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Niu S, Guan D, Shi L, Fonseca V, Svensson M, Ali MK, Sun YV, Hu X, Su C, Yang C, Shao H. Capturing the Additional Cardiovascular Benefits of SGLT2 Inhibitors and GLP-1 Receptor Agonists Beyond the Control of Traditional Risk Factors in People With Diabetes. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2025; 28:762-768. [PMID: 39922304 PMCID: PMC12147311 DOI: 10.1016/j.jval.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 02/10/2025]
Abstract
OBJECTIVES This study aimed to quantify the additional cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) beyond the traditional risk factors control in individuals with type 2 diabetes. This helps calibrate the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model to capture the total cardiovascular benefits of new diabetes medications accurately. METHODS We extracted patient characteristics and treatment efficacy data from 4 cardiovascular outcome trials (CVOTs) of SGLT2is and 4 CVOTs of GLP-1RAs completed before May 2023. Using the BRAVO diabetes simulation model, we translated reductions in traditional risk factors (ie, glycated hemoglobin, systolic blood pressure, low-density lipids, and body mass index) from the newer drugs into risk reductions in cardiovascular outcomes (ie, myocardial infarction [MI], stroke, congestive heart failure [CHF], and mortality), assuming that the drug-associated risk reductions were only driven by traditional risk factors. Then, we compared the simulated risk-factor-driven risk reductions of cardiovascular outcomes with observed risk reductions from the trials and calculated drug-specific incremental benefits (DIB). RESULTS After accounting for the cardiovascular effects from traditional risk factors control, SGLT2is was associated with an additional 19% risk reduction in CHF (DIB: 0.81, 95% CI 0.72-0.90). Furthermore, the uncalibrated model predicted a risk reduction in stroke with SGLT2is, which was not observed in CVOTs. This discrepancy highlights the need for an SGLT2i-specific calibrator to align the simulation results with the observed outcomes. In contrast, no additional cardiovascular benefit was associated with GLP-1RAs after controlling for traditional risk factors. CONCLUSIONS Our study revealed that SGLT2is could further reduce CHF risk beyond the control of traditional risk factors but may offer additional pathways to offset the overall benefits of traditional risk factor control in stroke risk. No additional cardiovascular benefits were observed for GLP-1RAs beyond traditional risk factor control. The BRAVO model calibration enhances cardiovascular outcome prediction with these newer antidiabetic therapies.
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Affiliation(s)
- Shu Niu
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Dawei Guan
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Lizheng Shi
- Department of Health Policy and Management, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
| | - Vivian Fonseca
- Section of Endocrinology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Mikael Svensson
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA; School of Public Health and Community Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Mohammed K Ali
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA; Department of Family and Preventive Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | - Yan V Sun
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Xin Hu
- Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Chang Su
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Carl Yang
- Department of Computer Science, College of Art and Sciences, Emory University, Atlanta, GA, USA
| | - Hui Shao
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA; Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA; Department of Family and Preventive Medicine, School of Medicine, Emory University, Atlanta, GA, USA.
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Kumar N, Kumar B, Ashique S, Yasmin S, Venkatesan K, Islam A, Ghosh S, Sahu A, Bhui U, Ansari MY. A critical review on SGLT2 inhibitors for diabetes mellitus, renal health, and cardiovascular conditions. Diabetes Res Clin Pract 2025; 221:112050. [PMID: 39965722 DOI: 10.1016/j.diabres.2025.112050] [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: 12/31/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally formulated to reduce blood glucose levels in individuals with diabetes. Recent clinical trials indicate that this compound can be repurposed for other critical conditions. A literature search was performed on PubMed, Scopus, Embase, ProQuest, and Google Scholar, utilizing key terms such as SGLT2i, diabetes, and oxidative stress. SGLT2i has significant beneficial effects not only in cardiovascular disease but also in renal dysfunction. SGLT2i therapy can mitigate critical cardiovascular complications like heart attacks, strokes, mortality rates, and hospitalization duration, as well as delay the necessity for dialysis irrespective of diabetic condition. Evidence supports potential advantages of SGLT2 inhibitors for individuals with renal problems and heart failure, regardless of diabetes status. In addition to diabetic mellitus, this analysis explores the latest updates on SGLT2i and the therapeutic advantages it offers in many renal and cardiovascular diseases (CVDs).
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Affiliation(s)
- Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Bimlesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sumel Ashique
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.
| | - Sabina Yasmin
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Kumar Venkatesan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Suman Ghosh
- Division of Pharmaceutical Chemistry, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Kolkata, West Bengal 700114, India
| | - Anwesha Sahu
- Division of Pharmacology, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Utpal Bhui
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Mohammad Yousuf Ansari
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana 133207, India; Ibne Seena College of Pharmacy, Azmi Vidya Nagri Anjhi Shahabad, Hardoi, Uttar Pradesh (U.P.) 241124, India.
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Zhang W, Zhang Y, Lv W, Kong Z, Wang F, Wang Y. Isoquercitrin improves diabetes nephropathy by inhibiting the sodium-glucose co-transporter-2 pathway. Biochem Biophys Res Commun 2025; 744:151142. [PMID: 39708395 DOI: 10.1016/j.bbrc.2024.151142] [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: 07/31/2024] [Revised: 10/21/2024] [Accepted: 12/04/2024] [Indexed: 12/23/2024]
Abstract
Diabetic nephropathy (DN) is one of the most severe kidney complications and the primary contributor to end-stage renal disease on a global scale. It exacerbates the morbidity, mortality, and financial burden for individuals with diabetes. Isoquercitrin, a natural compound found in various plants, has demonstrated potential as an antidiabetic agent. However, it remains uncertain whether isoquercitrin exerts a protective effect on DN. Therefore, the objective of this study was to explore whether isoquercitrin confers a protective effect on DN and its potential mechanism. In vivo, a mouse model of DN induced by streptozotocin was established in the study. The hypoglycemic effect of isoquercitrin was assessed by measuring fasting blood glucose levels, insulin tolerance tests, and glucose tolerance test in animals. Urinary albumin creatinine ratio, serum lipid levels, and pathological changes in renal tissues were measured to evaluate the protective effect of isoquercitrin against DN. The expression of Sodium glucose co-transporter-2(SGLT2) was analyzed using real-time quantitative PCR and immunohistochemistry. The studies suggest that isoquercitrin significantly reduces fasting blood glucose levels, enhances the body's capacity to regulate blood glucose and insulin resistance, and facilitates renal pathology and renal function. Simultaneously, it can lower blood lipids (total cholesterol and triglyceride) and improve the risk factors of DN. Meanwhile, isoquercitrin suppressed the expression of SGLT2 in renal tissues of DN mouse models. In vitro, real-time quantitative PCR and Western blot were used to detect the expression of SGLT2 in the human renal tubular epithelial (HK-2) cells. The effects of isoquercitrin on the survival rate and glucose uptake capacity of HK-2 cells were determined by Cell-Counting-Kit-8 and glucose uptake methods. The results demonstrate that isoquercitrin suppressed the up-regulation of SGLT2 mRNA and protein in high-glucose-induced HK-2 cells. Additionally, isoquercitrin inhibited glucose uptake in HK-2 cells and mitigated high-sugar-induced damage. Thus, this study has concluded that isoquercitrin exhibits hypoglycemic and renal protective effects by inhibiting the SGLT2 pathway, indicating its potential as a promising anti-DN drug deserving further clinical investigation.
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Affiliation(s)
- Wenjie Zhang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China; Qingdao Key Laboratory of Thyroid Diseases, Medical Research Cente, Qingdao, China.
| | - Yongxiang Zhang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Wenshan Lv
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Zili Kong
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China; Qingdao Key Laboratory of Thyroid Diseases, Medical Research Cente, Qingdao, China.
| | - Fang Wang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Yangang Wang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China; Qingdao Key Laboratory of Thyroid Diseases, Medical Research Cente, Qingdao, China.
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Katsimardou A, Theofilis P, Vordoni A, Doumas M, Kalaitzidis RG. The Effects of SGLT2 Inhibitors on Blood Pressure and Other Cardiometabolic Risk Factors. Int J Mol Sci 2024; 25:12384. [PMID: 39596449 PMCID: PMC11594301 DOI: 10.3390/ijms252212384] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Beyond their established hypoglycemic, cardioprotective, and nephroprotective properties, sodium-glucose cotransporters 2 (SGLT2) inhibitors exert other pleiotropic actions on blood pressure levels, body weight, and lipid metabolism. Blood pressure (BP) reduction varies based on the background history, including an effect on systolic, diastolic BP, and 24 h BP measurements. The reduction in body weight between 1 and 2 kg for the first months is caused by a reduction in visceral and subcutaneous fat due to glycosuria and loss of calories. Regarding lipid metabolism, a reduction in triglycerides and an increase in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) have been reported, although these alterations are small and could provide additional cardiovascular protection. Various pathophysiologic mechanisms have been proposed to explain the above-mentioned pleiotropic actions of SGLT2 inhibitors. Natriuresis, osmotic diuresis, body weight reduction, amelioration of endothelial dysfunction and arterial stiffness, sympathetic tone decrease, and uric acid reduction are among those that have been suggested for BP reduction. Apart from glycosuria and calorie loss, other mechanisms seem to contribute to body weight reduction, such as the beiging of white adipose tissue, while the mechanisms involved in lipid metabolism alterations have not been clearly determined.
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Affiliation(s)
- Alexandra Katsimardou
- 2nd Department of Internal Medicine, 401 General Military Hospital of Athens, 11525 Athens, Greece; (A.K.); (M.D.)
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital “Hippokration”, 54642 Thessaloniki, Greece
| | - Panagiotis Theofilis
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia-Piraeus “Ag. Panteleimon”, 18454 Nikaia, Greece; (P.T.); (A.V.)
| | - Aikaterini Vordoni
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia-Piraeus “Ag. Panteleimon”, 18454 Nikaia, Greece; (P.T.); (A.V.)
| | - Michael Doumas
- 2nd Department of Internal Medicine, 401 General Military Hospital of Athens, 11525 Athens, Greece; (A.K.); (M.D.)
| | - Rigas G. Kalaitzidis
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia-Piraeus “Ag. Panteleimon”, 18454 Nikaia, Greece; (P.T.); (A.V.)
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Saad G, El Maghraby GM, Sultan AA. Olive oil and flaxseed oil incorporating niosomes for enhanced in vivo anti-diabetic efficacy of canagliflozin. Drug Dev Ind Pharm 2024:1-9. [PMID: 39319618 DOI: 10.1080/03639045.2024.2409167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/30/2024] [Accepted: 09/20/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND Canagliflozin (CFZ) is broadly implicated for the management of type 2 diabetes mellitus. Unfortunately, it has low oral bioavailability due to poor solubility behavior and restricted membrane permeability. OBJECTIVE The current work focuses on development of CFZ encapsulated niosomes for enhanced oral anti-diabetic efficacy. METHODOLOGY Niosomes comprising Span 60 and cholesterol were formulated both in absence and presence of olive oil or flaxseed oil. These were evaluated in vitro for average vesicular size, structural morphology, CFZ entrapment efficiency, and drug release. Additionally, the oral hypoglycemic effect of CFZ encapsulated niosomes was explored in diabetic rats. RESULTS The fabricated niosomes were negatively charged spherical vesicles with a size range of 103.0-141.7 nm. These entrapped CFZ with efficiency ranging from 92.3% to 96.0%. Drug release investigations reflected that incorporating CFZ into niosomes significantly sustained drug release compared to the aqueous drug dispersion. Oral administration of niosomal formulations significantly enhanced the oral antidiabetic effect of CFZ. Comparing the tested niosomes, similar efficiency was shown eliminating the effect of composition. CONCLUSION The enhanced oral bioavailability of niosomes' encapsulated drugs is related to niosomal vesicular structure which allows intact niosomes absorption. The study presented niosomes as promising carriers for improved oral anti-diabetic activity of CFZ.
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Affiliation(s)
- Ghada Saad
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Horus University, Damietta, Egypt
| | - Gamal M El Maghraby
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Amal A Sultan
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
- Department of Pharmaceutics, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin, Saudi Arabia
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Mani S, Balasubramanian A, Veluswami K, Rao S, Aggarwal S. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors and Cardiovascular Outcomes: A Review of Literature. Cureus 2024; 16:e63796. [PMID: 39099905 PMCID: PMC11297731 DOI: 10.7759/cureus.63796] [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] [Accepted: 07/03/2024] [Indexed: 08/06/2024] Open
Abstract
Coronary arterial diseases are a major contributor to disease and death worldwide and are most often compounded by several other underlying medical conditions. A key concern is type 2 diabetes mellitus (T2DM). Despite progress in medical advancements, these life-threatening illnesses are still underdiagnosed and undermanaged. A relatively newer class of anti-diabetic drugs, the sodium-glucose cotransporter-2 inhibitors (SGL2-Is), also termed gliflozins, have shown promising results in reducing cardiovascular risk, regardless of diabetic status. These drugs have on-target (promoting renal glycosuria and diuresis by acting on the SGLT-2 channels in the proximal convoluted tubule) and off-target effects contributing to the reported cardiovascular benefit. Some emerging theories about its impact on myocardial energetics, calcium balance, and renal physiology exist. In this review article, we explored three major cardiovascular outcome trials: the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, the CANagliflozin cardioVascular Assessment Study (CANVAS) program, and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial to evaluate the cardiovascular effects of SGLT2-Is.
