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Crispino SP, Segreti A, Nafisio V, Valente D, Crisci F, Ferro A, Cavallari I, Nusca A, Ussia GP, Grigioni F. The Role of SGLT2-Inhibitors Across All Stages of Heart Failure and Mechanisms of Early Clinical Benefit: From Prevention to Advanced Heart Failure. Biomedicines 2025; 13:608. [PMID: 40149587 DOI: 10.3390/biomedicines13030608] [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: 01/29/2025] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as antihyperglycemic agents, have revolutionized heart failure (HF) management, offering substantial benefits across all stages and phenotypes of the disease. Regardless of left ventricular ejection fraction (LVEF), these agents have proven efficacy in both chronic and acute HF presentations. This review explores SGLT2i applications spanning the HF continuum, from early stages (Stage A) in at-risk individuals to the mitigation of progression in advanced HF (Stage D). Evidence from numerous trials has shown that SGLT2i significantly lower rates of HF hospitalization, improve renal function, and decreases cardiovascular mortality, highlighting their multifaced mechanisms of action in HF care. This review also highlights the potential mechanisms by which SGLT2i exert their beneficial effects on the cardiovascular and renal systems, each contributing to early and sustained clinical improvements. However, the integration of SGLT2i into guideline-directed medical therapy poses practical challenges, including initiation timing, dosing, and monitoring, which are addressed to support effective treatment adaptation across patient populations. Ultimately, this review provides a comprehensive assessment of SGLT2i as a foundational therapy in HF, emphasizing their role as an intervention across multiple stages aimed at improving outcomes across the entire HF spectrum.
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Affiliation(s)
- Simone Pasquale Crispino
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Andrea Segreti
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", 00135 Rome, Italy
| | - Vincenzo Nafisio
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Daniele Valente
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Filippo Crisci
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Aurora Ferro
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Ilaria Cavallari
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Annunziata Nusca
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Gian Paolo Ussia
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Francesco Grigioni
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy
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Thaibah HA, Banji OJF, Banji D, Alshammari TM. Diabetic Ketoacidosis and the Use of New Hypoglycemic Groups: Real-World Evidence Utilizing the Food and Drug Administration Adverse Event Reporting System. Pharmaceuticals (Basel) 2025; 18:214. [PMID: 40006028 PMCID: PMC11858861 DOI: 10.3390/ph18020214] [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: 12/30/2024] [Revised: 02/01/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Diabetic ketoacidosis (DKA), a life-threatening complication, can occur in individuals with type 2 diabetes during illness, stress, or medication use. This study examines DKA signals in type 2 diabetes, focusing on sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors. Methods: DKA reports from Q1 2019 to Q3 2024 were retrieved from the FDA Adverse Event Reporting System (FAERS). Associations between primary exposure and outcomes were ascertained using four key metrics: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Component (IC). Results: SGLT2 inhibitors exhibited the higher DKA risk in 2019-2021 (ROR: 314.86 [95% CI 301.76-328.53], PRR of 245.69 [95% CI 235.47-256.36], IC of 6.90, and EBGM of 120), declining in 2022-2024. GLP-1 receptor agonists showed an ROR increase from 2.88 [95% CI 2.56-3.25] in 2019-2021 to 4.64 [95% CI 4.06-5.29] in 2022-2023, slightly declining to 3.95 [95% CI 3.27-4.74] in 2024. DPP-4 inhibitors exhibited a steady ROR rise from 6.81 [95% CI 5.52-8.40] in 2019-2021 to 8.57 [95% CI 6.24-11.76] in 2022-2023 and further to 11.02 [95% CI 6.71-18.10] in 2024. PRR, EBGM, and IC values followed similar trends. The age groups 41-60 and 61-91 years were the most affected, with hospitalization at its highest rate for DPP4-inhibitors in Q1-Q3 of 2024. Hospitalizations were also observed with GLP-1 receptor agonists and SGLT2 inhibitors. Life-threatening events and fatalities were also reported, with physicians contributing to most reports. Conclusions: DKA signals were observed for all three drug classes, particularly among elderly patients, highlighting the need for careful monitoring, especially during periods of illness or stress. However, the risk was higher in the SGLT2 inhibitor group than in the other groups.
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Affiliation(s)
- Hilal A. Thaibah
- Department of Clinical Practice, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (H.A.T.); (O.J.F.B.)
- Pharmacy Practice Research Unit, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Otilia J. F. Banji
- Department of Clinical Practice, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (H.A.T.); (O.J.F.B.)
- Pharmacy Practice Research Unit, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - David Banji
- Pharmacy Practice Research Unit, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
- Department of Pharmacology & Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Thamir M. Alshammari
- Department of Clinical Practice, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (H.A.T.); (O.J.F.B.)
- Pharmacy Practice Research Unit, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
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3
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Meier M, Ansong B, Awobusuyi D, Lee-Oyagha R, Lopez S. Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitor-Related Euglycemic Diabetic Ketoacidosis: A Case Series. J Pharm Pract 2025; 38:193-197. [PMID: 39123293 DOI: 10.1177/08971900241273169] [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] [Indexed: 08/12/2024]
Abstract
Objectives: Sodium-glucose transporter-2 inhibitors (SGLT2i) are commonly used for the treatment of Type 2 Diabetes Mellitus, offering additional benefits in non-diabetic patients with conditions such as chronic kidney disease and heart failure. However, SGLT2i have been associated with an increased risk of euglycemic diabetic ketoacidosis (DKA). This case series describes three cases of patients who developed euglycemic DKA while taking SGLT2i. Key Findings: Each of the three patients with euglycemic DKA were taking SGLT2i for the treatment of diabetes and all had additional risk factors for the development of DKA. These factors included reduced oral intake, major acute illness, chronic pancreatitis, and a history of previous DKA episodes. Unfortunately, the absence of hallmark symptoms like hyperglycemia, polyuria, and polydipsia led to delayed diagnosis of euglycemic DKA in two of the three patients. Conclusion: Early recognition of risk factors and a high level of suspicion are critical in identifying euglycemic DKA in patients taking SGLT2i. Healthcare providers should conduct thorough medication reconciliation upon admission and closely monitor patients for concurrent issues, especially in cases of minimal oral intake, acute illnesses, and chronic pancreatitis. Prompt diagnosis and management of euglycemic DKA can significantly improve patient outcomes.
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Affiliation(s)
- Mackenzi Meier
- Department of Pharmacy, St. Joseph's/Candler Health System, Savannah, GA, USA
- School of Pharmacy, South University, Savannah, GA, USA
| | | | | | | | - Sarah Lopez
- Department of Pharmacy, St. Joseph's/Candler Health System, Savannah, GA, USA
- School of Pharmacy, South University, Savannah, GA, USA
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Ojaimi RE, Cheisson G, Cosson E, Ichai C, Jacqueminet S, Nicolescu-Catargi B, Ouattara A, Tauveron I, Valensi P, Benhamou D. Recent advances in perioperative care of patients using new antihyperglycaemic drugs and devices dedicated to diabetes. Anaesth Crit Care Pain Med 2025; 44:101468. [PMID: 39743045 DOI: 10.1016/j.accpm.2024.101468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/28/2024] [Indexed: 01/04/2025]
Affiliation(s)
- Rami El Ojaimi
- Department of Anaesthesia and Intensive Care Medicine, Hôpital Henri Mondor, AP-HP, 1, rue Gustave Eiffel, 94000, Créteil, France.
| | - Gaëlle Cheisson
- Department of Anaesthesia and Intensive Care Medicine, Hôpital Bicêtre, AP-HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France
| | - Emmanuel Cosson
- Department of Endocrinology-Diabetology-Nutrition, Avicenne Hospital, University of Paris 13, Sorbonne Paris Cité, CRNH-IdF, CINFO, AP-HP, Bobigny, France; Recherche en Epidémiologie Nutritionnelle (EREN), Université Sorbonne Paris Nord and Université Paris Cité, INSERM, INRAE, CNAM, Center of Research in Epidemiology and StatisticS (CRESS), Bobigny, France
| | - Carole Ichai
- Department of Intensive Care Medicine, Université Côte d'Azur, Hôpital Pasteur 2, CHU de Nice, 30, voie Romaine, 06001 Nice cedex 1, France
| | - Sophie Jacqueminet
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Institute of Cardiometabolism and Nutrition ICAN, Paris, France
| | - Bogdan Nicolescu-Catargi
- Department of Endocrinology ad Metabolic Diseases, Hôpital Saint-André, Bordeaux University Hospital, 1, rue Jean-Burguet, 33000 Bordeaux, France
| | - Alexandre Ouattara
- CHU Bordeaux, Department of Cardiovascular Anaesthesia and Critical Care, F-33000 Bordeaux, France; Univ. Bordeaux, INSERM, UMR 1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
| | - Igor Tauveron
- Department of Endocrinology and Diabetology, Clermont Ferrand University Hospital, 58, rue Montalembert, 63000 Clermont-Ferrand, France
| | - Paul Valensi
- Polyclinique d'Aubervilliers, Aubervilliers and Université Paris-Nord, Bobigny, France
| | - Dan Benhamou
- Department of Anaesthesia and Intensive Care Medicine, Hôpital Bicêtre, AP-HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France.
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Mederle AL, Dumitrescu P, Borza C, Kundnani NR. Cutaneous Adverse Drug Reactions Associated with SGLT2 Inhibitors. J Clin Med 2024; 14:188. [PMID: 39797270 PMCID: PMC11721703 DOI: 10.3390/jcm14010188] [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: 11/29/2024] [Revised: 12/24/2024] [Accepted: 12/28/2024] [Indexed: 01/13/2025] Open
Abstract
Diabetes is a complex global healthcare burden involving multiple organ systems with its prevalence on the rise. SGLT2 inhibitors enhance glucose excretion. The objective of our literature review was to determine the association between cutaneous adverse drug reactions (CADRs) and the use of SGLT2 inhibitors. We collected data on CADRs related to the use of SGLT2 inhibitors from all available published articles and studied their details to understand the patterns of their association. PubMed, Cochrane, Google, and Embase were searched for relevant articles. A total of 37 papers were included and studied. Most articles were case reports followed by pharmacovigilance studies, case series, and reviews. The cutaneous findings ranged from benign eruptions to severe reactions. The available literature suggests a strong link between the use of SGLT2 inhibitors and Fournier's gangrene/necrotizing fasciitis. T2DM patients using SGLT2 inhibitors have also developed fixed drug eruptions, drug-induced pruritus, and Sweet syndrome/acute febrile neutrophilic dermatosis, among other skin lesions. We found that SGLT2 inhibitors present a risk of developing CADRs. Raising awareness among healthcare providers regarding CADRs to SGLT2 inhibitors can reduce complications, minimize hospitalizations, and improve patient care in the vulnerable population of diabetes patients.
