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Cuttone A, Cannavò V, Abdullah RMS, Fugazzotto P, Arena G, Brancati S, Muscarà A, Morace C, Quartarone C, Ruggeri D, Squadrito G, Russo GT. Expanding the Use of SGLT2 Inhibitors in T2D Patients Across Clinical Settings. Cells 2025; 14:668. [PMID: 40358192 PMCID: PMC12071329 DOI: 10.3390/cells14090668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/30/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025] Open
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are currently recommended in patients with type 2 diabetes (T2D) to reduce serum glucose levels. Moreover, robust evidence has clearly demonstrated their beneficial cardiovascular and renal effects, making this class of drugs pivotal for the treatment of T2D, especially when complicated by diabetic kidney disease or heart failure. However, several other comorbidities are frequently encountered in T2D patients beyond these long-term diabetes complications, especially in the internal medicine setting. For some of these comorbidities, such as MAFLD and cognitive impairment, the association with diabetes is increasingly recognized, with the hypothesis of a common pathophysiologic background, whereas, for others, a coincident epidemiology linked to the ageing of populations, including that of T2D subjects, may be advocated. In the effort of personalizing T2D treatment, evidence on the potential effects of SGLT2i in these different clinical conditions is accumulating. The purpose of this narrative review is to update current literature on the effects of SGLT2i for the treatment of T2D in different clinical settings beyond glycaemic control, and to elucidate potential molecular mechanisms by which they exert these effects.
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Affiliation(s)
- Alessandro Cuttone
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Vittorio Cannavò
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Raouf Mastan Sheik Abdullah
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Pierluigi Fugazzotto
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Giada Arena
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Simona Brancati
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Andrea Muscarà
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Carmela Morace
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Cristina Quartarone
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (C.Q.); (D.R.)
| | - Domenica Ruggeri
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (C.Q.); (D.R.)
| | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
| | - Giuseppina Tiziana Russo
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy; (V.C.); (R.M.S.A.); (P.F.); (G.A.); (S.B.); (A.M.); (C.M.); (G.S.); (G.T.R.)
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Raven LM, Lever W, MacIsaac RJ, Greenfield JR, Deane A, Plummer M, Umapathysivam M. Heterogeneity in the management of diabetic ketoacidosis in Australia: a national survey. Intern Med J 2025; 55:728-733. [PMID: 40045881 PMCID: PMC12077586 DOI: 10.1111/imj.70024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/06/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Diabetic ketoacidosis (DKA) is a hyperglycaemic emergency, and insulin administration is highly protocolised with either variable- or fixed-rate intravenous infusions. There are limited data supporting superiority of one regimen over another; however, international guidelines recommend fixed-rate infusions. AIM To characterise DKA management protocols used in Australian hospitals. METHODS An online survey of Australian endocrinologists and intensive care physicians between May and July 2024. The main outcome measure was the proportion of respondents using a fixed or variable rate, or combination, for the management of DKA. Secondary outcomes were the location of management, definition of resolution and intravenous fluid specification. RESULTS There were 31 respondents from individual hospitals around Australia, with 84% of endocrinologists and 84% from metropolitan hospitals. There was wide variation in insulin regimens including fixed (n = 12), variable (n = 14) and combination (n = 5) infusion protocols. Most (23/30, 77%) respondents had worked at another hospital that had a different DKA management protocol. There was a 50% split (n = 14 each) in personal preference for fixed- or variable-rate infusion, with three respondents having no preference. Most (21/31, 68%) protocols defined resolution of DKA. Blood pH (15/21, 71%) and/or ketone level (18/21, 86%) were the most frequently used end points to define resolution. CONCLUSIONS There are substantial variations in insulin regimens and resolution criteria in DKA management protocols across Australian hospitals. Clinician preference was diverse. This likely reflects the lack of high-quality evidence to guide practice.
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Affiliation(s)
- Lisa M. Raven
- Department of Diabetes and EndocrinologySt Vincent's HospitalSydneyNew South WalesAustralia
- Clinical Diabetes, Appetite and Metabolism LaboratoryGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
- School of Clinical Medicine, St Vincent's Campus, Faculty of Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
| | - William Lever
- Faculty of Health and Medical SciencesUniversity of AdelaideAdelaideSouth AustraliaAustralia
- Department of Intensive CareRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Richard J. MacIsaac
- Department of Endocrinology & DiabetesSt Vincent's Hospital MelbourneMelbourneVictoriaAustralia
- University of Melbourne, Department of MedicineSt Vincent's Hospital MelbourneMelbourneVictoriaAustralia
- Australian Centre for Accelerating Diabetes InnovationsUniversity of MelbourneMelbourneVictoriaAustralia
| | - Jerry R. Greenfield
- Department of Diabetes and EndocrinologySt Vincent's HospitalSydneyNew South WalesAustralia
- Clinical Diabetes, Appetite and Metabolism LaboratoryGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
- School of Clinical Medicine, St Vincent's Campus, Faculty of Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
| | - Adam Deane
- University of Melbourne, Melbourne Medical SchoolDepartment of Critical CareMelbourneVictoriaAustralia
- Department of Intensive CareRoyal Melbourne HospitalMelbourneVictoriaAustralia
| | - Mark Plummer
- Faculty of Health and Medical SciencesUniversity of AdelaideAdelaideSouth AustraliaAustralia
- Department of Intensive CareRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Mahesh Umapathysivam
- Faculty of Health and Medical SciencesUniversity of AdelaideAdelaideSouth AustraliaAustralia
- Southern Adelaide Diabetes and Endocrine ServiceFlinders Medical CentreAdelaideSouth AustraliaAustralia
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Yamagishi H, Kawasaki A, Seki T, Ohshima A, Imai T. Comparison between blood ketone and blood gas analysis indices in management of diabetic ketoacidosis. J Rural Med 2025; 20:119-124. [PMID: 40182163 PMCID: PMC11962183 DOI: 10.2185/jrm.2024-032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 12/27/2024] [Indexed: 04/05/2025] Open
Abstract
Objective Blood ketone monitoring is commonly used in the management of diabetic ketoacidosis (DKA). However, bedside ketone meters have limited availability in hospitals. This study aimed to clarify the correlation between blood ketones and blood gas analysis (BGA) in the treatment of DKA and thereby identify parameters that can be used as surrogates for blood ketones. Patients and Methods This retrospective observational study included patients with DKA admitted to the JA Toride General Medical Center between November 2021 and March 2024. Multiple regression analysis was performed using blood ketone levels as the objective variable and BGA indices as explanatory variables. Additionally, the study evaluated 1) the time course of ketone levels and BGA indices during the DKA treatment and 2) the correlation between ketone levels and the BGA indices. Results Sixteen patients were enrolled. Multiple regression analysis showed that the corrected anion gap (cAG), defined as the anion gap minus lactate concentration, was a significant predictor of blood ketones. Among pH, HCO3 -, and cAG, only cAG had significant regression coefficients (-0.061 [95% confidence interval (CI): -3.49 to 1.98], -0.233 [-0.156 to 0.0118], 0.636 [0.129 to 0.246], respectively; coefficient of determination: 0.765). The correlation coefficient between cAG and blood ketone levels was high (0.9694). Conclusion cAG levels strongly correlate with blood ketone concentrations and may serve as a surrogate marker for blood ketones in the management of DKA. Because measurements of the anion gap and lactate concentrations are inexpensive and widely available in most medical facilities, cAG is a promising indicator for DKA management.
