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Laborante R, Paglianiti DA, Bianchini E, Galli M, Borovac JA, Savarese G, Patti G, D'Amario D. Safety and efficacy of early initiation of sodium-glucose co-transporter inhibitors 2 in patients hospitalized for acute heart failure: A meta-analysis of randomized controlled trials. Eur J Intern Med 2025; 135:55-63. [PMID: 39843332 DOI: 10.1016/j.ejim.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
AIMS Data on the early use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with acute heart failure (HF) are conflicting, and mostly evaluating soft endpoints (i.e., indices of congestion, renal function, ejection fraction, and diuresis). The aim was to perform a meta-analysis of randomized controlled trials (RCTs) to assess their impact after an HF decompensation event. METHODS AND RESULTS Two electronic databases were screened for eligible studies. Efficacy endpoints were all-cause death, cardiovascular death, HF hospitalization, length of hospital stay, and N-terminal pro-B-type natriuretic peptide (nt-proBNP). Safety endpoints included acute kidney injury (AKI), volume depletion, ketoacidosis, hypotension, hypoglycemia, non-cardiovascular death, urinary tract infection, genital infections, serious adverse events (AE), and AE leading to treatment discontinuation. Two pre-specified subgroup analyses were planned according to the specific SGLT2i and clinical setting [i.e., acute myocardial infarction (MI) versus non-acute MI]. 16 RCTs enrolling 15,073 patients were considered. Early initiation of SGLT2i significantly reduced the risk of HF hospitalizations [Risk ratio (RR) 0.79, 95 % Confidence interval (CI) 0.72-0.87], AKI (RR 0.76, 95 % CI 0.59-0.99), and nt-proBNP levels (MD -354 pg/mL). No significant difference was detected for any of the other endpoints. In the pre-specified subgroup analysis, a significant interaction was found between the SGLT2i type and the risk of AKI, in favor of empagliflozin. CONCLUSIONS In patients recently hospitalized for acute HF, early administration of SGLT2i was associated with fewer readmissions for HF and AKI, as well as decongestant effects, without raising any safety concern.
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Affiliation(s)
- Renzo Laborante
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Donato Antonio Paglianiti
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Emiliano Bianchini
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Mattia Galli
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; Maria Cecilia Hospital, GVM Care & Research, Cotignola, Ravenna, Italy
| | - Josip Andelo Borovac
- Division of Interventional Cardiology, Cardiovascular Diseases Department, University Hospital of Split, Split, Croatia
| | - Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Heart and Vascular and Neurology Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Giuseppe Patti
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy; Division of Cardiology, AOU Maggiore della Carità, Novara, Italy.
| | - Domenico D'Amario
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy; Division of Cardiology, AOU Maggiore della Carità, Novara, Italy.
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Kim H, Won H, Park S, Lee H, Cho H, Kim JA, Jeong N, Shin H, Kim Y, Choi N. Risk of acute kidney injury in dapagliflozin users with type 2 diabetes: A nationwide propensity score-matched cohort study in Korea. Pharmacotherapy 2025; 45:282-290. [PMID: 40211830 PMCID: PMC12087813 DOI: 10.1002/phar.70015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 02/18/2025] [Accepted: 02/25/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND Several previous studies have identified a potential risk of acute kidney injury (AKI) associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, based on adverse event reports. However, recent European observational studies have shown conflicting results. OBJECTIVE To evaluate the risk of AKI in patients with type 2 diabetes (T2DM) who were treated with dapagliflozin compared with sitagliptin. METHOD We conducted a retrospective cohort study on patients with T2DM who were newly prescribed dapagliflozin or sitagliptin between September 1, 2014, and June 30, 2021, using the nationwide National Health Insurance Review and Assessment (HIRA) Service database in Korea. Propensity scores were estimated using a multivariable logistic regression model, and matching was performed at a 1:1 ratio to balance the dapagliflozin and sitagliptin groups. The outcome of interest was the occurrence of AKI hospitalization 90 days post-exposure, captured by a validated algorithm based on the International Classification of Diseases 10th Revision (ICD-10) code: N17. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using a Cox proportional hazards model. RESULTS Among 94,977 dapagliflozin users matched to sitagliptin users, AKI events occurred in 132 dapagliflozin users versus 198 sitagliptin users, with incidence rates of 2.92 and 8.93 per 1000 person-years, respectively. The risk of AKI events was 34% lower in dapagliflozin users (HR: 0.66, 95% CI: 0.53-0.83) compared with sitagliptin users. This protective effect remained consistent in sensitivity analyses. CONCLUSION Contrary to the United States Food and Drug Administration's safety warning, our findings suggest that dapagliflozin may have a protective effect against AKI in patients with T2DM. This is consistent with recent findings from European post-marketing safety studies and may serve as supportive evidence.
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Affiliation(s)
- Hee‐Jin Kim
- Department of Health ConvergenceEwha Womans UniversitySeoulKorea
| | - Heehyun Won
- Department of Health ConvergenceEwha Womans UniversitySeoulKorea
| | - Suvin Park
- Department of Health ConvergenceEwha Womans UniversitySeoulKorea
| | - Hui‐Eon Lee
- Department of Industrial Pharmaceutical ScienceEwha Womans UniversitySeoulKorea
| | - Haerin Cho
- Department of Health ConvergenceEwha Womans UniversitySeoulKorea
| | - Jeong Ah. Kim
- Department of Health ConvergenceEwha Womans UniversitySeoulKorea
| | - Na‐Young Jeong
- Department of Health ConvergenceEwha Womans UniversitySeoulKorea
| | - HoJin Shin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of MedicineBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Ye‐Jee Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
| | - Nam‐Kyong Choi
- Department of Health ConvergenceEwha Womans UniversitySeoulKorea
- Department of Industrial Pharmaceutical ScienceEwha Womans UniversitySeoulKorea
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Tallarico RT, Jing B, Lu K, Chawla SA, Luo Y, Badathala A, Chen CL, Wallace AW, Legrand M. Postoperative Outcomes Among Sodium-Glucose Cotransporter 2 Inhibitor Users. JAMA Surg 2025:2833369. [PMID: 40305034 PMCID: PMC12044541 DOI: 10.1001/jamasurg.2025.0940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 03/02/2025] [Indexed: 05/02/2025]
Abstract
Importance Case reports and small retrospective studies have suggested that there is an increased risk of postoperative euglycemic ketoacidosis (eKA) and acute kidney injury (AKI) among patients using sodium-glucose cotransporter 2 inhibitors (SGLT2i) preoperatively. However, there has not been a representative assessment of the risks of these agents among patients undergoing surgery. Objective To evaluate the risk of postoperative eKA, AKI, and mortality within 30 days after surgery among preoperative long-term SGLT2i users compared with nonusers. Design, Settings, and Participants This is a multicenter, propensity-matched, retrospective case-control study from the Veterans Affairs Health Care System (VAHCS) National Registry performed from January 1, 2014, to December 31, 2022. Adult patients using SGLT2i preoperatively who underwent inpatient surgical procedures were compared with a 1:5 matched control group using propensity score matching, including the patient's demographic characteristics, comorbidities, and surgical characteristics. Data analysis was performed from June 2023 to August 2024. Exposure Long-term use of SGLT2i, defined as having more than 3 fills of outpatient prescription or less than a 180-day gap of the last fill according to the VAHCS pharmacy registries. Main Outcomes and Measures The primary outcome was the rate of postoperative eKA among SGLT2i users vs control patients. Secondary outcomes included postoperative AKI and 30-day mortality after surgery. Results Among 462 968 patients undergoing surgery, 7448 SGLT2i users (mean [SD] age, 67.7 [8.1] years; 7204 [96.7%] male) and 455 520 nonusers (mean [SD] age, 65.8 [11.0] years; 424 785 [93.3%] male) were identified. After propensity score matching, 7439 patients were identified as SGLT2i users and compared with 33 489 control patients. SGLT2i use was associated with an increased risk of eKA (odds ratio [OR], 1.11; 95% CI, 1.05-1.17) but reduced risks of perioperative AKI (OR, 0.69; 95% CI, 0.62-0.78) and 30-day mortality (OR, 0.70; 95% CI, 0.55-0.88). The mortality rate 30 days after surgery was 1.1% among SGLT2i users vs 1.6% among control patients. The median hospital length of stay among the patients presenting with eKA increased by 3 days (median [IQR], 6 [3-10] days for those with eKA vs 3 [2-6] days for those without eKA). Conclusions and Relevance Patients treated with SGLT2i had a small but significantly higher risk of postoperative eKA but lower risks of postoperative AKI and 30-day mortality.
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Affiliation(s)
- Roberta Teixeira Tallarico
- Department of Anesthesia and Perioperative Care, University of California, San Francisco
- Department of Anesthesiology, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Bocheng Jing
- Division of Geriatrics, University of California, San Francisco
- Northern California Institute for Research and Education, San Francisco
| | - Kaiwei Lu
- Northern California Institute for Research and Education, San Francisco
| | | | - Yanting Luo
- Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco
| | | | - Catherine L. Chen
- Department of Anesthesia and Perioperative Care, University of California, San Francisco
- Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco
| | - Arthur W. Wallace
- Department of Anesthesia and Perioperative Care, University of California, San Francisco
- Veterans Affairs Medical Center, San Francisco, California
| | - Matthieu Legrand
- Department of Anesthesia and Perioperative Care, University of California, San Francisco
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Yang S, Hao H, Zhai X, Zhang P, Fu N. Effect of sodium-glucose co-transporter 2 inhibitor on contrast-induced acute kidney injury and prognosis in type 2 diabetes patients undergoing percutaneous coronary intervention. Front Med (Lausanne) 2025; 12:1552539. [PMID: 40109729 PMCID: PMC11920171 DOI: 10.3389/fmed.2025.1552539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 02/18/2025] [Indexed: 03/22/2025] Open
Abstract
Introduction Contrast-induced acute kidney injury (CIAKI) is a common and serious complication following contrast administration in patients undergoing percutaneous coronary intervention (PCI). dapagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), has demonstrated renal protective effects in various clinical settings. However, the impact of dapagliflozin on the incidence of CIAKI in patients with type 2 diabetes mellitus (T2DM) undergoing PCI is not yet fully understood. Objective To evaluate the impact of dapagliflozin on CIAKI and long-term prognosis in T2DM patients undergoing PCI. Methods This retrospective cohort study included T2DM patients who underwent PCI at the Department of Cardiology, Tianjin University Chest Hospital, from January 2022 to June 2023. Patients were grouped based on dapagliflozin use (dapagliflozin vs. no dapagliflozin). Renal function was assessed before PCI, 48 h, and 1 week post-PCI, measuring serum creatinine, estimated glomerular filtration rate, cystatin C, and neutrophil gelatinase-associated lipocalin. All patients were followed for at least 1 year. The primary endpoint was CIAKI incidence, with secondary endpoints including renal function changes and major adverse cardiovascular events (MACE). Results CIAKI occurred less frequently in the dapagliflozin group compared to the control group (5.8% vs. 11.7%, χ2 = 4.494, p = 0.033). After adjusting for confounders, dapagliflozin was an independent predictor of reduced CIAKI risk (OR = 0.365, 95% CI: 0.176-0.767, p = 0.008). During a median 15-month follow-up, the dapagliflozin group had a lower incidence of MACE compared to the control group (Log-rank χ 2 = 6.719, p = 0.009). Cox regression analysis showed that dapagliflozin reduced the risk of MACE (HR = 0.484, 95% CI: 0.246-0.955, p = 0.036). Conclusion Chronic administration of dapagliflozin can reduces the risk of CIAKI and improves long-term cardiovascular outcomes in T2DM patients undergoing PCI. These findings support its potential use as adjunctive therapy to mitigate kidney injury and improve prognosis in this high-risk population.