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Affiliation(s)
- Alexandra Laura Mederle
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Patrick Dumitrescu
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Claudia Borza
- Discipline of Pathophysiology, Department of Functional Science, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Centre of Cognitive Research in Pathological Neuro-Psychiatry NEUROPSY-COG, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Nilima Rajpal Kundnani
- Department of Cardiology—Internal Medicine and Ambulatory Care, Prevention and Cardiovascular Recovery, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Research Centre of Timișoara Institute of Cardiovascular Diseases, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Hung CH, Lu LY. New Insights into the Role of SGLT-2 Inhibitors in the Prevention of Dementia. Neurol Int 2024; 16:1717-1730. [PMID: 39728750 DOI: 10.3390/neurolint16060124] [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: 09/25/2024] [Revised: 11/21/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic disease associated with numerous complications, including cardiovascular diseases, nephropathy, and neuropathy. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, a class of novel antidiabetic agents, have demonstrated promising therapeutic effects beyond glycemic control, with potential benefits extending to the cardiovascular and renal systems. Recently, research has increasingly focused on exploring the potential role of SGLT-2 inhibitors in preventing dementia. The aim of this review is to summarize the current research suggesting that SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, may have neuroprotective effects that reduce dementia risk and improve cognitive function in type 2 diabetes patients. These benefits are likely due to better glycemic control, reduced oxidative stress, and less advanced glycation end-product (AGE) formation, all linked to neurodegeneration. Despite these promising findings, existing studies are limited by small sample sizes and short follow-up durations, which may not adequately capture long-term outcomes. To establish more robust evidence, larger-scale, long-term randomized controlled trials (RCTs) involving diverse populations are needed. These studies should involve diverse populations and focus on understanding the mechanisms behind the neuroprotective effects. Addressing these limitations will provide clearer guidelines for using SGLT-2 inhibitors in dementia prevention and management. This will help improve therapeutic strategies for cognitive health in diabetic patients.
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Affiliation(s)
- Cheng-Hsien Hung
- Department of Pharmacy, Chang Bing Show Chwan Memorial Hospital, Changhua 50544, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Li-Yu Lu
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
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7
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Qiang W, Yang F, Liu L, Dong R, Sun Y, Mondal A, Guo H. SGLT-2 inhibitors and high-dose acarbose as potential high-risk combinations for ketosis and ketoacidosis in Asian patients with T2DM: A case series. Clin Case Rep 2024; 12:e9282. [PMID: 39267955 PMCID: PMC11390491 DOI: 10.1002/ccr3.9282] [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: 03/30/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 09/15/2024] Open
Abstract
Key Clinical Message High-dose acarbose may increase the risk of diabetic ketosis/diabetic ketoacidosis in Asian patients on sodium-glucose cotransporter-2 inhibitors. Healthcare providers and patients should be cautious to avoid this combination. Abstract Low-calorie diets should be avoided in patients receiving sodium-glucose cotransporter-2 (SGLT-2) inhibitors to decrease the risk of diabetic ketoacidosis (DKA). High-dose acarbose can decelerate carbohydrate absorption. We detail three cases of diabetic ketosis (DK) following concurrent SGLT-2 inhibitor and high-dose acarbose therapy (acarbose 300 mg/day and dapagliflozin 10 mg/day). Patients, aged 38-63 years with 3-10 years of type 2 diabetes mellitus (T2DM), developed DK, indicated by moderate urinary ketones and high glucose (urine ketone 2+ to 3+ and glucose 3+ to 4+) without acidosis, within 4 days to 1 month post-therapy initiation. Serum glucose was 172.8-253.8 mg/dL; HbA1c was 9.97%-10.80%. The combination therapy was halted, and DK was managed with low-dose intravenous insulin and fluids, followed by intensive insulin therapy. High-dose acarbose with SGLT-2 inhibitors may increase the risk of DK/DKA in Asian patients.
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Affiliation(s)
- Wei Qiang
- Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University Xi'an P. R. China
| | - Fei Yang
- Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University Xi'an P. R. China
- Department of Endocrinology The First Affiliated Hospital of Xi'an Medical University Xi'an P. R. China
| | - Ling Liu
- Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University Xi'an P. R. China
- Department of Endocrinology Chang Qing Oil Field Worker's Hospital Xi'an P. R. China
| | - Ruiqing Dong
- Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University Xi'an P. R. China
| | - Yushi Sun
- Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University Xi'an P. R. China
| | - Ahona Mondal
- Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University Xi'an P. R. China
| | - Hui Guo
- Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University Xi'an P. R. China
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Morace C, Lorello G, Bellone F, Quartarone C, Ruggeri D, Giandalia A, Mandraffino G, Minutoli L, Squadrito G, Russo GT, Marini HR. Ketoacidosis and SGLT2 Inhibitors: A Narrative Review. Metabolites 2024; 14:264. [PMID: 38786741 PMCID: PMC11122992 DOI: 10.3390/metabo14050264] [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: 03/08/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/25/2024] Open
Abstract
An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.
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Affiliation(s)
- Carmela Morace
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Lipid Clinic and Cardiometabolic Disease Center, University Hospital of Messina, 98124 Messina, Italy
| | - Giuseppe Lorello
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Federica Bellone
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Lipid Clinic and Cardiometabolic Disease Center, University Hospital of Messina, 98124 Messina, Italy
| | - Cristina Quartarone
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Domenica Ruggeri
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Annalisa Giandalia
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
- Department of Human Pathology of Adulthood and Childhood “G. Barresi”, University of Messina, 98125 Messina, Italy
| | - Giuseppe Mandraffino
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Lipid Clinic and Cardiometabolic Disease Center, University Hospital of Messina, 98124 Messina, Italy
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
| | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Giuseppina T. Russo
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Herbert Ryan Marini
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
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Zhou Y, Wang FR, Wen FF, Li C, Ye TT. The association between sodium/glucose cotransporter-2 inhibitors and adverse clinical events in patients with chronic kidney disease: a systematic review and meta-analysis of randomised controlled trials. Acta Cardiol 2024; 79:274-283. [PMID: 37642395 DOI: 10.1080/00015385.2023.2250949] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/26/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND The purpose of this systematic review and meta-analysis was to evaluate the common clinical adverse events associated with sodium/glucose cotransporter-2 inhibitor (SGLT2i) use compared to placebo in patients with chronic kidney disease (CKD) with or without type 2 diabetes. METHODS Twelve articles were chosen via a systematic search of the PubMed, Embase, and Cochrane Library databases. We screened for randomised placebo-controlled trials. The main clinical adverse events included diabetes ketoacidosis (DKA), amputation, and volume depletion. We performed heterogeneity testing and assessment of publication bias. RESULTS In all, 65 600 patients were included in the analysis. Compared to placebo, SGLT2i may increase the risk of DKA and volume depletion in patients with CKD with or without type 2 diabetes. For DKA, compared with placebo, the combined effect of SGLT2i was OR 2.03 (95% CI: 1.28 to 3.23 I2: 2.3%, P: 0.420). For volume depletion, compared with placebo, the combined effect of SGLT2i was OR 1.24 (95% CI: 1.13 to 1.37 I2: 0.0%, P: 0.484). For the risk of amputation, despite low heterogeneity for amputation, the forest plot indicated no statistical significance, and thus it cannot be concluded that SGLT2i increases the risk of amputation. Compared with placebo, the combined effect of SGLT2i was OR 1.10 (95% CI: 0.94 to 1.29 I2: 0.0%, P: 0.642). CONCLUSION The use of SGLT2i may increase the risk of DKA and volume depletion in patients with chronic renal insufficiency with or without type 2 diabetes.
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Affiliation(s)
- Yi Zhou
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Feng-Rong Wang
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Fei-Fei Wen
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Chao Li
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
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Kim HA, Kim JY, Kim YH, Lee YT, Park PW. Missed postoperative metabolic acidosis associated with sodium-glucose transporter 2 inhibitors in cardiac surgery patients: a retrospective analysis. Sci Rep 2024; 14:8087. [PMID: 38582803 PMCID: PMC10998860 DOI: 10.1038/s41598-024-58853-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 04/03/2024] [Indexed: 04/08/2024] Open
Abstract
The increasing use of sodium glucose transporter 2 inhibitors (SGLT2i) for treating cardiovascular (CV) diseases and type 2 diabetes (T2D) is accompanied by a rise in euglycemic diabetic ketoacidosis occurrences in cardiac surgery patients. Patients undergoing cardiac surgery, due to their pre-existing CV disease which often requires SGLT2i prescriptions, face an increased risk of postoperative metabolic acidosis (MA) or ketoacidosis (KA) associated with SGLT2i, compounded by fasting and surgical stress. The primary aim of this study is to quantify the incidence of SGLT2i-related postoperative MA or KA and to identify related risk factors. We analyzed data retrospectively of 823 cardiac surgery patients, including 46 treated with SGLT2i from November 2019 to October 2022. Among 46 final cohorts treated preoperatively with SGLT2i, 29 (63%) developed postoperative metabolic complications. Of these 46 patients, stratified into two categories based on postoperative laboratory findings, risk factor analysis were conducted and compared. Analysis indicated a prescription duration over one week significantly elevated the risk of complications (Unadjusted OR, 11.7; p = 0.032*; Adjusted OR, 31.58; p = 0.014*). A subgroup analysis showed that a cardiopulmonary bypass duration of 60 min or less significantly raises the risk of SGLT2i-related postoperative MA in patients with a sufficient prescription duration. We omitted the term "diabetes" in describing complications related to SGLT2i, as these issues are not exclusive to T2D patients. Awareness of SGLT2i-related postoperative MA or KA can help clinicians distinguish between non-life-threatening conditions and severe causes, thereby preventing unnecessary tests and ensuring best practice.
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Affiliation(s)
- Hyeon A Kim
- Department of Cardiovascular and Thoracic Surgery, Ewha Womans University Medical Center, Seoul, Republic of Korea
| | - Joo Yeon Kim
- Department of Cardiovascular and Thoracic Surgery, Ewha Womans University Medical Center, Seoul, Republic of Korea.