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Affiliation(s)
- Hirofumi Yamagishi
- Department of Endocrinology and Metabolism, JA Toride General
Medical Center, Japan
| | - Akiko Kawasaki
- Department of Endocrinology and Metabolism, Tokyo Teishin
Hospital, Japan
| | - Takami Seki
- Department of Diabetology and Endocrinology, Tokyo
Metropolitan Hiroo Hospital, Japan
| | - Atsushi Ohshima
- Department of Diabetology and Endocrinology, Ome Medical
Center, Japan
| | - Taihei Imai
- Department of Endocrinology and Metabolism, JA Toride General
Medical Center, Japan
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Sebastian-Valles F, Tapia-Sanchiz MS, Navas-Moreno V, Lopez-Ruano M, Martínez-Otero C, Carrillo-López E, Sager La Ganga C, Raposo-López JJ, Amar S, González-Castañar S, Von Wernitz Teleki A, Del Arco C, Arranz-Martín JA, Marazuela M. Chronic treatment with SGLT-2 inhibitors is associated with ICU admission and disease severity in patients with diabetic ketoacidosis: a propensity score-matched cohort study. Intern Emerg Med 2025; 20:431-440. [PMID: 39556290 DOI: 10.1007/s11739-024-03813-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/28/2024] [Indexed: 11/19/2024]
Abstract
SGLT-2 inhibitors (SGLT-2i) are linked to a higher risk of diabetic ketoacidosis (DKA). However, it is still unclear whether the severity of SGLT-2i associated DKA is higher. This is a retrospective cohort study with patients admitted for DKA at a tertiary hospital (2013-2024). Patients were matched by propensity score for age, sex, diabetes duration, type, and ischemic heart disease. ICU admission risk and clinical severity were compared between SGLT-2i users and controls. The matched sample included 105 subjects (35 SGLT-2i users, 70 controls). The average age was 63.1 ± 15.4 years, and 40 (38.1%) patients were women. ICU admission was higher in the treatment group (65.7% versus 24.6%, p < 0.001). A conditional logistic regression showed higher risk of ICU admission in the treatment group (odds ratio 12.7, 95% confidence interval 1.9-84.3, p = 0.009) after adjusting for confounding factors. The treatment group exhibited less favorable blood gas results (pH 7.10 ± 0.17 vs 7.18 ± 0.16, p = 0.024) and shorter symptom duration (2 [1-3] vs 3 [2-7] days, p < 0.002). No significant differences were found in diabetes type, ketonemia, creatinine, or DKA precipitating factors. DKA in patients with diabetes treated with SGLT-2i is associated with more severe acidosis with quicker onset, leading to higher risk of ICU admission compared to patients not receiving this treatment. We recommend temporary discontinuation of SGLT-2i during any acute event until resolution, regardless of diabetes type or the patient's glycemic control.
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Affiliation(s)
- Fernando Sebastian-Valles
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain.
| | - Maria Sara Tapia-Sanchiz
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Victor Navas-Moreno
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Marta Lopez-Ruano
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Carmen Martínez-Otero
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Elena Carrillo-López
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Carolina Sager La Ganga
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Juan José Raposo-López
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Selma Amar
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Sara González-Castañar
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | | | - Carmen Del Arco
- Emergency Department, Hospital Universitario de La Princesa, Madrid, Spain
| | - Jose Alfonso Arranz-Martín
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
| | - Mónica Marazuela
- Department of Endocrinology and Nutrition, Universidad Autónoma de Madrid, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria de La Princesa, Diego de León 62, 28005, Madrid, Spain
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Panda P, Mohapatra R, Samantaray B. Insightful Perspectives on Sodium-glucose Co-transporter 2 Inhibitors: Navigating Safety Updates and Beyond. Curr Drug Res Rev 2025; 17:19-32. [PMID: 40183146 DOI: 10.2174/0125899775332399240806101923] [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: 06/13/2024] [Revised: 07/04/2024] [Accepted: 07/22/2024] [Indexed: 04/05/2025]
Abstract
SGLT2 (Sodium-Glucose Co-transporter 2) inhibitors, also known as gliflozin class, are a novel family of oral drugs being used to treat type 2 diabetes. SGLT2 inhibitors can work alone or in conjunction with other medications. This class includes five drugs, including canagliflozin, ertugliflozin, sotagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors inhibit the SGLT2 cotransporter in the proximal tubules of the kidney, reducing glucose and sodium reabsorption. It promotes the elimination of sugar in urine (diabetes mellitus) and lowers blood sugar levels. SGLT2 inhibitors also have pleiotropic effects on cardiac and renal function, broadening their therapeutic applications in heart failure. Despite the clinical benefits, regulators have placed secondary warnings in product information since the medications first hit the market. SGLT2 inhibitors, in particular, have had a significant impact on a variety of risk factors. This can lead to hypoglycaemia, urinary tract infections, diabetic ketoacidosis, lower limb amputation, and fractures. Although some of these events are uncommon, they can lead to severe and deadly consequences; therefore, patients must be closely monitored. In general, SLGT2 inhibitors are an efficient diabetes treatment with strong cardiovascular and renal protection and a favourable safety overview. This review sought to summarise the safety overview of commercially available SGLT2 inhibitors.