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Affiliation(s)
- Shicheng Yang
- Department of Cardiology, Tianjin University Chest Hospital, Tianjin, China
| | - Huifang Hao
- Department of Nephrology, Tianjin TEDA Hospital, Tianjin, China
| | - Xiufeng Zhai
- Tianjin Rehabilitation and Recuperation Center, Joint Logistics Support Force, Tianjin, China
| | - Peng Zhang
- Department of Cardiology, Tianjin University Chest Hospital, Tianjin, China
| | - Naikuan Fu
- Department of Cardiology, Tianjin University Chest Hospital, Tianjin, China
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Heyman SN, Aronson D, Abassi Z. SGLT2 Inhibitors and the Risk of Contrast-Associated Nephropathy Following Angiographic Intervention: Contradictory Concepts and Clinical Outcomes. Int J Mol Sci 2024; 25:10759. [PMID: 39409086 PMCID: PMC11477343 DOI: 10.3390/ijms251910759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/29/2024] [Accepted: 10/03/2024] [Indexed: 10/19/2024] Open
Abstract
The use of SGLT2 inhibitors (SGLT2is) has been found in large clinical studies to slow the progression of chronic kidney disease (CKD) and to lower the risk of acute kidney injury (AKI). Recent reports suggest that SGLT2is may also reduce the likelihood of developing radiocontrast-associated nephropathy (CAN) following contrast-enhanced imaging and intravascular interventions. This review underscores potential pitfalls and confounders in these studies and calls for caution in adopting their conclusions regarding the safety and renoprotective potency of SGLT2is, in particular in patients at high risk, with advanced CKD and hemodynamic instability undergoing coronary intervention. This caution is particularly warranted since both SGLT2is and contrast media intensify medullary hypoxia in the already hypoxic diabetic kidney and their combination may lead to medullary hypoxic damage, a principal component of CAN. Further studies are needed to evaluate this dispute, particularly in patients at high risk, and to reveal whether SGLT2is indeed provide renal protection or are hazardous during contrast-enhanced imaging and vascular interventions.
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Affiliation(s)
- Samuel N. Heyman
- Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus, Jerusalem 91240, Israel
| | - Doron Aronson
- Department of Cardiology, Rambam Health Care Campus, Haifa 3109601, Israel;
| | - Zaid Abassi
- Department of Physiology, Bruce Rappaport School of Medicine, Technion, Haifa 3525433, Israel
- Department of Laboratory Medicine, Rambam Health Care Campus, Haifa 3109601, Israel
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Wang Q, Yu J, Deng W, Liu C, Yang J, Li Y, Cai G, Chen X, Dong Z. Influence of sodium/glucose cotransporter-2 inhibitors on the incidence of acute kidney injury: a meta-analysis. Front Pharmacol 2024; 15:1372421. [PMID: 38983922 PMCID: PMC11231204 DOI: 10.3389/fphar.2024.1372421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 06/05/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are associated with cardiovascular benefits. The aim of this systematic review and meta-analysis is to summarize the influence of SGLT2i on the incidence of acute kidney injury (AKI), and to ascertain whether it is affected by confounding variables such as age, baseline renal function and concurrent use of renin-angiotensin-aldosterone system inhibitors (RAASi) or mineralocorticoid receptor antagonists (MRA). METHODS PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials comparing the influence of SGLT2i versus placebo/blank treatment on AKI in the adult population. A fixed-effect model was used if the heterogeneity was not significant; otherwise, a randomized-effect model was used. RESULTS Eighteen studies comprising 98,989 patients were included. Compared with placebo/blank treatment, treatment with SGLT2i significantly reduced the risk of AKI (risk ratio [RR]: 0.78, 95% confidence interval [CI]: 0.71 to 0.84, p < 0.001; I 2 = 0%). Subgroup analysis suggested consistent results in patients with diabetes, chronic kidney disease, and heart failure (for subgroup difference, p = 0.32). Finally, univariate meta-regression suggested that the influence of SGLT2i on the risk of AKI was not significantly modified by variables such as age (coefficient: 0.011, p = 0.39), baseline estimated glomerular filtration rate (coefficient: -0.0042, p = 0.13) or concomitant use of RAASi (coefficient: 0.0041, p = 0.49) or MRA (coefficient: -0.0020, p = 0.34). CONCLUSION SGLT2i may be effective in reducing the risk of AKI, and the effect might not be modified by age, baseline renal function and concurrent use of RAASi or MRA.
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Affiliation(s)
- Qian Wang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Jianmin Yu
- Department of Diagnosis and Treatment, The Eighth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weizhu Deng
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Chao Liu
- Department of Critical Care Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jian Yang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Yaqing Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Zheyi Dong
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
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Mondal S, Pramanik S, Khare VR, Fernandez CJ, Pappachan JM. Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives. World J Cardiol 2024; 16:240-259. [PMID: 38817648 PMCID: PMC11135334 DOI: 10.4330/wjc.v16.i5.240] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 05/23/2024] Open
Abstract
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospitals, Siliguri 734010, West Bengal, India
| | - Vibhu Ranjan Khare
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Cornelius James Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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Polychronopoulou E, Bourdon F, Teta D. SGLT2 inhibitors in diabetic and non-diabetic kidney transplant recipients: current knowledge and expectations. FRONTIERS IN NEPHROLOGY 2024; 4:1332397. [PMID: 38685973 PMCID: PMC11056593 DOI: 10.3389/fneph.2024.1332397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 04/03/2024] [Indexed: 05/02/2024]
Abstract
The beneficial effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown recently in numerous randomized controlled trials (RCT) and systematic reviews. According to KDIGO guidelines, SGLT2i currently represent a first choice for diabetic patients with chronic kidney disease (CKD). In addition, a recent meta-analysis of 13 large led by the 'SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium' (SMART-C) provided solid evidence of SGLT2i beneficial effects in CKD or in patients with heart failure, with and without diabetes. Collectively, the patients treated with SGLT2i had a decreased risk of CKD progression, acute kidney injury (AKI), end-stage kidney disease (ESKD) or death from heart failure. Whether these cardio-renal benefits should be extrapolated to kidney transplant recipients (KTR) needs to be assessed in further studies. In this article, we report recent data accumulated so far in the literature, looking at the efficacy and safety of SGLT2i in diabetic and non-diabetic KTR. We found encouraging data regarding the use of SGLT2i in KTR with diabetes. These agents appeared to be safe, and they reduced body weight and blood pressure in this group of patients. Potential effects on kidney graft function and survival are yet to be investigated.
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Affiliation(s)
- Erietta Polychronopoulou
- Service of Nephrology, Hôpital du Valais, Sion, Switzerland
- Transplantation Center, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Fanny Bourdon
- Service of Nephrology, Hôpital du Valais, Sion, Switzerland
| | - Daniel Teta
- Service of Nephrology, Hôpital du Valais, Sion, Switzerland
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Kani R, Watanabe A, Miyamoto Y, Ejiri K, Iwagami M, Takagi H, Slipczuk L, Tsugawa Y, Aikawa T, Kuno T. Comparison of Effectiveness Among Different Sodium-Glucose Cotransoporter-2 Inhibitors According to Underlying Conditions: A Network Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 2024; 13:e031805. [PMID: 38293914 PMCID: PMC11056162 DOI: 10.1161/jaha.123.031805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 12/27/2023] [Indexed: 02/01/2024]
Abstract
BACKGROUND To investigate the individual profile of each SGLT2 (sodium-glucose cotransoporter-2) inhibitor in patients with different backgrounds. METHODS AND RESULTS This study included 21 placebo-controlled randomized controlled trials with a total of 96 196 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. The primary efficacy end point was the composite of cardiovascular death and hospitalizations for heart failure. The secondary efficacy end points were all-cause death, cardiovascular death, hospitalizations for heart failure, kidney disease progression, and acute kidney injury. We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease. Safety end points were also assessed among SGLT2 inhibitors in the overall cohort. In the overall cohort, there were no significant differences in the primary efficacy outcome among the SGLT2 inhibitors, while empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53-0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56-0.96]) were associated with lower risk of acute kidney injury than sotagliflozin. The presence or absence of diabetes did not alter the results. In patients with chronic kidney disease, there were no differences in the efficacy outcomes among SGLT2 inhibitors, while in patients without chronic kidney disease, empagliflozin was associated with lower risk of the primary outcome compared with ertugliflozin (HR, 0.77 [95% CI, 0.60-0.98]). For safety outcomes, no significant differences were observed in amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis. CONCLUSIONS The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.
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Affiliation(s)
- Ryoma Kani
- Postgraduate Education Center, Kameda Medical CenterChibaJapan
| | - Atsuyuki Watanabe
- Department of MedicineIcahn School of Medicine at Mount Sinai, Mount Sinai Beth IsraelNew YorkNY
| | - Yoshihisa Miyamoto
- Division of Nephrology and EndocrinologyThe University of Tokyo HospitalTokyoJapan
| | - Kentaro Ejiri
- Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreMD
| | - Masao Iwagami
- Department of Health Services Research, Institute of MedicineUniversity of TsukubaTsukubaJapan
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUnited Kingdom
| | - Hisato Takagi
- Department of Cardiovascular SurgeryShizuoka Medical CenterShizuokaJapan
| | - Leandro Slipczuk
- Division of CardiologyMontefiore Medical Center, Albert Einstein College of MedicineNew YorkNY
| | - Yusuke Tsugawa
- Division of General Internal Medicine and Health Services ResearchDavid Geffen School of Medicine at UCLALos AngelesCA
- Department of Health Policy and ManagementUCLA Fielding School of Public HealthLos AngelesCA
| | - Tadao Aikawa
- Department of CardiologyJuntendo University Urayasu HospitalUrayasuJapan
| | - Toshiki Kuno
- Division of CardiologyMontefiore Medical Center, Albert Einstein College of MedicineNew YorkNY
- Division of CardiologyJacobi Medical Center, Albert Einstein College of MedicineNew YorkNY
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Xu L, Chen B, Zhang H, Zhu D. Combined effects of sodium-glucose cotransporter 2 inhibitor and angiotensin receptor-neprilysin inhibitor on renal function in cardiovascular disease patients with type 2 diabetes mellitus: a retrospective cohort study. Front Endocrinol (Lausanne) 2024; 14:1326611. [PMID: 38274236 PMCID: PMC10808758 DOI: 10.3389/fendo.2023.1326611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/20/2023] [Indexed: 01/27/2024] Open
Abstract
Background Angiotensin receptor/neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) have shown a significant protective role against cardiovascular diseases and type 2 diabetes mellitus (T2DM), and there is a growing proportion of patients who are undergoing combined therapy with the two drugs. However, the effect of this combination treatment on renal function has not yet been determined. Methods This study included 539 patients who were diagnosed with cardiovascular disease combined with T2DM. According to the use of SGLT2i and ARNI, patients were divided into the combination treatment group, SGLT2i group, ARNI group and control group. Primary outcomes were serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) changes in the 6th month and 12th month. Results In the ARNI group, no significant changes in Scr or eGFR were observed during the follow-up period, while the above indicators showed a trend of deterioration in the other three groups. The univariate analysis results showed that at 6 months of follow-up, the renal function indicators of patients treated with ARNI (either alone or in combination) were better than those treated with SGLT2i alone. After 12 months of follow-up, the Scr results were the same as before, while the difference in eGFR between groups disappeared. After multivariate analysis, in terms of delaying the progression of Scr, the ARNI group was superior to the other groups at the end of follow-up. No significant difference in eGFR was observed between groups during follow-up. Conclusion In patients with cardiovascular disease and T2DM, combination therapy with ARNI and SGLT2i did not show an advantage over monotherapy in delaying renal insufficiency progression, and renal function seems to be better preserved in patients treated with ARNI alone. Clinical trial registration clinicaltrials.gov, identifier NCT05922852.