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Affiliation(s)
- Sweatha Mani
- Internal Medicine, K.A.P. Viswanatham Government Medical College, Tiruchirappalli, IND
| | | | | | - Sudipta Rao
- Internal Medicine, JSS Medical College, Mysore, IND
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Box JR, Oyama MA, Mosenco AS, Hess RS. Effect of sodium-glucose cotransporter 2 inhibitor canagliflozin on interstitial glucose concentration in insulin-treated diabetic dogs. J Vet Intern Med 2024; 38:1353-1358. [PMID: 38528660 PMCID: PMC11099740 DOI: 10.1111/jvim.17053] [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: 10/27/2023] [Accepted: 03/08/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND The utility of sodium-glucose cotransporter 2 inhibitors (SGLT2i) has not been reported in insulin-treated diabetic dogs. HYPOTHESIS Canagliflozin, a PO-administered SGLT2i, decreases interstitial glucose concentration (IG) in insulin-treated diabetic dogs. ANIMALS Five insulin-treated diabetic dogs. METHODS Uncontrolled open label longitudinal study. Canagliflozin (2-4 mg/kg/day PO) was added to an unchanged insulin dose for 7 days. Fractional excretion of glucose was calculated by dividing the product of urine glucose and serum creatinine concentrations by the product of serum glucose and urine creatinine concentrations. Hypoglycemia was defined as IG <60 mg/dL. RESULTS Median IG in 2869 measurements obtained while dogs were treated with insulin and canagliflozin was 87 mg/dL (range, 40-500 mg/dL) and was significantly lower than median IG in 1426 measurements obtained while dogs were treated with insulin alone (212 mg/dL; range, 41-500 mg/dL; P < .001). Median fractional excretion of glucose when dogs were treated with insulin and canagliflozin was 1.1% (range, 0.9%-2.0%), significantly higher than when dogs were treated with insulin alone (0.3%; range, 0.01%-1.0%; P = .04). The frequency of hypoglycemia was higher in dogs treated with insulin and canagliflozin (544 of 2869 IG measurements, 19%) compared with the frequency of hypoglycemia in dogs treated with insulin alone (52 of 1426 IG measurements, 4%; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE Canagliflozin may have a role in improving glycemic control in insulin-treated diabetic dogs, but the dose of insulin should be decreased when adding canagliflozin to insulin treatment.
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Affiliation(s)
- Jessica R. Box
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Mark A. Oyama
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Ariel S. Mosenco
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Rebecka S. Hess
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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Preda A, Montecucco F, Carbone F, Camici GG, Lüscher TF, Kraler S, Liberale L. SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits. Cardiovasc Res 2024; 120:443-460. [PMID: 38456601 PMCID: PMC12001887 DOI: 10.1093/cvr/cvae047] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/03/2024] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.
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Affiliation(s)
- Alberto Preda
- Department of Clinical Cardiology, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Royal Brompton and Harefield Hospitals and Imperial College and King’s College, London, United Kingdom
| | - Simon Kraler
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
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Liu T, Fan Z, Xiao B, He C, Wang S. Association of sodium-glucose cotransporter 2 inhibitors with risk of major adverse cardiovascular events in type 2 diabetes patients with acute coronary syndrome: a propensity score‑matched analysis. Cardiovasc Diabetol 2024; 23:106. [PMID: 38528542 PMCID: PMC10964669 DOI: 10.1186/s12933-024-02200-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 03/14/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND This study aimed to investigate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) use with cardiovascular (CV) clinical outcomes in type 2 diabetes (T2D) patients with acute coronary syndrome (ACS). METHODS Data of T2D patients hospitalized for ACS at Civil Aviation General Hospital from January 2019 to December 2022 were collected. Based on SGLT2i use or not, patients were stratified as SGLT2i group and SGLT2i-free group. A 1:1 nearest-neighbor propensity score-matched (PSM) was performed to adjust for the confounding factors and facilitate the robust comparisons between groups. The first occurrence of major adverse cardiovascular events (MACE) with 1 year follow-up, which consisted of CV death, all cause death, non-fatal myocardial infarction or stroke, coronary revascularization or heart failure readmission, was assessed. Kaplan-Meier analysis and Cox regressions were conducted to evaluate the prognostic significance of SGLT2i use. Subgroup analyses were performed to assess the interaction between subgroups and SGLT2i use. RESULTS A total of 925 patients were included, and the SGLT2i use increased from 9.9% in 2019 to 43.8% in 2022. 226 pairs were finally matched using the PSM model. During 1 year follow-up period, a total of 110 patients experienced MACE in the matched cohort, with a rate of 24.3%. Survival analyses showed cumulative incidence of MACE, CV death, and heart failure readmission in the SGLT2i group were significantly lower than the SGLT2i-free group. Additionally, the adjusted Cox analyses demonstrated that SGLT2i was associated with a 34.1% lower risk of MACE (HR 0.659, 95% CI 0.487-0.892, P = 0.007), which was primarily driven by a decrease in the risk of CV death by 12.0% (HR 0.880, 95% CI 0.7830.990, P = 0.033), and heart failure readmission by 45.5% (HR 0.545, 95% CI 0.332-0.893, P = 0.016). This MACE preventive benefit was consistent across different subgroups (P interaction > 0.05 for all comparisons). CONCLUSIONS In T2D patients with ACS, there was a clear increasing trend in SGLT2i use. SGLT2i was associated with a significantly lower risk of MACE, driven by the decrease in the risk of CV death, and heart failure readmission. Our study confirmed real-world use and efficacy of SGLT2i in a general T2D population with ACS.
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Affiliation(s)
- Tao Liu
- Department of Coronary Heart Disease, Civil Aviation General Hospital, No. 1 Gaojingjia Road, Chaoyang District, Beijing, China
| | - Zeyuan Fan
- Department of Coronary Heart Disease, Civil Aviation General Hospital, No. 1 Gaojingjia Road, Chaoyang District, Beijing, China.
| | - Bing Xiao
- Department of Coronary Heart Disease, Civil Aviation General Hospital, No. 1 Gaojingjia Road, Chaoyang District, Beijing, China
| | - Chang He
- Department of Coronary Heart Disease, Civil Aviation General Hospital, No. 1 Gaojingjia Road, Chaoyang District, Beijing, China
| | - Shicong Wang
- Department of Coronary Heart Disease, Civil Aviation General Hospital, No. 1 Gaojingjia Road, Chaoyang District, Beijing, China
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Judge PK, Staplin N, Mayne KJ, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Ng SYA, Roddick AJ, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu WJ, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Massey D, Landray MJ, Baigent C, Haynes R, Herrington WG, Abat S, Abd Rahman R, Abdul Cader R, Abdul Hafidz MI, Abdul Wahab MZ, Abdullah NK, Abdul-Samad T, Abe M, Abraham N, Acheampong S, Achiri P, Acosta JA, Adeleke A, Adell V, Adewuyi-Dalton R, Adnan N, Africano A, Agharazii M, Aguilar F, Aguilera A, Ahmad M, Ahmad MK, Ahmad NA, Ahmad NH, Ahmad NI, Ahmad Miswan N, Ahmad Rosdi H, Ahmed I, Ahmed S, Ahmed S, Aiello J, Aitken A, AitSadi R, Aker S, Akimoto S, Akinfolarin A, Akram S, Alberici F, Albert C, Aldrich L, Alegata M, Alexander L, Alfaress S, Alhadj Ali M, Ali A, Ali A, Alicic R, Aliu A, Almaraz R, Almasarwah R, Almeida J, Aloisi A, Al-Rabadi L, Alscher D, Alvarez P, Al-Zeer B, Amat M, Ambrose C, Ammar H, An Y, Andriaccio L, Ansu K, Apostolidi A, et alJudge PK, Staplin N, Mayne KJ, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Ng SYA, Roddick AJ, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu WJ, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Massey D, Landray MJ, Baigent C, Haynes R, Herrington WG, Abat S, Abd Rahman R, Abdul Cader R, Abdul Hafidz MI, Abdul Wahab MZ, Abdullah NK, Abdul-Samad T, Abe M, Abraham N, Acheampong S, Achiri P, Acosta JA, Adeleke A, Adell V, Adewuyi-Dalton R, Adnan N, Africano A, Agharazii M, Aguilar F, Aguilera A, Ahmad M, Ahmad MK, Ahmad NA, Ahmad NH, Ahmad NI, Ahmad Miswan N, Ahmad Rosdi H, Ahmed I, Ahmed S, Ahmed S, Aiello J, Aitken A, AitSadi R, Aker S, Akimoto S, Akinfolarin A, Akram S, Alberici F, Albert C, Aldrich L, Alegata M, Alexander L, Alfaress S, Alhadj Ali M, Ali A, Ali A, Alicic R, Aliu A, Almaraz R, Almasarwah R, Almeida J, Aloisi A, Al-Rabadi L, Alscher D, Alvarez P, Al-Zeer B, Amat M, Ambrose C, Ammar H, An Y, Andriaccio L, Ansu K, Apostolidi A, Arai N, Araki H, Araki S, Arbi A, Arechiga O, Armstrong S, Arnold T, Aronoff S, Arriaga W, Arroyo J, Arteaga D, Asahara S, Asai A, Asai N, Asano S, Asawa M, Asmee MF, Aucella F, Augustin M, Avery A, Awad A, Awang IY, Awazawa M, Axler A, Ayub W, Azhari Z, Baccaro R, Badin C, Bagwell B, Bahlmann-Kroll E, Bahtar AZ, Baigent C, Bains D, Bajaj H, Baker R, Baldini E, Banas B, Banerjee D, Banno S, Bansal S, Barberi S, Barnes S, Barnini C, Barot C, Barrett K, Barrios R, Bartolomei Mecatti B, Barton I, Barton J, Basily W, Bavanandan S, Baxter A, Becker L, Beddhu S, Beige J, Beigh S, Bell S, Benck U, Beneat A, Bennett A, Bennett D, Benyon S, Berdeprado J, Bergler T, Bergner A, Berry M, Bevilacqua M, Bhairoo J, Bhandari S, Bhandary N, Bhatt A, Bhattarai M, Bhavsar M, Bian W, Bianchini F, Bianco S, Bilous R, Bilton J, Bilucaglia D, Bird C, Birudaraju D, Biscoveanu M, Blake C, Bleakley N, Bocchicchia K, Bodine S, Bodington R, Boedecker S, Bolduc M, Bolton S, Bond C, Boreky F, Boren K, Bouchi R, Bough L, Bovan D, Bowler C, Bowman L, Brar N, Braun C, Breach A, Breitenfeldt M, Brenner S, Brettschneider B, Brewer A, Brewer G, Brindle V, Brioni E, Brown C, Brown H, Brown L, Brown R, Brown S, Browne D, Bruce K, Brueckmann M, Brunskill N, Bryant M, Brzoska M, Bu Y, Buckman C, Budoff M, Bullen M, Burke A, Burnette S, Burston C, Busch M, Bushnell J, Butler S, Büttner C, Byrne C, Caamano A, Cadorna J, Cafiero C, Cagle M, Cai J, Calabrese K, Calvi C, Camilleri B, Camp S, Campbell D, Campbell R, Cao H, Capelli I, Caple M, Caplin B, Cardone A, Carle J, Carnall V, Caroppo M, Carr S, Carraro G, Carson M, Casares P, Castillo C, Castro C, Caudill B, Cejka V, Ceseri M, Cham L, Chamberlain A, Chambers J, Chan CBT, Chan JYM, Chan YC, Chang E, Chang E, Chant T, Chavagnon T, Chellamuthu P, Chen F, Chen J, Chen P, Chen TM, Chen Y, Chen Y, Cheng C, Cheng H, Cheng MC, Cherney D, Cheung AK, Ching CH, Chitalia N, Choksi R, Chukwu C, Chung K, Cianciolo G, Cipressa L, Clark S, Clarke H, Clarke R, Clarke S, Cleveland B, Cole E, Coles H, Condurache L, Connor A, Convery K, Cooper A, Cooper N, Cooper Z, Cooperman L, Cosgrove L, Coutts P, Cowley A, Craik R, Cui G, Cummins T, Dahl N, Dai H, Dajani L, D'Amelio A, Damian E, Damianik K, Danel L, Daniels C, Daniels T, Darbeau S, Darius H, Dasgupta T, Davies J, Davies L, Davis A, Davis J, Davis L, Dayanandan R, Dayi S, Dayrell R, De Nicola L, Debnath S, Deeb W, Degenhardt S, DeGoursey K, Delaney M, Deo R, DeRaad R, Derebail V, Dev D, Devaux M, Dhall P, Dhillon G, Dienes J, Dobre M, Doctolero E, Dodds V, Domingo D, Donaldson