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Affiliation(s)
- Pratikeswar Panda
- Department of Pharmaceutics, School of Pharmaceutical Science, Siksha 'O' Anusandhan University, Bhubaneswar, Odisha, India
| | - Rajaram Mohapatra
- Department of Pharmaceutics, School of Pharmaceutical Science, Siksha 'O' Anusandhan University, Bhubaneswar, Odisha, India
| | - Biswajit Samantaray
- Department of Pharmaceutics, School of Pharmaceutical Science, Siksha 'O' Anusandhan University, Bhubaneswar, Odisha, India
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Devkota B, Maxwell T, Schaedel J, Wagener BM, Song W, Nooli NP. Intraoperative Diagnosis of Sodium-Glucose Transporter-2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis. Cureus 2024; 16:e71931. [PMID: 39564057 PMCID: PMC11575501 DOI: 10.7759/cureus.71931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2024] [Indexed: 11/21/2024] Open
Abstract
Sodium-glucose transporter 2 inhibitors (SGLT2i) are increasingly used in diabetic patients having cardiovascular and renal comorbidities. Despite their benefits for glucose control and reducing cardiovascular complications, they are not without risks. We present a case of euglycemic diabetic ketoacidosis (DKA) in a 60-year-old male with metastatic melanoma and type 2 diabetes mellitus (DM) on empagliflozin, undergoing craniotomy for brain tumor resection. Intraoperatively, high anion gap metabolic acidosis with normal blood sugar levels was observed, leading to the diagnosis of euglycemic DKA. Management included immediate initiation of intravenous insulin with dextrose, which was continued in the neuro-intensive care unit (NICU) postoperatively for three days. Euglycemic DKA is sometimes tricky to diagnose due to the absence of significant hyperglycemia as the name suggests, potentially delaying recognition by clinicians. Early detection, intravenous insulin with dextrose, correction of metabolic derangements, and discontinuation of SGLT2i are essential components of management. This case underscores the necessity of considering euglycemic DKA in SGLT2i-treated patients undergoing surgery, particularly when metabolic acidosis with a high anion gap is present despite normal blood glucose levels.
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Affiliation(s)
- Bibek Devkota
- Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, USA
| | - Timothy Maxwell
- Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, USA
| | - Jessica Schaedel
- Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, USA
| | - Brant M Wagener
- Anesthesiology and Critical Care, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, USA
| | - Weifeng Song
- Anesthesiology and Critical Care, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, USA
| | - Nishank Patel Nooli
- Cardiac Anesthesiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, USA
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Lee MKH, Ball PA. Euglycemic diabetic ketoacidosis in the setting of acute intracerebral hemorrhage. Surg Neurol Int 2024; 15:284. [PMID: 39246790 PMCID: PMC11380825 DOI: 10.25259/sni_295_2024] [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: 04/17/2024] [Accepted: 07/12/2024] [Indexed: 09/10/2024] Open
Abstract
Background Diabetic ketoacidosis (DKA) is a life-threatening condition among diabetic patients characterized by metabolic anion gap (AG) acidosis of arterial pH <7.30, glucose >250 mg/dL, and positive ketones. The triggers for DKA can be infection, surgery, and, in reported cases, intraparenchymal hemorrhage (IPH). In rare cases of DKA, despite being in active ketoacidosis, glucose levels may be within normal or accepted range. Such a condition is called euglycemic DKA. It has been recently recognized in association with the use of sodium glucose co-transporter-2 (SGLT-2) inhibitors in the treatment of type 2 diabetes. Case Description An 83-year-old male taking an SGLT-2 inhibitor (empagliflozin) for type 2 diabetes presented with an IPH. His laboratory studies revealed an elevated AG acidosis, an elevated beta hydroxybutyrate, and serum glucose levels within the acceptable range. Urine studies revealed elevated ketones and glucose. The diagnosis of euglycemic DKA was made, and the patient was treated with insulin and glucose infusions. Conclusion Like hyperglycemic ketoacidosis, euglycemic DKA requires prompt recognition and immediate aggressive medical therapy, but the diagnosis can be challenging, and the treatment using insulin in the setting of a normal glucose can be counterintuitive. Euglycemic DKA can often be missed in the setting of blood glucose not being elevated. Prompt recognition and treatment are critical for successful management.
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Affiliation(s)
| | - Perry A Ball
- Department of Surgery, Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, United States
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Seki H, Kuratani N, Shiga T, Iwasaki Y, Karita K, Yasuda K, Yamamoto N, Nakanishi Y, Shigematsu K, Kobayashi K, Saito J, Kondo I, Yaida N, Watanabe H, Higashi M, Shirasaka T, Doshu-Kajiura A, Edanaga M, Tanaka S, Ikumi S, Ito S, Okada M, Yorozu T. Incidence of sodium-glucose cotransporter-2 inhibitor-associated perioperative ketoacidosis in surgical patients: a prospective cohort study. J Anesth 2024; 38:464-474. [PMID: 38494577 PMCID: PMC11284185 DOI: 10.1007/s00540-024-03335-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/04/2024] [Indexed: 03/19/2024]
Abstract
PURPOSE Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients. METHODS We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis. RESULTS In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%). CONCLUSIONS The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases.