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Affiliation(s)
- Ling Xu
- Department of Cardiology, Peking University Third Hospital, NHC Key, Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China
| | - Bo Chen
- Department of Cardiology, Peking University Third Hospital, NHC Key, Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China
| | - Hua Zhang
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Peking University, Beijing, China
| | - Dan Zhu
- Department of Cardiology, Peking University Third Hospital, NHC Key, Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China
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11
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Aldafas R, Crabtree T, Alkharaiji M, Vinogradova Y, Idris I. Sodium-glucose cotransporter-2 inhibitors (SGLT2) in frail or older people with type 2 diabetes and heart failure: a systematic review and meta-analysis. Age Ageing 2024; 53:afad254. [PMID: 38287703 PMCID: PMC10825241 DOI: 10.1093/ageing/afad254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/09/2023] [Indexed: 01/31/2024] Open
Abstract
OBJECTIVE Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in older or frail individuals remains unclear. METHODS We searched PubMed, Scopus, Web of Science, Cochrane CENTRA and Google Scholar and selected randomised controlled trials and observational studies comparing SGLT2Is versus placebo/other glucose-lowering agent for people with frailty or older individuals (>65 years) with T2D and heart failure (HF). Extracted data on the change in HbA1c % and safety outcomes were pooled in a random-effects meta-analysis model. RESULTS We included data from 20 studies (22 reports; N = 77,083 patients). SGLT2Is did not significantly reduce HbA1c level (mean difference -0.13, 95%CI: -0.41 to 0.14). SGLT2Is were associated with a significant reduction in the risk of all-cause mortality (risk ratio (RR) 0.81, 95%CI: -0.69 to 0.95), cardiac death (RR 0.80, 95%CI: -0.94 to 0.69) and hospitalisation for heart failure (HHF) (RR 0.69, 95%CI: 0.59-0.81). However, SGLT2Is did not demonstrate significant effect in reducing in the risk of macrovascular events (acute coronary syndrome or cerebral vascular occlusion), renal progression/composite renal endpoint, acute kidney injury, worsening HF, atrial fibrillation or diabetic ketoacidosis. CONCLUSIONS In older or frail patients with T2D and HF, SGLT2Is are consistently linked with a decrease in total mortality and the overall burden of cardiovascular (CV) events, including HHF events and cardiac death, but not protective for macrovascular death or renal events. Adverse events were more difficult to quantify but the risk of diabetic ketoacidosis or acute kidney injury was not significantly increase.
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Affiliation(s)
- Rami Aldafas
- Division of Graduate Entry Medicine and Health Sciences, University of Nottingham, Derby, UK
- Faculty of Public Health, College of Health Science, The Saudi Electronic University, Riyadh, Saudi Arabia
| | - Tomas Crabtree
- Division of Graduate Entry Medicine and Health Sciences, University of Nottingham, Derby, UK
- Department of Endocrinology and Diabetes, University Hospitals Derby and Burton NHS Foundation Trust, Derby, UK
| | - Mohammed Alkharaiji
- Faculty of Public Health, College of Health Science, The Saudi Electronic University, Riyadh, Saudi Arabia
| | - Yana Vinogradova
- Division of Primary Care, University of Nottingham, Nottingham NG2 7RD, UK
| | - Iskandar Idris
- Division of Graduate Entry Medicine and Health Sciences, University of Nottingham, Derby, UK
- Department of Endocrinology and Diabetes, University Hospitals Derby and Burton NHS Foundation Trust, Derby, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, NIHR, Nottingham BRC, University of Nottingham, Derby, UK
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12
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Bilen Y, Almoushref A, Alkwatli K, Osman O, Mehdi A, Sawaf H. Treatment and practical considerations of diabetic kidney disease. Front Med (Lausanne) 2023; 10:1264497. [PMID: 38105902 PMCID: PMC10722293 DOI: 10.3389/fmed.2023.1264497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 10/19/2023] [Indexed: 12/19/2023] Open
Abstract
Diabetic kidney disease (DKD) is a complication of diabetes that can lead to kidney failure. Over the years, several drugs have been developed to combat this disease. In the early 90s, angiotensin blockade (ACEi and ARBs) was introduced, which revolutionized the treatment of DKD. In recent years, newer drugs such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, endothelin antagonists, and mineralocorticoid receptor antagonists (MRA) have shown great promise in reducing albuminuria and protecting the kidneys. These drugs are being used in combination with lifestyle modifications, patient education, and risk factor modification to effectively manage DKD. In this review, we will explore the latest pharmacological options, their efficacy, and their potential to revolutionize the management of this debilitating disease.
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Affiliation(s)
- Yara Bilen
- Cleveland Clinic, Department of Internal Medicine, Cleveland, OH, United States
| | - Allaa Almoushref
- Cleveland Clinic, Department of Kidney Medicine, Cleveland, OH, United States
| | - Kenda Alkwatli
- Cleveland Clinic, Department of Endocrinology, Cleveland, OH, United States
| | - Omar Osman
- Cleveland Clinic, Department of Kidney Medicine, Cleveland, OH, United States
| | - Ali Mehdi
- Cleveland Clinic, Department of Kidney Medicine, Cleveland, OH, United States
| | - Hanny Sawaf
- Cleveland Clinic, Department of Kidney Medicine, Cleveland, OH, United States
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13
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Assaly M, Gorelik Y, Heyman SN, Abassi Z, Khamaisi M. Renal safety and survival among acutely ill hospitalized patients treated by blockers of the Renin-Angiotensin axis or loop diuretics: a single-center retrospective analysis. Ren Fail 2023; 45:2282707. [PMID: 37975172 PMCID: PMC11001312 DOI: 10.1080/0886022x.2023.2282707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Concern exists regarding the renal safety of blocking the renin-angiotensin system (RAS) during acute illness, especially in the presence of volume depletion and hemodynamic instability. METHODS We explored the impact of loop diuretics and RAS blockers on the likelihood of developing acute kidney injury (AKI) or acute kidney functional recovery (AKR) among inpatients. Adjusted odds ratio for AKI, AKR and mortality was calculated, using logistic regression models, with subgroup analysis for patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2, corrected for blood pressure measurements. RESULTS 53,289 patients were included. RAS blockade was associated with reduced adjusted odds ratio for both AKI (0.76, CI 0.70-0.83) AKR (0.55, 0.52-0.58), and mortality within 30 days (0.44, 0.41-0.48), whereas loop diuretics were associated with increased risk of AKI (3.75, 3.42-4.12) and mortality (1.71, 1.58-1.85) and reduced AKR (0.71, 0.66-0.75). Comparable impact of RAS blockers and loop diuretics on renal outcomes and death was found among 6,069 patients with eGFR < 30 ml/min/1.73m2. RAS inhibition and diuretics tended to increase the adjusted odds ratios for AKI and to reduce the likelihood of AKR in hypotensive patients. CONCLUSIONS Reduced blood pressure, RAS blockers and diuretics affect the odds of developing AKI or AKR among inpatients, suggesting possible disruption in renal functional reserve (RFR). As long as blood pressure is maintained, RAS inhibition seems to be safe and renoprotective in this population, irrespective of kidney function upon admission, and is associated with reduced mortality.
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Affiliation(s)
- May Assaly
- Department of Medicine D, Rambam Health Care Campus, Haifa, Israel
| | - Yuri Gorelik
- Department of Medicine D, Rambam Health Care Campus, Haifa, Israel
| | - Samuel N. Heyman
- Department of Medicine, Hadassah Hebrew University hospital, Jerusalem, Israel
| | - Zaid Abassi
- Department of Physiology, Bruce Rappaport School of Medicine, Technion, Haifa, Israel
| | - Mogher Khamaisi
- Department of Medicine D, Rambam Health Care Campus, Haifa, Israel
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14
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Karimzadeh I, Barreto EF, Kellum JA, Awdishu L, Murray PT, Ostermann M, Bihorac A, Mehta RL, Goldstein SL, Kashani KB, Kane-Gill SL. Moving toward a contemporary classification of drug-induced kidney disease. Crit Care 2023; 27:435. [PMID: 37946280 PMCID: PMC10633929 DOI: 10.1186/s13054-023-04720-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023] Open
Abstract
Drug-induced kidney disease (DIKD) accounts for about one-fourth of all cases of acute kidney injury (AKI) in hospitalized patients, especially in critically ill setting. There is no standard definition or classification system of DIKD. To address this, a phenotype definition of DIKD using expert consensus was introduced in 2015. Recently, a novel framework for DIKD classification was proposed that incorporated functional change and tissue damage biomarkers. Medications were stratified into four categories, including "dysfunction without damage," "damage without dysfunction," "both dysfunction and damage," and "neither dysfunction nor damage" using this novel framework along with predominant mechanism(s) of nephrotoxicity for drugs and drug classes. Here, we briefly describe mechanisms and provide examples of drugs/drug classes related to the categories in the proposed framework. In addition, the possible movement of a patient's kidney disease between certain categories in specific conditions is considered. Finally, opportunities and barriers to adoption of this framework for DIKD classification in real clinical practice are discussed. This new classification system allows congruencies for DIKD with the proposed categorization of AKI, offering clarity as well as consistency for clinicians and researchers.
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Affiliation(s)
- Iman Karimzadeh
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - John A Kellum
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Linda Awdishu
- Division of Clinical Pharmacy, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA, USA
| | | | - Marlies Ostermann
- Department of Intensive Care, King's College London, Guy's and St Thomas' Hospital, London, UK
| | - Azra Bihorac
- Department of Medicine, University of Florida, Gainesville, FL, USA
- Intelligent Critical Care Center, University of Florida, Gainesville, FL, USA
| | - Ravindra L Mehta
- Department of Medicine, University of California, San Diego, CA, USA
| | - Stuart L Goldstein
- Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Kianoush B Kashani
- Division of Nephrology and Hypertension, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Sandra L Kane-Gill
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Pharmacy, UPMC, Pittsburgh, PA, USA.
- Department of Critical Care Medicine, Department of Biomedical Informatics, School of Medicine and the Clinical Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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15
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Heyman SN, Abassi Z. Gliflozins, Erythropoietin, and Erythrocytosis: Is It Renal Normoxia- or Hypoxia-Driven? J Clin Med 2023; 12:4871. [PMID: 37510986 PMCID: PMC10381125 DOI: 10.3390/jcm12144871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 07/06/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
The introduction of gliflozins in the management of type 2 diabetes mellitus leads to a better control of hyperglycemia, obesity, hypertension, dyslipidemia, and fluid retention. Most importantly, it also improves renal survival and reduces major cardiovascular events and mortality. Gliflozins were also found to induce erythropoietin (EPO) synthesis, leading to reticulocytosis and erythropoiesis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Although the canonical pathway of triggering EPO synthesis is through renal tissue hypoxia, it has been suggested that improved renal oxygenation may facilitate EPO synthesis via non-canonical routes. The latter proposes that the recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium re-uptake by proximal tubules in uncontrolled diabetes generates cortical hypoxia, with injury to these cells. Once transport workload declines with the use of SGLT2i, they recover and regain their capacity to produce EPO. In this short communication, we argue that this hypothesis may be wrong and propose that gliflozins likely induce EPO through the documented intensification of renal hypoxia at the corticomedullary junction, related to the translocation of tubular transport from cortical segments to medullary thick ascending limbs. We propose that gliflozins, through intensified hypoxia in this region, trigger local EPO synthesis in peritubular interstitial cells via the canonical pathway of blocking HIF-prolyl hydroxylases (that initiate HIF alpha degradation), with the consequent stabilization of HIF-2 signal and an apocrinic induction of EPO in these same cells.