D, Donaldson P, Donhauser C, Donley V, Dorestin S, Dorey S, Doulton T, Draganova D, Draxlbauer K, Driver F, Du H, Dube F, Duck T, Dugal T, Dugas J, Dukka H, Dumann H, Durham W, Dursch M, Dykas R, Easow R, Eckrich E, Eden G, Edmerson E, Edwards H, Ee LW, Eguchi J, Ehrl Y, Eichstadt K, Eid W, Eilerman B, Ejima Y, Eldon H, Ellam T, Elliott L, Ellison R, Emberson J, Epp R, Er A, Espino-Obrero M, Estcourt S, Estienne L, Evans G, Evans J, Evans S, Fabbri G, Fajardo-Moser M, Falcone C, Fani F, Faria-Shayler P, Farnia F, Farrugia D, Fechter M, Fellowes D, Feng F, Fernandez J, Ferraro P, Field A, Fikry S, Finch J, Finn H, Fioretto P, Fish R, Fleischer A, Fleming-Brown D, Fletcher L, Flora R, Foellinger C, Foligno N, Forest S, Forghani Z, Forsyth K, Fottrell-Gould D, Fox P, Frankel A, Fraser D, Frazier R, Frederick K, Freking N, French H, Froment A, Fuchs B, Fuessl L, Fujii H, Fujimoto A, Fujita A, Fujita K, Fujita Y, Fukagawa M, Fukao Y, Fukasawa A, Fuller T, Funayama T, Fung E, Furukawa M, Furukawa Y, Furusho M, Gabel S, Gaidu J, Gaiser S, Gallo K, Galloway C, Gambaro G, Gan CC, Gangemi C, Gao M, Garcia K, Garcia M, Garofalo C, Garrity M, Garza A, Gasko S, Gavrila M, Gebeyehu B, Geddes A, Gentile G, George A, George J, Gesualdo L, Ghalli F, Ghanem A, Ghate T, Ghavampour S, Ghazi A, Gherman A, Giebeln-Hudnell U, Gill B, Gillham S, Girakossyan I, Girndt M, Giuffrida A, Glenwright M, Glider T, Gloria R, Glowski D, Goh BL, Goh CB, Gohda T, Goldenberg R, Goldfaden R, Goldsmith C, Golson B, Gonce V, Gong Q, Goodenough B, Goodwin N, Goonasekera M, Gordon A, Gordon J, Gore A, Goto H, Goto S, Goto S, Gowen D, Grace A, Graham J, Grandaliano G, Gray M, Green JB, Greene T, Greenwood G, Grewal B, Grifa R, Griffin D, Griffin S, Grimmer P, Grobovaite E, Grotjahn S, Guerini A, Guest C, Gunda S, Guo B, Guo Q, Haack S, Haase M, Haaser K, Habuki K, Hadley A, Hagan S, Hagge S, Haller H, Ham S, Hamal S, Hamamoto Y, Hamano N, Hamm M, Hanburry A, Haneda M, Hanf C, Hanif W, Hansen J, Hanson L, Hantel S, Haraguchi T, Harding E, Harding T, Hardy C, Hartner C, Harun Z, Harvill L, Hasan A, Hase H, Hasegawa F, Hasegawa T, Hashimoto A, Hashimoto C, Hashimoto M, Hashimoto S, Haskett S, Hauske SJ, Hawfield A, Hayami T, Hayashi M, Hayashi S, Haynes R, Hazara A, Healy C, Hecktman J, Heine G, Henderson H, Henschel R, Hepditch A, Herfurth K, Hernandez G, Hernandez Pena A, Hernandez-Cassis C, Herrington WG, Herzog C, Hewins S, Hewitt D, Hichkad L, Higashi S, Higuchi C, Hill C, Hill L, Hill M, Himeno T, Hing A, Hirakawa Y, Hirata K, Hirota Y, Hisatake T, Hitchcock S, Hodakowski A, Hodge W, Hogan R, Hohenstatt U, Hohenstein B, Hooi L, Hope S, Hopley M, Horikawa S, Hosein D, Hosooka T, Hou L, Hou W, Howie L, Howson A, Hozak M, Htet Z, Hu X, Hu Y, Huang J, Huda N, Hudig L, Hudson A, Hugo C, Hull R, Hume L, Hundei W, Hunt N, Hunter A, Hurley S, Hurst A, Hutchinson C, Hyo T, Ibrahim FH, Ibrahim S, Ihana N, Ikeda T, Imai A, Imamine R, Inamori A, Inazawa H, Ingell J, Inomata K, Inukai Y, Ioka M, Irtiza-Ali A, Isakova T, Isari W, Iselt M, Ishiguro A, Ishihara K, Ishikawa T, Ishimoto T, Ishizuka K, Ismail R, Itano S, Ito H, Ito K, Ito M, Ito Y, Iwagaitsu S, Iwaita Y, Iwakura T, Iwamoto M, Iwasa M, Iwasaki H, Iwasaki S, Izumi K, Izumi K, Izumi T, Jaafar SM, Jackson C, Jackson Y, Jafari G, Jahangiriesmaili M, Jain N, Jansson K, Jasim H, Jeffers L, Jenkins A, Jesky M, Jesus-Silva J, Jeyarajah D, Jiang Y, Jiao X, Jimenez G, Jin B, Jin Q, Jochims J, Johns B, Johnson C, Johnson T, Jolly S, Jones L, Jones L, Jones S, Jones T, Jones V, Joseph M, Joshi S, Judge P, Junejo N, Junus S, Kachele M, Kadowaki T, Kadoya H, Kaga H, Kai H, Kajio H, Kaluza-Schilling W, Kamaruzaman L, Kamarzarian A, Kamimura Y, Kamiya H, Kamundi C, Kan T, Kanaguchi Y, Kanazawa A, Kanda E, Kanegae S, Kaneko K, Kaneko K, Kang HY, Kano T, Karim M, Karounos D, Karsan W, Kasagi R, Kashihara N, Katagiri H, Katanosaka A, Katayama A, Katayama M, Katiman E, Kato K, Kato M, Kato N, Kato S, Kato T, Kato Y, Katsuda Y, Katsuno T, Kaufeld J, Kavak Y, Kawai I, Kawai M, Kawai M, Kawase A, Kawashima S, Kazory A, Kearney J, Keith B, Kellett J, Kelley S, Kershaw M, Ketteler M, Khai Q, Khairullah Q, Khandwala H, Khoo KKL, Khwaja A, Kidokoro K, Kielstein J, Kihara M, Kimber C, Kimura S, Kinashi H, Kingston H, Kinomura M, Kinsella-Perks E, Kitagawa M, Kitajima M, Kitamura S, Kiyosue A, Kiyota M, Klauser F, Klausmann G, Kmietschak W, Knapp K, Knight C, Knoppe A, Knott C, Kobayashi M, Kobayashi R, Kobayashi T, Koch M, Kodama S, Kodani N, Kogure E, Koizumi M, Kojima H, Kojo T, Kolhe N, Komaba H, Komiya T, Komori H, Kon SP, Kondo M, Kondo M, Kong W, Konishi M, Kono K, Koshino M, Kosugi T, Kothapalli B, Kozlowski T, Kraemer B, Kraemer-Guth A, Krappe J, Kraus D, Kriatselis C, Krieger C, Krish P, Kruger B, Ku Md Razi KR, Kuan Y, Kubota S, Kuhn S, Kumar P, Kume S, Kummer I, Kumuji R, Küpper A, Kuramae T, Kurian L, Kuribayashi C, Kurien R, Kuroda E, Kurose T, Kutschat A, Kuwabara N, Kuwata H, La Manna G, Lacey M, Lafferty K, LaFleur P, Lai V, Laity E, Lambert A, Landray MJ, Langlois M, Latif F, Latore E, Laundy E, Laurienti D, Lawson A, Lay M, Leal I, Leal I, Lee AK, Lee J, Lee KQ, Lee R, Lee SA, Lee YY, Lee-Barkey Y, Leonard N, Leoncini G, Leong CM, Lerario S, Leslie A, Levin A, Lewington A, Li J, Li N, Li X, Li Y, Liberti L, Liberti ME, Liew A, Liew YF, Lilavivat U, Lim SK, Lim YS, Limon E, Lin H, Lioudaki E, Liu H, Liu J, Liu L, Liu Q, Liu WJ, Liu X, Liu Z, Loader D, Lochhead H, Loh CL, Lorimer A, Loudermilk L, Loutan J, Low CK, Low CL, Low YM, Lozon Z, Lu Y, Lucci D, Ludwig U, Luker N, Lund D, Lustig R, Lyle S, Macdonald C, MacDougall I, Machicado R, MacLean D, Macleod P, Madera A, Madore F, Maeda K, Maegawa H, Maeno S, Mafham M, Magee J, Maggioni AP, Mah DY, Mahabadi V, Maiguma M, Makita Y, Makos G, Manco L, Mangiacapra R, Manley J, Mann P, Mano S, Marcotte G, Maris J, Mark P, Markau S, Markovic M, Marshall C, Martin M, Martinez C, Martinez S, Martins G, Maruyama K, Maruyama S, Marx K, Maselli A, Masengu A, Maskill A, Masumoto S, Masutani K, Matsumoto M, Matsunaga T, Matsuoka N, Matsushita M, Matthews M, Matthias S, Matvienko E, Maurer M, Maxwell P, Mayne KJ, Mazlan N, Mazlan SA, Mbuyisa A, McCafferty K, McCarroll F, McCarthy T, McClary-Wright C, McCray K, McDermott P, McDonald C, McDougall R, McHaffie E, McIntosh K, McKinley T, McLaughlin S, McLean N, McNeil L, Measor A, Meek J, Mehta A, Mehta R, Melandri M, Mené P, Meng T, Menne J, Merritt K, Merscher S, Meshykhi C, Messa P, Messinger L, Miftari N, Miller R, Miller Y, Miller-Hodges E, Minatoguchi M, Miners M, Minutolo R, Mita T, Miura Y, Miyaji M, Miyamoto S, Miyatsuka T, Miyazaki M, Miyazawa I, Mizumachi R, Mizuno M, Moffat S, Mohamad Nor FS, Mohamad Zaini SN, Mohamed Affandi FA, Mohandas C, Mohd R, Mohd Fauzi NA, Mohd Sharif NH, Mohd Yusoff Y, Moist L, Moncada A, Montasser M, Moon A, Moran C, Morgan N, Moriarty J, Morig G, Morinaga H, Morino K, Morisaki T, Morishita Y, Morlok S, Morris A, Morris F, Mostafa S, Mostefai Y, Motegi M, Motherwell N, Motta D, Mottl A, Moys R, Mozaffari S, Muir J, Mulhern J, Mulligan S, Munakata Y, Murakami C, Murakoshi M, Murawska A, Murphy K, Murphy L, Murray S, Murtagh H, Musa MA, Mushahar L, Mustafa R, Mustafar R, Muto M, Nadar E, Nagano R, Nagasawa T, Nagashima E, Nagasu H, Nagelberg S, Nair H, Nakagawa Y, Nakahara M, Nakamura J, Nakamura R, Nakamura T, Nakaoka M, Nakashima E, Nakata J, Nakata M, Nakatani S, Nakatsuka A, Nakayama Y, Nakhoul G, Nangaku M, Naverrete G, Navivala A, Nazeer I, Negrea L, Nethaji C, Newman E, Ng SYA, Ng TJ, Ngu LLS, Nimbkar T, Nishi H, Nishi M, Nishi S, Nishida Y, Nishiyama A, Niu J, Niu P, Nobili G, Nohara N, Nojima I, Nolan J, Nosseir H, Nozawa M, Nunn M, Nunokawa S, Oda M, Oe M, Oe Y, Ogane K, Ogawa W, Ogihara T, Oguchi G, Ohsugi M, Oishi K, Okada Y, Okajyo J, Okamoto S, Okamura K, Olufuwa O, Oluyombo R, Omata A, Omori Y, Ong LM, Ong YC, Onyema J, Oomatia A, Oommen A, Oremus R, Orimo Y, Ortalda V, Osaki Y, Osawa Y, Osmond Foster J, O'Sullivan A, Otani T, Othman N, Otomo S, O'Toole J, Owen L, Ozawa T, Padiyar A, Page N, Pajak S, Paliege A, Pandey A, Pandey R, Pariani H, Park J, Parrigon M, Passauer J, Patecki M, Patel M, Patel R, Patel T, Patel Z, Paul R, Paul R, Paulsen L, Pavone L, Peixoto A, Peji J, Peng BC, Peng K, Pennino L, Pereira E, Perez E, Pergola P, Pesce F, Pessolano G, Petchey W, Petr EJ, Pfab T, Phelan P, Phillips R, Phillips T, Phipps M, Piccinni G, Pickett T, Pickworth S, Piemontese M, Pinto D, Piper J, Plummer-Morgan J, Poehler D, Polese L, Poma V, Pontremoli R, Postal A, Pötz C, Power A, Pradhan N, Pradhan R, Preiss D, Preiss E, Preston K, Prib N, Price L, Provenzano C, Pugay C, Pulido R, Putz F, Qiao Y, Quartagno R, Quashie-Akponeware M, Rabara R, Rabasa-Lhoret R, Radhakrishnan D, Radley M, Raff R, Raguwaran S, Rahbari-Oskoui F, Rahman M, Rahmat K, Ramadoss S, Ramanaidu S, Ramasamy S, Ramli R, Ramli S, Ramsey T, Rankin A, Rashidi A, Raymond L, Razali WAFA, Read K, Reiner H, Reisler A, Reith C, Renner J, Rettenmaier B, Richmond L, Rijos D, Rivera R, Rivers V, Robinson H, Rocco M, Rodriguez-Bachiller I, Rodriquez R, Roesch C, Roesch J, Rogers J, Rohnstock M, Rolfsmeier S, Roman M, Romo A, Rosati A, Rosenberg S, Ross T, Rossello X, Roura 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Takai T, Takaoka M, Takeoka J, Takesada A, Takezawa M, Talbot M, Taliercio J, Talsania T, Tamori Y, Tamura R, Tamura Y, Tan CHH, Tan EZZ, Tanabe A, Tanabe K, Tanaka A, Tanaka A, Tanaka N, Tang S, Tang Z, Tanigaki K, Tarlac M, Tatsuzawa A, Tay JF, Tay LL, Taylor J, Taylor K, Taylor K, Te A, Tenbusch L, Teng KS, Terakawa A, Terry J, Tham ZD, Tholl S, Thomas G, Thong KM, Tietjen D, Timadjer A, Tindall H, Tipper S, Tobin K, Toda N, Tokuyama A, Tolibas M, Tomita A, Tomita T, Tomlinson J, Tonks L, Topf J, Topping S, Torp A, Torres A, Totaro F, Toth P, Toyonaga Y, Tripodi F, Trivedi K, Tropman E, Tschope D, Tse J, Tsuji K, Tsunekawa S, Tsunoda R, Tucky B, Tufail S, Tuffaha A, Turan E, Turner H, Turner J, Turner M, Tuttle KR, Tye YL, Tyler A, Tyler J, Uchi H, Uchida H, Uchida T, Uchida T, Udagawa T, Ueda S, Ueda Y, Ueki K, Ugni S, Ugwu E, Umeno R, Unekawa C, Uozumi K, Urquia K, Valleteau A, Valletta C, van Erp R, Vanhoy C, Varad V, Varma R, Varughese A, Vasquez P, Vasseur A, Veelken R, 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J, Wu P, Xia S, Xiao H, Xiao X, Xie Y, Xu C, Xu Y, Xue H, Yahaya H, Yalamanchili H, Yamada A, Yamada N, Yamagata K, Yamaguchi M, Yamaji Y, Yamamoto A, Yamamoto S, Yamamoto S, Yamamoto T, Yamanaka A, Yamano T, Yamanouchi Y, Yamasaki N, Yamasaki Y, Yamasaki Y, Yamashita C, Yamauchi T, Yan Q, Yanagisawa E, Yang F, Yang L, Yano S, Yao S, Yao Y, Yarlagadda S, Yasuda Y, Yiu V, Yokoyama T, Yoshida S, Yoshidome E, Yoshikawa H, Young A, Young T, Yousif V, Yu H, Yu Y, Yuasa K, Yusof N, Zalunardo N, Zander B, Zani R, Zappulo F, Zayed M, Zemann B, Zettergren P, Zhang H, Zhang L, Zhang L, Zhang N, Zhang X, Zhao J, Zhao L, Zhao S, Zhao Z, Zhong H, Zhou N, Zhou S, Zhu D, Zhu L, Zhu S, Zietz M, Zippo M, Zirino F, Zulkipli FH. Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol 2024; 12:51-60. [PMID: 38061372 DOI: 10.1016/s2213-8587(23)00322-4] [Show More Authors] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. METHODS EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. FINDINGS Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62-0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16-1·59), representing a 50% (42-58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). INTERPRETATION In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. FUNDING Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council.