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Affiliation(s)
- Hiroyuki Seki
- Department of Anesthesiology, Kyorin University School of Medicine, Tokyo, Japan.
| | - Norifumi Kuratani
- Department of Anesthesia, Saitama Children's Medical Center, Saitama, Japan
| | - Toshiya Shiga
- Department of Anesthesiology, School of Medicine, International University of Health and Welfare, Chiba, Japan
| | - Yudai Iwasaki
- Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Kanae Karita
- Department of Hygiene and Public Health, Kyorin University School of Medicine, Tokyo, Japan
| | - Kazuki Yasuda
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan
| | - Natsuko Yamamoto
- Department of Anaesthesia and Intensive Care Medicine, Graduate School of Medicine and Faculty of Medicine, Akita University, Akita, Japan
| | - Yuko Nakanishi
- Department of Anesthesiology and Reanimatology, University of Fukui Hospital, Fukui, Japan
| | - Kenji Shigematsu
- Department of Anesthesiology, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Kensuke Kobayashi
- Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Junichi Saito
- Department of Anesthesiology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan
| | - Ichiro Kondo
- Department of Anesthesiology, The Jikei University School of Medicine, Tokyo, Japan
| | - Nozomu Yaida
- Department of Anesthesiology and Intensive Care Medicine, Kawasaki Medical School, Okayama, Japan
| | - Hidenobu Watanabe
- Department of Anesthesiology, Kyorin University School of Medicine, Tokyo, Japan
| | - Midoriko Higashi
- Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tetsuro Shirasaka
- Department of Anesthesiology and Intensive Care, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Akira Doshu-Kajiura
- Department of Anesthesiology, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsutaka Edanaga
- Department of Anesthesiology, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Satoshi Tanaka
- Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, Nagano, Japan
| | - Saori Ikumi
- Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Shingo Ito
- Department of Anesthesiology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Masayuki Okada
- Department of Anesthesiology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Tomoko Yorozu
- Department of Anesthesiology, Kyorin University School of Medicine, Tokyo, Japan
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Kamath SD, Kumar U, Shrivastava V. Sodium-Glucose Cotransporter 2 Inhibitor-Induced Euglycemic Diabetic Ketoacidosis: The Other Side of the Coin! Cureus 2024; 16:e58341. [PMID: 38756291 PMCID: PMC11095996 DOI: 10.7759/cureus.58341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2024] [Indexed: 05/18/2024] Open
Abstract
Euglycemic diabetic ketoacidosis (EDKA) though rare is a life-threatening complication of sodium-glucose cotransporter 2 (SGLT2) inhibitors. With their increasing use in the management of type 2 diabetes mellitus (T2DM) due to long-term beneficial effects, the incidence of this complication is on the rise. We report a case of a 58-year-old lady with a history of T2DM on multiple anti-diabetes medications including dapagliflozin for one year, who during intercurrent illness developed EDKA. Her blood sugar on admission was 203 mg/dL, and arterial blood gas showed high anion-gap metabolic acidosis (HAGMA) with ketonuria and ketonemia (blood beta-hydroxybutyric (BOHB) acid level: 5.4 mmol/L). Low carbohydrate intake, dehydration resulting from repeated vomiting, and skipping the previous two days' dose of insulin could have precipitated this condition. She was treated with intravenous fluids, insulin, 5% dextrose infusion, and potassium supplements with complete resolution of acidosis after about 90 hours. This case signifies the importance of awareness of the link between the use of SGLT2 inhibitors and EDKA and early recognition of this complication to reduce morbidity and mortality. Furthermore, it also emphasizes the need for clinicians to educate their patients taking these drugs to stop them during the intercurrent illness to prevent them from developing EDKA.
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Affiliation(s)
| | - Umesh Kumar
- General Medicine, Tata Main Hospital, Jamshedpur, IND
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10
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Umapathysivam MM, Gunton J, Stranks SN, Jesudason D. Euglycemic Ketoacidosis in Two Patients Without Diabetes After Introduction of Sodium-Glucose Cotransporter 2 Inhibitor for Heart Failure With Reduced Ejection Fraction. Diabetes Care 2024; 47:140-143. [PMID: 37988720 PMCID: PMC10733652 DOI: 10.2337/dc23-1163] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 10/17/2023] [Indexed: 11/23/2023]
Abstract
OBJECTIVE Ketoacidosis induced by sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment has been consistently observed in clinical practice in patients with type 2 diabetes despite minimal indication from the landmark cardiovascular outcome trials. It has been postulated that individuals without diabetes will not develop this complication due to an adequate insulin secretory capacity, which will protect against significant ketone formation. Cardiovascular outcome trials examining SGLT2i use in individuals with heart failure but not diabetes have not reported ketoacidosis. RESEARCH DESIGN AND METHODS We describe the first two case reports of severe nondiabetic ketoacidosis after initiation of an SGLT2i for the treatment of heart failure with reduced ejection fraction, and we describe the management strategies employed and implication for the pathophysiology of SGLT2i-associated ketoacidosis. RESULTS Each individual presented with ketoacidosis triggered by reduced oral nutrition intake. For both individuals, ketoacidosis resolved with intravenous glucose administration, encouragement of consumption of oral glucose-containing fluid, and minimal insulin administration. CONCLUSIONS These two cases demonstrate that SGLT2i-associated ketoacidosis is possible in individuals without diabetes.
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Affiliation(s)
- Mahesh M. Umapathysivam
- Southern Adelaide Diabetes and Endocrine Services, Flinders Medical Centre, Adelaide, South Australia, Australia
- Endocrine Department, Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- University of Adelaide, Adelaide, South Australia, Australia
- Basil Hetzel Institute, Woodville South, South Australia, Australia
| | - James Gunton
- Flinders University, Adelaide, South Australia, Australia
- Department of Cardiovascular Medicine, Flinders Medical Centre, Adelaide, South Australia, Australia
| | - Steve N. Stranks
- Southern Adelaide Diabetes and Endocrine Services, Flinders Medical Centre, Adelaide, South Australia, Australia
- Flinders University, Adelaide, South Australia, Australia
| | - David Jesudason
- Endocrine Department, Queen Elizabeth Hospital, Woodville South, South Australia, Australia
- University of Adelaide, Adelaide, South Australia, Australia
- Basil Hetzel Institute, Woodville South, South Australia, Australia
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11
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Koutentakis M, Kuciński J, Świeczkowski D, Surma S, Filipiak KJ, Gąsecka A. The Ketogenic Effect of SGLT-2 Inhibitors-Beneficial or Harmful? J Cardiovasc Dev Dis 2023; 10:465. [PMID: 37998523 PMCID: PMC10672595 DOI: 10.3390/jcdd10110465] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 11/25/2023] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, also called gliflozins or flozins, are a class of drugs that have been increasingly used in the management of type 2 diabetes mellitus (T2DM) due to their glucose-lowering, cardiovascular (CV), and renal positive effects. However, recent studies suggest that SGLT-2 inhibitors might also have a ketogenic effect, increasing ketone body production. While this can be beneficial for some patients, it may also result in several potential unfavorable effects, such as decreased bone mineral density, infections, and ketoacidosis, among others. Due to the intricate and multifaceted impact caused by SGLT-2 inhibitors, this initially anti-diabetic class of medications has been effectively used to treat both patients with chronic kidney disease (CKD) and those with heart failure (HF). Additionally, their therapeutic potential appears to extend beyond the currently investigated conditions. The objective of this review article is to present a thorough summary of the latest research on the mechanism of action of SGLT-2 inhibitors, their ketogenesis, and their potential synergy with the ketogenic diet for managing diabetes. The article particularly discusses the benefits and risks of combining SGLT-2 inhibitors with the ketogenic diet and their clinical applications and compares them with other anti-diabetic agents in terms of ketogenic effects. It also explores future directions regarding the ketogenic effects of SGLT-2 inhibitors.