| | - Young Hwan Kim
- Department of Cardiovascular and Thoracic Surgery, Incheon Sejong Hospital, Incheon, Republic of Korea
| | - Young Tak Lee
- Department of Cardiovascular and Thoracic Surgery, Incheon Sejong Hospital, Incheon, Republic of Korea
| | - Pyo Won Park
- Department of Cardiovascular and Thoracic Surgery, Incheon Sejong Hospital, Incheon, Republic of Korea
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11
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Verdone M, Bauman J, Iversen E, Schulman-Rosenbaum R, Antonacci A, Leffe S, Simpson J, Harris YT, Marino J. Novel Approach to Continuation of Elective Procedures in People at Risk for Sodium-Glucose Cotransporter 2 Inhibitor-Associated Euglycemic Ketoacidosis. Diabetes Spectr 2024; 37:165-169. [PMID: 38756433 PMCID: PMC11093762 DOI: 10.2337/ds23-0040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Affiliation(s)
- Matthew Verdone
- Northwell, New Hyde Park, NY
- Endoscopic and Advanced Endoscopic Anesthesia Services, Long Island Center for Digestive Health, Northwell Health, Uniondale, NY
| | - Jonathan Bauman
- Northwell, New Hyde Park, NY
- Department of Anesthesiology, Northwell Health, New Hyde Park, NY
| | - Esben Iversen
- Northwell, New Hyde Park, NY
- Department of Clinical Research, Copenhagen University Hospital Amager & Hvidovre, Hvidovre, Denmark
| | - Rifka Schulman-Rosenbaum
- Northwell, New Hyde Park, NY
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Northwell Health, New Hyde Park, NY
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Anthony Antonacci
- Northwell, New Hyde Park, NY
- Lenox Hill Hospital, Northwell Health, New York, NY
| | - Sabatino Leffe
- Northwell, New Hyde Park, NY
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
- South Shore University Hospital, Northwell Health, Bay Shore, NY
| | | | - Yael Tobi Harris
- Northwell, New Hyde Park, NY
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Northwell Health, New Hyde Park, NY
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Joseph Marino
- Northwell, New Hyde Park, NY
- Department of Anesthesiology, Northwell Health, New Hyde Park, NY
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
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12
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Monteiro Lopes S, Maia A, Melo P, Abreu S, Paiva I, Barros L. [Non-Insulin Antidiabetic Agents in the Management of Hyperglycaemia of Non-Critical Hospitalized Patients]. ACTA MEDICA PORT 2024; 37:207-214. [PMID: 38316163 DOI: 10.20344/amp.20858] [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: 10/24/2023] [Accepted: 01/16/2024] [Indexed: 02/07/2024]
Abstract
Hyperglycaemia affects more than 30% of adults hospitalized for non-critical illness and is associated with an increased risk of adverse clinical outcomes. Insulin therapy is widely used for its safety and efficacy. However, given the growing availability of new drugs and new classes of antidiabetic agents with benefits beyond glycaemic control, challenges arise regarding their use in the hospital setting. This article aims to review and summarize the most recently available evidence and recommendations on the role of non-insulin antidiabetic agents in the management of hyperglycaemia in hospitalized patients. Insulin therapy remains the method of choice. Dipeptidyl peptidase 4 inhibitors can be considered in mild to moderate hyperglycaemia. Glucagon-like peptide 1 receptor agonists have recently shown promising results, with high efficacy in glycaemic control and low risk of hypoglycaemia. There are concerns regarding the increased risk of acidosis with metformin use, especially in cases of acute illness, although there is no evidence to support its suspension in selected patients with relative clinical stability. Sodium-glucose cotransporter-2 inhibitors should be discontinued in clinical situations that may predispose to ketoacidosis, including episodes of acute illness. The hospital use of sulfonylureas and thiazolidinediones is not advised.
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Affiliation(s)
- Sofia Monteiro Lopes
- Grupo de Estudos de Diabetes. Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Lisboa; Serviço de Endocrinologia, Diabetes e Metabolismo. Centro Hospitalar e Universitário de Coimbra. Coimbra. Portugal
| | - Ariana Maia
- Grupo de Estudos de Diabetes. Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Lisboa; Serviço de Endocrinologia. Centro Hospitalar Universitário do Porto. Porto. Portugal
| | - Pedro Melo
- Grupo de Estudos de Diabetes. Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Lisboa; Serviço de Endocrinologia. Unidade Local de Saúde de Matosinhos. Portugal
| | - Silvestre Abreu
- Grupo de Estudos de Diabetes. Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Lisboa; Serviço Regional de Saúde da Região Autónoma da Madeira. Funchal. Portugal
| | - Isabel Paiva
- Grupo de Estudos de Diabetes. Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Lisboa; Serviço de Endocrinologia, Diabetes e Metabolismo. Centro Hospitalar e Universitário de Coimbra. Coimbra. Portugal
| | - Luísa Barros
- Grupo de Estudos de Diabetes. Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Lisboa; Serviço de Endocrinologia, Diabetes e Metabolismo. Centro Hospitalar e Universitário de Coimbra. Coimbra. Portugal
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13
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Hawker K, Akter R, Molnar F, Frank C. Prise en charge du diabète de type 2 chez les patients fragiles. CANADIAN FAMILY PHYSICIAN MEDECIN DE FAMILLE CANADIEN 2024; 70:e10-e13. [PMID: 38262767 PMCID: PMC11126283 DOI: 10.46747/cfp.7001e10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Affiliation(s)
- Kara Hawker
- Résidente en médecine interne au Département de médecine de l'Université d'Ottawa (Ontario)
| | - Ripa Akter
- Directrice du programme de formation postdoctorale à la Division de médecine gériatrique de l'Université d'Ottawa et clinicienne chercheuse à l'Institut de recherche de l'Hôpital d'Ottawa
| | - Frank Molnar
- Spécialiste en médecine gériatrique; il exerce au Département de médecine de l'Université d'Ottawa et à l'Institut de recherche de l'Hôpital d'Ottawa
| | - Chris Frank
- Médecin de famille; il se concentre sur les soins palliatifs et aux personnes âgées, et est professeur au Département de médecine de l'Université Queen's à Kingston (Ontario)
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14
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Hawker K, Akter R, Molnar F, Frank C. Management of type 2 diabetes in patients with frailty. CANADIAN FAMILY PHYSICIAN MEDECIN DE FAMILLE CANADIEN 2024; 70:30-32. [PMID: 38262761 PMCID: PMC11126279 DOI: 10.46747/cfp.700130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Affiliation(s)
- Kara Hawker
- Internal medicine resident in the Department of Medicine at the University of Ottawa in Ontario
| | - Ripa Akter
- Residency Training Program Director in the Division of Geriatric Medicine in the Department of Medicine at the University of Ottawa and Clinician Investigator at the Ottawa Hospital Research Institute
| | - Frank Molnar
- Specialist in geriatric medicine practising in the Department of Medicine at the University of Ottawa and at the Ottawa Hospital Research Institute
| | - Chris Frank
- Family physician focusing on care of the elderly and palliative care and Professor in the Department of Medicine at Queen's University in Kingston, Ont
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15
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Abstract
This article reviews the most current literature on diabetic ketoacidosis, including how to make the diagnosis and management. It discusses euglycemic diabetic ketoacidosis and the risk factors for this rare but dangerous disease process. Pertinent pearls and pitfalls encountered by the emergency physician when managing these patients are included. Because these patients often stay in the emergency department for prolonged periods, recommendations on transitioning to subcutaneous insulin are included, along with dosing recommendations. Finally, the article reviews how to disposition patients with diabetic ketoacidosis and examines important factors that lead to a successful discharge home.
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Affiliation(s)
- Bobbi-Jo Lowie
- Department of Emergency Medicine, University of Maryland Medical Center, 110 South Paca Street, Sixth Floor, Suite 200, Baltimore, MD 21201, USA
| | - Michael C Bond
- Department of Emergency Medicine, University of Maryland School of Medicine; University of Maryland Medical Center, 110 South Paca Street, Sixth Floor, Suite 200, Baltimore, MD 21201, USA.
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16
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Cavallari I, Crispino SP, Segreti A, Ussia GP, Grigioni F. Practical Guidance for the Use of SGLT2 Inhibitors in Heart Failure. Am J Cardiovasc Drugs 2023; 23:609-621. [PMID: 37620653 DOI: 10.1007/s40256-023-00601-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/30/2023] [Indexed: 08/26/2023]
Abstract
Despite continuous advances in both diagnosis and management, heart failure (HF) still represents a major worldwide health issue. Recently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated to reduce cardiovascular death and hospitalization for HF across the entire spectrum of left ventricular ejection fraction. Therefore, dapagliflozin, empagliflozin and sotagliflozin are now recommended as part of the foundational therapy of HF. These agents are characterized by limited contraindications, low cost, non-relevant adverse effects and no need for titration. Although they have a prominent role in the latest recommendations for HF, drug prescriptions are definitely lower than the number of potentially eligible patients. In fact, awareness gaps, therapeutic inertia, concerns about safety and simultaneous initiation of comprehensive medical therapy may represent barriers to their use. This article aims to offer an overview of current knowledge on SGLT2i in HF and provide a comprehensive and updated practical guide on their use in de novo and chronic HF, including potential scenarios that a clinician, cardiologist or others, may face in everyday clinical practice.
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Affiliation(s)
- Ilaria Cavallari
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy.
| | - Simone Pasquale Crispino
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy
| | - Andrea Segreti
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy
- Department of Movement, Human and Health Sciences, University of Rome, Foro Italico, Rome, Italy
| | - Gian Paolo Ussia
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy
| | - Francesco Grigioni
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy
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17
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Chow E, Clement S, Garg R. Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Res Care 2023; 11:e003666. [PMID: 37797963 PMCID: PMC10551972 DOI: 10.1136/bmjdrc-2023-003666] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/19/2023] [Indexed: 10/07/2023] Open
Abstract
Euglycemic diabetic ketoacidosis (EDKA) is an emerging complication of diabetes associated with an increasing use of sodium-glucose transporter type 2 (SGLT-2) inhibitor drugs. This review highlights the growing incidence of EDKA and its diagnostic challenges due to the absence of hallmark hyperglycemia seen in diabetic ketoacidosis (DKA). The paper presents a classification system for the severity of EDKA, categorizing it into mild, moderate, and severe based on serum pH and bicarbonate levels. Another classification system is proposed to define stages of EDKA based on anion gap and ketones at the time of diagnosis and during the treatment period. A treatment algorithm is proposed to guide clinicians in managing EDKA. This treatment algorithm includes monitoring anion gap and ketones to guide insulin and fluid management, and slower transition to subcutaneous insulin to prevent a relapse. Increased awareness of EDKA is essential for a timely diagnosis because an early diagnosis and treatment can improve clinical outcomes.
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Affiliation(s)
- Erica Chow
- Division of Endocrinology, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Stephen Clement
- Division of Endocrinology, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Rajesh Garg
- Division of Endocrinology, Harbor-UCLA Medical Center, Torrance, California, USA
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18
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Juneja D, Nasa P, Jain R, Singh O. Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis: A meta summary of case reports. World J Diabetes 2023; 14:1314-1322. [PMID: 37664476 PMCID: PMC10473945 DOI: 10.4239/wjd.v14.i8.1314] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/20/2023] [Accepted: 06/19/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are commonly prescribed to manage patients with diabetes mellitus. These agents may rarely lead to the development of euglycemic diabetic ketoacidosis (EDKA), which may complicate the disease course of these patients. AIM To analyze the demographic profile, predisposing factors, symptomology, clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series. METHODS We performed a systematic search of PubMed, Science Direct, Google Scholar and Reference Citation Analysis databases using the terms "canagliflozin" OR "empagliflozin" OR "dapagliflozin" OR "SGLT2 inhibitors" OR "Sodium-glucose cotransporter-2" AND "euglycemia" OR "euglycemic diabetic ketoacidosis" OR "metabolic acidosis". The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported EDKA secondary to SGLT2i. Furthermore, the data were filtered from the literature published in the English language and on adults (> 18 years). We excluded: (1) Conference abstracts; and (2) Case reports or series which did not have individual biochemical data. All the case reports and case series were evaluated. The data extracted included patient demographics, clinical symptomatology, clinical interventions, intensive care unit course, need for organ support and outcomes. RESULTS Overall, 108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included. The majority of patients were females (54.4%, n = 92), and the commonly reported symptoms were gastrointestinal (nausea/vomiting 65.1%, abdominal pain 37.3%) and respiratory (breathlessness 30.8%). One hundred and forty-nine (88.2%) patients had underlying type II diabetes, and the most commonly involved SGLT-2 inhibitor reported was empagliflozin (46.8%). A triggering factor was reported in most patients (78.7%), the commonest being acute severe infection (37.9%), which included patients with sepsis, coronavirus disease 2019, other viral illnesses, and acute pancreatitis. 61.5% were reported to require intensive unit care, but only a minority of patients required organ support in the form of invasive mechanical ventilation (13%), vasopressors (6.5%) or renal replacement therapy (5.9%). The overall mortality rate was only 2.4%. CONCLUSION Patients on SGLT2i may rarely develop EDKA, especially in the presence of certain predisposing factors, including severe acute infections and following major surgery. The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels, which may make the diagnosis challenging. Outcomes of EDKA are good if recognized early and corrective actions are taken. Hence, physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management.