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Li M, Liu Z, Yang X, Zhang J, Han M, Zhang Y, Liu Y. The effect of sodium-glucose cotransporter 2 inhibitors as an adjunct to insulin in patients with type 1 diabetes assessed by continuous glucose monitoring: A systematic review and meta-analysis. J Diabetes Complications 2023; 37:108632. [PMID: 37907042 DOI: 10.1016/j.jdiacomp.2023.108632] [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: 06/16/2023] [Revised: 10/07/2023] [Accepted: 10/19/2023] [Indexed: 11/02/2023]
Abstract
AIMS Patients undergoing insulin-based therapy for type 1 diabetes often experience poor glycemic control characterized by significant fluctuations. This study was undertaken to analyze the effect of sodium-glucose cotransporter 2 inhibitors (SGLT2Is), as an adjunct to insulin, on time in range (TIR) and glycemic variability in patients with type 1 diabetes, using continuous glucose monitoring (CGM). In addition, we examined which type of SGLT2I yielded a superior effect compared to others. METHODS We conducted a comprehensive search of PubMed, EMBASE, the Cochrane Library, Web of Science, and clinical trial registry websites, retrieving all eligible randomized clinical trials (RCTs) published up until February 2023. We analyzed the mean TIR, mean amplitude of glucose excursions (MAGE), mean daily glucose (MDG), diabetic ketoacidosis (DKA), standard deviation (SD), total insulin dose, and severe hypoglycemia to evaluate the efficacy and safety of SGLT2Is. A random-effects model was also employed. RESULTS This study encompassed 15 RCTs. The meta-analysis revealed that the use of SGLT2Is as an adjuvant therapy to insulin led to a significant increase in TIR (MD = 10.78, 95%CI = 9.33-12.23, I2 = 42 %, P < 0.00001) and a decrease in SD (MD = -0.38, 95%CI = -0.50 to -0.26, I2 = 0 %, P < 0.00001), MAGE (MD = -0.92, 95%CI = -1.17 to -0.67, I2 = 19 %, P < 0.00001), MDG(MD = -1.01, 95%CI = -1.32 to -0.70, I2 = 48 %, P < 0.00001), and total insulin dose (MD = -5.81, 95%CI = -7.81 to -3.82, I2 = 32 %, P < 0.00001). No significant increase was observed in the rate of severe hypoglycemia (RR = 1.04, 95 % CI = 0.76-1.43, P = 0.80). However, SGLT2I therapy was associated with increased DKA occurrence (RR = 2.79, 95 % CI = 1.42-5.48; P = 0.003, I2 = 16 %). In addition, the subgroup analyses based on the type of SGLT2Is revealed that dapagliflozin might exhibit greater efficacy compared to other SGLT2Is across most outcomes. CONCLUSIONS SGLT2Is exhibited a positive effect on improving blood glucose level fluctuations. Subgroup analysis showed that dapagliflozin appeared to have more advantages. However, giving due consideration to preventing adverse effects, particularly DKA, is paramount. REGISTRATION Prospero CRD42023408276.
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Affiliation(s)
- Mengnan Li
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China; First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Zi'ang Liu
- The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Xifeng Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China; First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Jiaxin Zhang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China; First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Minmin Han
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China; First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China.
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Meng Y, Wang Y, Fu W, Zhang M, Huang J, Wu H, Sun L. Global trends and focuses of GLP-1RA in renal disease: a bibliometric analysis and visualization from 2005 to 2022. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3347-3361. [PMID: 37389601 DOI: 10.1007/s00210-023-02575-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/12/2023] [Indexed: 07/01/2023]
Abstract
Glucagon-like peptide 1 receptor agonist (GLP-1RA) is a new class of glucose-lowing agents with the kidney benefit effect. This paper aims at finding the current state and hotspots of the research on GLP-1RA in kidney disease by using bibliometric methodologies and visualization maps to analyze publications and provide the direction for future studies on that topic. Literature information was obtained by retrieving the WoSCC database. Then, software like Microsoft Excel, VOSviewer, and CiteSpace was used to analyze and process obtained data. Bibliometric analysis and visualization of nations, authors, organizations, journals, keywords, and references were also done by VOSviewer and CiteSpace. A total of 991 publications written by 4747 authors from 1637 organizations in 75 countries on GLP-1RA in renal disease in Web of Science Core Collection were retrieved. The number of publications and citations kept growing from 2015 to 2022. The USA, Univ Copenhagen, and Rossing Peter are the leading country, organization, and author on this topic, respectively. All literature was published in 346 journals, and DIABETES OBESITY & METABOLISM is the journal with the most contributions. Meanwhile, most references are from DIABETES CARE. "Cardiovascular outcome" is the most frequent keyword in the total publications, and the reference cited most times is "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes" by Marso SP. The topic of GLP-1RA in renal disease has attracted more and more attention all over the world. Existing studies are mainly about clinical use in patients with diabetes, and studies on the mechanism are lacking.
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Affiliation(s)
- Yilin Meng
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yaqing Wang
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Wenjing Fu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Mingyu Zhang
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Jiayi Huang
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Haoze Wu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Li Sun
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, People's Republic of China.
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Shi Y, Bhalla V. Kidney single-cell transcriptomes uncover SGLT2i-induced metabolic reprogramming via restoring glycolysis and fatty acid oxidation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.31.564836. [PMID: 37961186 PMCID: PMC10634955 DOI: 10.1101/2023.10.31.564836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Approximately 40% of individuals with chronic kidney disease have type 2 diabetes mellitus, and diabetic kidney disease is the leading cause of end-stage kidney disease worldwide. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been demonstrated to be effective in glucose control, improving cardiovascular outcomes and the progression of kidney disease. However, the protective role of SGLT2 inhibition on kidney metabolism is not fully understood. To explore these mechanisms further, we conducted analysis of publicly available single-cell RNA sequencing data of db/db mice treated with an SGLT2 inhibitor(dapagliflozin) and accompanying controls. We found that proximal tubule cells exhibited impaired glycolysis and high fatty acid oxidation in diabetes compared with control mice. SGLT2 inhibition reversed this metabolic dysfunction by reducing glycolysis and its substrate accumulation. SGLT2 inhibition also upregulates high fatty oxidation without increasing the uptake of fatty acids and elongation, along with low lipotoxicity. Surprisingly, both SGLT2(+) and SGLT2(-) cells show gene consistent changes in expression of metabolic genes, consistent with a non-cell autonomous effect of dapagliflozin treatment. This study demonstrates the protective role of SGLT2 inhibition via restoring metabolic dysfunction.
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Martínez-Hernández SL, Muñoz-Ortega MH, Ávila-Blanco ME, Medina-Pizaño MY, Ventura-Juárez J. Novel Approaches in Chronic Renal Failure without Renal Replacement Therapy: A Review. Biomedicines 2023; 11:2828. [PMID: 37893201 PMCID: PMC10604533 DOI: 10.3390/biomedicines11102828] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/28/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Chronic kidney disease (CKD) is characterized by renal parenchymal damage leading to a reduction in the glomerular filtration rate. The inflammatory response plays a pivotal role in the tissue damage contributing to renal failure. Current therapeutic options encompass dietary control, mineral salt regulation, and management of blood pressure, blood glucose, and fatty acid levels. However, they do not effectively halt the progression of renal damage. This review critically examines novel therapeutic avenues aimed at ameliorating inflammation, mitigating extracellular matrix accumulation, and fostering renal tissue regeneration in the context of CKD. Understanding the mechanisms sustaining a proinflammatory and profibrotic state may offer the potential for targeted pharmacological interventions. This, in turn, could pave the way for combination therapies capable of reversing renal damage in CKD. The non-replacement phase of CKD currently faces a dearth of efficacious therapeutic options. Future directions encompass exploring vaptans as diuretics to inhibit water absorption, investigating antifibrotic agents, antioxidants, and exploring regenerative treatment modalities, such as stem cell therapy and novel probiotics. Moreover, this review identifies pharmaceutical agents capable of mitigating renal parenchymal damage attributed to CKD, targeting molecular-level signaling pathways (TGF-β, Smad, and Nrf2) that predominate in the inflammatory processes of renal fibrogenic cells.
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Affiliation(s)
- Sandra Luz Martínez-Hernández
- Departamento de Microbiología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes 20100, Ags, Mexico
| | - Martín Humberto Muñoz-Ortega
- Departamento de Química, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes 20100, Ags, Mexico
| | - Manuel Enrique Ávila-Blanco
- Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes 20100, Ags, Mexico
| | - Mariana Yazmin Medina-Pizaño
- Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes 20100, Ags, Mexico
| | - Javier Ventura-Juárez
- Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes 20100, Ags, Mexico
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Saha S, Fang X, Green CD, Das A. mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy. Int J Mol Sci 2023; 24:15078. [PMID: 37894760 PMCID: PMC10606418 DOI: 10.3390/ijms242015078] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023] Open
Abstract
Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.
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Affiliation(s)
- Sumit Saha
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Xianjun Fang
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Christopher D. Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; (S.S.); (X.F.); (C.D.G.)
| | - Anindita Das
- Division of Cardiology, Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
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Mahato A, Jain A, Prakash V, Nair R, Joshi R, Paliwal D, Tiwari A, Khandpur S, Singh H. Use of Oral Empagliflozin to Obtain Optimal Blood Sugar Levels for Conducting 18 F-FDG PET-CT in Patients with Hyperglycemia-A Pilot Study. World J Nucl Med 2023; 22:191-195. [PMID: 37854083 PMCID: PMC10581752 DOI: 10.1055/s-0043-1771283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2023] Open
Abstract
Background Flourine-18 fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET-CT) is a well-established imaging modality for the evaluation of patients with oncological and nononcological conditions. The underlying principle of imaging is the preferentially increased glucose consumption by cancer cells, due to overexpression of glucose type 1 receptors that are insulin independent. Thus, one of the factors that leads to decreased sensitivity of an 18 F-FDG PET-CT is elevated blood sugar levels, leading to decreased glucose uptake by cancer cells due to competitive inhibition. A significant percentage of patients scheduled for PET-CT scan has diabetes mellitus type II as a comorbid condition and often has elevated random blood sugar (RBS) precluding an upfront PET-CT evaluation. Such cases must be rescheduled. This causes delay in the evaluation and management of such patients. Empagliflozin is a novel sodium glucose type 2 inhibitor that prevents tubular reabsorption of glucose and increases renal glycosuria resulting in decreased blood sugar. This drug does not cause significant hypoglycemia or increase endogenous insulin secretion. This study was undertaken to evaluate a potential role for empagliflozin in facilitating optimal blood sugar control in patients with hyperglycemia on the day of the scheduled PET scan. Methods This is an interventional prospective study and patients detected to have RBS more than 200 mg/dL on the day of the scheduled scan were included in the study. The patients were administered two tablets of 10 mg empagliflozin and kept under observation. Samples for RBS were taken at approximately 2nd and 4th hour post administration by bedside method. These patients underwent scan on the same day after adequate sugar control and when an RBS of less than 200 mg/dL was achieved. The primary outcome studied was change in RBS values in the patient cohort and evaluation of PET SUV (standardized uptake value) compared with the rest of the patients scheduled on the same day. Secondary outcome was assessment of any side effects in the patients. Results Total of 10 patients were found to have elevated blood sugar (RBS > 200 mg/dL; irrespective of being on medication) and did not meet the evaluation criteria for a PET-CT scan on the scheduled day. Following administration of the drug, all 10 patients were able to attain blood sugar levels and fulfill the criteria for undergoing a PET-CT scan. No obvious side effect was noted in any of the patient. The SUV values of the patient cohort were comparable with the rest of the patient scanned on the day. Conclusion In this pilot study, 20 mg of empagliflozin (2 tablets of 10 mg) appears to be a safe and effective method for achieving optimal decrease in the RBS without causing hypoglycemia or hyperinsulinemia. It can be safely employed in the subset of population with RBS between 201 and 300 mg/dL to adequately bring the sugar levels at acceptable levels RBS less than 200 mg/dl and fulfill the FDG PET-CT criteria as per European Association of Nuclear Medicine (EANM) norms.