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Affiliation(s)
- Michail Koutentakis
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
| | - Jakub Kuciński
- Central Clinical Hospital, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
| | - Damian Świeczkowski
- Department of Toxicology, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdańsk, Poland;
| | - Stanisław Surma
- Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland;
| | - Krzysztof J. Filipiak
- Department of Clinical Sciences, Maria Sklodowska-Curie Medical Academy, 00-001 Warsaw, Poland;
- Department of Hypertensiology, Angiology and Internal Medicine, Poznań University of Medical Sciences, 61-848 Poznań, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
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12
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Kirk JK, Gonzales CF. Preoperative considerations for patients with diabetes. Expert Rev Endocrinol Metab 2023; 18:503-512. [PMID: 37937905 DOI: 10.1080/17446651.2023.2272865] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 10/16/2023] [Indexed: 11/09/2023]
Abstract
INTRODUCTION Patients undergoing surgery require a thorough assessment preoperatively. Hyperglycemia is associated with poor outcomes, and stability of glucose levels is an important factor in preoperative management. Diabetes presents a particular challenge since patients are often on multiple medications encompassing glycemic management and cardiovascular therapies. AREAS COVERED A PubMed search of published data and reviews on preoperative approaches in diabetes was conducted. Consensus opinion drives most of the guidelines and recommendations for management of diabetes in surgical patients. Pathophysiology is often complex with varying levels of glucose and surgical stress. Establishing well-controlled diabetes prior to surgical intervention should be standard practice in non-emergent procedures. We review the best practices for implementing preoperative assessment, with diabetes with a focus on diabetes medications. EXPERT OPINION The management of a patient preoperatively varies by region and country. Institutions differ in approaches to preoperative evaluation and the establishment of consistent approaches would provide a platform for monitoring patient outcomes. Multidisciplinary teams and pre-assessment clinics for preoperative evaluation can enhance patient care for those undergoing surgery.
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Affiliation(s)
- Julienne K Kirk
- Department of Family and Community Medicine, Medical Center Boulevard, Atrium Health Wake Forest Baptist, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
| | - Clifford F Gonzales
- Academic Nursing, Wake Forest University School of Medicine, Winston Salem, North Carolina
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13
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Khedr A, Hennawi HA, Khan MK, Eissa A, Mir M, Rauf I, Nitesh J, Surani S, Khan SA. Sodium-glucose cotransporter-2 inhibitor-associated euglycemic diabetic ketoacidosis in COVID-19-infected patients: A systematic review of case reports. World J Clin Cases 2023; 11:5700-5709. [PMID: 37727728 PMCID: PMC10506011 DOI: 10.12998/wjcc.v11.i24.5700] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/13/2023] [Accepted: 07/28/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Diabetic ketoacidosis (DKA) manifests as hyperglycemia, metabolic acidosis, and ketosis. However, euglycemic DKA (eu-DKA) conceals severe DKA with glucose levels below 200 mg/dL. Sodium-glucose cotransporter-2 (SGLT2) inhibitors can induce eu-DKA in diabetic patients. Notably, coronavirus disease 2019 (COVID-19) -infected individuals with diabetes using SGLT2 inhibitors face an augmented risk of eu-DKA due to the direct toxic impact of the virus on pancreatic islets. This study aims to comprehensively investigate the association between SGLT2 inhibitors and eu-DKA in COVID-19 patients through meticulous case report analysis. Additionally, we endeavor to examine the outcomes and treatment approaches for COVID-19-infected diabetics receiving SGLT2 inhibitors, providing indispensable insights for healthcare professionals managing this specific patient population. AIM To investigate the connection between SGLT2 inhibitors and euglycemic DKA in COVID-19 patients through a meticulous analysis of case reports. METHODS We conducted an exhaustive search across prominent electronic databases, including PubMed, SCOPUS, Web of Science, and Google Scholar. This search encompassed the period from December 2019 to May 2022, incorporating published studies and pre-prints. The search terms employed encompassed "SGLT2 inhibitors", "euglycemic DKA", "COVID-19", and related variations. By incorporating these diverse sources, our objective was to ensure a thorough exploration of the existing literature on this subject, thereby augmenting the validity and robustness of our findings. RESULTS Our search yielded a total of seven case reports and one case series, collectively comprising a cohort of twelve patients. These reports detailed instances of eu-DKA in individuals with COVID-19. Crucially, all twelve patients were utilizing SGLT2 as their primary anti-diabetic medication. Upon admission, all oral medications were promptly discontinued, and the patients were initiated on intravenous insulin therapy to effectively manage the DKA. Encouragingly, eleven patients demonstrated a favorable outcome, while regrettably, one patient succumbed to the condition. Subsequently, SGLT2 were discontinued for all patients upon their discharge from the hospital. These findings provide valuable insights into the clinical management and outcomes of eu-DKA cases associated with COVID-19 and SGLT2, underscoring the critical importance of prompt intervention and vigilant medication adjustments. CONCLUSION Our study sheds light on the possibility of diabetic patients developing both drug-related and unrelated DKA, as well as encountering adverse outcomes in the context of COVID-19, despite maintaining satisfactory glycemic control. The relationship between glycemic control and clinical outcomes in COVID-19 remains ambiguous. Consequently, this systematic review proposes that COVID-19-infected diabetic patients using SGLT2 should contemplate alternative treatment protocols until their recovery from the disease.