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Affiliation(s)
- Deven Juneja
- Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
| | - Prashant Nasa
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
- Department of Internal Medicine, College of Medicine and Health Sciences, Al Ain 15551, Abu Dhabi, United Arab Emirates
| | - Ravi Jain
- Department of Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302022, Rajasthan, India
| | - Omender Singh
- Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
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19
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Yang S, Liu Y, Zhang S, Wu F, Liu D, Wu Q, Zheng H, Fan P, Su N. Risk of diabetic ketoacidosis of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials. Front Pharmacol 2023; 14:1145587. [PMID: 37397500 PMCID: PMC10311413 DOI: 10.3389/fphar.2023.1145587] [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: 01/16/2023] [Accepted: 05/23/2023] [Indexed: 07/04/2023] Open
Abstract
Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM. Methods: We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388). Conclusion: Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.
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Affiliation(s)
- Shiwen Yang
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Ying Liu
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Shengzhao Zhang
- Department of Pharmacy, Karamay Central Hospital, Karamay, China
| | - Fengbo Wu
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Dan Liu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| | - Qingfang Wu
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Hanrui Zheng
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Ping Fan
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Na Su
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
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20
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Sodium-glucose cotransporter 2 inhibitor-associated perioperative ketoacidosis: a systematic review of case reports. J Anesth 2023; 37:465-473. [PMID: 36849747 DOI: 10.1007/s00540-023-03174-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 02/18/2023] [Indexed: 03/01/2023]
Abstract
Although the recommended preoperative cessation period for sodium-glucose cotransporter 2 inhibitors (SGLT2is) changed in 2020 (from 24 h to 3-4 days preoperatively) to reduce the risk of SGLT2i-associated perioperative ketoacidosis (SAPKA), the validity of the new recommendation has not been verified. Using case reports, we assessed the new recommendation effectiveness and extrapolated precipitating factors for SAPKA. We searched electronic databases up to June 1, 2022 to assess SAPKA (blood pH < 7.3 and blood or urine ketone positivity within 30 days postoperatively in patients taking SGLT2i). We included 76 publications with 99 cases. The preoperative SGLT2i cessation duration was reported for 59 patients (59.6%). In all cases with available cessation periods, the SGLT2is were interrupted < 3 days preoperatively. No SAPKA cases with > 2-day preoperative cessation periods were found. Many case reports lack important information for estimating precipitating factors, including preoperative SGLT2i cessation period, body mass index, baseline hemoglobin A1c level, details of perioperative fluid management, and type of anesthesia. Our study suggested that preoperative SGLT2i cessation for at least 3 days could prevent SAPKA. Large prospective epidemiologic studies are needed to identify risk factors for SAPKA.
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21
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Sodium-Glucose Co-transporter-2 Inhibitors Induced Diabetic Ketoacidosis in Patients Undergoing Bariatric Surgery: a Systematic Review of Case Reports and Case Series. Obes Surg 2023; 33:339-344. [PMID: 36418772 DOI: 10.1007/s11695-022-06368-3] [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: 08/30/2022] [Revised: 10/26/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are glucose-lowering agents being increasingly used for cardio-renal protection in patients with or without type 2 diabetes (T2DM). This systematic review identified the clinical risk factors and outcomes of diabetic ketoacidosis (DKA) in patients undergoing bariatric and metabolic surgery (BMS) on SGLT2i. We found 12 studies with a total of 16 patients (10 females; mean age of 51 years). Apart from one patient, all patients developed DKA in the post-operative period presenting at a median of 5 days after surgery. Most of the patients were euglycaemic on presentation with DKA. Patients undergoing BMS on SGLT2i are at increased risk of developing DKA that can mimic post-operative surgical complications causing diagnostic dilemmas, especially with the euglycaemic variant, and delaying treatment.
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22
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Davidson JA, Sukor N, Hew F, Mohamed M, Hussein Z. Safety of sodium-glucose cotransporter 2 inhibitors in Asian type 2 diabetes populations. J Diabetes Investig 2022; 14:167-182. [PMID: 36260389 PMCID: PMC9889611 DOI: 10.1111/jdi.13915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/02/2022] [Accepted: 09/10/2022] [Indexed: 02/04/2023] Open
Abstract
The prevalence of type 2 diabetes mellitus continues to increase in many Asian countries, with possible contributing factors, such as younger-onset disease, diabetes development at lower body mass index, higher visceral fat accumulation and poorer β-cell function, among Asian populations. Sodium-glucose cotransporter 2 inhibitors have been shown to confer favorable effects in type 2 diabetes mellitus patients, such as improved glycemic control, weight and blood pressure reduction, and importantly, cardiorenal benefits. Sodium-glucose cotransporter 2 inhibitors are generally well-tolerated, and have a well-defined safety profile based on evidence from numerous clinical trials and post-marketing pharmacovigilance reporting. To our knowledge, this review is the first to provide a comprehensive coverage of the adverse events of sodium-glucose cotransporter 2 inhibitors, as well as their management and counseling aspects for Asian type 2 diabetes mellitus populations.
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Affiliation(s)
- Jaime A Davidson
- Touchstone Diabetes CenterThe University of Texas Southwestern Medical CenterDallasTexasUSA
| | - Norlela Sukor
- Universiti Kebangsaan Malaysia Medical CentreKuala LumpurMalaysia
| | - Fen‐Lee Hew
- Subang Jaya Medical CentreSubang JayaSelangorMalaysia
| | - Mafauzy Mohamed
- School of Medical SciencesUniversiti Sains MalaysiaKelantanMalaysia
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23
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Patel K, Nair A. A Literature Review of the Therapeutic Perspectives of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor-Induced Euglycemic Diabetic Ketoacidosis. Cureus 2022; 14:e29652. [PMID: 36320965 PMCID: PMC9611643 DOI: 10.7759/cureus.29652] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Euglycemic diabetic ketoacidosis (DKA), a side effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors, is a triad of high metabolic anion gap acidosis, raised serum and urine ketones, and serum glucose <250 mg/dl. SGLT2 inhibitors cause a carbohydrate deficit by glucosuria, which leads to an increased glucagon/insulin ratio, the metabolic shift from glucose to lipid utilization causing ketogenesis, and hence euglycemic DKA. Additional factors like the ketogenic diet, illness, surgery, and pregnancy contribute to precipitating these episodes. Keywords search included “Euglycemic DKA and SGLT2 inhibitors” in PubMed and Google Scholar, to compile data from existing articles that provide information on the withholding and restarting period of the drug after a euglycemic DKA episode. SGLT2 inhibitors, used in the treatment of type 2 DM, have an average half-life of 11-13 hours, so most articles suggested withholding the drug three days before any elective surgery but some articles suggested a longer withholding period based on other precipitating factors contributing to euglycemic DKA. Hence, we came up with patient inclusion criteria and concomitant therapies review that we need to consider in making this decision. In addition, a multidisciplinary approach is required when laying out guidelines for restarting the drug to have a unanimous approach. After reviewing the existing literature, it is clear that concrete guidelines are required to decide on drug withholding and restarting periods after a euglycemic DKA episode, as they vary among different institutions and different specialties. We believe it is crucial to consider patient inclusion criteria and concomitant therapies in forming those guidelines.
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KHAKDE S, JAWAID H, YASMIN F, BINTE ALI M, REHMAN A. Is there a paradigm shift in preventing diabetic heart failure? A review of SGLT2 inhibitors. Minerva Endocrinol (Torino) 2022; 47:344-357. [DOI: 10.23736/s2724-6507.20.03221-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Khunti K, Jabbour S, Cos X, Mudaliar S, Mende C, Bonaca M, Fioretto P. Sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes: Barriers and solutions for improving uptake in routine clinical practice. Diabetes Obes Metab 2022; 24:1187-1196. [PMID: 35238129 PMCID: PMC9313799 DOI: 10.1111/dom.14684] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/22/2022] [Accepted: 02/28/2022] [Indexed: 02/06/2023]
Abstract
Recent advances in type 2 diabetes (T2D) research have highlighted the benefits of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, including cardiovascular and renal protection. However, uptake rates of these drugs remain low in patients with T2D, particularly in subpopulations most likely to benefit from them. This review considers the potential barriers to prescribing SGLT-2 inhibitors in T2D in clinical practice and outlines potential multidisciplinary recommendations to overcome these barriers. Safety concerns and a lack of clarity in and divergence of guidelines around the introduction of SGLT-2 inhibitors into treatment regimens may represent a barrier to uptake from the clinicians' perspective, including a general lack of understanding of the benefits associated with SGLT-2 inhibitors. Patient characteristics, such as socioeconomic status, may influence uptake because of the cost of SGLT-2 inhibitors, especially in the United States, where health insurance coverage could be a concern. SGLT-2 inhibitor prescription rates vary between clinical specialty (endocrinology, primary care, cardiology, and nephrology) and country, with cardiologists the lowest prescribers, and endocrinologists the highest. Primary care practitioners may experience more challenges in following SGLT-2 inhibitor-related guidelines than diabetes specialists as there may be fewer opportunities for education on how this drug class improves cardiovascular and renal outcomes in patients with T2D. Uptake rates appear to vary between countries because of differences in guidelines and health insurance systems. The amendment of SGLT-2 inhibitor-related guidelines for more multidisciplinary use and the implementation of patient and clinician education may encourage uptake of these drugs, potentially improving long-term health outcomes among patients with T2D.