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Affiliation(s)
- Abhishek Mahato
- Department of Nuclear Medicine, Command Hospital, Lucknow, Uttar Pradesh, India
| | - Anurag Jain
- Department of Nuclear Medicine, Command Hospital, Lucknow, Uttar Pradesh, India
| | - V.S Prakash
- Department of Medical Oncology, Command Hospital, Lucknow, Uttar Pradesh, India
| | - Rajesh Nair
- Department of Medical Oncology, Command Hospital, Lucknow, Uttar Pradesh, India
| | - Richa Joshi
- Department of Surgical Oncology, Command Hospital, Lucknow, Uttar Pradesh, India
| | - Dharmesh Paliwal
- Department of Nuclear Medicine, Command Hospital, Pune, Maharashtra, India
| | - Awadhesh Tiwari
- Department of Nuclear Medicine, Command Hospital, Lucknow, Uttar Pradesh, India
| | - Sukhanshi Khandpur
- Department of Biostatistics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGI), Lucknow, Uttar Pradesh, India
| | - Harkirat Singh
- Department of Nuclear Medicine, Command Hospital, Lucknow, Uttar Pradesh, India
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Tommerdahl KL, Kula AJ, Bjornstad P. Pharmacological management of youth with type 2 diabetes and diabetic kidney disease: a comprehensive review of current treatments and future directions. Expert Opin Pharmacother 2023; 24:913-924. [PMID: 37071054 PMCID: PMC10198950 DOI: 10.1080/14656566.2023.2203319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 04/12/2023] [Indexed: 04/19/2023]
Abstract
INTRODUCTION Diabetic kidney disease (DKD) is a leading cause of mortality in people with type 2 diabetes (T2D), and over 50% of individuals with youth-onset T2D will develop DKD as a young adult. Diagnosis of early-onset DKD remains a challenge in young persons with T2D secondary to a lack of available biomarkers for early DKD, while the injuries may still be reversible. Furthermore, multiple barriers exist to initiate timely prevention and treatment strategies for DKD, including a lack of Food and Drug Administration approval of medications in pediatrics; provider comfort with medication prescription, titration, and monitoring; and medication adherence. AREAS COVERED Therapies that have promise for slowing DKD progression in youth with T2D include metformin, renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide-1 receptor agonists, sodium glucose co-transporter 2 inhibitors, thiazolidinediones, sulfonylureas, endothelin receptor agonists, and mineralocorticoid antagonists. Novel agents are also in development to act synergistically on the kidneys with the aforementioned medications. We comprehensively review the available pharmacologic strategies for DKD in youth-onset T2D including mechanisms of action, potential adverse effects, and kidney-specific effects, with an emphasis on published pediatric and adult trials. EXPERT OPINION Large clinical trials evaluating pharmacologic interventions targeting the treatment of DKD in youth-onset T2D are strongly needed.
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Affiliation(s)
- Kalie L. Tommerdahl
- Department of Pediatrics, Section of Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
- Ludeman Family Center for Women’s Health Research, Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alexander J. Kula
- Department of Pediatrics, Section of Pediatric Nephrology, Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Petter Bjornstad
- Department of Pediatrics, Section of Pediatric Endocrinology, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Ludeman Family Center for Women’s Health Research, Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Verissimo T, Dalga D, Arnoux G, Sakhi I, Faivre A, Auwerx H, Bourgeois S, Paolucci D, Gex Q, Rutkowski JM, Legouis D, Wagner CA, Hall AM, de Seigneux S. PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells. Am J Physiol Renal Physiol 2023; 324:F532-F543. [PMID: 37102687 PMCID: PMC10202477 DOI: 10.1152/ajprenal.00038.2023] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/28/2023] [Accepted: 04/12/2023] [Indexed: 04/28/2023] Open
Abstract
Phosphoenolpyruvate carboxykinase 1 (PCK1 or PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis, and cataplerosis in the liver. Kidney proximal tubule cells display high expression of this enzyme, whose importance is currently not well defined. We generated PCK1 kidney-specific knockout and knockin mice under the tubular cell-specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal conditions and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia, and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1-deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule, and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigation of PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid-base control, mitochondrial function, and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function.NEW & NOTEWORTHY Phosphoenolpyruvate carboxykinase 1 (PCK1) is highly expressed in the proximal tubule. We show here that this enzyme is crucial for the maintenance of normal tubular physiology, lactate, and glucose homeostasis. PCK1 is a regulator of acid-base balance and ammoniagenesis. Preventing PCK1 downregulation during renal injury improves renal function, rendering it an important target during renal disease.
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Affiliation(s)
- Thomas Verissimo
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
- Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland
| | - Delal Dalga
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
- Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland
| | - Grégoire Arnoux
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Imene Sakhi
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Anna Faivre
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Hannah Auwerx
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Soline Bourgeois
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Deborah Paolucci
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Quentin Gex
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | | | - David Legouis
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
- Division of Intensive Care, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Andrew M Hall
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Sophie de Seigneux
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
- Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland
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Li M, Zhang J, Yang G, Zhang J, Han M, Zhang Y, Liu Y. Effects of sodium-glucose cotransporter 2 inhibitors on renal risk factors in patients with abnormal glucose metabolism: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol 2023; 79:859-871. [PMID: 37097298 DOI: 10.1007/s00228-023-03490-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 03/28/2023] [Indexed: 04/26/2023]
Abstract
AIMS Several trials have assessed the antihyperglycemic effects of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) in patients with type 2 diabetes mellitus (T2DM). We conducted a quantitative analysis to assess the effects of SGLT2Is on renal risk factors in patients with abnormal glucose metabolism. MATERIALS AND METHODS Randomized controlled trials (RCTs) were identified by searching the PubMed, Embase, Scopus, and Web of Science databases published before September 30, 2022. The intervention group received SGLT2Is as monotherapy or add-on treatment, and the control group received placebos, standard care, or active control. Risk of bias assessment was performed using the Cochrane risk of bias assessment tool. Meta-analysis was performed on studies with abnormal glucose metabolism populations and studies using the weighted mean differences (WMDs) as the measure of the effect size. Clinical trials providing changes in serum uric acid (SUA) were included. The mean change of SUA, glycated hemoglobin (HbA1c), body mass index (BMI), and estimated glomerular filtration rate (eGFR) were calculated. RESULTS After a literature search and detailed evaluation, a total of 11 RCTs were included for quantitative analysis to analyze the differences between the SGLT2I group and the control group. The results showed that SGLT2I significantly reduced SUA (MD = -0.56, 95% CI = -0.66 ~ -0.46, I2 = 0%, P < 0.00001), HbA1c (MD = -0.20, 95% CI = -0.26 ~ -0.13, I2 = 0%, P < 0.00001), and BMI (MD = -1.19, 95% CI = -1.84 ~ -0.55, I2 = 0%, P = 0.0003). There was no significant difference in the reduction of eGFR observed in the SGLT2I group (MD = -1.60, 95% CI = -3.82 ~ 0.63, I2 = 13%, P = 0.16). CONCLUSIONS These results showed that the SGLT2I group caused greater reductions in SUA, HbA1c, and BMI but had no effect on eGFR. These data suggested that SGLT2Is may have numerous potentially beneficial clinical effects in patients with abnormal glucose metabolism. However, these results need to be consolidated by further studies.
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Affiliation(s)
- Mengnan Li
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Jian Zhang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Guimei Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Jiaxin Zhang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Minmin Han
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China.
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Theofilis P, Oikonomou E, Tsioufis K, Tousoulis D. Diabetes Mellitus and Heart Failure: Epidemiology, Pathophysiologic Mechanisms, and the Role of SGLT2 Inhibitors. Life (Basel) 2023; 13:497. [PMID: 36836854 PMCID: PMC9968235 DOI: 10.3390/life13020497] [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: 01/15/2023] [Revised: 02/04/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
Diabetes mellitus (DM) and heart failure (HF) are frequently encountered afflictions that are linked by a common pathophysiologic background. According to landmark studies, those conditions frequently coexist, and this interaction represents a poor prognostic indicator. Based on mechanistic studies, HF can be propagated by multiple pathophysiologic pathways, such as inflammation, oxidative stress, endothelial dysfunction, fibrosis, cardiac autonomic neuropathy, and alterations in substrate utilization. In this regard, DM may augment myocardial inflammation, fibrosis, autonomic dysfunction, and lipotoxicity. As the interaction between DM and HF appears critical, the new cornerstone in DM and HF treatment, sodium-glucose cotransporter-2 inhibitors (SGLT2i), may be able to revert the pathophysiology of those conditions and lead to beneficial HF outcomes. In this review, we aim to highlight the deleterious pathophysiologic interaction between DM and HF, as well as demonstrate the beneficial role of SGLT2i in this field.
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Affiliation(s)
- Panagiotis Theofilis
- Department of Cardiology, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Evangelos Oikonomou
- Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
| | - Konstantinos Tsioufis
- Department of Cardiology, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Dimitris Tousoulis
- Department of Cardiology, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
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21
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SGLT2 Inhibitors in Diabetic and Non-Diabetic Chronic Kidney Disease. Biomedicines 2023; 11:biomedicines11020279. [PMID: 36830815 PMCID: PMC9953060 DOI: 10.3390/biomedicines11020279] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/20/2023] Open
Abstract
Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to independently protect from cardiovascular events and to reduce the progression of chronic kidney disease (CKD) in these patients. The magnitude of the nephroprotective effect observed in these studies is likely to make SGLT2 inhibitors the most impactful drug class for the treatment of diabetic patients with CKD since the discovery of renin-angiotensin system inhibitors. Even more surprisingly, SGLT2 inhibitors have also been shown to slow CKD progression in non-diabetic individuals with varying degrees of proteinuria, suggesting that activation of SGLT2 is involved in the pathogenesis of CKD independent of its etiology. As indications continue to expand, it is still unclear whether the observed benefits of SGLT2 inhibitors may extend to CKD patients at lower risk of progression and if their association with other agents may confer additional protection.
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22
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Tang X, Xiao B, Zhao Q, Hu W, McKenery A, Zhong Z. Renal glucose transporters play a role in removal of cadmium from kidney cells mediated by GMDTC - A novel metal chelator. Hum Exp Toxicol 2023; 42:9603271231183056. [PMID: 37295442 DOI: 10.1177/09603271231183056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Cadmium (Cd) is a toxic heavy metal, exposure to which leads to adverse health effects including chronic kidney damage. Tremendous efforts have been explored in identifying safe chelating agents for removing accumulated Cd from kidney, but with limited success owing to their associated side effects and the ineffectiveness in eliminating Cd. A newly developed chelating agent, sodium (S)-2-(dithiocarboxylato((2S,3 R,4R,5 R)-2,3,4,5,6-pentahydroxyhexyl) amino)-4(methylthio)butanoate (GMDTC), has been shown to effectively mobilize Cd from kidney. However, the mechanism(s) of removal are unclear, while it has been hypothesized that renal glucose transporters potentially play key roles mainly because GMDTC contains an open chain glucose moiety. To test this hypothesis, we utilized the CRISPR/Cas9 technology and human kidney tubule HK-2 cells, and constructed sodium-dependent glucose transporter 2 (SGLT2) or glucose transporter 2 (GLUT2) gene knockout cell lines. Our data showed that GMDTC's ability in removing Cd from HK-2 cells was significantly reduced both in GLUT2-/- or SGLT2-/- cells, with a removal ratio reduced from 28.28% in the parental HK-2 cells to 7.37% in GLUT2-/- cells and 14.6% in SGLT2-/- cells. Similarly, knocking out the GLUT2 or SGLT2 led to a compromised protective effect of GMDTC in reducing cytotoxicity of HK-2 cells. This observation was further observed in animal studies, in which the inhibition of GLUT2 transporter by phloretin treatment resulted in reduced efficiency of GMDTC in removing Cd from the kidney. Altogether, our results show that GMDTC is safe and highly efficient in removing Cd from the cells, and this effect is mediated by renal glucose transporters.
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Affiliation(s)
- Xiaojiang Tang
- School of Public Health, Southern Medical University, Guangzhou, China
- Jianersheng (Zhuhai) Pharmtech Co., Ltd., Zhuhai, China
| | - Bo Xiao
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Qile Zhao
- School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Wei Hu
- Jianersheng (Zhuhai) Pharmtech Co., Ltd., Zhuhai, China
- Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, China
| | - Amber McKenery
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Zhiyong Zhong
- Jianersheng (Zhuhai) Pharmtech Co., Ltd., Zhuhai, China
- Guangdong e-fang Pharmaceutical Co., Ltd., Foshan, China
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Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Siasos G, Tsioufis K, Tousoulis D. The Anti-Inflammatory Effect of Novel Antidiabetic Agents. Life (Basel) 2022; 12:1829. [PMID: 36362984 PMCID: PMC9696750 DOI: 10.3390/life12111829] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/28/2022] [Accepted: 11/05/2022] [Indexed: 08/10/2023] Open
Abstract
The incidence of type 2 diabetes (T2DM) has been increasing worldwide and remains one of the leading causes of atherosclerotic disease. Several antidiabetic agents have been introduced in trying to regulate glucose control levels with different mechanisms of action. These agents, and sodium-glucose cotransporter-2 inhibitors in particular, have been endorsed by contemporary guidelines in patients with or without T2DM. Their widespread usage during the last three decades has raised awareness in the scientific community concerning their pleiotropic mechanisms of action, including their putative anti-inflammatory effect. In this review, we delve into the anti-inflammatory role and mechanism of the existing antidiabetic agents in the cardiovascular system and their potential use in other chronic sterile inflammatory conditions.