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Affiliation(s)
- Anwar Khedr
- Department of Medicine, Bronx Care Health System, Bronx, NY 10457, United States
| | - Hussam Al Hennawi
- Department of Internal Medicine, Jefferson Abington Hospital, Abington, PA 19001, United States
| | - Muhammed Khuzzaim Khan
- Department of Internal Medicine, Dow University of Health Science, Karachi 74200, Pakistan
| | - Aalaa Eissa
- Department of Medicine, Kafrelsheikh University, KFS 33511, Egypt
| | - Mikael Mir
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States
| | - Ibtisam Rauf
- Department of Medicine, St. George’s University, School of Medicine, St. George SW17 0RE, Grenada
| | - Jain Nitesh
- Department of Critical Care, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Salim Surani
- Department of Medicine & Pharmacology, Texas A&M University, College Station, TX 77843, United States
| | - Syed Anjum Khan
- Department of Critical Care Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
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Thiruvenkatarajan V, Inglis JM, Meyer E, Umapathysivam MM, Nanjappa N, Van Wijk R, Jesudason D. Peri-colonoscopy Implications of Sodium-Glucose Cotransporter-2 Inhibitor Therapy: A Mini-review of Available Evidence. Can J Diabetes 2023; 47:287-291. [PMID: 36739255 DOI: 10.1016/j.jcjd.2022.12.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/26/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a class of oral glucose-lowering agents commonly used for the treatment of type 2 diabetes. With increased use, there has been an increase in the incidence of the rare but life-threatening complication of euglycemic diabetic ketoacidosis. A common but underappreciated precipitant is colonoscopy. In this work, we outline the pathophysiology of the interaction between colonoscopy and SGLT2i use, the evidence regarding SGLT2i use in the periprocedural setting and Australian Diabetes Society guidelines.
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Affiliation(s)
- Venkatesan Thiruvenkatarajan
- Department of Anaesthesia, Queen Elizabeth Hospital, South Australia, Australia; Discipline of Acute Care Medicine, University of Adelaide, South Australia, Australia; Basil Hetzel Institute, South Australia, Australia.
| | - Joshua M Inglis
- Department of Endocrinology and Diabetes, Queen Elizabeth Hospital, South Australia, Australia; School of Medicine, University of Adelaide, South Australia, Australia; College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Emily Meyer
- Department of Endocrinology and Diabetes, Queen Elizabeth Hospital, South Australia, Australia; School of Medicine, University of Adelaide, South Australia, Australia
| | - Mahesh M Umapathysivam
- Department of Endocrinology and Diabetes, Queen Elizabeth Hospital, South Australia, Australia; School of Medicine, University of Adelaide, South Australia, Australia
| | - Nagesh Nanjappa
- Department of Anaesthesia, Queen Elizabeth Hospital, South Australia, Australia; Discipline of Acute Care Medicine, University of Adelaide, South Australia, Australia; Basil Hetzel Institute, South Australia, Australia
| | - Roelof Van Wijk
- Department of Anaesthesia, Queen Elizabeth Hospital, South Australia, Australia; Discipline of Acute Care Medicine, University of Adelaide, South Australia, Australia; Basil Hetzel Institute, South Australia, Australia
| | - David Jesudason
- Department of Endocrinology and Diabetes, Queen Elizabeth Hospital, South Australia, Australia; School of Medicine, University of Adelaide, South Australia, Australia
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15
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He Z, Lam K, Zhao W, Yang S, Li Y, Mo J, Gao S, Liang D, Qiu K, Huang M, Wu J. SGLT-2 inhibitors and euglycemic diabetic ketoacidosis/diabetic ketoacidosis in FAERS: a pharmacovigilance assessment. Acta Diabetol 2023; 60:401-411. [PMID: 36576563 DOI: 10.1007/s00592-022-02015-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/05/2022] [Indexed: 12/29/2022]
Abstract
AIMS To investigate the main feature and the association between euglycemic diabetic ketoacidosis (euDKA) /diabetic ketoacidosis (DKA) and sodium-dependent glucose transporters 2 inhibitors (SGLT-2i) from the FDA adverse event reporting system (FAERS). METHODS Cases of SGLT-2i-associated with euDKA/DKA were extracted from the FAERS database and compared with the reports for other hypoglycemia agents (ATC10 class). Disproportionality analyses used the reporting odds ratio (ROR) and information components (IC). The lower limit of the IC 95% credibility interval for IC > 0 is considered a reported signal, with at least 3 cases. RESULTS A total of 10,195 cases of euDKA (n = 1680) and DKA (n = 8515) associated with SGLT-2i were identified from the FAERS. The SGLT-2i was associated with higher reporting of euDKA and DKA compared to other hypoglycemia agents (ROR = 16.69 [95% CI 14.89-18.70], IC = 3.27 [95% CI 2.91-3.66] for euDKA; ROR = 16.44 [95% CI 15.72-17.20], IC = 3.19 [95% CI 3.05-3.34] for DKA). In available data, the median onset time of euDKA/DKA was 31 days, and canagliflozin had the longest onset time (96.5 days for euDKA and 75 days for DKA) compared with dapagliflozin and empagliflozin (p < 0.05). Male patients predominate in euDKA (51.9%), and female patients predominate in DKA (53.7%). Most patients discontinue the treatment (95.5% for euDKA, 93.9% for DKA), and approximately 49.0% (n = 3658) of patients had symptomatic remission after discontinuation of SGLT-2i, and 2.3% (n = 173) of patients had no remission. About 75.6% (n = 6126) of patients need hospitalization after euDKA/DKA. CONCLUSIONS Post-marketing data showed that SGLT-2i was significantly associated with higher reporting of euDKA/DKA. Although euDKA/DKA is rare, clinicians should be aware of SGLT-2i-associated euDKA/DKA events.
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Affiliation(s)
- Zhichao He
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People's Republic of China
| | - Kakei Lam
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 Waihuan East Road, Guangzhou, 511400, People's Republic of China
| | - Wenxia Zhao
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People's Republic of China
| | - Shan Yang
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People's Republic of China
| | - Yu Li
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 Waihuan East Road, Guangzhou, 511400, People's Republic of China
| | - Jiayao Mo
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 Waihuan East Road, Guangzhou, 511400, People's Republic of China
| | - Siyuan Gao
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People's Republic of China
| | - Dan Liang
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People's Republic of China
| | - Kaifeng Qiu
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People's Republic of China.
| | - Min Huang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 Waihuan East Road, Guangzhou, 511400, People's Republic of China.
| | - Junyan Wu
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, People's Republic of China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People's Republic of China.