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Affiliation(s)
- Kamlesh Khunti
- Diabetes Research Centre, College of Medicine, Biological Sciences and PsychologyUniversity of LeicesterLeicesterUK
- NIHR Applied Research Collaboration ‐ East MidlandsLeicesterUK
| | - Serge Jabbour
- Thomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Xavier Cos
- Sant Marti de Provençals Primary Care CentresBarcelonaSpain
- Institut Català de la Salut. IDIAP Jordi Gol. DAP_Cat Study Group CIBERDEMUniversitat Autonoma de BarcelonaBarcelonaSpain
| | - Sunder Mudaliar
- Department of MedicineUniversity of California, San Diego School of MedicineSan DiegoCaliforniaUSA
- Veterans Affairs Medical CenterSan DiegoCaliforniaUSA
| | - Christian Mende
- Department of MedicineUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Marc Bonaca
- Department of Medicine, Division of CardiologyUniversity of Colorado School of Medicine, Aurora CO; CPC Clinical ResearchAuroraColoradoUSA
| | - Paola Fioretto
- Department of MedicineUniversity of Padua, Unite of Medical Clinic 3, Hospital of PaduaPaduaItaly
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de Souza Cordeiro LM, Bainbridge L, Devisetty N, McDougal DH, Peters DJM, Chhabra KH. Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity. Diabetologia 2022; 65:1032-1047. [PMID: 35290476 PMCID: PMC9081162 DOI: 10.1007/s00125-022-05676-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 01/05/2022] [Indexed: 01/14/2023]
Abstract
AIMS/HYPOTHESIS Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity. METHODS We used the tamoxifen-inducible CreERT2-Lox system in mice to knockout Glut2 specifically in the kidneys (Ks-Glut2 KO) to establish the contribution of renal GLUT2 to systemic glucose homeostasis in health and in insulin-dependent as well as non-insulin-dependent diabetes. We measured circulating glucose and insulin levels in response to OGTT or IVGTT under different experimental conditions in the Ks-Glut2 KO and their control mice. Moreover, we quantified urine glucose levels to explain the phenotype of the mice independently of insulin actions. We also used a transcription factor array to identify mechanisms underlying the crosstalk between renal GLUT2 and sodium-glucose cotransporter 2 (SGLT2). RESULTS The Ks-Glut2 KO mice exhibited improved glucose tolerance and massive glucosuria. Interestingly, this improvement in blood glucose control was eliminated when we knocked out Glut2 in the liver in addition to the kidneys, suggesting that the improvement is attributable to the lack of renal GLUT2. Remarkably, induction of renal Glut2 deficiency reversed hyperglycaemia and normalised body weight in mouse models of diabetes and obesity. Longitudinal monitoring of renal glucose transporters revealed that Sglt2 (also known as Slc5a2) expression was almost abolished 3 weeks after inducing renal Glut2 deficiency. To identify a molecular basis for this crosstalk, we screened for renal transcription factors that were downregulated in the Ks-Glut2 KO mice. Hnf1α (also known as Hnf1a) was among the genes most downregulated and its recovery restored Sglt2 expression in primary renal proximal tubular cells isolated from the Ks-Glut2 KO mice. CONCLUSIONS/INTERPRETATION Altogether, these results demonstrate a novel crosstalk between renal GLUT2 and SGLT2 in regulating systemic glucose homeostasis via glucose reabsorption. Our findings also indicate that inhibiting renal GLUT2 is a potential therapy for diabetes and obesity.
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Affiliation(s)
- Leticia Maria de Souza Cordeiro
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Lauren Bainbridge
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Nagavardhini Devisetty
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - David H McDougal
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Dorien J M Peters
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Kavaljit H Chhabra
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.
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Kang DY, Kim H, Ko S, Kim H, Shinn J, Kang MG, Byeon SJ, Choi JH, Shin SY, Kim HS. Sodium-Glucose Cotransporter-2 Inhibitor-Related Diabetic Ketoacidosis: Accuracy Verification of Operational Definition. J Korean Med Sci 2022; 37:e53. [PMID: 35191230 PMCID: PMC8860766 DOI: 10.3346/jkms.2022.37.e53] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 01/05/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The most important aspect of a retrospective cohort study is the operational definition (OP) of the disease. We developed a detailed OP for the detection of sodium-glucose cotransporter-2 inhibitors (SGLT2i) related to diabetic ketoacidosis (DKA). The OP was systemically verified and analyzed. METHODS All patients prescribed SGLT2i at four university hospitals were enrolled in this experiment. A DKA diagnostic algorithm was created and distributed to each hospital; subsequently, the number of SGLT2i-related DKAs was confirmed. Then, the algorithm functionality was verified through manual chart reviews by an endocrinologist using the same OP. RESULTS A total of 8,958 patients were initially prescribed SGLT2i. According to the algorithm, 0.18% (16/8,958) were confirmed to have SGLT2i-related DKA. However, based on manual chart reviews of these 16 cases, there was only one case of SGLT2i-related DKA (positive predictive value = 6.3%). Even after repeatedly narrowing the diagnosis range of the algorithm, the effect of a positive predictive value was insignificant (6.3-10.0%, P > 0.999). CONCLUSION Owing to the nature of electronic medical record data, we could not create an algorithm that clearly differentiates SGLT2i-related DKA despite repeated attempts. In all retrospective studies, a portion of the samples should be randomly selected to confirm the accuracy of the OP through chart review. In retrospective cohort studies in which chart review is not possible, it will be difficult to guarantee the reliability of the results.
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Affiliation(s)
- Dong Yoon Kang
- Drug Safety Monitoring Center, Seoul National University Hospital, Seoul, Korea
| | - Hyunah Kim
- College of Pharmacy, Sookmyung Women's University, Seoul, Korea
| | - SooJeong Ko
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - HyungMin Kim
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jiwon Shinn
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Min-Gyu Kang
- Division of Allergy and Clinical Immunology, Departmemt of Internal Medicine, Chungbuk National University Hospital, Chungbuk National College of Medicine, Cheongju, Korea
| | - Sun-Ju Byeon
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Jeong-Hee Choi
- Department of Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Soo-Yong Shin
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Hun-Sung Kim
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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Zughaib MT, Patel K, Leka M, Affas S. Self-Induced Euglycemic Diabetic Ketoacidosis: When to Stop the Drip. Cureus 2022; 14:e21768. [PMID: 35251838 PMCID: PMC8890007 DOI: 10.7759/cureus.21768] [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] [Accepted: 01/30/2022] [Indexed: 11/19/2022] Open
Abstract
Diabetic ketoacidosis (DKA) is a well-known, serious complication that many patients with type 1 and 2 diabetes face due to either a relative or absolute insulin deficiency. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have gained increased popularity due to their diabetic, cardiovascular, and renal benefits. An associated complication of SGLT2 inhibitors is euglycemic DKA. A 56-year-old male with a history of type 2 diabetes mellitus and peripheral neuropathy presented with right foot pain secondary to a diabetic foot ulcer. The ulcer was present for one year, but the patient noticed increased pain and purulent discharge over the three days prior to presentation. While being treated inpatient for the foot ulcers, the patient repeatedly refused to receive standard hospital diabetes management of insulin injections. He instead insisted to take his home medications against medical advice, which were metformin and Glyxambi® (empagliflozin/linagliptin, Boehringer Ingelheim, Ingelheim am Rhein, Germany). His diabetic foot ulcer was medically managed with IV antibiotics. On day 4 of admission, his anion gap increased to 23 mEq/L, and serum bicarbonate (CO2) decreased to 8 mEq/L, raising concerns of diabetic ketoacidosis. His glucose was 141 mg/dL, his beta-hydroxybutyrate was high at 5.5 mmol/L. An arterial blood gas (ABG) test demonstrated anion gap metabolic acidosis with secondary respiratory alkalosis. A urinalysis demonstrated glucose 1000 mg/dL and ketones of 150 mg/dL. The patient was diagnosed with euglycemic DKA. Due to the patient having normal glucose levels, an insulin drip and a 5% dextrose with 0.45% normal saline drip were started. Basic metabolic profiles were ordered every four hours, with glucose checks every hour. Once the anion gap was closed and his urinary ketones disappeared, the patient transitioned to subcutaneous insulin. He was able to be discharged home with basal subcutaneous insulin and metformin with instructions to avoid SGLT2 inhibitors in the future. Unfortunately, there are currently no guidelines from endocrinology or internal medicine societies regarding the management of euglycemic DKA. As the typical DKA diagnostic criteria of elevated blood glucose level are not present, it is easy to overlook euglycemic DKA. As these SGLT2 inhibitors become more prevalent, careful monitoring of all potential side effects as well as the contraindications are prudent to successful management of complex disease states.
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Zuo M, Meng C, Song Q, Gao Z, Cui X, Wang J, Li Y, Li X, Shan C, Yang J, Chang B. Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway. J Diabetes Res 2022; 2022:3411123. [PMID: 36330072 PMCID: PMC9626228 DOI: 10.1155/2022/3411123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/26/2022] [Indexed: 11/22/2022] Open
Abstract
AIM Patients with diabetic ketosis often exhibit albuminuria. We previously found that acute hyperglycaemia can cause nephrotoxic injury. Here, we explored whether an excessive ketone body level causes kidney injury and the potential underlying mechanism. METHODS Fifty-six type 2 diabetes without ketosis (NDK group), 81 type 2 diabetes with ketosis (DK group), and 38 healthy controls (NC group) were enrolled. Clinical data were collected before and after controlling diabetic ketosis. Beta-hydroxybutyric acid (BOHB), an AKT activator, an AKT inhibitor, or plasmids encoding DAB2 were transformed into human renal proximal tubule epithelial cells (HK-2 cells). RESULTS The urinary albumin-to-creatinine ratio (ACR), transferrin (TF), immunoglobulin G (IgG), Beta2-microglobulin (β2-MG), retinol-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), and Beta-galactosidase (GAL) were higher in the DK than NC and NDK groups. The proportion of patients with an increased urinary level of TF, IgG, β2-MG, RBP, NAG, or GAL was higher in the DK group too. After controlling ketosis, urinary microalbumin, TF, IgG, β2-MG, and RBP decreased significantly. In HK-2 cells, albumin endocytosis and megalin expression decreased with increasing BOHB concentration. Compared with BOHB treatment, BOHB with AKT activator significantly increased the DAB2, megalin levels and albumin endocytosis; the AKT inhibitor treatment exhibited the opposite effects. Compared with BOHB treatment, megalin expression and albumin endocytosis were significantly increased after BOHB with DAB2 overexpression treatment. CONCLUSIONS Patients with diabetic ketosis may suffer from glomerular and tubular injuries that recover after ketosis control. High concentrations of BOHB downregulate megalin expression by inhibiting the AKT/DAB2/megalin signalling pathway and albumin endocytosis in proximal renal tubules.
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Affiliation(s)
- Minxia Zuo
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430070, China
| | - Cheng Meng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Qian Song
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Zhongai Gao
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xiao Cui
- Department of Respiratory and Infectious Diseases, Beijing You An Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Yongmei Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xiaochen Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Chunyan Shan
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Baocheng Chang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
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Wan Azman SS, Sukor N, Abu Shamsi MY, Ismail I, Kamaruddin NA. Case Report: High-Calorie Glucose Infusion and Tight Glycemic Control in Ameliorating Refractory Acidosis of Empagliflozin-Induced Euglycemic Diabetic Ketoacidosis. Front Endocrinol (Lausanne) 2022; 13:867647. [PMID: 35712244 PMCID: PMC9197436 DOI: 10.3389/fendo.2022.867647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/11/2022] [Indexed: 01/10/2023] Open
Abstract
The current widespread use of sodium-glucose co-transporter 2 (SGLT2) inhibitors has triggered an increase in reported cases of euglycemic diabetic ketoacidosis (EDKA), often characterized by a protracted metabolic acidosis that is resistant to conventional DKA treatment. We report a case of empagliflozin-induced EDKA with severe metabolic acidosis intractable to aggressive fluid resuscitation and boluses of bicarbonate infusion. Following the introduction of high-calorie glucose infusion coupled with tight glycemic control, the recalcitrant acidosis was successfully corrected. This is the first case report that adopts the above approach, representing a paradigm shift in the management of SGLT2 inhibitor-induced EDKA.