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Affiliation(s)
- Panagiotis Theofilis
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Marios Sagris
- 3rd Cardiology Department, Thoracic Diseases Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
| | - Evangelos Oikonomou
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
- 3rd Cardiology Department, Thoracic Diseases Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
| | - Alexios S. Antonopoulos
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Gerasimos Siasos
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
- 3rd Cardiology Department, Thoracic Diseases Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
| | - Kostas Tsioufis
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Dimitris Tousoulis
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
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Gong C, Shen SC, Zhang K, Zhou L, Shen JJ, Zhao JY, Ding SG, Ma LK, Gao H. Association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcome and safety events: A meta-analysis of randomized controlled clinical trials. Front Cardiovasc Med 2022; 9:926979. [PMID: 36312269 PMCID: PMC9613919 DOI: 10.3389/fcvm.2022.926979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/28/2022] [Indexed: 11/22/2022] Open
Abstract
Background The clinical benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for preventing and treating cardiovascular events remains controversial. We aimed to study the effect of SGLT2 inhibitors on cardiovascular outcomes and safety events, giving particular attention to the benefits in subgroups of patients with different diseases. Method Randomized controlled trials (RCTs) reporting cardiovascular outcomes following the administration of SGLT2 inhibitors and placebo were included in this study. Cardiovascular outcomes included all-cause death, major adverse cardiovascular events (MACEs), cardiovascular (CV) death, myocardial infarction (MI), stroke, and hospitalization for heart failure (HHF). We also focused on the cardiovascular benefits of SGLT2 inhibitor application in subgroups of patients with different diseases, including type 2 diabetes (T2D), heart failure (HF), high risk of atherosclerotic cardiovascular disease (ACD), diagnosed ACD, and chronic kidney disease (CKD). Safety events associated with SGLT2 inhibitors, including acute kidney injury (AKI), diabetic ketoacidosis (DKA), hypoglycemia, urinary tract infection, thromboembolic event, bone fracture, volume depletion, and amputation, were also reported. Results This meta-analysis included 15 RCTs with 78,212 participants. SGLT2 inhibitors reduced the risk of all-cause death (RR 0.89; 95% CI: 0.85-0.94; I2 = 32%; p < 0.01), CV death (RR 0.87; 95% CI: 0.82-0.93; I2 = 11%; p < 0.01), MACEs (RR 0.89; 95% CI: 0.84-0.94; I2 = 46%; p < 0.01), HHF (RR 0.70; 95% CI: 0.66-0.74; I2 = 0%; p < 0.01), and AKI (RR 0.81; 95% CI: 0.73-0.90; I2 = 0%; p < 0.01) but increased the risk of DKA (RR 2.56; 95% CI: 1.72-3.80; I2 = 0%; p < 0.01). However, no apparent benefit in MI and stroke was observed between the SGLT2 inhibitor and control groups. SGLT2 inhibitors reduced the risk of all-cause death, MACEs, CV death, and HHF in diabetic patients; reduced the risk of all-cause death, MACEs, CV death, MI, and HHF in primary prevention; reduced the risk of all-cause death, CV death, and HHF in patients with ACD and HF; and reduced the risk of MACEs, CV death, and HHF in patients with CKD. Conclusion SGLT2 inhibitors have a positive effect in reducing the risk of all-cause death, CV death, MACE, HHF, and AKI and increasing the risk of DKA. The application of SGLT2 inhibitors in the primary prevention of ACD also has certain clinical benefits in reducing MI. Systematic review registration [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022306490].
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Affiliation(s)
- Chen Gong
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shi-Chun Shen
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ke Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lei Zhou
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jun-Jie Shen
- Second School of Clinical Medicine of Anhui Medical University, Hefei, China
| | - Jia-Ying Zhao
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Sheng-Gang Ding
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li-kun Ma
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hui Gao
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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25
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Kula AJ. Considerations and possibilities for sodium-glucose cotransporter 2 inhibitors in pediatric CKD. Pediatr Nephrol 2022; 37:2267-2276. [PMID: 35088160 DOI: 10.1007/s00467-022-05456-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 10/19/2022]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were originally developed as glucose-lowering agents. These medications function by inhibiting glucose and sodium reabsorption in the S1 segment of the proximal tubule. Early clinical trials in adults with type 2 diabetes mellitus (T2DM) suggested a significant improvement in kidney and cardiovascular outcomes with SGLT2i therapy. Since then, SGLT2is have become a mainstay treatment for adult patients with CKD. A growing body of research has explored deploying these medications in new clinical contexts and investigated the mechanisms underlying their physiologic effects. However, patients under the age of 18 years have been largely excluded from all major trials of SGLT2i. This review aims to summarize the available clinical evidence, physiology, and mechanisms relating to SGLT2is to inform discussions about their implementation in pediatrics.
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Affiliation(s)
- Alexander J Kula
- Division of Pediatric Nephrology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. .,Division of Pediatric Nephrology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 Chicago Ave., IL, Chicago, USA.
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26
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Li J, Zhou L, Gong H. New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure. Front Cardiovasc Med 2022; 9:903902. [PMID: 36186974 PMCID: PMC9520058 DOI: 10.3389/fcvm.2022.903902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are newly emerging insulin-independent anti-hyperglycemic agents that work independently of β-cells. Quite a few large-scale clinical trials have proven the cardiovascular protective function of SGLT2is in both diabetic and non-diabetic patients. By searching all relevant terms related to our topics over the previous 3 years, including all the names of agents and their brands in PubMed, here we review the mechanisms underlying the improvement of heart failure. We also discuss the interaction of various mechanisms proposed by diverse works of literature, including corresponding and opposing viewpoints to support each subtopic. The regulation of diuresis, sodium excretion, weight loss, better blood pressure control, stimulation of hematocrit and erythropoietin, metabolism remodeling, protection from structural dysregulation, and other potential mechanisms of SGLT2i contributing to heart failure improvement have all been discussed in this manuscript. Although some remain debatable or even contradictory, those newly emerging agents hold great promise for the future in cardiology-related therapies, and more research needs to be conducted to confirm their functionality, particularly in metabolism, Na+-H+ exchange protein, and myeloid angiogenic cells.
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Affiliation(s)
- Juexing Li
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Zhou
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Gong
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Hui Gong
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Schmidt H, Schlitt A. [Hypoglycemia in a patient treated with a SGLT2-inhibitor with HFrEF without diabetes mellitus]. Dtsch Med Wochenschr 2022; 147:1195-1198. [PMID: 36070737 DOI: 10.1055/a-1892-4104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
ANAMNESE HFrEF (heart failure with reduced ejection fraction) with a left ventricular ejection fraction of 25-30 % was detected in a 79-year-old man. For further treatment, inpatient cardiac rehabilitation war carried out. CLINICAL FINDINGS At the start of the cardiac rehabilitation, patient complained of shortness of breath with little exertion, corresponding to NYHA III. Drug therapy included empagliflozin 10 mg, sacubitril/valsartan 24/26 mg, edoxaban 60 mg, torasemide 5 mg, verapamil 80 mg and amiodarone 200 mg. INVESTIGATIONS The daily blood sugar profile showed hypoglycemia with values < 3.7 mmol/l (< 67 mg/dl). After consultation with the patient, these occurred with normal food intake and were symptomatic in form of dizziness during the period of hypoglycaemia. DIAGNOSIS Symptomatic hypoglycaemia on SGLT2(sodium-glucose linked transporter 2)-inhibitor therapy in a patient with HFrEF without diabetes mellitus. THERAPY AND PROGRESS The therapy with empaglifozin was stopped and a new daily blood sugar profile was carried out, which no longer showed any hypoglycaemic values. CONCLUSION The presented case raises awareness of the side effect of hypoglycaemia, which occurs very rarely with SGLT2 inhibitors in studies in patients with HFrEF without the presence of diabetes mellitus.
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Affiliation(s)
- Hendrik Schmidt
- Klinik für Kardiologie und Diabetologie, Klinikum Magdeburg.,Medizinische Fakultät der Martin-Luther-Universität Halle-Wittenberg
| | - Axel Schlitt
- Medizinische Fakultät der Martin-Luther-Universität Halle-Wittenberg.,Abteilung für Kardiologie und Diabetologie, Paracelsus-Harz-Klinik Bad Suderode
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Molecular Mechanisms of Acute Organophosphate Nephrotoxicity. Int J Mol Sci 2022; 23:ijms23168855. [PMID: 36012118 PMCID: PMC9407954 DOI: 10.3390/ijms23168855] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 11/29/2022] Open
Abstract
Organophosphates (OPs) are toxic chemicals produced by an esterification process and some other routes. They are the main components of herbicides, pesticides, and insecticides and are also widely used in the production of plastics and solvents. Acute or chronic exposure to OPs can manifest in various levels of toxicity to humans, animals, plants, and insects. OPs containing insecticides were widely used in many countries during the 20th century, and some of them continue to be used today. In particular, 36 OPs have been registered in the USA, and all of them have the potential to cause acute and sub-acute toxicity. Renal damage and impairment of kidney function after exposure to OPs, accompanied by the development of clinical manifestations of poisoning back in the early 1990s of the last century, was considered a rare manifestation of their toxicity. However, since the beginning of the 21st century, nephrotoxicity of OPs as a manifestation of delayed toxicity is the subject of greater attention of researchers. In this article, we present a modern view on the molecular pathophysiological mechanisms of acute nephrotoxicity of organophosphate compounds.
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Höcht C, Allo MA, Polizio AH, Morettón MA, Carranza A, Chiappetta DA, Choi MR. New and developing pharmacotherapies for hypertension. Expert Rev Cardiovasc Ther 2022; 20:647-666. [PMID: 35880547 DOI: 10.1080/14779072.2022.2105204] [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: 04/04/2022] [Accepted: 07/20/2022] [Indexed: 10/16/2022]
Abstract
INTRODUCTION Despite the significant contribution of hypertension to the global burden of disease, disease control remains poor worldwide. Considering this unmet clinical need, several new antihypertensive drugs with novel mechanisms of action are under development. AREAS COVERED The present review summarizes the recent advances in the development of emerging pharmacological agents for the management of hypertension. The latest technological innovations in the design of optimized formulations of available antihypertensive drugs and the potential role of the modification of intestinal microbiota to improve blood pressure (BP) control are also covered. EXPERT OPINION Significant efforts have been made to develop new antihypertensive agents with novel actions that target the main mechanisms involved in resistant hypertension. Sacubitril/valsartan may emerge as a potential first-line drug due to its superiority over renin angiotensin system inhibitors, and SGLT2 inhibitors can reduce BP in difficult-to-control hypertensive patients with type 2 diabetes. In addition, firibastat and aprocitentan may expand the therapeutic options for resistant hypertension by novel mechanism of actions. Since gut dysbiosis not only leads to hypertension but also causes direct target organ damage, prebiotics and probiotics could represent a potential strategy to prevent or reduce the development of hypertension and to contribute to BP control.
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Affiliation(s)
- Christian Höcht
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Buenos Aires, Argentinaa
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentinab
| | - Miguel A Allo
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Buenos Aires, Argentinaa
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentinab
| | - Ariel Héctor Polizio
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Buenos Aires, Argentinaa
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentinab
| | - Marcela A Morettón
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentinab
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentinac
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
| | - Andrea Carranza
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Buenos Aires, Argentinaa
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentinae
| | - Diego A Chiappetta
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentinab
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentinac
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
| | - Marcelo Roberto Choi
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentinae
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Buenos Aires, Argentina f
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Krittayaphong R, Permsuwan U. Cost-Utility Analysis of Combination Empagliflozin and Standard Treatment Versus Standard Treatment Alone in Thai Heart Failure Patients with Reduced or Preserved Ejection Fraction. Am J Cardiovasc Drugs 2022; 22:577-590. [PMID: 35796952 DOI: 10.1007/s40256-022-00542-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/03/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Clinical trials reported the benefit of empagliflozin when combined with standard treatment relative to cardiovascular death or heart failure (HF) hospitalization in patients with heart failure with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). We conducted a cost-utility analysis of combination empagliflozin and standard treatment (ST) versus ST alone in Thai HF patients with HFrEF or HFpEF. METHODS A Markov model was employed to capture lifetime direct medical costs and outcomes from a healthcare system perspective. Two cohorts (HFrEF and HFpEF) with an average age of 60 years were enrolled. The clinical inputs were the results of the EMPEROR-Reduced and EMPEROR-Preserved studies, and a Thai database. Costs were gathered from published studies or from a Thai hospital database. Utilities were obtained from published studies. All costs and outcomes were discounted at a rate of 3% per annum. Incremental cost-effectiveness ratios (ICERs) were estimated, and sensitivity analyses were performed. RESULTS In patients with HFrEF, add-on empagliflozin yielded a life-year gain of 0.26, and a quality-adjusted life-year (QALY) gain of 0.20 at an increased total cost of 409.82 USD compared to ST alone [ICER: 69,218 THB/QALY (2064.98 USD/QALY gained)]. Among HFpEF patients, add-on empagliflozin yielded a life-year gain of 0.07, and a QALY gain of 0.05 at an increased total cost of 622.49 USD compared to ST alone [ICER: 395,826 THB/QALY (11,809 USD/QALY gained)]. CONCLUSIONS At the local Thai threshold of 4773.27 USD/QALY, empagliflozin is a cost-effective add-on treatment for patients with HFrEF, but not for patients with HFpEF.
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Affiliation(s)
- Rungroj Krittayaphong
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Unchalee Permsuwan
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand. .,Center for Medical and Health Technology Assessment, Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand.