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Affiliation(s)
- Samuel N Heyman
- Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus and Herzog Hospital, Jerusalem 9765422, Israel
| | - Zaid Abassi
- Department of Laboratory Medicine, Rambam Health Care Campus, Haifa 3109601, Israel
- Department of Physiology & Biophysics, The Rappaport Faculty of Medicine, Technion IIT, Haifa 3200003, Israel
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16
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Mårtensson J, Cutuli SL, Osawa EA, Yanase F, Toh L, Cioccari L, Luethi N, Maeda A, Bellomo R. Sodium glucose co-transporter-2 inhibitors in intensive care unit patients with type 2 diabetes: a pilot case control study. Crit Care 2023; 27:189. [PMID: 37194077 PMCID: PMC10186281 DOI: 10.1186/s13054-023-04481-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/08/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND Sodium glucose co-transporter-2 (SGLT2) inhibitors improve long-term cardiovascular and renal outcomes in individuals with type 2 diabetes. However, the safety of SGLT2 inhibitors in ICU patients with type 2 diabetes is uncertain. We aimed to perform a pilot study to assess the relationship between empagliflozin therapy and biochemical, and clinical outcomes in such patients. METHODS We included 18 ICU patients with type 2 diabetes receiving empagliflozin (10 mg daily) and insulin to target glucose range of 10-14 mmol/l according to our liberal glucose control protocol for patients with diabetes (treatment group). Treatment group patients were matched on age, glycated hemoglobin A1c, and ICU duration with 72 ICU patients with type 2 diabetes exposed to the same target glucose range but who did not receive empagliflozin (control group). We compared changes in electrolyte and acid-base parameters, hypoglycemia, ketoacidosis, worsening kidney function, urine culture findings, and hospital mortality between the groups. RESULTS Median (IQR) maximum increase in sodium and chloride levels were 3 (1-10) mmol/l and 3 (2-8) mmol/l in the control group and 9 (3-12) mmol/l and 8 (3-10) mmol/l in the treatment group (P = 0.045 for sodium, P = 0.059 for chloride). We observed no differences in strong ion difference, pH or base excess. Overall, 6% developed hypoglycemia in each group. No patient in the treatment group and one patient in the control group developed ketoacidosis. Worsening kidney function occurred in 18% and 29% of treatment and control group patients, respectively (P = 0.54). Urine cultures were positive in 22% of treatment group patients and 13% of control group patients (P = 0.28). Overall, 17% of treatment group patients and 19% of control group patients died in hospital (P = 0.79). CONCLUSIONS In our pilot study of ICU patients with type 2 diabetes, empagliflozin therapy was associated with increases in sodium and chloride levels but was not significantly associated with acid-base changes, hypoglycemia, ketoacidosis, worsening kidney function, bacteriuria, or mortality.
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Affiliation(s)
- Johan Mårtensson
- Department of Physiology and Pharmacology, Section of Anaesthesia and Intensive Care, Karolinska Institutet, Stockholm, Sweden.
- Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, 171 76, Stockholm, Sweden.
| | - Salvatore Lucio Cutuli
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, L.Go F. Vito 1, 00168, Rome, Italy
| | - Eduardo A Osawa
- Cardiology Intensive Care Unit, Hospital DF-Star, Brasília, Brazil
| | - Fumitaka Yanase
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia
| | - Lisa Toh
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia
| | - Luca Cioccari
- Department of Intensive Care Medicine, Kantonsspital Aarau, Aarau, Switzerland
| | - Nora Luethi
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia
| | - Akinori Maeda
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia
- Department of Emergency and Critical Care Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Health, Melbourne, VIC, Australia
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia
- Department of Critical Care, Melbourne University, Melbourne, VIC, Australia
- Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia
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17
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Chen C, Wu B, Zhang C, Xu T. Angiotensin receptor-neprilysin inhibitor and sodium-dependent glucose cotransporter-2 inhibitor-associated renal injury: a pharmacovigilance study. Expert Opin Drug Saf 2023; 22:259-266. [PMID: 36044355 DOI: 10.1080/14740338.2022.2120609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 08/05/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-dependent glucose cotransporter-2 inhibitors (SGLT-2Is) had a certain risk of renal injury. However, overlapping nephrotoxicity of combination therapy was unclear. RESEARCH DESIGN AND METHODS We performed a disproportionality analysis based on the Food and Drug Administration Adverse Event Reporting System from 1 January 2004 to 31 December 2020. Renal injury cases were defined as acute kidney injury (AKI) and chronic kidney disease (CKD) cases. RESULTS We detected a significant association between ARNI, SGLT-2Is, the combination therapy and AKI as well as CKD, in which the combination therapy generated the highest strength association with both AKI (ROR: 8.06, 95% CI 5.41-12.01) and CKD (ROR: 2.69, 95% CI 1.27-5.71). Compared with ARNI or SGLT-2I alone, the combination therapy generated AKI signals. There were no differences in the onset time of renal injury cases between the combination therapy and monotherapy. Compared to cases without renal injury, the combination therapy did not increase the proportion of fatality and hospitalizations in cases with AKI or CKD. CONCLUSION The combination of ARNI and SGLT-2Is was associated with a significantly increased reporting proportion of AKI. However, due to the limitations of the FAERS database, our results required further studies to assess our findings.
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Affiliation(s)
- Chen Chen
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chenyu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ting Xu
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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18
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Ge S, Liu R, Mao Y, Geng C, Wang H, Song K, Tian QB. Safety of SGLT2 Inhibitors in Three Chronic Diseases. Int Heart J 2023; 64:246-251. [PMID: 37005318 DOI: 10.1536/ihj.22-441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
This study aimed to assess the safety of SGLT2 inhibitors in type 2 diabetes, chronic kidney disease, and chronic heart failure considering the number needed to treat (NNT).Methods: Data were obtained from 10 morbidity-mortality trials and were pooled to calculate the NNTs. The number needed to treat to benefit (NNTB) is used to express beneficial outcomes, whereas the number needed to treat to be harmed (NNTH) is used for harmful outcomes. The eight safety outcomes of interest were fracture, diabetic ketoacidosis, amputation, urinary tract infection, genital infection, acute kidney injury, severe hypoglycemia, and volume depletion.A total of 10 trials involving 76319 patients were included in this meta-analysis. The mean follow-up was 2.35 years. SGLT2 inhibitors play a positive role in acute kidney injury and severe hypoglycemia, with the corresponding mean NNTBs being 157 and 561, respectively. SGLT2 inhibitors significantly increased the risk of diabetic ketoacidosis, genital infection, and volume depletion, with the corresponding mean NNTHs being 1014, 41, and 139. It was found that the safety of SGLT2 inhibitors was the same in three diseases and five SGLT2 inhibitors.SGLT2 inhibitors have a positive impact on acute kidney injury and severe hypoglycemia, but they increase the incidence of diabetic ketoacidosis, genital infection, and volume depletion.
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Affiliation(s)
- Shiyao Ge
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University
- Hebei Province Key Laboratory of Environment and Human Health
| | - Ruobin Liu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University
- Hebei Province Key Laboratory of Environment and Human Health
| | - Yucheng Mao
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University
- Hebei Province Key Laboratory of Environment and Human Health
| | - Chang Geng
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University
| | - Hongfei Wang
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University
| | - Kai Song
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University
| | - Qing-Bao Tian
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University
- Hebei Province Key Laboratory of Environment and Human Health
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19
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Duo Y, Gao J, Yuan T, Zhao W. Effect of sodium-glucose cotransporter 2 inhibitors on the rate of decline in kidney function: A systematic review and meta-analysis. J Diabetes 2023; 15:58-70. [PMID: 36610036 PMCID: PMC9870734 DOI: 10.1111/1753-0407.13348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 01/09/2023] Open
Abstract
AIM To investigate the influence of sodium/glucose cotransporter-2 inhibitors (SGLT-2i) on renal function during the course of its administration, particularly in the initial weeks. MATERIALS AND METHODS Randomized controlled trials (RCTs) related to SGLT-2i were searched in databases (MEDLINE, EMBASE, and Cochrane Central Register) from the database's inception to August 31, 2021. All RCTs reported the kidney outcomes of SGLT2i versus active or placebo control were included, regardless of the presence of diabetes in the patients and the baseline estimated glomerular filtration rate (eGFR). The Cochrane Collaboration risk of bias tool was used to assess the quality of the included studies. All outcome comparisons were performed using the RevMan 5.4 software. RESULTS Eleven RCTs with 58 534 participants reporting prespecified renal outcomes were identified. There was no heterogeneity in the baseline eGFR and urine albumin-to-creatinine ratio in the included studies. In the initial 2-4 weeks, there was an acute decline of eGFR in the SGLT-2i group compared with placebo group (weighted mean difference [WMD] -3.35 ml/min/1.73 m2 ; 95% CI, -3.81 to -2.90; I2 = 35%, p = .15); When compared to baseline eGFR in the SGLT-2i group, the WMD was -4.02 ml/min/1.73 m2 (95% confidence interval [CI], -3.61 to -4.44; I2 = 0%, p = .45). The renoprotective effect gradually appeared, and the decline rate of eGFR in the SGLT-2i group was sustained slower than placebo. However, the statistically significant benefit of SGLT-2i did not appear until the 104th week (the second year) (WMD 0.35 ml/min/1.73 m2 , 95% CI, 0.04 to 0.66; I2 = 45%, p = .08). Subgroup analysis showed SGLT-2i had a similar benefit on renal function regardless of baseline eGFR values. CONCLUSION SGLT-2i consistently slowed the deterioration of eGFR since the early stage of administration, even in patients with chronic kidney disease. However, there was an acute decline in eGFR in the initial 2-4 weeks; afterwards the renoprotective effect of SGLT-2i gradually appeared and remained stable in the next few years.
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Affiliation(s)
- Yanbei Duo
- Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingChina
| | - Junxiang Gao
- Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingChina
| | - Tao Yuan
- Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingChina
| | - Weigang Zhao
- Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingChina
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20
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Copur S, Yildiz A, Basile C, Tuttle KR, Kanbay M. Is there any robust evidence showing that SGLT2 inhibitor use predisposes to acute kidney injury? J Nephrol 2023; 36:31-43. [PMID: 35962863 DOI: 10.1007/s40620-022-01422-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/28/2022] [Indexed: 02/07/2023]
Abstract
A novel class of oral glucose lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2is), has shown additional beneficial effects on body weight, serum uric acid levels, blood pressure, and cardiac and renal function. Conflicting data have been published regarding the potential risk of acute kidney injury (AKI) when using SGLT2is. Aim of this manuscript was to review the current literature on this issue. SGLT2is induce a mild acute decline in estimated glomerular filtration rate, attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback through increased macula densa sodium delivery, leading to afferent arteriole vasoconstriction and reduced intraglomerular pressure. This functional effect with a subsequent rise in serum creatinine fulfills the creatinine-based criteria for AKI, as defined in clinical practice and trial settings. Other proposed potential mechanisms as to how SGLT2is lead to AKI include osmotic diuresis leading to volume depletion, increased urinary uric acid levels, intratubular oxidative stress, local inflammation and tubular injury. Despite the warning published by the US Food and Drug Administration in 2016 about a potential risk of AKI and the report of some clinical cases of AKI after treatment with SGLT2is, large observational real-life retrospective studies, randomized controlled trials and propensity-matched analyses of data from clinical practice unambiguously demonstrate that SGLT2is are safe for the kidney and do not predispose to AKI. In conclusion, while we can probably stop worrying about AKI risk when using SGLT2is, the question whether these agents should be withheld in the presence of clinical situations at high risk for AKI remains unaddressed.
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Affiliation(s)
- Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Abdullah Yildiz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Carlo Basile
- Associazione Nefrologica Gabriella Sebastio, Martina Franca, Italy.
| | - Katherine R Tuttle
- Division of Nephrology, University of Washington, Seattle, WA, USA.,Providence Medical Research Center, Providence Health Care, Washington, USA
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
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21
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Kim D, Jang G, Hwang J, Wei X, Kim H, Son J, Rhee SJ, Yun KH, Oh SK, Oh CM, Park R. Combined Therapy of Low-Dose Angiotensin Receptor-Neprilysin Inhibitor and Sodium-Glucose Cotransporter-2 Inhibitor Prevents Doxorubicin-Induced Cardiac Dysfunction in Rodent Model with Minimal Adverse Effects. Pharmaceutics 2022; 14:pharmaceutics14122629. [PMID: 36559124 PMCID: PMC9788442 DOI: 10.3390/pharmaceutics14122629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/20/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Although cancer-therapy-related cardiac dysfunction (CTRCD) is a critical issue in clinical practice, there is a glaring lack of evidence regarding cardiotoxicity management. To determine an effective and suitable dosage of treatment using angiotensin receptor-neprilysin inhibitors (ARNI) with sodium-glucose cotransporter 2 inhibitors (SGLT2i), we adopted a clinically relevant rodent model with doxorubicin, which would mimic cardiac dysfunction in CTRCD patients. After the oral administration of drugs (vehicle, SGLT2i, ARNI, Low-ARNI/SGLT2i, ARNI/SGLT2i), several physiologic parameters, including hemodynamic change, cardiac function, and histopathology, were evaluated. Bulk RNA-sequencing was performed to obtain insights into the molecular basis of a mouse heart response to Low-ARNI/SGLT2i treatment. For the first time, we report that the addition of low-dose ARNI with SGLT2i resulted in greater benefits than ARNI, SGLT2i alone or ARNI/SGLT2i combination in survival rate, cardiac function, hemodynamic change, and kidney function against doxorubicin-induced cardiotoxicity through peroxisome proliferator-activated receptor signaling pathway. Low-dose ARNI with SGLT2i combination treatment would be practically beneficial for improving cardiac functions against doxorubicin-induced heart failure with minimal adverse effects. Our findings suggest the Low-ARNI/SGLT2i combination as a feasible novel strategy in managing CTRCD patients.