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Gomez-Sanchez CM, Wu BX, Gotts JE, Chang RW. Euglycemic diabetic ketoacidosis following major vascular surgery is a new item on the differential for postoperative acidosis. J Vasc Surg Cases Innov Tech 2021; 7:778-780. [PMID: 34816071 PMCID: PMC8591455 DOI: 10.1016/j.jvscit.2021.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/13/2021] [Indexed: 11/23/2022] Open
Abstract
New pharmacologic advances in the treatment of diabetes include SGLT-2 inhibitors, which have been demonstrated in randomized-controlled clinical trials to reduce overall and cardiac-specific mortality and slow progression of chronic kidney disease. Euglycemic diabetic ketoacidosis is a rare but life-threatening complication associated with the use of SGLT-2 inhibitors. Here we describe a case of severe euglycemic diabetic ketoacidosis after lower extremity bypass in a patient taking an SGLT-2 inhibitor. Awareness of this potential complication is essential as these novel agents are increasingly used in patients with cardiovascular disease.
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Alhumaid S, Al Mutair A, Al Alawi Z, Rabaan AA, Alomari MA, Al Salman SA, Al-Alawi AS, Al Hassan MH, Alhamad H, Al-kamees MA, Almousa FM, Mufti HN, Alwesabai AM, Dhama K, Al-Tawfiq JA, Al-Omari A. Diabetic ketoacidosis in patients with SARS-CoV-2: a systematic review and meta-analysis. Diabetol Metab Syndr 2021; 13:120. [PMID: 34702335 PMCID: PMC8547563 DOI: 10.1186/s13098-021-00740-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 10/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND One possible reason for increased mortality due to SARS-CoV-2 in patients with diabetes is from the complication of diabetic ketoacidosis (DKA). OBJECTIVES To re-evaluate the association of SARS-CoV-2 and development of DKA and analyse the demographic and biochemical parameters and the clinical outcomes in COVID-19 patients with DKA. DESIGN A systematic review and meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed. METHODS Electronic databases (Proquest, Medline, Embase, Pubmed, CINAHL, Wiley online library, Scopus and Nature) were searched from 1 December 2019 to 30 June 2021 in the English language using the following keywords alone or in combination: COVID-19 OR SARS-CoV-2 AND diabetic ketoacidosis OR DKA OR ketosis OR ketonemia OR hyperglycaemic emergency OR hyperglycaemic crisis. We included studies in adults and children of all ages in all healthcare settings. Binary logistic regression model was used to explore the effect of various demographic and biochemical parameters variables on patient's final treatment outcome (survival or death). RESULTS Of the 484 papers that were identified, 68 articles were included in the systematic review and meta-analysis (54 case report, 10 case series, and 4 cohort studies). Studies involving 639 DKA patients with confirmed SARS-CoV-2 [46 (7.2%) were children and 334 (52.3%) were adults] were analyzed. The median or mean patient age ranged from < 1 years to 66 years across studies. Most of the patients (n = 309, 48.3%) had pre-existing type 2 diabetes mellitus. The majority of the patients were male (n = 373, 58.4%) and belonged to Hispanic (n = 156, 24.4%) and black (n = 98, 15.3%) ethnicity. The median random blood glucose level, HbA1c, pH, bicarbonate, and anion gap in all included patients at presentation were 507 mg/dl [IQR 399-638 mg/dl], 11.4% [IQR 9.9-13.5%], 7.16 [IQR 7.00-7.22], 10 mmol/l [IQR 6.9-13 mmol/l], and 24.5 mEq/l [18-29.2 mEq/l]; respectively. Mortality rate was [63/243, 25.9%], with a majority of death in patients of Hispanic ethnicity (n = 17, 27%; p = 0.001). The odd ratios of death were significantly high in patients with pre-existing diabetes mellitus type 2 [OR 5.24, 95% CI 2.07-15.19; p = 0.001], old age (≥ 60 years) [OR 3.29, 95% CI 1.38-7.91; p = 0.007], and male gender [OR 2.61, 95% CI 1.37-5.17; p = 0.004] compared to those who survived. CONCLUSION DKA is not uncommon in SARS-CoV-2 patients with diabetes mellitus and results in a mortality rate of 25.9%. Mortality key determinants in DKA patients with SARS-CoV-2 infection are individuals with pre-existing diabetes mellitus type 2, older age [≥ 60 years old], male gender, BMI ≥ 30, blood glucose level > 1000 mg/dl, and anion gap ≥ 30 mEq/l.
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Affiliation(s)
- Saad Alhumaid
- Administration of Pharmaceutical Care, Al-Ahsa Health Cluster, Ministry of Health, Rashdiah Street, P. O. Box 12944, Al-Ahsa, 31982 Saudi Arabia
| | - Abbas Al Mutair
- Research Center, Almoosa Specialist Hospital, Al-Ahsa, Saudi Arabia
- College of Nursing, Princess Norah Bint Abdul Rahman University, Riyadh, Saudi Arabia
- School of Nursing, University of Wollongong, Wollongong, Australia
| | - Zainab Al Alawi
- Division of Allergy and Immunology, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Ali A. Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, 11533 Saudi Arabia
- Department of Public Health and Nutrition, The University of Haripur, Haripur, 22610 Pakistan
| | | | - Sadiq A. Al Salman
- Division of Neurology, Internal Medicine Department, King Fahad Hofuf Hospital, Ministry of Health, Al-Ahsa, Saudi Arabia
| | - Ahmed S. Al-Alawi
- Administration of Pharmaceutical Care, Al-Ahsa Health Cluster, Ministry of Health, Rashdiah Street, P. O. Box 12944, Al-Ahsa, 31982 Saudi Arabia
| | - Mohammed H. Al Hassan
- Administration of Nursing, Al-Ahsa Health Cluster, Ministry of Health, Al-Ahsa, Saudi Arabia
| | - Hesham Alhamad
- Regional Medical Supply, Al-Ahsa Health Cluster, Ministry of Health, Al-Ahsa, Saudi Arabia
| | - Mustafa A. Al-kamees
- Primary Care Medicine, Al-Ahsa Health Cluster, Ministry of Health, Al-Ahsa, Saudi Arabia
| | - Fawzi M. Almousa
- Department of Pharmacy, Al Jaber Hospital for Eye, Ear, Nose and Throat, Al-Ahsa, Saudi Arabia
| | - Hani N. Mufti
- Department of Cardiac Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
- Department Cardiac Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
- Department of Medical Research, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Ali M. Alwesabai
- Department of Restorative Dentistry, King Faisal General Hospital, Ministry of Health, Al-Ahsa, Saudi Arabia
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Uttar Pradesh, Izatnagar, Bareilly, 243122 India
| | - Jaffar A. Al-Tawfiq
- Infectious Disease Unit, Specialty Internal Medicine, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
- Infectious Disease Division, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN USA
- Infectious Disease Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Awad Al-Omari
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Research Center, Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia
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Anderson JC, Mattar SG, Greenway FL, Lindquist RJ. Measuring ketone bodies for the monitoring of pathologic and therapeutic ketosis. Obes Sci Pract 2021; 7:646-656. [PMID: 34631141 PMCID: PMC8488448 DOI: 10.1002/osp4.516] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/29/2021] [Accepted: 04/11/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The ketone bodies β-hydroxybutyrate (BOHB) and acetone are generated as a byproduct of the fat metabolism process. In healthy individuals, ketone body levels are ∼0.1 mM for BOHB and ∼1 part per million for breath acetone (BrAce). These levels can increase dramatically as a consequence of a disease process or when used therapeutically for disease treatment. For example, increased ketone body concentration during weight loss is an indication of elevated fat metabolism. Ketone body measurement is relatively inexpensive and can provide metabolic insights to help guide disease management and optimize weight loss. METHODS This review of the literature provides metabolic mechanisms and typical concentration ranges of ketone bodies, which can give new insights into these conditions and rationale for measuring ketone bodies. RESULTS Diseases such as heart failure and ketoacidosis can affect caloric intake and macronutrient management, which can elevate BOHB 30-fold and BrAce 1000-fold. Other diseases associated with obesity, such as brain dysfunction, cancer, and diabetes, may cause dysfunction because of an inability to use glucose, excessive reliance on glucose, or poor insulin signaling. Elevating ketone body concentrations (e.g., nutritional ketosis) may improve these conditions by forcing utilization of ketone bodies, in place of glucose, for fuel. During weight loss, monitoring ketone body concentration can demonstrate program compliance and can be used to optimize the weight-loss plan. CONCLUSIONS The role of ketone bodies in states of pathologic and therapeutic ketosis indicates that accurate measurement and monitoring of BOHB or BrAce will likely improve disease management. Bariatric surgery is examined as a case study for monitoring both types of ketosis.
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Affiliation(s)
- Joseph C. Anderson
- Department of BioengineeringUniversity of WashingtonSeattleWashingtonUSA
| | - Samer G. Mattar
- Department of SurgeryBaylor College of MedicineHoustonTexasUSA
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Palmer BF, Clegg DJ. Euglycemic Ketoacidosis as a Complication of SGLT2 Inhibitor Therapy. Clin J Am Soc Nephrol 2021; 16:1284-1291. [PMID: 33563658 PMCID: PMC8455044 DOI: 10.2215/cjn.17621120] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are drugs designed to lower plasma glucose concentration by inhibiting Na+-glucose-coupled transport in the proximal tubule. Clinical trials demonstrate these drugs have favorable effects on cardiovascular outcomes to include slowing the progression of CKD. Although most patients tolerate these drugs, a potential complication is development of ketoacidosis, often with a normal or only a minimally elevated plasma glucose concentration. Inhibition of sodium-glucose cotransporter-2 in the proximal tubule alters kidney ATP turnover so that filtered ketoacids are preferentially excreted as Na+ or K+ salts, leading to indirect loss of bicarbonate from the body and systemic acidosis under conditions of increased ketogenesis. Risk factors include reductions in insulin dose, increased insulin demand, metabolic stress, low carbohydrate intake, women, and latent autoimmune diabetes of adulthood. The lack of hyperglycemia and nonspecific symptoms of ketoacidosis can lead to delays in diagnosis. Treatment strategies and various precautions are discussed that can decrease the likelihood of this complication.
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Affiliation(s)
- Biff F. Palmer
- Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Deborah J. Clegg
- Associate Dean for Research, College of Nursing and Health Professionals, Drexel University, Philadelphia, Pennsylvania
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Papanastasiou L, Glycofridi S, Gravvanis C, Skarakis N, Papadimitriou I, Kanti G, Kapsali C, Kounadi T. Diabetic ketoacidosis in patients treated with SGLT2 inhibitors: experience at a tertiary hospital. Hormones (Athens) 2021; 20:369-376. [PMID: 33151508 DOI: 10.1007/s42000-020-00256-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/23/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE Diabetic ketoacidosis (DKA) is a rare and life-threatening complication in patients with diabetes. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have rarely been associated with ketoacidosis. The aim of this retrospective study was to investigate DKA episodes occurring after SGLT2i treatment and to compare them to DKA episodes due to other causes. METHODS The medical records of the years 2018-2020 related to clinical and biochemical characteristics and to treatment of six patients with DKA due to SGLT2i were reviewed. They were compared to those of 12 patients with DKA due to other causes. RESULTS On admission, the most common symptom was abdominal pain. Glucose levels (median, min-max) were lower in patients with SGLT2i-induced DKA compared to those with DKA due to other causes (229 (150-481) vs. 458.5 (332-695) mg/dl, p = 0.007), whereas no statistical difference was observed in HbA1c and in the severity of DKA (pH, HCO3, CO2, and anion gap). The duration of insulin infusion (41 (33-124) vs. 21.50 (11-32) h, p < 0.001) and the time required until DKA resolution (39 (31-120) vs. 19 (9-28) h, p < 0.001) were higher in patients with SGLT2i-induced DKA than those with DKA due to other causes. In addition, there were increased fluid requirements (14 (8-22.75) vs. 5.5 (2-24) L, p = 0.013) and longer hospitalization time (11 (6-22) vs. 5.5 (2-14) days, p = 0.024) in patients with SGLT2i-induced DKA. No statistically significant differences were observed in total intravenous insulin and potassium administration until DKA resolution. CONCLUSIONS Patients with SGLT2i-induced DKA had lower serum glucose levels on admission and required increased fluid administration and longer time to recover from acidosis compared to patients with DKA from other causes.