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The Efficacy and Safety of SGLT2 Inhibitor in Diabetic Kidney Transplant Recipients. Transplantation 2022; 106:e404-e412. [PMID: 35768908 DOI: 10.1097/tp.0000000000004228] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND The efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been investigated in kidney transplant recipients (KTRs) with diabetes. We evaluated the impact of SGLT2i in a multicenter cohort of diabetic KTRs. METHODS A total of 2083 KTRs with diabetes were enrolled from 6 transplant centers in Korea. Among them, 226 (10.8%) patients were prescribed SGLT2i for >90 d. The primary outcome was a composite outcome of all-cause mortality, death-censored graft failure (DCGF), and serum creatinine doubling. An acute dip in estimated glomerular filtration rate (eGFR) over 10% was surveyed after SGLT2i use. RESULTS During the mean follow-up of 62.9 ± 42.2 mo, the SGLT2i group had a lower risk of primary composite outcome than the control group in the multivariate and propensity score-matched models (adjusted hazard ratio, 0.43; 95% confidence interval, 0.24-0.78; P = 0.006 and adjusted hazard ratio, 0.45; 95% confidence interval, 0.24-0.85; P = 0.013, respectively). Multivariate analyses consistently showed a decreased risk of DCGF and serum creatinine doubling in the SGLT2i group. The overall eGFR remained stable without the initial dip after SGLT2i use. A minority (15.6%) of the SGLT2i users showed acute eGFR dip during the first month, but the eGFR recovered thereafter. The risk factors for the eGFR dip were time from transplantation to SGLT2i usage and mean tacrolimus trough level. CONCLUSIONS SGLT2i improved a composite of all-cause mortality, DCGF, or serum creatinine doubling in KTRs. SGLT2i can be used safely and have beneficial effects on preserving graft function in diabetic KTRs.
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Wu K, Fei L, Wang X, Lei Y, Liu Y, Xu W, Chen J, Zhu E, Zhong M, Huang M, Jiang X, Yin F, Yan Z, Zhao X, Tang C, Patzak A, Liu X, Zheng Z. ZIP14 is involved in iron deposition and triggers ferroptosis in diabetic nephropathy. Metallomics 2022; 14:6596292. [PMID: 35641158 DOI: 10.1093/mtomcs/mfac034] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 05/25/2022] [Indexed: 11/12/2022]
Abstract
Ferroptosis is caused by lipid peroxidation and iron accumulation and can cause cell death. Abnormally expressed iron transporters are involved in ferroptosis in a variety of diseases. ZRT/IRT-like protein 14 (ZIP14) is a transport protein that can mediate cellular uptake of iron, zinc and manganese. Herein, we have tested the hypothesis that the divalent metal transporter ZIP14 is involved in the initiation of ferroptosis in diabetic nephropathy (DN). DN was induced in eight-week old male rats by streptozotocin (STZ) before analysis of the degree of renal tubular injury. In addition, an in vitro model of DN in HK2 cells was used. We showed that ZIP14 was upregulated and Fe2+ levels increased both in vivo and in vitro. Expression of glutathione peroxidase 4 (GPX4) and the level of glutathione (GSH) were reduced, whereas that of malondialdehyde (MDA) increased. Ferrostatin-1(Fer-1) treatment reduced the expression of ZIP14 and the levels of Fe2+ and MDA, which is consistent with ferroptosis. Fer-1 improved kidney function in DN rats. This was characterized by urine levels of protein-to-creatinine ratio, α 1-microglobulin and N-acetyl-β-D-glucosaminidase. Our study demonstrates a novel role for ZIP14 in diabetic kidney injury mediated by ferroptosis, and suggests a potential new therapeutic approach for the treatment of diabetic nephropathy.
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Affiliation(s)
- Keping Wu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lingyan Fei
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Institute of Translation Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin.,Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaohua Wang
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yan Lei
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yu Liu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Wenqian Xu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jiasi Chen
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Enyi Zhu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Ming Zhong
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Mingcheng Huang
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xi Jiang
- Department of Clinical Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Fei Yin
- Department of Thoracic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhijun Yan
- Department of Anesthesia, The First Affiliated Hospital of Nanhua University, Hunan, China
| | - Xinying Zhao
- Department of Hematology, Guangzhou Women and Children's Medical center, Guangzhou Medical University, Guangzhou, China
| | - Chun Tang
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Andreas Patzak
- Institute of Translation Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
| | - Xiaoping Liu
- Department of Hematology, Guangzhou Women and Children's Medical center, Guangzhou Medical University, Guangzhou, China
| | - Zhihua Zheng
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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Tang J, Ye L, Yan Q, Zhang X, Wang L. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Water and Sodium Metabolism. Front Pharmacol 2022; 13:800490. [PMID: 35281930 PMCID: PMC8905496 DOI: 10.3389/fphar.2022.800490] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 01/24/2022] [Indexed: 12/19/2022] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypoglycemic and diuretic effects by inhibiting the absorption of sodium and glucose from the proximal tubule. Currently available data indicate that SGLT2 inhibitors transiently enhance urinary sodium excretion and urinary volume. When combined with loop diuretics, SGLT2 inhibitors exert a synergistic natriuretic effect. The favorable diuretic profile of SGLT2 inhibitors may confer benefits to volume management in patients with heart failure but this natriuretic effect may not be the dominant mechanism for the superior long-term outcomes observed with these agents in patients with heart failure. The first part of this review explores the causes of transient natriuresis and the diuretic mechanisms of SGLT2 inhibitors. The second part provides an overview of the synergistic effects of combining SGLT2 inhibitors with loop diuretics, and the third part summarizes the mechanisms of cardiovascular protection associated with the diuretic effects of SGLT2 inhibitors.
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Affiliation(s)
- Jun Tang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Lifang Ye
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qiqi Yan
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xin Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Lihong Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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Abstract
The kidney maintains electrolyte, water, and acid-base balance, eliminates foreign and waste compounds, regulates blood pressure, and secretes hormones. There are at least 16 different highly specialized epithelial cell types in the mammalian kidney. The number of specialized endothelial cells, immune cells, and interstitial cell types might even be larger. The concerted interplay between different cell types is critical for kidney function. Traditionally, cells were defined by their function or microscopical morphological appearance. With the advent of new single-cell modalities such as transcriptomics, epigenetics, metabolomics, and proteomics we are entering into a new era of cell type definition. This new technological revolution provides new opportunities to classify cells in the kidney and understand their functions.
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Affiliation(s)
- Michael S Balzer
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, Philadelphia, USA
| | - Tibor Rohacs
- Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - Katalin Susztak
- Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
- Institute of Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, Philadelphia, USA
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35
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Fonseca-Correa JI, Correa-Rotter R. Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review. Front Med (Lausanne) 2022; 8:777861. [PMID: 34988095 PMCID: PMC8720766 DOI: 10.3389/fmed.2021.777861] [Citation(s) in RCA: 96] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/22/2021] [Indexed: 12/25/2022] Open
Abstract
Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.
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Affiliation(s)
- Jorge I Fonseca-Correa
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Ricardo Correa-Rotter
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Varthya S, Dutta S, Kumar T, Singh S, Ambwani S, Charan J. Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors: A systematic review and quantitative analysis. J Family Med Prim Care 2022; 11:927-940. [PMID: 35495849 PMCID: PMC9051698 DOI: 10.4103/jfmpc.jfmpc_644_21] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/15/2021] [Accepted: 07/16/2021] [Indexed: 11/04/2022] Open
Abstract
Background: Methods: Results: Conclusion:
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37
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Yang Y, Xu G. Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2022; 13:872918. [PMID: 35663316 PMCID: PMC9161673 DOI: 10.3389/fendo.2022.872918] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium-glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin-angiotensin-aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.
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38
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Sobolev VE, Sokolova MO, Jenkins RO, Goncharov NV. Nephrotoxic Effects of Paraoxon in Three Rat Models of Acute Intoxication. Int J Mol Sci 2021; 22:13625. [PMID: 34948422 PMCID: PMC8709234 DOI: 10.3390/ijms222413625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022] Open
Abstract
The delayed effects of acute intoxication by organophosphates (OPs) are poorly understood, and the various experimental animal models often do not take into account species characteristics. The principal biochemical feature of rodents is the presence of carboxylesterase in blood plasma, which is a target for OPs and can greatly distort their specific effects. The present study was designed to investigate the nephrotoxic effects of paraoxon (O,O-diethyl O-(4-nitrophenyl) phosphate, POX) using three models of acute poisoning in outbred Wistar rats. In the first model (M1, POX2x group), POX was administered twice at doses 110 µg/kg and 130 µg/kg subcutaneously, with an interval of 1 h. In the second model (M2, CBPOX group), 1 h prior to POX poisoning at a dose of 130 µg/kg subcutaneously, carboxylesterase activity was pre-inhibited by administration of specific inhibitor cresylbenzodioxaphosphorin oxide (CBDP, 3.3 mg/kg intraperitoneally). In the third model (M3), POX was administered subcutaneously just once at doses of LD16 (241 µg/kg), LD50 (250 µg/kg), and LD84 (259 µg/kg). Animal observation and sampling were performed 1, 3, and 7 days after the exposure. Endogenous creatinine clearance (ECC) decreased in 24 h in the POX2x group (p = 0.011). Glucosuria was observed in rats 24 h after exposure to POX in both M1 and M2 models. After 3 days, an increase in urinary excretion of chondroitin sulfate (CS, p = 0.024) and calbindin (p = 0.006) was observed in rats of the CBPOX group. Morphometric analysis revealed a number of differences most significant for rats in the CBPOX group. Furthermore, there was an increase in the area of the renal corpuscles (p = 0.0006), an increase in the diameter of the lumen of the proximal convoluted tubules (PCT, p = 0.0006), and narrowing of the diameter of the distal tubules (p = 0.001). After 7 days, the diameter of the PCT lumen was still increased in the nephrons of the CBPOX group (p = 0.0009). In the M3 model, histopathological and ultrastructural changes in the kidneys were revealed after the exposure to POX at doses of LD50 and LD84. Over a period from 24 h to 3 days, a significant (p = 0.018) expansion of Bowman's capsule was observed in the kidneys of rats of both the LD50 and LD84 groups. In the epithelium of the proximal tubules, stretching of the basal labyrinth, pycnotic nuclei, and desquamation of microvilli on the apical surface were revealed. In the epithelium of the distal tubules, partial swelling and destruction of mitochondria and pycnotic nuclei was observed, and nuclei were displaced towards the apical surface of cells. After 7 days of the exposure to POX, an increase in the thickness of the glomerular basement membrane (GBM) was observed in the LD50 and LD84 groups (p = 0.019 and 0.026, respectively). Moreover, signs of damage to tubular epithelial cells persisted with blockage of the tubule lumen by cellular detritus and local destruction of the surface of apical cells. Comparison of results from the three models demonstrates that the nephrotoxic effects of POX, evaluated at 1 and 3 days, appear regardless of prior inhibition of carboxylesterase activity.
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Affiliation(s)
- Vladislav E. Sobolev
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez 44, 194223 St. Petersburg, Russia; (V.E.S.); (M.O.S.)
| | - Margarita O. Sokolova
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez 44, 194223 St. Petersburg, Russia; (V.E.S.); (M.O.S.)
| | - Richard O. Jenkins
- Leicester School of Allied Health Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK;
| | - Nikolay V. Goncharov
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez 44, 194223 St. Petersburg, Russia; (V.E.S.); (M.O.S.)
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Wen L, Li Y, Li S, Hu X, Wei Q, Dong Z. Glucose Metabolism in Acute Kidney Injury and Kidney Repair. Front Med (Lausanne) 2021; 8:744122. [PMID: 34912819 PMCID: PMC8666949 DOI: 10.3389/fmed.2021.744122] [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: 07/19/2021] [Accepted: 10/19/2021] [Indexed: 12/13/2022] Open
Abstract
The kidneys play an indispensable role in glucose homeostasis via glucose reabsorption, production, and utilization. Conversely, aberrant glucose metabolism is involved in the onset, progression, and prognosis of kidney diseases, including acute kidney injury (AKI). In this review, we describe the regulation of glucose homeostasis and related molecular factors in kidneys under normal physiological conditions. Furthermore, we summarize recent investigations about the relationship between glucose metabolism and different types of AKI. We also analyze the involvement of glucose metabolism in kidney repair after injury, including renal fibrosis. Further research on glucose metabolism in kidney injury and repair may lead to the identification of novel therapeutic targets for the prevention and treatment of kidney diseases.
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Affiliation(s)
- Lu Wen
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Ying Li
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Siyao Li
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Xiaoru Hu
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Qingqing Wei
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Zheng Dong
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
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Masajtis-Zagajewska A, Hołub T, Pęczek K, Makówka A, Nowicki M. Different Effects of Empagliflozin on Markers of Mineral-Bone Metabolism in Diabetic and Non-Diabetic Patients with Stage 3 Chronic Kidney Disease. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1352. [PMID: 34946298 PMCID: PMC8705759 DOI: 10.3390/medicina57121352] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 12/02/2021] [Accepted: 12/08/2021] [Indexed: 02/07/2023]
Abstract
Background and objectives: Treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors decrease tubular reabsorption of phosphate, which may explain the reduction of bone mineral density and an excess of bone fractures observed in some studies with this class of drugs. Since an increased risk of bone fractures may also be a result of diabetes itself, our study aimed to compare the effect of empagliflozin on the markers of mineral-bone metabolism between diabetic (DKD) and non-diabetic (ND-CKD) patients with stage 3 chronic kidney disease (CKD). Materials and Methods: Forty-two patients with stage 3 CKD and A2 albuminuria, including 18 with DKD and 24 ND-CKD, were investigated. All subjects received 10 mg empagliflozin for 7 days. Serum calcium, phosphate, parathormone (PTH), calcitriol, bone alkaline phosphatase (BAP), FGF-23 and urine calcium, phosphate, albumin and the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP-GFR) were measured before and after empagliflozin administration. Differences in biomarkers response to empagliflozin between DKD and ND-CKD were the main measures of outcome. Results: There was a significant increase of PTH, FGF-23 and phosphate in DKD but not in ND-CKD whereas BAP and TmP/GFR did not change in either group. The reduction of albuminuria was only significant in ND-CKD. Conclusions: The effect of SGLT2 inhibitor on serum mineral and bone markers and on albuminuria in patients with CKD may be differently modified by the presence of diabetes mellitus.