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Affiliation(s)
- Donghyun Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Gyuho Jang
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Jaetaek Hwang
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Xiaofan Wei
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Hyunsoo Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Jinbae Son
- CNCure Biotech, Hwasun 58128, Republic of Korea
| | - Sang-Jae Rhee
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan 54538, Republic of Korea
| | - Kyeong-Ho Yun
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan 54538, Republic of Korea
| | - Seok-Kyu Oh
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan 54538, Republic of Korea
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Raekil Park
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
- Correspondence: ; Tel.: +82-62-715-5361; Fax: +82-62-715-3244
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22
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Davidson JA, Sukor N, Hew F, Mohamed M, Hussein Z. Safety of sodium-glucose cotransporter 2 inhibitors in Asian type 2 diabetes populations. J Diabetes Investig 2022; 14:167-182. [PMID: 36260389 PMCID: PMC9889611 DOI: 10.1111/jdi.13915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/02/2022] [Accepted: 09/10/2022] [Indexed: 02/04/2023] Open
Abstract
The prevalence of type 2 diabetes mellitus continues to increase in many Asian countries, with possible contributing factors, such as younger-onset disease, diabetes development at lower body mass index, higher visceral fat accumulation and poorer β-cell function, among Asian populations. Sodium-glucose cotransporter 2 inhibitors have been shown to confer favorable effects in type 2 diabetes mellitus patients, such as improved glycemic control, weight and blood pressure reduction, and importantly, cardiorenal benefits. Sodium-glucose cotransporter 2 inhibitors are generally well-tolerated, and have a well-defined safety profile based on evidence from numerous clinical trials and post-marketing pharmacovigilance reporting. To our knowledge, this review is the first to provide a comprehensive coverage of the adverse events of sodium-glucose cotransporter 2 inhibitors, as well as their management and counseling aspects for Asian type 2 diabetes mellitus populations.
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Affiliation(s)
- Jaime A Davidson
- Touchstone Diabetes CenterThe University of Texas Southwestern Medical CenterDallasTexasUSA
| | - Norlela Sukor
- Universiti Kebangsaan Malaysia Medical CentreKuala LumpurMalaysia
| | - Fen‐Lee Hew
- Subang Jaya Medical CentreSubang JayaSelangorMalaysia
| | - Mafauzy Mohamed
- School of Medical SciencesUniversiti Sains MalaysiaKelantanMalaysia
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23
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Heyman SN, Raz I, Dwyer JP, Weinberg Sibony R, Lewis JB, Abassi Z. Diabetic Proteinuria Revisited: Updated Physiologic Perspectives. Cells 2022; 11:2917. [PMID: 36139492 PMCID: PMC9496872 DOI: 10.3390/cells11182917] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/11/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular hemodynamics and hyperfiltration, as well as by the inability of renal tubular cells to fully retrieve filtered albumin. Albuminuria further plays a role in the progression of diabetic nephropathy, and the suppression of glomerular albumin leak is a key factor in its prevention. Although microalbuminuria is a classic manifestation of diabetic nephropathy, often progressing to macroalbuminuria or overt proteinuria over time, it does not always precede renal function loss in diabetes. The various components leading to diabetic albuminuria and their associations are herein reviewed, and the physiologic rationale and efficacy of therapeutic interventions that reduce glomerular hyperfiltration and proteinuria are discussed. With these perspectives, we propose that these measures should be initiated early, before microalbuminuria develops, as substantial renal injury may already be present in the absence of proteinuria. We further advocate that the inhibition of the renin-angiotensin axis or of sodium-glucose co-transport likely permits the administration of a normal recommended or even high-protein diet, highly desirable for sarcopenic diabetic patients.
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Affiliation(s)
- Samuel N. Heyman
- Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus, Jerusalem 9765422, Israel
- Division of Geriatrics, Herzog Hospital, Jerusalem 9765422, Israel
| | - Itamar Raz
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9765422, Israel
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 9124001, Israel
| | - Jamie P. Dwyer
- Clinical and Translational Science Institute, University of Utah Health, Salt Lake City, UT 84112, USA
| | | | - Julia B. Lewis
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Departments of Medicine and Nephrology, Vanderbilt University Medical Center, Nashville, TN 37011, USA
| | - Zaid Abassi
- Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel
- Department of Laboratory Medicine, Rambam Health Care Campus, Haifa 3109601, Israel
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24
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Frent I, Leucuta D, Bucsa C, Farcas A, Casoinic F, Mogosan C. A Description of Acute Renal Failure and Nephrolithiasis Associated With Sodium–Glucose Co-Transporter 2 Inhibitor Use: A VigiBase Study. Front Pharmacol 2022; 13:925805. [PMID: 36003521 PMCID: PMC9393368 DOI: 10.3389/fphar.2022.925805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The Food and Drug Administration issued a warning on the risk of acute kidney injury and a signal of nephrolithiasis for patients using sodium–glucose co-transporter 2 inhibitors (SGLT2i). We performed a descriptive analysis on acute renal failure (ARF) and nephrolithiasis cases reported to SGLT2i in the VigiBase®, in the scope of characterizing the patients and reactions and to report on the disproportionality analysis. Methods: We analyzed all ARF and nephrolithiasis reports for SGLT2i in VigiBase from inception to September 2021. ARF cases were defined as reports containing at least one of the preferred terms (PTs) included in the ARF narrow Medical Dictionary for Regulatory Activities Standardised Queries (MedDRA SMQ). SGLT2i exposure was considered for reports with at least one gliflozin as a suspected/interacting drug. We characterized the patients, reporters, and reactions, and we present the proportional reporting ratio (PRR). Results: Of 27,370,413 total reports in VigiBase, we found 3,972 ARF reactions to gliflozins as suspected/interacting drugs in 3,751 patients and 231 nephrolithiasis reactions in 227 patients. Most cases were reported from American regions (3057; 81.49%), for patients of age group 45–64 years (1590; 59%). About 30% (1156) of the ARF reports were registered in 2018, most from spontaneous reporting, and from consumers followed by healthcare professionals (2,235; 61% and 1440; 38%, respectively). Canagliflozin was the most involved gliflozin in the ARF and nephrolithiasis cases (2,640; 67% and 109; 47%, respectively). The great majority of ARF and nephrolithiasis reports were serious (3,761; 95% and 182; 79%, respectively). Of the total ARF cases reported, 51 had fatal outcome, while 152 had not recovered/not resolved outcome. No fatal outcome was reported for nephrolithiasis. Disproportionality analysis in full database showed a PRR of 4.68 (95% CI 4.53–4.83) for all gliflozins–ARF and a PRR of 3.44 (95% CI 3.00–3.95) for all gliflozins–nephrolithiasis. Conclusion: Most of ARF reports associated with gliflozins were serious, with an important number of cases with fatal outcome. A drug safety signal was found between ARF narrow SMQ and gliflozins. Also, gliflozins were associated with an increase in the proportion of nephrolithiasis reports compared to other medications.
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Affiliation(s)
- Ioana Frent
- Department of Pharmacology, Physiology and Physiopathology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Daniel Leucuta
- Department of Medical Informatics and Biostatistics, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
- *Correspondence: Daniel Leucuta,
| | - Camelia Bucsa
- Pharmacovigilance Research Center, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Andreea Farcas
- Pharmacovigilance Research Center, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Florin Casoinic
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina Mogosan
- Department of Pharmacology, Physiology and Physiopathology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
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25
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Heyman SN, Abassi Z. Gliflozins in the Management of Cardiovascular Disease. N Engl J Med 2022; 387:478. [PMID: 35921467 DOI: 10.1056/nejmc2208130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
| | - Zaid Abassi
- Technion Israel Institute of Technology, Haifa, Israel
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26
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Zhuo M, Paik JM, Wexler DJ, Bonventre JV, Kim SC, Patorno E. SGLT2 Inhibitors and the Risk of Acute Kidney Injury in Older Adults With Type 2 Diabetes. Am J Kidney Dis 2022; 79:858-867.e1. [PMID: 34762974 PMCID: PMC9079190 DOI: 10.1053/j.ajkd.2021.09.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/13/2021] [Indexed: 12/28/2022]
Abstract
RATIONALE & OBJECTIVE Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to have many benefits for patients with type 2 diabetes. However, whether SGLT2 inhibitors increase the risk of acute kidney injury (AKI) remains unknown. We examined the association of AKI hospitalization with prior initiation of an SGLT2 inhibitor compared with initiation of a dipeptidyl peptidase 4 (DPP-4) inhibitor or a glucagon-like peptide 1 receptor agonist (GLP-1RA) among older adults with type 2 diabetes in routine practice. STUDY DESIGN Population-based cohort study. SETTING & PARTICIPANTS Older adults aged at least 66 years with type 2 diabetes enrolled in Medicare fee-for-service and who were new users of SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1RA agents in the interval from March 2013 to December 2017. EXPOSURES New use of an SGLT2 inhibitor versus new use of a DPP-4 inhibitor or GLP-1RA. OUTCOME The primary outcome was hospitalization for AKI, defined as a discharge diagnosis of AKI in the primary or secondary position. ANALYTICAL APPROACH New users of SGLT2 inhibitors were matched at a 1:1 ratio to new users of DPP-4 inhibitors or GLP-1RAs using propensity scores in 2 pairwise comparisons. Cox proportional hazards regression models generated hazard ratios (HRs) with 95% CIs in propensity score-matched groups. RESULTS Totals of 68,130 and 71,477 new users of SGLT2 inhibitors were matched to new users of DPP-4 inhibitors or GLP-1RAs, respectively. Overall, the mean age of study participants was 72 years. The risk of AKI was lower in the SGLT2 inhibitor group than in the DPP-4 inhibitor group (HR, 0.71 [95% CI, 0.65-0.76]) or the GLP-1RA group (HR, 0.81 [95% CI, 0.75-0.87]). LIMITATIONS Residual confounding and lack of laboratory data. CONCLUSIONS Among older adults with type 2 diabetes, initiation of an SGLT2 inhibitor was associated with a reduced risk of AKI compared with initiation of a DPP-4 inhibitor or a GLP-1RA.
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Affiliation(s)
- Min Zhuo
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Julie M Paik
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; New England Geriatric Research, Education and Clinical Center, VA Boston Healthcare System, Boston, Massachusetts
| | - Deborah J Wexler
- Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Joseph V Bonventre
- Division of Renal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Seoyoung C Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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27
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Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022; 21:83. [PMID: 35614469 PMCID: PMC9134641 DOI: 10.1186/s12933-022-01512-w] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve β-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.