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16
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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: 20] [Impact Index Per Article: 10.0] [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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Lejlic S, Holmaas G, Løvås K, Ueland GÅ. Diabetic ketoacidosis with SGLT2 inhibitor use - a patient series. TIDSSKRIFT FOR DEN NORSKE LEGEFORENING 2023; 143:22-0485. [PMID: 36811444 DOI: 10.4045/tidsskr.22.0485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Inhibitors of sodium glucose cotransporter 2 (SGLT2 inhibitors) are increasingly being used to treat type 2 diabetes. Results from previous studies suggest a rising incidence of diabetic ketoacidosis with the use of this medication. MATERIAL AND METHOD We performed a diagnosis search in the electronic patient records at Haukeland University Hospital for the period 1 January 2013-31 May 2021 with the aim of identifying patients with diabetic ketoacidosis who used SGLT2 inhibitors. A total of 806 patient records were reviewed. RESULTS Twenty-one patients were identified. Thirteen had severe ketoacidosis, and ten had normal blood glucose levels. Probable triggering causes were found in 10 of the 21, with recent surgery being the most common (n = 6). Three of the patients were not tested for ketones, and 9 were not tested for antibodies to rule out type 1 diabetes. INTERPRETATION The study showed that severe ketoacidosis occurs in patients with type 2 diabetes using SGLT2 inhibitors. It is important to be aware of this risk and the fact that ketoacidosis can occur without hyperglycaemia. Arterial blood gas and ketone tests must be performed to make the diagnosis.
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Affiliation(s)
| | - Gunhild Holmaas
- Intensivmedisinsk seksjon, Kirurgisk serviceklinikk, Haukeland universitetssjukehus
| | - Kristian Løvås
- Seksjon for hormonsjukdommar, Medisinsk klinikk, Haukeland universitetssjukehus
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18
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Zhao Z, Zhao F, Zhang Y, Hu X, Li J, Tian C, Jin P, Liu D. Risk factors of dapagliflozin-associated diabetic ketosis/ketoacidosis in patients with type 2 diabetes mellitus: A matched case-control study. Diabetes Res Clin Pract 2023; 196:110236. [PMID: 36610546 DOI: 10.1016/j.diabres.2023.110236] [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: 11/07/2022] [Revised: 12/20/2022] [Accepted: 12/23/2022] [Indexed: 01/06/2023]
Abstract
OBJECTIVE To investigate the risk factors of dapagliflozin-associated diabetic ketosis/ketoacidosis (DK/DKA) in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS A case-control study was conducted in a general hospital in China from 2018 to 2021. T2DM patients who developed DK/DKA after dapagliflozin treatment were identified. Each patient in the DA/DKA group was matched with a patient in the non-DK/DKA group in terms of the baseline characteristics. Receiver operating characteristic (ROC) curve analysis and logistic regressions were performed. RESULTS Out of 1,684 hospitalized patients taking dapagliflozin, 170 were diagnosed with dapagliflozin-associated DK/DKA. A total of 137 cases were matched with 137 controls. The mean time-to-onset (TTO) of DK/DKA was 28.59 days. Logistic regression showed that current drinking (OR = 7.656, p < 0.001), T2DM duration ≥ 7.625 years (OR = 2.399, p = 0.017), acute ST-elevations myocardial infarction (STEMI) (OR = 12.770, p = 0.028), acute infection (OR = 2.862, p = 0.043), insulin dose reduction/cessation before dapagliflozin exposure (OR = 6.751, p < 0.001), and a major plus or major operation (OR = 2.652, p = 0.022) were risk factors for dapagliflozin-associated DK/DKA. Furthermore, T2DM duration ≥ 7.625 years (p = 0.046) and acute STEMI (p < 0.001) were independently associated with more severe DK/DKA. CONCLUSION Current drinking, long T2DM duration, STEMI, acute infection, insulin deficiency, and major operation are the risk factors associated with DK/DKA in T2DM patients. Furthermore, long T2DM duration and STEMI were associated with more severe DK/DKA situations.
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Affiliation(s)
- Zinan Zhao
- Department of Pharmacy, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences; Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application (Beijing Hospital), Beijing, PR China
| | - Fei Zhao
- Department of Pharmacy, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences; Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application (Beijing Hospital), Beijing, PR China
| | - Yatong Zhang
- Department of Pharmacy, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences; Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application (Beijing Hospital), Beijing, PR China
| | - Xin Hu
- Department of Pharmacy, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences; Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application (Beijing Hospital), Beijing, PR China
| | - Jianchun Li
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, PR China
| | - Chao Tian
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, PR China
| | - Pengfei Jin
- Department of Pharmacy, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences; Beijing Key Laboratory of Assessment of Clinical Drugs Risk and Individual Application (Beijing Hospital), Beijing, PR China.
| | - Deping Liu
- Department of Cardiology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China.
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Pathak BD, Dhakal B, Bhattarai AM, Regmi BU, Mandal SK, Panta PR, Khadka S, Simkhada N. Euglycemic diabetic ketoacidosis in a patient with acute stroke taking sodium glucose co-transporter 2 inhibitor. Ann Med Surg (Lond) 2022; 79:104118. [PMID: 35860094 PMCID: PMC9289500 DOI: 10.1016/j.amsu.2022.104118] [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: 05/19/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 12/05/2022] Open
Abstract
Introduction Diabetic Ketoacidosis is characterized by a triad of metabolic acidosis, hyperglycemia, and ketonemia. It is a medical emergency that needs urgent and aggressive management. In some cases, the blood glucose level may be relatively normal. Such a condition is known as Euglycemic Diabetic Ketoacidosis. Case presentation We present a case of Euglycemic Diabetic Ketoacidosis, who was initially brought to the emergency room with the features of acute stroke. There was a diagnostic dilemma among the treating physicians due to his relatively normal blood glucose levels while he developed ketoacidosis. Discussion Presentation of the patients includes similar to DKA such as nausea, vomiting, malaise, fatigue, and Kussmaul's respiration. The diabetic patients under sodium glucose co-transporter-2 inhibitor therapy may develop it under the setting of different precipitating factors like infection, trauma/surgery, strenuous physical exercise, fasting, alcohol intake and acute vascular events. Conclusion Euglycemic DKA is a rare condition and its diagnosis is a challenging task. So, we should always consider it as a differential whenever any diabetic patient shows with increased anion gap metabolic acidosis with or without typical symptoms and signs. Also, we need to be aware to discontinue of SGLT-2 medication during the time of infection, surgery, severe trauma, acute illness and dehydration in the diabetic patients.