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Affiliation(s)
| | | | | | | | - Michał Nowicki
- Department of Nephrology, Hypertension and Kidney Transplantation, Medical University of Lodz, Central University Hospital, 92-213 Lodz, Poland; (A.M.-Z.); (T.H.); (K.P.); (A.M.)
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41
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Abstract
Patients with type 2 diabetes mellitus (T2D) are at increased risk of cardiovascular (CV) disease. Sodium glucose cotransporter 2 (SGLT2) inhibitors, also known as gliflozins, are a class of medications used to treat T2D by preventing the reabsorption of glucose filtered through the kidney and thereby facilitating glucose excretion in the urine. Over the past 5 years, many cardiovascular outcome trials (CVOTs) have evaluated the safety and efficacy of SGLT2 inhibitors in preventing CV events. The results of 7 CVOTs have provided solid evidence that the use of SGLT2 in patients with T2D and at high CV risk significantly reduced the risk of death from CV causes. Moreover, in patient with heart failure with reduced ejection fraction, regardless of the presence or absence of T2D, SGLT2 inhibitors use significantly reduced the risk of worsening heart failure and death from CV causes. Although the exact mechanism of the cardiorenal benefit of SGLT2 inhibitors is still unknown, studies have shown that the beneficial effect of these drugs cannot be exclusively explained by their glucose lowering effect, and several possible mechanisms have been proposed. This review will explore the changing role of SGLT2 inhibitors from a diabetes drug to clinical practice guideline-supported therapy for the prevention and treatment of CV diseases, including heart failure.
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Affiliation(s)
- Reza Mohebi
- Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - James L Januzzi
- Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Baim Institute for Clinical Research, Boston, MA, USA
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Jenssen TG. Efficacy and safety of Sodium-Glucose-Transporter-2 inhibitors in kidney transplant patients. Curr Opin Nephrol Hypertens 2021; 30:577-583. [PMID: 34507336 DOI: 10.1097/mnh.0000000000000749] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW This review discusses current evidence and future perspectives for use of SLT2 inhibitors in kidney transplant recipients (KTRs). RECENT FINDINGS Sodium-Glucose-Transporter-2 inhibitors (SGLT2is) lower plasma glucose in patients with type 2 diabetes, and protect against heart failure and progression of chronic kidney disease by a glucose-independent mechanism. Most of the current studies with SGLT2is in kidney transplant patients are however short-term retrospective case studies. These, together with one small randomized clinical trial, show that SGLT2is lower glucose also in KTRs with type 2 diabetes or posttransplant diabetes mellitus. Larger reductions in HbA1c (-0.5 to 1.5% points) are seen only in patients with estimated GFR > 60 ml/min/1.73m2 and HbA1c > 8%. With lower gomerular filtration rate (GFR) or glycated hemoglobin (HbA1c) the glucose-lowering effect is trivial. However, a reduction in body weight, blood pressure and uric acid is also seen, whereas the frequency of side effects (mycotic or urinary tract infections) does not seem to exceed what is seen in nontransplanted patients. Long-term effects on GFR have not been studied in kidney transplanted patients, but SGLT2is induce an early dip in GFR also in these patients. This could signal a beneficial long-term effect on renal hemodynamics. SUMMARY SGLT2is lower glucose safely also in patients with single kidney grafts, but long-term kidney function and patient survival are yet to be explored.
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Affiliation(s)
- Trond G Jenssen
- University Hospital of Oslo, Rikshospitalet, Department of Organ Transplantation, University of Oslo, Institute of Clinical Medicine, Oslo, Norway
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Suryavanshi VD, Sharma S, Sahu JK. Review on Characteristics and Analytical Methods of Remogliflozin etabonate: An Update. Mini Rev Med Chem 2021; 22:1341-1350. [PMID: 34620050 DOI: 10.2174/1389557521666211007115611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/24/2021] [Accepted: 08/10/2021] [Indexed: 11/22/2022]
Abstract
Hyperglycemia and its associated disorders like Diabetes mellitus are engulfing the world's population at a faster pace. New-age medications like the SGLT 2 inhibitors have found their place in the run to combat DM. Drugs with these properties have proven to be effective in treating hyperglycemia, Obesity, and major Cardiac disorders. The interesting fact about these drugs is that they act independently of insulin levels in the patient's body. The fact that they even bypass the side effects shown by currently used anti-diabetic medications has attracted the world's hope to neutralize diabetes mellitus. The invention of Remogliflozin etabonate (RGE), an SGLT 2 inhibitor, has therefore added a silver lining to the gliflozin-family of drugs in the fight against DM. This is due to its least side effects as well as its effective mechanisms to treat hyperglycemia. It can be administered not only as a single entity but also can be co-administered in combination with other anti-hyperglycemic agents. RGE is already sold in the Indian market as REMO-ZEN, by Glenmark Pharmaceuticals. It has been studied thoroughly for its pharmacokinetic & pharmacodynamic profile. It is a benzylpyrazole glucoside. Various analytical methods have been formulated for its detection, quantification, and routine quality control activities. RGE can be studied with the help of UV-visible spectrophotometry, High-Performance Liquid Chromatography (HPLC) & Hyphenated techniques like Liquid Chromatography-Mass Spectroscopy (LC-MS/MS). This review briefs about overall chemical, pharmacological, pharmacokinetic & pharmacodynamics properties of RGE. It mainly discusses about various analytical techniques used for determining & estimating RGE.
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Affiliation(s)
- Vallabh D Suryavanshi
- Quality Assurance, SVKM'S NMIMS, School of Pharmacy and Technology Management, Shirpur, Maharashtra. India
| | - Sanjay Sharma
- Quality Assurance, SVKM'S NMIMS, School of Pharmacy and Technology Management, Shirpur, Maharashtra. India
| | - Jagdish K Sahu
- Pharmaceutical Chemistry, SVKM'S NMIMS, School of Pharmacy and Technology Management, Shirpur, Maharashtra. India
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Chiang CE, Ueng KC, Chao TH, Lin TH, Wu YJ, Wang KL, Sung SH, Yeh HI, Li YH, Liu PY, Chang KC, Shyu KG, Huang JL, Tsai CD, Hung HF, Liu ME, Chao TF, Cheng SM, Cheng HM, Chu PH, Yin WH, Wu YW, Chen WJ, Lai WT, Lin SJ, Yeh SJ, Hwang JJ, Hou CJY. 2021 Consensus Pathway of the Taiwan Society of Cardiology on Novel Therapy for Type 2 Diabetes. JACC. ASIA 2021; 1:129-146. [PMID: 36338159 PMCID: PMC9627904 DOI: 10.1016/j.jacasi.2021.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/28/2021] [Accepted: 08/09/2021] [Indexed: 06/16/2023]
Abstract
Type 2 diabetes is a major threat to human health in the 21st century. More than half a billion people may suffer from this pandemic disease in 2030, leading to a huge burden of cardiovascular complications. Recently, 2 novel antidiabetic agents, glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, reduced cardiovascular complications in a number of randomized control trials. To integrate new information and to achieve a streamlined process for better patient care, a working group was appointed by the Taiwan Society of Cardiology to formulate a stepwise consensus pathway for these therapies to reduce cardiovascular events in patients with type 2 diabetes. This consensus pathway is complementary to clinical guidelines, acting as a reference to improve patient care.
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Affiliation(s)
- Chern-En Chiang
- General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Kwo-Chang Ueng
- Department of Internal Medicine, School of Medicine, Chung-Shan Medical University Hospital, Taichung, Taiwan
| | - Ting-Hsing Chao
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tsung-Hsien Lin
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yih-Jer Wu
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
- Cardiovascular Center, MacKay Memorial Hospital, Taipei, Taiwan
| | - Kang-Ling Wang
- General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shih-Hsien Sung
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hung-I Yeh
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
- Cardiovascular Center, MacKay Memorial Hospital, Taipei, Taiwan
| | - Yi-Heng Li
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ping-Yen Liu
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kuan-Cheng Chang
- Division of Cardiovascular Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Kou-Gi Shyu
- Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Jin-Long Huang
- Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Cheng-Dao Tsai
- Department of Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Huei-Fong Hung
- Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Ming-En Liu
- Division of Cardiology, Department of Internal Medicine, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan
| | - Tze-Fan Chao
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shu-Meng Cheng
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hao-Min Cheng
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Center for Evidence-Based Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pao-Hsien Chu
- Department of Cardiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Hsian Yin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Yen-Wen Wu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Cardiology, Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- Department of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- Department of Internal Medicine and Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Jone Chen
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Ter Lai
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shing-Jong Lin
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - San-Jou Yeh
- Department of Cardiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Juey-Jen Hwang
- Cardiovascular Division, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
- Cardiovascular Center, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
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Edel K, Mootz R. Optimale medikamentöse Therapie bei Typ‑2-Diabetikern mit einer koronaren Herzerkrankung – Update 2021. ZEITSCHRIFT FUR HERZ THORAX UND GEFASSCHIRURGIE 2021. [DOI: 10.1007/s00398-021-00446-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Alkabbani W, Gamble JM. Profile of Ipragliflozin, an Oral SGLT-2 Inhibitor for the Treatment of Type 2 Diabetes: The Evidence to Date. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:3057-3069. [PMID: 34285473 PMCID: PMC8286902 DOI: 10.2147/dddt.s281602] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/25/2021] [Indexed: 01/10/2023]
Abstract
Background Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a novel class of pharmacotherapeutics for type 2 diabetes management that work by reducing renal reabsorption of glucose. Ipragliflozin is a potent, selective SGLT-2 inhibitor used for the management of type 2 diabetes. Objective The primary aim of this review is to summarize the available evidence on the efficacy and safety of ipragliflozin for the management of type 2 diabetes. We also review the discovery, pharmacokinetic, and pharmacodynamic profile of ipragliflozin. Methods To inform our review, we searched MEDLINE, International Pharmaceutical Abstracts, and Embase to identify relevant papers to ipragliflozin use in type 2 diabetes. Clinical trial registries were also searched. Results Findings from randomized clinical trials demonstrate that compared to placebo, ipragliflozin significantly reduces glucose as measured via Hemoglobin A1c and fasting plasma glucose levels. Ipragliflozin is also associated with weight reduction and an improvement in some, but not all, cardiovascular risk markers. Ipragliflozin has a favourable safety profile with a low risk of hypoglycemia and the rates of common adverse events are not significantly different than placebo. Limited data are available to assess rare and long-term adverse effects. Conclusion Current evidence shows that ipragliflozin is an effective therapeutic option for the management of glucose control in type 2 diabetes. However, no cardiovascular outcome trials have been conducted to date. Real-world observational studies are still needed to accurately capture any possible rare or long-term adverse events.
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Affiliation(s)
- Wajd Alkabbani
- School of Pharmacy, Faculty of Science, University of Waterloo, Kitchener, ON, Canada
| | - John-Michael Gamble
- School of Pharmacy, Faculty of Science, University of Waterloo, Kitchener, ON, Canada
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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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Kuchay MS, Mishra SK, Mehta Y. Empagliflozin induced euglycemic diabetic ketoacidosis in a patient undergoing coronary artery bypass graft despite discontinuation of the drug 48 hours prior to the surgery. Diabetes Metab Syndr 2021; 15:909-911. [PMID: 33915345 DOI: 10.1016/j.dsx.2021.04.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/10/2021] [Accepted: 04/14/2021] [Indexed: 01/15/2023]
Affiliation(s)
- Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta The Medicity Hospital, Gurugram, 122001, Haryana, India.
| | - Sunil Kumar Mishra
- Division of Endocrinology and Diabetes, Medanta The Medicity Hospital, Gurugram, 122001, Haryana, India
| | - Yatin Mehta
- Institute of Critical Care, Medanta The Medicity Hospital, Gurugram, 122001, Haryana, India
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Cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors in diabetic and nondiabetic patients. Cardiovasc Diabetol 2021; 20:78. [PMID: 33827579 PMCID: PMC8028072 DOI: 10.1186/s12933-021-01266-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/19/2021] [Indexed: 12/25/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were developed as antidiabetic agents, but accumulating evidence has shown their beneficial effects on the cardiovascular system. Analyses of the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) suggested that these benefits are independent of glycemic control. Several large-scale outcome trials of SGLT2i also showed cardiovascular benefits in nondiabetic patients, strengthening this perspective. Extensive animal and clinical studies have likewise shown that mechanisms other than the antihyperglycemic effect underlie the cardiovascular benefits. Recent clinical guidelines recommend the use of SGLT2i in patients with type 2 diabetes mellitus and cardiovascular diseases because of the proven cardiovascular protective effects. Since the cardiovascular benefits are independent of glycemic control, the therapeutic spectrum of SGLT2i will likely be extended to nondiabetic patients.
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50
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Euglycemic Diabetic Ketoacidosis after a Single Dose of Empagliflozin in a Patient with Pancreatitis. Clin Pract 2021; 11:216-218. [PMID: 33917274 PMCID: PMC8167627 DOI: 10.3390/clinpract11020031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/22/2021] [Accepted: 03/29/2021] [Indexed: 11/18/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recently approved drug class for the treatment of type 2 diabetes mellitus (T2D). Although they are largely well-tolerated, their intake has been associated with euglycemic diabetic ketoacidosis (DKA) in some rare cases. We report the case of a 70-year-old male with type 2 diabetes and no history of DKA, who started therapy with empagliflozin one day before presenting with acute pancreatitis and laboratory findings consistent with euglycemic DKA. SGLT2i can induce euglycemic DKA from the first dose. Given the atypical presentation, a high degree of clinical suspicion is required to recognize this complication.
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