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Affiliation(s)
- Bo Xu
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shaoqian Li
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Bo Kang
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiecan Zhou
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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28
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Documento de información y consenso para la detección y manejo de la enfermedad renal crónica. Nefrologia 2022. [DOI: 10.1016/j.nefro.2021.07.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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29
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García-Maset R, Bover J, Segura de la Morena J, Goicoechea Diezhandino M, Cebollada Del Hoyo J, Escalada San Martin J, Fácila Rubio L, Gamarra Ortiz J, García-Donaire JA, García-Matarín L, Gràcia Garcia S, Isabel Gutiérrez Pérez M, Hernández Moreno J, Mazón Ramos P, Montañés Bermudez R, Muñoz Torres M, de Pablos-Velasco P, Pérez-Maraver M, Suárez Fernández C, Tranche Iparraguirre S, Luis Górriz J. Information and consensus document for the detection and management of chronic kidney disease. Nefrologia 2022; 42:233-264. [PMID: 36210616 DOI: 10.1016/j.nefroe.2022.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 06/16/2023] Open
Abstract
Chronic kidney disease (CKD) is a major public health problem worldwide that affects more than 10% of the Spanish population. CKD is associated with high comorbidity rates, poor prognosis and major consumption of health system resources. Since the publication of the last consensus document on CKD seven years ago, little evidence has emerged and few clinical trials on new diagnostic and treatment strategies in CKD have been conducted, apart from new trials in diabetic kidney disease. Therefore, CKD international guidelines have not been recently updated. The rigidity and conservative attitude of the guidelines should not prevent the publication of updates in knowledge about certain matters that may be key in detecting CKD and managing patients with this disease. This document, also prepared by 10 scientific associations, provides an update on concepts, clarifications, diagnostic criteria, remission strategies and new treatment options. The evidence and the main studies published on these aspects of CKD have been reviewed. This should be considered more as an information document on CKD. It includes an update on CKD detection, risk factors and screening; a definition of renal progression; an update of remission criteria with new suggestions in the older population; CKD monitoring and prevention strategies; management of associated comorbidities, particularly in diabetes mellitus; roles of the Primary Care physician in CKD management; and what not to do in Nephrology. The aim of the document is to serve as an aid in the multidisciplinary management of the patient with CKD based on current recommendations and knowledge.
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Affiliation(s)
| | | | - Julián Segura de la Morena
- Sociedad Española de Hipertensión-Liga Española para la Lucha contra la Hipertensión Arterial (SEH-LELHA)
| | | | | | | | | | | | - Jose A García-Donaire
- Sociedad Española de Hipertensión-Liga Española para la Lucha contra la Hipertensión Arterial (SEH-LELHA)
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30
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Chieng JHL, Sia TK, Teo YH, Wong JZA, Ng TJY, Teo YN, Syn NL, Cherian R, Lim YC, Chai P, Lin W, Wong RC, Sia CH. Evaluating the Initiation of Sodium/Glucose Cotransporter 2 Inhibitors within 2 Weeks of an Acute Hospital Admission: A Systematic Review and Meta-Analysis of Nine Clinical Trials. Med Princ Pract 2022; 31:215-223. [PMID: 35378527 PMCID: PMC9274826 DOI: 10.1159/000524435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 03/20/2022] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE Recent studies have increasingly shown the benefits of using sodium/glucose cotransporter 2 inhibitor (SGLT2i). However, there are concerns regarding the initiation of SGLT2i during acute hospital admissions due to the potential increased risk of complications. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of SGLT2i initiation within 2 weeks of an acute hospital admission. METHODS Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for articles published from inception up to 27 March 2021 that evaluated the efficacy and/or safety of SGLT2i initiation within 2 weeks of an acute hospital admission. Random-effects pair-wise meta-analysis models were utilized to summarize the studies. The protocol was registered with PROSPERO (CRD42021245492). RESULTS Nine clinical trials were included with a combined cohort of 1,758 patients. Patients receiving SGLT2i had a mean increase in 24-h urine volume of +487.55 mL (95% CI 126.86-848.25; p = 0.008) compared to those not started on SGLT2i. Patients with heart failure treated with SGLT2i had a 27% relative risk reduction in rehospitalizations for heart failure, compared to controls (risk ratio 0.73; p = 0.005). There were no differences in other efficacy and safety outcomes examined. CONCLUSION There was no increased harm with initiation of SGLT2i within 2 weeks of an acute hospital admission, and its use reduced the relative risk of rehospitalizations for heart failure in patients with heart failure. It was also associated with increased urine output. However, current evidence pool is limited, especially in specific population subtypes.
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Affiliation(s)
- Jenny Hui Ling Chieng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tze Kai Sia
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yao Hao Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Joseph Zi An Wong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tricia Jing Ying Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yao Neng Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nicholas L.X. Syn
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Robin Cherian
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, Singapore, Singapore
| | - Yoke-Ching Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, Singapore, Singapore
| | - Ping Chai
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, Singapore, Singapore
| | - Weiqin Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, Singapore, Singapore
| | - Raymond C.C. Wong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, Singapore, Singapore
| | - Ching-Hui Sia
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, Singapore, Singapore
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Scheen AJ, Delanaye P. Acute renal injury events in diabetic patients treated with SGLT2 inhibitors: A comprehensive review with a special reference to RAAS blockers. DIABETES & METABOLISM 2021; 48:101315. [PMID: 34910981 DOI: 10.1016/j.diabet.2021.101315] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/03/2021] [Indexed: 01/13/2023]
Abstract
Renin-angiotensin-aldosterone system (RAAS) blockers and sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are two pharmacological classes that proved a remarkable nephroprotective effect, yet a risk of acute kidney injury (AKI) was also pointed out. In 2016, the US Food and Drug Administration recommended caution with the concomitant use of these medications. While the literature devoted to RAAS blockers remained surprisingly limited, numerous articles were published in recent years with SGLT2is. Safety analyses of large prospective cardiorenal trials showed a reduced rather than an increased number of AKI events in patients with type 2 diabetes treated with SGLT2is compared with those treated with placebo, despite the fact that a majority of patients received RAAS blockers at baseline. Interestingly, retrospective observational studies confirmed these reassuring findings in real-life conditions in more heterogeneous and possibly more frailty populations also commonly treated with RAAS blockers by showing a reduced risk of AKI with SGLT2is compared with other glucose-lowering drugs. Currently, there are no evidence of an increased risk of AKI with RAAS blocker-SGLT2i combinations in absence of haemodynamic instability. Several underlying mechanisms could explain a decreased rather than an increased risk of AKI with SGLT2is, including in patients treated with RAAS blockers.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium; Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège (ULiege), Liège, Belgium.
| | - Pierre Delanaye
- Department of Nephrology-Dialysis-Transplantation, University of Liège (ULiege), CHU Sart Tilman, Liège, Belgium; Department of Nephrology-Dialysis-Apheresis, Hôpital Universitaire Carémeau, Nîmes, France
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Alkabbani W, Zongo A, Minhas-Sandhu JK, Eurich DT, Shah BR, Alsabbagh MW, Gamble JM. Renal effectiveness and safety of the sodium-glucose cotransporter-2 inhibitors: a population-based cohort study. BMJ Open Diabetes Res Care 2021; 9:9/2/e002496. [PMID: 34906925 PMCID: PMC8671915 DOI: 10.1136/bmjdrc-2021-002496] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/23/2021] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION To assess the comparative effectiveness and safety of renal-related outcomes associated with sodium-glucose cotransporter-2 inhibitors (SGLT2-i) initiation among patients with type 2 diabetes using real-world data. RESEARCH DESIGN AND METHODS We conducted a population-based cohort study using administrative healthcare data from Alberta (AB), Canada and primary care data from the Clinical Practice Research Datalink (CPRD), UK. From a cohort of new metformin users, we identified initiators of a SGLT2-i or dipeptidyl peptidase-4 inhibitor (DPP4-i) between January 1, 2014 and March 30, 2018 (AB) or between January 1, 2013 and November 29, 2018 (CPRD). Initiators of an SGLT2-i or DPP4-i were followed until death, disenrolment, therapy discontinuation, or study end date. The effectiveness outcome was renal disease progression, defined as a composite of new-onset macroalbuminuria, serum creatinine doubling with estimated glomerular filtration rate of ≤45 mL/min/1.73 m2, renal replacement therapy, hospital admission or death from renal causes. The safety outcome was hospitalization due to acute kidney injury (AKI). We adjusted for confounding using high-dimensional propensity score matching and estimated HRs using Cox proportional hazards regression. Aggregate data from each database were combined by random-effects meta-analysis. RESULTS Among the 29 465 included patients (20 564 AB, 8901 CPRD), 37.5% were new SGLT2-i users in AB and 21.3% in CPRD. Compared with DPP4 initiators, SGLT2-i initiators were associated with a reduced risk of renal disease progression (pooled HR 0.79, 95% CI 0.62 to 1.00); however, there was no significant difference in the risk of AKI (pooled HR 0.89, 95% CI 0.58 to 1.36). These findings were consistent with other exposure definitions and antidiabetic comparators. CONCLUSIONS Our findings support a renoprotective effect of SGLT2-i without an increased risk of AKI, compared with clinically relevant active comparators.
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Affiliation(s)
- Wajd Alkabbani
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
| | - Arsene Zongo
- Faculté de pharmacie, Université Laval, Laval, Quebec, Canada
- CHU de Québec-Université Laval Research Center, Québec City, Québec, Canada
| | - Jasjeet K Minhas-Sandhu
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - Dean T Eurich
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - Baiju R Shah
- Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
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Ravindran S, Munusamy S. Renoprotective mechanisms of sodium-glucose co-transporter 2 (SGLT2) inhibitors against the progression of diabetic kidney disease. J Cell Physiol 2021; 237:1182-1205. [PMID: 34713897 DOI: 10.1002/jcp.30621] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/02/2021] [Accepted: 10/08/2021] [Indexed: 12/19/2022]
Abstract
Sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) have emerged as a promising class of antidiabetic drugs with cardioprotective and renoprotective effects in patients with type 2 diabetes (T2D). The sodium-glucose co-transporters 1 and 2 (SGLT 1 and SGLT2) located in the renal proximal tubules are responsible for glucose reabsorption from the glomerular filtrate back into the systemic circulation. Inhibition of SGLT2, which accounts for about 90% of the glucose reabsorption, leads to a significant reduction in blood glucose levels and a concomitant increase in the urinary excretion of glucose (glycosuria). Multiple mechanisms contribute to the nephroprotective effects of SGLT2-Is in T2D patients. These include: (1) Restoration of the tubuloglomerular feedback by increasing sodium delivery at macula densa, leading to afferent arteriolar constriction and reduced glomerular hyperfiltration, (2) Decreased activation of the intra-renal renin-angiotensin-aldosterone system, which also contributes to reducing glomerular hyperfiltration, (3) Increased production of ketone bodies, which serves as an alternate fuel for adenosine triphosphate production in mitochondria, which helps in attenuating inflammation, and (4) Protection against hypoxia, oxidative stress, and fibrosis. This review elaborates on the key mechanisms that underlie the nephroprotective effects and the adverse effects of SGLT2-Is in T2D patients with progressive diabetic kidney disease.
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Affiliation(s)
| | - Shankar Munusamy
- Department of Pharmaceutical and Administrative Sciences, Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa, USA
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34
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Bnaya A, Itzkowitz E, Atrash J, Abu-Alfeilat M, Shavit L. Acute interstitial nephritis related to SGLT-2 inhibitor. Postgrad Med J 2021; 98:740-741. [PMID: 34244379 DOI: 10.1136/postgradmedj-2020-139490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 06/26/2021] [Indexed: 11/03/2022]
Affiliation(s)
- Alon Bnaya
- Nephrology unit, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Eyal Itzkowitz
- Nephrology unit, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Jawad Atrash
- Nephrology unit, Shaare Zedek Medical Center, Jerusalem, Israel
| | | | - Linda Shavit
- Nephrology unit, Shaare Zedek Medical Center, Jerusalem, Israel
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35
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Darawshi S, Yaseen H, Gorelik Y, Faor C, Szalat A, Abassi Z, Heyman SN, Khamaisi M. Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors. Ren Fail 2021; 42:836-844. [PMID: 32787602 PMCID: PMC7472507 DOI: 10.1080/0886022x.2020.1801466] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background Inhibitors of sodium-glucose co-transporter-2 (SGLT2i) were found to improve renal outcome in diabetic patients in large prospective randomized trials. Yet, SGLT2i may acutely reduce kidney function through volume depletion, altered glomerular hemodynamics or intensified medullary hypoxia leading to acute tubular injury (ATI). The aim or this study was to prospectively assess the pathophysiology of acute kidney injury (AKI) in patients hospitalized while on SGLT2i, differing ATI from pre-renal causes using renal biomarkers. Methods Serum and urine Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Ischemia Molecule (KIM)-1, markers of distal and proximal tubular injury, respectively, were determined in 46 diabetic patients who were on SGLT2i upon hospitalization with an acute illness. Results Serum and urine NGAL, but not KIM-1, were significantly increased in 21 of the patients who presented with AKI upon admission, as compared with 25 patients that maintained kidney function. Both serum and urinary NGAL correlated with the degree of impaired renal function, which in many cases was likely the result of additional acute renal perturbations, such as sepsis. Conclusions Increased urinary and serum NGAL indicates that ATI, principally affecting distal tubular segments, may develop in some of the patients hospitalized with an acute illness and AKI while on SGLT2i. It is suggested that intensified medullary hypoxia by SGLT2i might be detrimental in this injury. By contrast, concomitantly unaltered KIM-1 might reflect improved cortical oxygenation by SGLT2i, and may explain an overall reduced risk of AKI with SGLT1i in large series. The independent potential of SGLT2i to inflict medullary hypoxic damage should be explored further.