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Affiliation(s)
- Labrini Papanastasiou
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece.
| | - Spyridoula Glycofridi
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece
| | - Christos Gravvanis
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece
| | - Nikitas Skarakis
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece
| | - Irene Papadimitriou
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece
| | - Georgia Kanti
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece
| | - Chara Kapsali
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece
| | - Theodora Kounadi
- Unit of Endocrinology and Diabetes Center, Athens General Hospital "G. Gennimatas", 154 Mesogion Avenue, 115 27, Athens, Greece
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36
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Itzhak B, Home P. Heart failure management; a perspective from diabetes care. Diabetes Res Clin Pract 2021; 176:108849. [PMID: 33957144 DOI: 10.1016/j.diabres.2021.108849] [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: 03/30/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 10/21/2022]
Abstract
People with type 2 diabetes (T2DM) are recognized as having a 2-4 times increased risk of heart failure (HF). Ambulatory diabetes care has long concentrated on the prevention of microvascular and arterial disease, and surveillance for manageable problems such as with the feet and retinae. Accordingly, management of heart failure has never been a specific focus, although the preventative management of cardiac and kidney disease through glucose-lowering, blood pressure (BP) control, and blood lipid control, have had a positive impact on its incidence. Indeed, the very complexity of routine diabetes care, and its enormous prevalence, has generally excluded the management of any of the advanced late complications, whether cardiac, arterial, retinal, renal, or neurodegenerative. Furthermore, advances in HF management itself, in diagnostics, medications, and technology, has carried it deeper into the remit of specialist cardiological care. More recently and in addition to medications already routinely used in diabetes care such as renin-angiotensin system (RAS) blockers, some glucose-lowering therapies such as sodium glucose transporter inhibitors 2 (SGLT-2 inhibitors), have been found to have very positive effects on hospitalization for HF, indeed even in people who do not have T2DM. Here, from the perspective of the diabetologist, we review the clinical scenario of ambulatory diabetes care, in regard of how HF prevention and management should fit in to clinical practice.
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Affiliation(s)
| | - Philip Home
- Newcastle University, Newcastle upon Tyne, UK
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37
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Nasa P, Chaudhary S, Shrivastava PK, Singh A. Euglycemic diabetic ketoacidosis: A missed diagnosis. World J Diabetes 2021; 12:514-523. [PMID: 33995841 PMCID: PMC8107974 DOI: 10.4239/wjd.v12.i5.514] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/01/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Euglycemic diabetic ketoacidosis (DKA) is an acute life-threatening metabolic emergency characterized by ketoacidosis and relatively lower blood glucose (less than 11 mmol/L). The absence of hyperglycemia is a conundrum for physicians in the emergency department and intensive care units; it may delay diagnosis and treatment causing worse outcomes. Euglycemic DKA is an uncommon diagnosis but can occur in patients with type 1 or type 2 diabetes mellitus. With the addition of sodium/ glucose cotransporter-2 inhibitors in diabetes mellitus management, euglycemic DKA incidence has increased. The other causes of euglycemic DKA include pregnancy, fasting, bariatric surgery, gastroparesis, insulin pump failure, cocaine intoxication, chronic liver disease and glycogen storage disease. The pathophysiology of euglycemic DKA involves a relative or absolute carbohydrate deficit, milder degree of insulin deficiency or resistance and increased glucagon/insulin ratio. Euglycemic DKA is a diagnosis of exclusion and should be considered in the differential diagnosis of a sick patient with a history of diabetes mellitus despite lower blood glucose or absent urine ketones. The diagnostic workup includes arterial blood gas for metabolic acidosis, serum ketones and exclusion of other causes of high anion gap metabolic acidosis. Euglycemic DKA treatment is on the same principles as for DKA with correction of dehydration, electrolytes deficit and insulin replacement. The dextrose-containing fluids should accompany intravenous insulin to correct metabolic acidosis, ketonemia and to avoid hypoglycemia.
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Affiliation(s)
- Prashant Nasa
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
| | - Sandeep Chaudhary
- Department of Endocrinology, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
| | | | - Aanchal Singh
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
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38
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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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39
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Ferrannini E, Rosenstock J. Clinical Translation of Cardiovascular Outcome Trials in Type 2 Diabetes: Is There More or Is There Less Than Meets the Eye? Diabetes Care 2021; 44:641-646. [PMID: 33608325 PMCID: PMC7896267 DOI: 10.2337/dc20-0913] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 11/30/2020] [Indexed: 02/03/2023]
Abstract
Randomized controlled trials (RCTs) have become the gold standard of clinical evidence and the staple of guided clinical practice. RCTs are based on a complex set of principles and procedures heavily strung by statistical analysis, primarily designed to answer a specific question in a clinical experiment. Readers of clinical trials need to apply critical appraisal skills before blindly accepting the results and conclusions of trials, lest they misinterpret and misapply the findings. We introduce the fundamentals of an RCT and discuss the relationship between relative risk (RR) and absolute risk (AR) in terms of the different information each conveys. The top results of some recent cardiovascular outcome trials using sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes are used to exemplify the merit of assessing both RR and AR changes for a balanced translation of findings into shrewd clinical judgment. We also suggest practical points to assist with a clinically useful interpretation of both within-trial and across-trial reports. Finally, we mention an alternative approach, namely, the restricted mean survival time, to obtaining unbiased estimates of the mean time of missed events in the treatment versus placebo arm for the duration of the trial.
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40
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Vadasz B, Arazi M, Shukha Y, Koren O, Taher R. Sodium-glucose cotransporter-2-induced euglycemic diabetic ketoacidosis unmasks latent autoimmune diabetes in a patient misdiagnosed with type 2 diabetes mellitus: a case report. J Med Case Rep 2021; 15:62. [PMID: 33581735 PMCID: PMC7882073 DOI: 10.1186/s13256-020-02607-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 11/30/2020] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Euglycemic diabetic ketoacidosis is an uncommon but life-threatening complication associated with the use of sodium-glucose cotransporter 2 inhibitors that causes lower than expected blood glucose levels typically seen in diabetic ketoacidosis. CASE PRESENTATION We present a case of 64-year-old Caucasian male patient previously diagnosed with type 2 diabetes treated with a sodium-glucose cotransporter 2 inhibitor who developed severe ketoacidosis. Serum glucose levels on initial presentation were slightly above normal baseline level. The patient was revealed to have latent autoimmune diabetes in adults. CONCLUSION This case highlights the importance of prescribing sodium-glucose cotransporter 2 inhibitors to the correct patient population and the significance of accurately differentiating between various types of diabetes.
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Affiliation(s)
- Brian Vadasz
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Mattan Arazi
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Yousef Shukha
- Internal Medicine Department E, Rambam HealthCare Campus, Ein IbrahimUmm alfahm, POD 4147, 300100 Haifa, Israel
| | - Ofir Koren
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Heart Institute, Emek Medical Center, Afula, Israel
| | - Riad Taher
- Internal Medicine Department E, Rambam HealthCare Campus, Ein IbrahimUmm alfahm, POD 4147, 300100 Haifa, Israel
- Department of Endocrinology, Rambam HealthCare Campus, Haifa, Israel
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41
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Meena P, Bhargava V, Bhalla A, Rana D, Mantri A. Effect of sodium-glucose cotransporter-2 inhibitors on renal handling of electrolytes. Postgrad Med J 2021; 97:819-824. [PMID: 33563713 DOI: 10.1136/postgradmedj-2020-139348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/12/2021] [Accepted: 01/15/2021] [Indexed: 01/19/2023]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the latest introduction into the armamentarium of diabetes care in the present decade. By virtue of their beneficial effects, such as blood pressure-lowering, bodyweight reduction and significant renal and cardioprotective effects which extends beyond their glycaemic control effects, SGLT2i have become one of the most preferred oral antihyperglycaemic agents of recent times. However, they can influence tubular handling of electrolytes that can result in some electrolyte disturbances such as alteration in the serum levels of magnesium, potassium and phosphate levels. Some of these changes are mild or transient and may not have significant clinical implications. The underlying putative mechanism(s) responsible for disturbances of electrolytes are yet to be deciphered. In this review, we aim to describe electrolytes and acid-base abnormalities due to SGLT2i as well as to elucidate the underlying mechanism.
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Affiliation(s)
- Priti Meena
- Nephrology, Sir Ganga Ram Hospital, New Delhi, Delhi, India
| | | | - Anil Bhalla
- Nephrology, Sir Ganga Ram Hospital, New Delhi, Delhi, India
| | - Devinder Rana
- Nephrology, Sir Ganga Ram Hospital, New Delhi, Delhi, India
| | - Alok Mantri
- Medicine, GB Pant Hospital, New Delhi, Delhi, India
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Dashora U, Patel DC, Gregory R, Winocour P, Dhatariya K, Rowles S, Macklin A, Rayman G, Nagi D. Association of British Clinical Diabetologists (ABCD) and Diabetes UK joint position statement and recommendations on the use of sodium-glucose cotransporter inhibitors with insulin for treatment of type 1 diabetes (Updated October 2020). Diabet Med 2021; 38:e14458. [PMID: 33179277 DOI: 10.1111/dme.14458] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 10/29/2020] [Accepted: 11/06/2020] [Indexed: 12/30/2022]
Abstract
Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two of the drugs of SGLT inhibitor class which have been recommended by the National Institute for Health and Care Excellence (NICE) in people with type 1 diabetes with BMI ≥27 kg/m2 . Dapagliflozin is licensed in the UK for use in the NHS while sotagliflozin may be available in future. These and possibly other SGLT inhibitors may be increasingly used in people with type 1 diabetes as new licences are obtained. These drugs have the potential to improve glycaemic control in people with type 1 diabetes with the added benefit of weight loss, better control of blood pressure and more time in optimal glucose range. However, SGLT inhibitors are associated with a higher incidence of diabetic ketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK joint updated position statement is to guide people with type 1 diabetes and clinicians using these drugs help mitigate this risk and other potential complications. Particularly, caution needs to be exercised in people who are at risk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, starvation, excessive exercise, excessive alcohol consumption and reduced insulin administration among other precipitating factors for diabetic ketoacidosis.
