE, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
- 4 Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-24.
- 5 Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Piña IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CS, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-61.
- 6 Solomon SD, McMurray JJ, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CS, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang CE, Borleffs CJ, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Cabrera Honorio JW, Janssens SP, Katova T, Kitakaze M, Merkely B, O’Meara E, Saraiva JF, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilderäng U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089-98.
- 7 Voors AA, Angermann CE, Teerlink JR, Collins SP, Kosiborod M, Biegus J, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-74.
- 8 Heerspink HJ, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JF, McMurray JJ, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-46.
- 9 The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117-27.
- 10 Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(4):422-34.
- 11 Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016;2:16045.
- 12 Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190-5.
- 13 Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115-22.
- 14 Solini A, Giannini L, Seghieri M, Vitolo E, Taddei S, Ghiadoni L, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138.
- 15 Birnbaum Y, Bajaj M, Yang HC, Ye Y. Combined SGLT2 and DPP4 inhibition reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic nephropathy in mice with type 2 diabetes. Cardiovasc Drugs Ther. 2018;32(2):135-45.
- 16 Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71(5):471-6.
- 17 Yaribeygi H, Atkin SL, Butler AE, Sahebkar A. Sodium-glucose cotransporter inhibitors and oxidative stress: an update. J Cell Physiol. 2019;234(4):3231-7.
- 18 Mazer CD, Hare GM, Connelly PW, Gilbert RE, Shehata N, Quan A, et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation. 2020;141(8):704-7.
- 19 Maayah ZH, Ferdaoussi M, Takahara S, Soni S, Dyck JR. Empagliflozin suppresses inflammation and protects against acute septic renal injury. Inflammopharmacology. 2021;29(1):269-79.
- 20 Niu Y, Chen Y, Sun P, Wang Y, Luo J, Ding Y, et al. Intragastric and atomized administration of canagliflozin inhibit inflammatory cytokine storm in lipopolysaccharide-treated sepsis in mice: a potential COVID-19 treatment. Int Immunopharmacol. 2021;96:107773.
- 21 Kosiborod MN, Esterline R, Furtado RH, Oscarsson J, Gasparyan SB, Koch GG, et al. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021;9(9):586-94.
- 22 Khunti K, Aroda VR, Bhatt DL, Bozkurt B, Buse JB, Heerspink HL, et al. Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: a perspective based on the updated evidence. Diabetes Obes Metab. 2022;24(11):2071-80.
- 23 Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.
- 24 Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208.
- 25 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):1788-801.
- 26 Salah HM, Al’Aref SJ, Khan MS, Al-Hawwas M, Vallurupalli S, Mehta JL, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors initiation in patients with acute heart failure, with and without type 2 diabetes: a systematic review and meta-analysis. Cardiovasc Diabetol. 2022;21(1):20.
- 27 Redfors B, Gregson J, Crowley A, McAndrew T, Ben-Yehuda O, Stone GW, et al. The win ratio approach for composite endpoints: practical guidance based on previous experience. Eur Heart J. 2020;41(46):4391-9.
- 28 Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012;33(2):176-82.
- 29 Zampieri FG, Casey JD, Shankar-Hari M, Harrell FE Jr, Harhay MO. Using bayesian methods to augment the interpretation of critical care trials. An overview of theory and example reanalysis of the alveolar recruitment for acute respiratory distress syndrome trial. Am J Respir Crit Care Med. 2021;203(5):543-52.
- 30 Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R, Heyland DK, Cook DJ, Battista MC, Day AG, Guyatt GH, Kanji S, Parke R, McGuinness SP, Tirupakuzhi Vijayaraghavan BK, Annane D, Cohen D, Arabi YM, Bolduc B, Marinoff N, Rochwerg B, Millen T, Meade MO, Hand L, Watpool I, Porteous R, Young PJ, D’Aragon F, Belley-Cote EP, Carbonneau E, Clarke F, Maslove DM, Hunt M, Chassé M, Lebrasseur M, Lauzier F, Mehta S, Quiroz-Martinez H, Rewa OG, Charbonney E, Seely AJ, Kutsogiannis DJ, LeBlanc R, Mekontso-Dessap A, Mele TS, Turgeon AF, Wood G, Kohli SS, Shahin J, Twardowski P, Adhikari NKJ; LOVIT Investigators and the Canadian Critical Care Trials Group. Intravenous vitamin C in adults with sepsis in the intensive care unit. N Engl J Med. 2022;386(25):2387-98.
- 31 Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, Udy AA, Orford N, Edney SJ, Hunt AL, Judd HL, Bitker L, Cioccari L, Naorungroj T, Yanase F, Bates S, McGain F, Hudson EP, Al-Bassam W, Dwivedi DB, Peppin C, McCracken P, Orosz J, Bailey M, Bellomo R; VITAMINS Trial Investigators. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA. 2020;323(5):423-31.
- 32 Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. 2019;322(13):1261-70.
- 33 Deshpande A, Pasupuleti V, Rothberg MB. Statin therapy and mortality from sepsis: a meta-analysis of randomized trials. Am J Med. 2015;128(4):410-7.e1.
- 34 Johnstone J, Meade M, Lauzier F, Marshall J, Duan E, Dionne J, Arabi YM, Heels-Ansdell D, Thabane L, Lamarche D, Surette M, Zytaruk N, Mehta S, Dodek P, McIntyre L, English S, Rochwerg B, Karachi T, Henderson W, Wood G, Ovakim D, Herridge M, Granton J, Wilcox ME, Goffi A, Stelfox HT, Niven D, Muscedere J, Lamontagne F, D’Aragon F, St-Arnaud C, Ball I, Nagpal D, Girard M, Aslanian P, Charbonney E, Williamson D, Sligl W, Friedrich J, Adhikari NK, Marquis F, Archambault P, Khwaja K, Kristof A, Kutsogiannis J, Zarychanski R, Paunovic B, Reeve B, Lellouche F, Hosek P, Tsang J, Binnie A, Trop S, Loubani O, Hall R, Cirone R, Reynolds S, Lysecki P, Golan E, Cartin-Ceba R, Taylor R, Cook D; Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) Investigators and the Canadian Critical Care Trials Group. Effect of probiotics on incident ventilator-associated pneumonia in critically ill patients: a randomized clinical trial. JAMA. 2021;326(11):1024-33.
- 35 Santacruz CA, Pereira AJ, Celis E, Vincent JL. Which multicenter randomized controlled trials in critical care medicine have shown reduced mortality? A systematic review. Crit Care Med. 2019;47(12):1680-91.
- 36 Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5(6):632-44.
Publication Dates
-
Publication in this collection
22 Dec 2023 -
Date of issue
2023
History
-
Received
26 May 2023 -
Accepted
09 June 2023