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Affiliation(s)
- Said Darawshi
- Department of Medicine D, Ruth & Bruce Rappaport Faculty of Medicine, Rambam Health Care Campus, Technion-IIT, Haifa, Israel.,Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
| | - Hiba Yaseen
- Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
| | - Yuri Gorelik
- Department of Medicine D, Ruth & Bruce Rappaport Faculty of Medicine, Rambam Health Care Campus, Technion-IIT, Haifa, Israel.,Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
| | - Caroline Faor
- Department of Medicine D, Ruth & Bruce Rappaport Faculty of Medicine, Rambam Health Care Campus, Technion-IIT, Haifa, Israel.,Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
| | - Auryan Szalat
- Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Zaid Abassi
- Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.,Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel
| | - Samuel N Heyman
- Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Mogher Khamaisi
- Department of Medicine D, Ruth & Bruce Rappaport Faculty of Medicine, Rambam Health Care Campus, Technion-IIT, Haifa, Israel.,Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
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Provenzano M, Pelle MC, Zaffina I, Tassone B, Pujia R, Ricchio M, Serra R, Sciacqua A, Michael A, Andreucci M, Arturi F. Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge. Front Med (Lausanne) 2021; 8:654557. [PMID: 34150796 PMCID: PMC8212983 DOI: 10.3389/fmed.2021.654557] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/11/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.
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Affiliation(s)
- Michele Provenzano
- Chair of Nephrology, Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Maria Chiara Pelle
- Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Isabella Zaffina
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Bruno Tassone
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Roberta Pujia
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Marco Ricchio
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Raffaele Serra
- Interuniversity Center of Phlebolymphology (CIFL), International Research and Educational Program in Clinical and Experimental Biotechnology at the Department of Surgical and Medical Sciences University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Angela Sciacqua
- Unit of Geriatric, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Ashour Michael
- Chair of Nephrology, Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Michele Andreucci
- Chair of Nephrology, Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Franco Arturi
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
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Kale A, Sankrityayan H, Anders HJ, Bhanudas Gaikwad A. Klotho: A possible mechanism of action of SGLT2 inhibitors preventing episodes of acute kidney injury and cardiorenal complications of diabetes. Drug Discov Today 2021; 26:1963-1971. [PMID: 33862192 DOI: 10.1016/j.drudis.2021.04.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/19/2021] [Accepted: 04/06/2021] [Indexed: 12/29/2022]
Abstract
Diabetes and cardiorenal comorbidities are major global health concerns, with high economic burdens and mortality rates. Sodium glucose co-transporter-2 inhibitors (SGLT2is) are novel US Food and Drug Administration (FDA)-approved antihyperglycemics with unexpected protective potential against cardiorenal diseases in patients with or without type 2 diabetes mellitus (T2DM). Despite initial concerns, the incidence of episodes of acute kidney injury (AKI) was significantly lower in patients taking SGLT2i compared with other therapies or placebo. Evolving data suggest a link between SGLT2is and the anti-aging protein Klotho in the amelioration of diabetes and cardiorenal diseases. Here, we consider Klotho and SGLT2is as a novel therapeutic approach for the management of AKI and other cardiorenal complications in patients with or without diabetes.
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Affiliation(s)
- Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Himanshu Sankrityayan
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, 80336 Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
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38
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Katsuhara Y, Ikeda S. Correlations Between SGLT-2 Inhibitors and Acute Renal Failure by Signal Detection Using FAERS: Stratified Analysis for Reporting Country and Concomitant Drugs. Clin Drug Investig 2021; 41:235-243. [PMID: 33564981 DOI: 10.1007/s40261-021-01006-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Previous studies have shown conflicting observations regarding the correlation between sodium-glucose-cotransporter-2 inhibitors (SGLT2i) and acute renal failure. Although wide use has contributed to the accumulation of safety information on SGLT2i, the examination of the countries reporting cases of SGLT2i use and influence of concomitant drugs has been insufficient in studies using spontaneous adverse event reporting databases. OBJECTIVE We aimed to re-examine the correlation between SGLT2i and acute renal failure using the latest United States Food and Drug Administration's Adverse Event Reporting System (FAERS) records and to conduct a stratified analysis for the reporting countries (Japan or other countries), as well as the concomitant use of drugs such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) with SGLT2i. PATIENTS AND METHODS The reporting odds ratio (ROR) and 95% confidence interval (CI) for cases recorded on FAERS from January 2013 to March 2020 were calculated. We then limited the cases to patients using SGLT2i and receiving treatment for diabetes mellitus and then calculated the ROR. A stratified analysis was performed for reporting countries (Japan or other countries), and the presence or absence of concomitant use of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) to examine their influence on the correlation between SGLT2i and acute renal failure. RESULTS Of the 5,337,069 cases of adverse events recorded on FAERS, 410,569 were cases in which patients had received treatment for diabetes. The ROR for SGLT2i calculated from the total analysis subjects was 4.16 (95% CI 4.01-4.31), suggesting its correlation with acute renal failure. Similar results were obtained for the cases in which patients had received treatment for diabetes. However, the stratified analysis of these diabetes-treatment cases for reporting countries showed no correlation between SGLT2i and acute renal failure in cases reported in Japan with ROR 0.58 (95% CI 0.49-0.69). In contrast, a correlation was suggested in cases reported in countries other than Japan with ROR 1.91 (95% CI 1.83-1.98). Moreover, the stratified analysis for the concomitant use of an ACEi or ARB showed that the ROR tended to be low in the cases with one of these drugs. CONCLUSION Examination with the signal detection method using FAERS suggested the correlation between SGLT2i and the onset of acute renal failure. However, when focusing on the cases reported in Japan, such a correlation was not suggested. In addition, this study indicated that the signal of acute renal failure tends to be reduced in cases with the concomitant use of either an ACEi or ARB. Through this study we suggest that patients should be closely monitored when they take SGLT2i without an ACEi or ARB.
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Affiliation(s)
- Yukari Katsuhara
- International University of Health and Welfare Graduate School Graduate School of Health and Welfare Sciences, 4-1-26 Akasaka, Minato-city, Tokyo, 107-8402, Japan.
| | - Shunya Ikeda
- International University of Health and Welfare Graduate School Graduate School of Health and Welfare Sciences, 4-1-26 Akasaka, Minato-city, Tokyo, 107-8402, Japan
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Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16:556-577. [PMID: 32855502 DOI: 10.1038/s41574-020-0392-2] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
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40
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Heyman SN, Gorelik Y, Zorbavel D, Rosenberger C, Abassi Z, Rosen S, Khamaisi M. Near-drowning: new perspectives for human hypoxic acute kidney injury. Nephrol Dial Transplant 2020; 35:206-212. [PMID: 30768198 DOI: 10.1093/ndt/gfz016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/07/2019] [Indexed: 11/13/2022] Open
Abstract
Concepts regarding hypoxic acute kidney injury (AKI) are derived from widely used warm ischemia-reflow (WIR) models, characterized by extensive proximal tubular injury and associated with profound inflammation. However, there is ample clinical and experimental data indicating that hypoxic AKI may develop without total cessation of renal blood flow, with a different injury pattern that principally affects medullary thick limbs in the outer medulla. This injury pattern likely reflects an imbalance between blood and oxygen supply and oxygen expenditure, principally for tubular transport. Experimental models of hypoxic AKI other than WIR are based on mismatched oxygen delivery and consumption, particularly within the physiologically hypoxic outer medulla. However, evidence for such circumstances in human AKI is lacking. Recent analysis of the clinical course and laboratory findings of patients following near-drowning (ND) provides a rare glimpse into such a scenario. This observation supports the role of renal hypoxia in the evolution of AKI, as renal impairment could be predicted by the degree of whole-body hypoxia (reflected by lactic acidosis). Furthermore, there was a close association of renal functional impairment with indices of reduced oxygen delivery (respiratory failure and features of intense sympathetic activity) and of enhanced oxygen consumption for active tubular transport (extrapolated from the calculated volume of consumed hypertonic seawater). This unique study in humans supports the concept of renal oxygenation imbalance in hypoxic AKI. The drowning scenario, particularly in seawater, may serve as an archetype of this disorder, resulting from reduced oxygen delivery, combined with intensified oxygen consumption for tubular transport.
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Affiliation(s)
- Samuel N Heyman
- Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus, Jerusalem, Israel
| | - Yuri Gorelik
- Department of Medicine D, Rambam Health Care Campus and Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel
| | - Danny Zorbavel
- Department of Medicine D, Rambam Health Care Campus and Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel
| | | | - Zaid Abassi
- Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.,Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel
| | - Seymour Rosen
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Mogher Khamaisi
- Department of Medicine D, Rambam Health Care Campus and Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel
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Castañeda AM, Dutra-Rufato A, Juarez MJ, Grosembacher L, Gonzalez-Torres H, Musso CG. Sodium-glucose cotransporter 2 inhibitors (SGLT2i): renal implications. Int Urol Nephrol 2020; 53:291-299. [PMID: 32767250 DOI: 10.1007/s11255-020-02585-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 07/25/2020] [Indexed: 11/26/2022]
Abstract
Type 2 diabetes mellitus (DM2) is a chronic condition that affects more than 400 million individuals worldwide. In DM2 patients, an appropriate glycemic control slows the onset and delays the progression of all its micro and macrovascular complications. Even though there are several glucose-lowering drugs, only approximately half of patients achieve glycemic control, while undesirable adverse effects (e.g., low serum glucose) normally affect treatment. Therefore, there is a need for new types of treatments. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have just been developed for treating DM2. Renal hyperfiltration as a marker of increased intraglomerular pressure in diabetic patients, and the role of renin-angiotensin-aldosterone system (RAAS) in this phenomenon have been studied. Nevertheless, RAAS blockade does not completely reduce hyperfiltration or diabetic renal damage. In this sense, the contribution of renal tubular factors to the hyperfiltration state, including sodium-glucose cotransporter (SGLT), has been currently studied. SGLT2i reduce proximal tubular sodium reabsorption, therefore increasing distal sodium delivery to the macula densa, causing tubule-glomerular feedback activation, afferent vasoconstriction, and reduced hyperfiltration in animal models. In humans, SGLT2i was recently shown to reduce hyperfiltration in normotensive, normoalbuminuric patients suffering from type 1 diabetes mellitus. In DM2 clinical trials, SGLT2 is associated with significant hyperfiltration and albuminuria reduction. The aim of this article is to compile the information regarding SGLT2i drugs, emphasizing its mechanism of renal repercussion.
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Affiliation(s)
- Alejandrina M Castañeda
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Amanda Dutra-Rufato
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Maria J Juarez
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Luis Grosembacher
- Endocrinology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Henry Gonzalez-Torres
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla, Colombia
- Universidad del Valle, Cali, Colombia
| | - Carlos G Musso
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla, Colombia.