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Affiliation(s)
| | - Dipesh C Patel
- Division of Medicine, University College London, Royal Free Campus, London, UK
| | - Robert Gregory
- University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Peter Winocour
- ENHIDE, East and North Hertfordshire NHS Trust, Hertfordshire, UK
| | - Ketan Dhatariya
- Norfolk and Norwich University Hospitals NHS Foundation Trust, UK
| | | | | | - Gerry Rayman
- Norfolk and Norwich University Hospitals NHS Foundation Trust, UK
| | - Dinesh Nagi
- Edna Coates Diabetes and Endocrine Unit, Pinderfields Hospital, Wakefield, UK
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Utsunomiya K, Koshida R, Kakiuchi S, Senda M, Fujii S, Kurihara Y, Gunji R, Kaku K. Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real-world clinical practice: Results of a 36-month post-marketing surveillance study (J-STEP/LT). J Diabetes Investig 2021; 12:184-199. [PMID: 32597517 PMCID: PMC7858109 DOI: 10.1111/jdi.13333] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/27/2020] [Accepted: 06/14/2020] [Indexed: 12/20/2022] Open
Abstract
AIMS/INTRODUCTION Tofogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3-year prospective observational post-marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J-STEP/LT]). MATERIALS AND METHODS This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. RESULTS Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion-related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were -0.68 ± 1.34% (n = 6,158, P < 0.0001) and -3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively. CONCLUSIONS J-STEP/LT, a 3-year, prospective, observational, post-marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus.
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Affiliation(s)
- Kazunori Utsunomiya
- Center for Preventive MedicineThe Jikei University School of MedicineTokyoJapan
| | | | - Seigo Kakiuchi
- Post Marketing Surveillance DepartmentKowa Company, Ltd.TokyoJapan
| | | | - Shoko Fujii
- Post Marketing Surveillance DepartmentKowa Company, Ltd.TokyoJapan
| | - Yuji Kurihara
- Post Marketing Surveillance DepartmentKowa Company, Ltd.TokyoJapan
| | - Ryoji Gunji
- Post Marketing Surveillance DepartmentKowa Company, Ltd.TokyoJapan
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44
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Latif A, Gastelum AA, Sood A, Reddy JT. Euglycaemic diabetic ketoacidosis in a 43-year-old woman with type 2 diabetes mellitus on SGLT-2 inhibitor (empagliflozin). Drug Ther Bull 2021; 59:93-95. [PMID: 33509834 DOI: 10.1136/dtb.2021.235117rep] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Azka Latif
- Internal Medicine, CHI Health Creighton University Medical Center Bergan Mercy, Omaha, Nebraska, USA.,CHI Creighton Health, Creighton University Medical Center-University Campus, Omaha, Nebraska, USA
| | - Aheli Arce Gastelum
- Internal Medicine, CHI Health Creighton University Medical Center Bergan Mercy, Omaha, Nebraska, USA
| | - Akshat Sood
- Internal Medicine, CHI Health Creighton University Medical Center Bergan Mercy, Omaha, Nebraska, USA
| | - Joseph Thilumala Reddy
- Internal Medicine, CHI Health Creighton University Medical Center Bergan Mercy, Omaha, Nebraska, USA
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45
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Mashraqi MM, Chaturvedi N, Alam Q, Alshamrani S, Bahnass MM, Ahmad K, Alqosaibi AI, Alnamshan MM, Ahmad SS, Beg MMA, Mishra A, Shaikh S, Rizvi SMD. Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs. Molecules 2021; 26:582. [PMID: 33499241 PMCID: PMC7866138 DOI: 10.3390/molecules26030582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/16/2021] [Accepted: 01/19/2021] [Indexed: 01/05/2023] Open
Abstract
The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (-)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH's adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of -5.65 kcal/mol and 71.95 µM, -5.50 kcal/mol and 92.97 µM, and -5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.
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Affiliation(s)
- Mutaib M. Mashraqi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia; (M.M.M.); (S.A.); (M.M.B.)
| | - Navaneet Chaturvedi
- Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India; (N.C.); (A.M.)
- Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester Henry Wellcome Building, Lancaster Road Leicester, Leicester LE1 7HB, UK
| | - Qamre Alam
- Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia;
| | - Saleh Alshamrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia; (M.M.M.); (S.A.); (M.M.B.)
| | - Mosa M. Bahnass
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia; (M.M.M.); (S.A.); (M.M.B.)
- Department of Animal Medicine (Infectious Diseases), Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Khurshid Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea; (K.A.); (S.S.A.); (M.M.A.B.)
| | - Amany I. Alqosaibi
- Department of Biology, College of Science, Imam Abdulrahman bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (A.I.A.); (M.M.A.)
| | - Mashael M. Alnamshan
- Department of Biology, College of Science, Imam Abdulrahman bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia; (A.I.A.); (M.M.A.)
| | - Syed Sayeed Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea; (K.A.); (S.S.A.); (M.M.A.B.)
| | - Mirza Masroor Ali Beg
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea; (K.A.); (S.S.A.); (M.M.A.B.)
| | - Abha Mishra
- Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India; (N.C.); (A.M.)
| | - Sibhghatulla Shaikh
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea; (K.A.); (S.S.A.); (M.M.A.B.)
| | - Syed Mohd Danish Rizvi
- Department of Pharmaceutics, College of Pharmacy, University of Hail, P.O. Box 2440, Hail 81451, Saudi Arabia
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46
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Großmann S, Hoffmann U, Girlich C. [Confusion, tachypnea, and tachycardia in a 71-year-old man with type 2 diabetes mellitus]. Internist (Berl) 2021; 62:672-678. [PMID: 33411015 PMCID: PMC7788531 DOI: 10.1007/s00108-020-00930-w] [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] [Accepted: 12/08/2020] [Indexed: 11/14/2022]
Abstract
Bei Patienten mit Diabetes mellitus Typ 2 muss im Falle einer unklaren Bewusstseinsstörung und/oder Bauchschmerzen eine Natrium/Glukose-Kotransporter-2(SGLT-2)-Inhibitor-induzierte diabetische Ketoazidose in die Differenzialdiagnose einbezogen werden. Dabei können die Blutzuckerspiegel trotz ausgeprägter Azidose nur moderat erhöht sein. Bei Nachweis ist eine umgehende intensivmedizinische Therapie unerlässlich.
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Affiliation(s)
- S Großmann
- Klinik für Pneumologie und konservative Intensivmedizin, Krankenhaus Barmherzige Brüder Regensburg, Prüfeninger Straße 86, 93049, Regensburg, Deutschland.
| | - U Hoffmann
- Klinik für Allgemeine Innere Medizin und Geriatrie, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Deutschland
| | - C Girlich
- Klinik für Allgemeine Innere Medizin und Geriatrie, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Deutschland
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Marrs JC, Anderson SL. Ertugliflozin in the treatment of type 2 diabetes mellitus. Drugs Context 2020; 9:dic-2020-7-4. [PMID: 33293984 PMCID: PMC7707814 DOI: 10.7573/dic.2020-7-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 12/17/2022] Open
Abstract
More than 422 million people worldwide have diabetes, with 90–95% having type 2 diabetes (T2D). Glycemic control of T2D has demonstrated reductions in microvascular complications but recent data have demonstrated improvements in macrovascular outcomes with sodium–glucose cotransporter 2 (SGLT2) inhibitors. Ertugliflozin is the most recent SGLT2 inhibitor approved in the USA and Europe for the treatment of T2D. This narrative review aims to present and discuss the efficacy, safety, cardiovascular (CV), and renal outcomes related to the use of ertugliflozin in T2D. Ertugliflozin has been evaluated in eight clinical trials (n=5248) with a focus on glycemic control. These trials have demonstrated improvement in glycosylated hemoglobin (0.6–1%), fasting plasma glucose (30–50 mg/dL), 2-hour postprandial glucose (60–70 mg/dL), decreased body weight (2–3 kg), and lowering of blood pressure (3–5 mmHg) in patients with T2D when ertugliflozin is used as monotherapy or in addition to metformin, sitagliptin, insulin, and/or sulfonylureas. The findings from the VERTIS-CV trial (n=8246) were recently published and demonstrated that ertugliflozin use in patients with T2D and atherosclerotic CV disease is safe but did not demonstrate superiority in the lowering of major CV events compared to placebo. Other SGLT2 inhibitors, such as empagliflozin and canagliflozin, have demonstrated this benefit. The VERTIS-CV trial demonstrated that the use of ertugliflozin led to a decrease in the number of hospitalizations for heart failure and this lends further support that this benefit is a class effect of SGLT2 inhibitors.
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Affiliation(s)
- Joel C Marrs
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Sarah L Anderson
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
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Giorgino F, Vora J, Fenici P, Solini A. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc Diabetol 2020; 19:196. [PMID: 33222693 PMCID: PMC7680601 DOI: 10.1186/s12933-020-01163-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin-angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.
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Affiliation(s)
- Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Policlinico, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
| | - Jiten Vora
- Diabetes and Endocrinology, University of Liverpool, Liverpool, UK
| | | | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
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Aggarwal A, Jain A, Sachdeva S, Kulairi ZI. Prolonged Glucosuria With Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Case Report and Review of Literature. Cureus 2020; 12:e11554. [PMID: 33365222 PMCID: PMC7748582 DOI: 10.7759/cureus.11554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors assert their role as an anti-diabetic medication by reversibly inhibiting sodium-glucose cotransporters in the renal proximal tubules and resulting in enhanced glucose excretion. Due to their reversible effect on the transporters in the proximal tubule, it is expected that all their metabolic effects, including glucose excretion, should also cease in two to three days, as per their half-life of 10-15 hours. However, it is increasingly being observed that the glycosuric effect of SGLT2 inhibitors persists beyond this duration and, in many cases, exceeds their other known metabolic effects, which resolve sooner. We present a case report of a 53-year-old diabetic male who developed SGLT2 inhibitor-related euglycemic diabetic ketoacidosis (EuDKA) two days after being discharged post a laparoscopic appendectomy procedure. The patient was treated as per the recommended protocols, after which ongoing metabolic acidosis abated, but the patient’s urinary glucose remained on the higher end. We present an up-to-date review of existing evidence on this rare but serious side effect of SGLT2 inhibitors.
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50
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Wiciński M, Wódkiewicz E, Górski K, Walczak M, Malinowski B. Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer's Disease and Ischemia-Related Brain Injury. Pharmaceuticals (Basel) 2020; 13:ph13110379. [PMID: 33187206 PMCID: PMC7697611 DOI: 10.3390/ph13110379] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/22/2020] [Accepted: 11/05/2020] [Indexed: 12/15/2022] Open
Abstract
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in cortical regions of APP/PS1xd/db mice. The same effect was noticed regarding tau pathology and brain atrophy volume. Empagliflozin presented beneficial effect on cognitive function, which may be connected to an increase in cerebral brain-derived neurotrophic factor. Canagliflozin and dapagliflozin may possess acetylcholinesterase inhibiting activity, resembling in this matter Alzheimer’s disease-registered therapies. SGLT2 inhibitors may prove to impact risk factors of atherosclerosis and pathways participating both in acute and late stage of stroke. Their mechanism of action can be related to induction in hepatocyte nuclear factor-1α, vascular endothelial growth factor-A, and proinflammatory factors limitation. Empagliflozin may have a positive effect on preservation of neurovascular unit in diabetic mice, preventing its aberrant remodeling. Canagliflozin seems to present some cytostatic properties by limiting both human and mice endothelial cells proliferation. The paper presents potential mechanisms of SGLT-2 inhibitors in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia.
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