- Ageing Biology Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
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Heyman SN, Khamaisi M, Zorbavel D, Rosen S, Abassi Z. Role of Hypoxia in Renal Failure Caused by Nephrotoxins and Hypertonic Solutions. Semin Nephrol 2020; 39:530-542. [PMID: 31836036 DOI: 10.1016/j.semnephrol.2019.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hypoxia plays a role in the pathogenesis of acute kidney injury under diverse clinical settings, including nephrotoxicity. Although some nephrotoxins exert direct renal parenchymal injury, likely with consequent altered oxygenation, others primarily reduce renal parenchymal oxygenation, leading to hypoxic tubular damage. As outlined in this review, nephrotoxin-related renal hypoxia may result from an altered renal oxygen supply (cyclosporine), enhanced oxygen consumption for tubular transport (agents inducing osmotic diuresis), or their combination (nonsteroidal anti-inflammatory drugs, radiocontrast agents, and others). Most agents causing hypoxic renal injury further supress physiologic low medullary Po2, in which a limited regional blood supply barely matches the intense regional tubular transport and oxygen consumption. The medullary tubular transport and blood supply are finely matched, securing oxygen sufficiency. Predisposition to hypoxia-mediated nephrotoxicity by medical conditions, such as chronic kidney disease or diabetes, may be explained by malfunctioning of control systems that normally maintain medullary oxygenation. However, this propensity may be diminished by hypoxia-mediated adaptive responses governed by hypoxia-inducible factors. Recent reports have suggested that inhibitors of sodium-glucose cotransporters and the administration of hypertonic saline may be added to the growing list of common therapeutic interventions that intensify medullary hypoxia, and potentially could lead to hypoxic acute kidney injury.
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Affiliation(s)
- Samuel N Heyman
- Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus, Jerusalem, Israel.
| | - Mogher Khamaisi
- Department of Medicine D, Rambam Health Care Campus, Haifa, Israel; Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus, Haifa, Israel
| | - Danny Zorbavel
- Department of Medicine D, Rambam Health Care Campus, Haifa, Israel
| | - Seymour Rosen
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA; Department of Pathology, Harvard Medical School, Boston, MA
| | - Zaid Abassi
- Department of Physiology, Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel; Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel
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Zhang X, Zhong Z, Li Y, Li W. Long-term renal outcomes associated with sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Metab Res Rev 2020; 36:e3303. [PMID: 32134558 DOI: 10.1002/dmrr.3303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 10/08/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022]
Abstract
AIMS The long-term impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on renal functions remains undefined. This study was undertaken to investigate the renal outcomes associated with SGLT2 inhibitors in patients with type 2 diabetes (T2DM) in the long term. METHODS A systematic literature search of PubMed and ClinicalTrials.gov was conducted. Randomized controlled trials which reported renal outcomes at the study endpoint in patients with T2DM receiving treatments of SGLT2 inhibitors were included. Renal adverse events were determined using prespecified lists from the Medical Dictionary for Regulatory Activities or laboratory values. Odds ratio with 95% confidence interval (CI) was used for assessment of dichotomous data. The mean difference or standardized mean difference with 95% CI was used for assessment of continuous data. Random effects models were adopted to measure the pooled outcomes. RESULTS Thirty-nine studies involving 35 trials were identified. Compared with placebo or other anti-diabetic medications, SGLT2 inhibitors were associated with significant lower incidence of composite renal outcome and acute renal failure or injury in patients with T2DM. The risk of progression of albuminuria also appeared to be decreased. No significant changes of estimated glomerular filtration rate levels or urine albumin-creatinine ratios were found in patients receiving SGLT2 inhibitors. CONCLUSIONS Overall renal safety and beneficial effects are indicated for SGLT2 inhibitors. Further confirmative data from large trials and real-world studies are needed.
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Affiliation(s)
- Xiaodan Zhang
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhen Zhong
- Department of Endocrinology, The First People's Hospital of Nankang District, Ganzhou, China
| | - Yanli Li
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wangen Li
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Zanchi A, Burnier M, Muller ME, Ghajarzadeh-Wurzner A, Maillard M, Loncle N, Milani B, Dufour N, Bonny O, Pruijm M. Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial. J Am Heart Assoc 2020; 9:e016173. [PMID: 32567439 PMCID: PMC7670540 DOI: 10.1161/jaha.119.016173] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background The sodium/glucose cotransporter 2 inhibitor empagliflozin has cardiorenal protective properties through mechanisms beyond glucose control. In this study we assessed whether empagliflozin modifies renal oxygenation as a possible mechanism of renal protection, and determined the metabolic, renal, and hemodynamic effects of empagliflozin in nondiabetic subjects. Methods and Results In this double‐blind, randomized, placebo‐controlled study, 45 healthy volunteers underwent blood and urine sampling, renal ultrasound, and blood‐oxygenation‐level–dependent magnetic resonance imaging before and 180 minutes after administration of 10 mg empagliflozin (n=30) or placebo (n=15). These examinations were repeated after 1 month of daily intake. Cortical and medullary renal oxygenation were not affected by the acute or chronic administration of empagliflozin, as determined by 148 renal blood‐oxygenation‐level–dependent magnetic resonance imaging examinations. Empagliflozin increased glucosuria (24‐hour glucosuria at 1 month: +50.1±16.3 g). The acute decrease in proximal sodium reabsorption, as determined by endogenous fractional excretion of lithium (−34.6% versus placebo), was compensated at 1 month by a rise in plasma renin activity (+28.6%) and aldosterone (+55.7%). The 24‐hour systolic and diastolic ambulatory blood pressures decreased significantly after 1 month of empagliflozin administration (−5.1 and −2.0 mm Hg, respectively). Serum uric acid levels decreased (−28.4%), hemoglobin increased (+1.7%), and erythropoietin remained the same. Conclusions Empagliflozin has a rapid and significant effect on tubular function, with sustained glucosuria and transient natriuresis in nondiabetic normotensive subjects. These effects favor blood pressure reduction. No acute or sustained changes were found in renal cortical or medullary tissue oxygenation. It remains to be determined whether this is the case in nondiabetic or diabetic patients with congestive heart failure or kidney disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03093103.
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Affiliation(s)
- Anne Zanchi
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland.,Service of Endocrinology, Diabetes and Metabolism Lausanne University Hospital and University of Lausanne Switzerland
| | - Michel Burnier
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Marie-Eve Muller
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Arlène Ghajarzadeh-Wurzner
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Marc Maillard
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Nicolas Loncle
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Bastien Milani
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Nathalie Dufour
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Olivier Bonny
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
| | - Menno Pruijm
- Service of Nephrology and Hypertension Department of Medicine Lausanne University Hospital and University of Lausanne Switzerland
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Scheen AJ. Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Expert Opin Drug Saf 2020; 19:243-256. [DOI: 10.1080/14740338.2020.1733967] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
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Baker ML, Perazella MA. SGLT2 inhibitor therapy in patients with type-2 diabetes mellitus: is acute kidney injury a concern? J Nephrol 2020; 33:985-994. [DOI: 10.1007/s40620-020-00712-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 02/11/2020] [Indexed: 12/11/2022]
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Hirai K, Morino J, Minato S, Kaneko S, Yanai K, Mutsuyoshi Y, Ishii H, Matsuyama M, Kitano T, Shindo M, Aomatsu A, Miyazawa H, Ito K, Ueda Y, Ookawara S, Morishita Y. The Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Advanced-Stage Diabetic Kidney Disease Taking Renin-Angiotensin System Blockers. Diabetes Metab Syndr Obes 2020; 13:215-225. [PMID: 32099428 PMCID: PMC7005728 DOI: 10.2147/dmso.s229046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 01/20/2020] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION AND OBJECTIVES We investigated the efficacy and safety of sodium-glucose cotransporter-2 (SGLT-2) inhibitors as an add-on therapy in patients with advanced-stage diabetic kidney disease taking renin-angiotensin system (RAS) blockers. MATERIALS AND METHODS Changes in glycated hemoglobin (HbA1c), urine protein-to-creatinine ratio (UACR), body weight, systolic blood pressure, and annual change in estimated glomerular filtration rate (eGFR) were retrospectively analyzed in 20 patients after 12 months of SGLT-2 inhibitor administration (mean eGFR: 22.8 ± 9.7 mL/min/1.73 m2). All patients had advanced-stage diabetic kidney disease and were taking RAS blockers. Twenty patients matched with similar propensity scores who were not taking SGLT-2 inhibitors served as the control group. RESULTS The annual change in eGFR improved significantly from -8.6 ± 12.5 mL/min/1.73 m2/year to -2.6 ± 5.0 mL/min/1.73 m2/year after 12 months by SGLT-2 inhibitor administration (p < 0.05), but did not change in the control group. Other clinical parameters, such as HbA1c, UACR, body weight, blood pressure, serum lipids, and electrolytes did not change in either group. No adverse effects were observed by taking SGLT-2 inhibitors. CONCLUSION Using SGLT-2 inhibitors as an add-on therapy may have beneficial effects on renal function in patients with advanced-stage diabetic kidney disease taking RAS blockers without any adverse effects.
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Affiliation(s)
- Keiji Hirai
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Junki Morino
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Saori Minato
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Shohei Kaneko
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Katsunori Yanai
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Yuko Mutsuyoshi
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Hiroki Ishii
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Momoko Matsuyama
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Taisuke Kitano
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Mitsutoshi Shindo
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Akinori Aomatsu
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Haruhisa Miyazawa
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kiyonori Ito
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Yuichiro Ueda
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Susumu Ookawara
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Yoshiyuki Morishita
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
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Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. PLoS Med 2019; 16:e1002983. [PMID: 31815931 PMCID: PMC6901179 DOI: 10.1371/journal.pmed.1002983] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 11/11/2019] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI). METHODS AND FINDINGS We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53-0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66-0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10-1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33-0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I-III). CONCLUSIONS SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.
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Affiliation(s)
- Jan Menne
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
- * E-mail:
| | - Eva Dumann
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Hermann Haller
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
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Papakitsou I, Vougiouklakis G, Elisaf MS, Filippatos TD. Differential pharmacology and clinical utility of dapagliflozin in type 2 diabetes. Clin Pharmacol 2019; 11:133-143. [PMID: 31572020 PMCID: PMC6756826 DOI: 10.2147/cpaa.s172353] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 05/08/2019] [Indexed: 12/12/2022] Open
Abstract
Dapagliflozin belongs in the family of sodium-glucose cotransporter 2 (SGLT2) inhibitors and acts by reducing glucose reabsorption in the proximal tubule. The aim of this review is to present the differential pharmacology and clinical utility of dapagliflozin. Dapagliflozin is orally administered, has a long half-life of 12.9 hours and (similar to empagliflozin) is a much weaker SGLT1 inhibitor compared with canagliflozin. Dapagliflozin significantly decreases glycated hemoglobin and fasting glucose levels in patients with type 2 diabetes mellitus (T2DM). The drug improves body weight, blood pressure, uric acid, triglycerides and high-density lipoprotein cholesterol. In the DECLARE-TIMI 58 trial, a large trial of 17,160 T2DM patients with established cardiovascular disease (CVD) or without established CVD but with multiple risk factors, dapagliflozin compared with placebo resulted in a significantly lower rate of the composite outcome of CVD death or hospitalization for heart failure (HHF); this effect was mainly due to a lower rate of HHF in the dapagliflozin group (HR: 0.73; 95%CI: 0.61–0.88), whereas no difference was observed in the rate of CVD death (HR: 0.98; 95%CI: 0.82–1.17). Moreover, dapagliflozin was noninferior to placebo with respect to major adverse CVD events. Dapagliflozin exerts beneficial effects on albuminuria. Additionally, in the DECLARE-TIMI 58 trial it significantly reduced the composite renal endpoint (40% decrease in glomerular filtration rate, end stage renal disease, or renal death) in both patients with established CVD and patients with multiple risk factors (overall HR: 0.53; 95%CI: 0.43–0.66). However dapagliflozin, like the other SGLT2 inhibitors, is associated with an increased risk of genital and urinary tract infections (usually mild mycotic infections) and acute kidney injury in cases of reduced extracellular volume. Dapagliflozin is a useful antidiabetic treatment which also exerts beneficial effects in the management of heart failure and diabetic kidney disease.
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Affiliation(s)
- Ioanna Papakitsou
- Department of Internal Medicine, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Crete, Greece
| | - George Vougiouklakis
- Department of Internal Medicine, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Crete, Greece
| | - Moses S Elisaf
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Theodosios D Filippatos
- Department of Internal Medicine, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Crete, Greece
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