Diabetic Ketoacidosis is a medical emergency with a triad of metabolic acidosis, hyperglycemia and ketonemia. The precipitating factors includes infection, surgery, fasting, alcohol intake, acute vascular events, trauma and prolonged physical exercise. Patient presents with complaints similar to DKA such as nausea, vomiting, malaise, fatigue, and Kussmaul's respiration. Management includes fluid resuscitation, insulin infusion, dextrose and potassium supplementation.
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20
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Noel JA, Hougen I, Sood MM. The Intersection of SGLT2 Inhibitors, Cognitive Impairment, and CKD. Front Neurol 2022; 13:823569. [PMID: 35800082 PMCID: PMC9253558 DOI: 10.3389/fneur.2022.823569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 05/26/2022] [Indexed: 12/24/2022] Open
Abstract
Impairment in cognition and decline in kidney function often converge in the aging individual with chronic kidney disease (CKD). Cognitive impairment (CI) may be preventable through modification of health behaviors and risk factors that contribute to the vascular disease burden. CKD patients often have multiple coexisting comorbid conditions contributing to vascular risk. These comorbidities include hypertension, diabetes, cerebrovascular disease, and cardiovascular disease. Emerging evidence suggests that the management and prevention of vascular risk factors and cardiovascular diseases may indirectly contribute to the prevention of CI in CKD. Sodium glucose transport protein 2 inhibitors (SGLT2i) are emerging as the standard of care for selected individuals with CKD, type 2 diabetes (T2DM), and heart failure with rapidly expanding indications being actively investigated. In this narrative review, we examine the intriguing hypothesis that SGLT2i demonstrate potential disease modifying properties in CI among individuals with CKD.
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Affiliation(s)
- J. Ariana Noel
- Department of Nephrology, The Ottawa Hospital, Ottawa, ON, Canada
- Postgraduate Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Ingrid Hougen
- Department of Nephrology, The Ottawa Hospital, Ottawa, ON, Canada
- Postgraduate Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Manish M. Sood
- Department of Nephrology, The Ottawa Hospital, Ottawa, ON, Canada
- *Correspondence: Manish M. Sood
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21
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Branco A, Fatima R, Liblik K, Jackson R, Payne D, El-Diasty M. Euglycemic DKA Associated with SGLT2 Inhibitors after Cardiac Surgery, Review of Current Literature. J Cardiothorac Vasc Anesth 2022; 36:3877-3886. [DOI: 10.1053/j.jvca.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/01/2022] [Accepted: 06/10/2022] [Indexed: 11/11/2022]
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22
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Kazakou P, Lambadiari V, Ikonomidis I, Kountouri A, Panagopoulos G, Athanasopoulos S, Korompoki E, Kalomenidis I, Dimopoulos MA, Mitrakou A. Diabetes and COVID-19; A Bidirectional Interplay. Front Endocrinol (Lausanne) 2022; 13:780663. [PMID: 35250853 PMCID: PMC8891603 DOI: 10.3389/fendo.2022.780663] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/11/2022] [Indexed: 01/08/2023] Open
Abstract
There seems to be a bidirectional interplay between Diabetes mellitus (DM) and coronavirus disease 2019 (COVID-19). On the one hand, people with diabetes are at higher risk of fatal or critical care unit-treated COVID-19 as well as COVID-19 related health complications compared to individuals without diabetes. On the other hand, clinical data so far suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may result in metabolic dysregulation and in impaired glucose homeostasis. In addition, emerging data on new onset DM in previously infected with SARS-CoV-2 patients, reinforce the hypothesis of a direct effect of SARS-CoV-2 on glucose metabolism. Attempting to find the culprit, we currently know that the pancreas and the endothelium have been found to express Angiotensin-converting enzyme 2 (ACE2) receptors, the main binding site of the virus. To move from bench to bedside, understanding the effects of COVID-19 on metabolism and glucose homeostasis is crucial to prevent and manage complications related to COVID-19 and support recovering patients. In this article we review the potential underlying pathophysiological mechanisms between COVID-19 and glucose dysregulation as well as the effects of antidiabetic treatment in patients with diabetes and COVID-19.
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Affiliation(s)
- Paraskevi Kazakou
- Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Vaia Lambadiari
- Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Ignatios Ikonomidis
- Laboratory of Preventive Cardiology, Second Cardiology Department, Attikon University Hospital National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Aikaterini Kountouri
- Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Georgios Panagopoulos
- Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavros Athanasopoulos
- Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni Korompoki
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Kalomenidis
- 1 Department of Intensive Care, Evangelismos Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Meletios A. Dimopoulos
- Unit of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Asimina Mitrakou
- Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Asimina Mitrakou,
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23
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Preoperative optimization of diabetes. Int Anesthesiol Clin 2022; 60:8-15. [PMID: 34897217 DOI: 10.1097/aia.0000000000000351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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24
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Seki H, Kuratani N, Shiga T, Iwasaki Y, Karita K, Yasuda K, Yorozu T. Multicentre prospective observational study of sodium-glucose cotransporter-2 inhibitor-associated postoperative ketoacidosis: the SAPKA study protocol. BMJ Open 2021; 11:e049592. [PMID: 34815277 PMCID: PMC8611445 DOI: 10.1136/bmjopen-2021-049592] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antihyperglycaemic agents that promote urinary glucose excretion in the renal proximal tubule and have cardio-protective and renal-protective properties. However, there are several safety concerns related to increased risks of hypoglycaemic, urinary tract infections and ketoacidosis. Ketoacidosis is a potentially fatal complication that often presents as euglycaemic ketoacidosis during SGLT2 inhibitor treatment. Furthermore, invasive treatment and related surgical stress may increase the risk of ketogenesis. Therefore, this study aims to clarify the incidence of SGLT2 inhibitor-associated postoperative ketoacidosis (SAPKA) among patients who are receiving SGLT2 inhibitors and undergoing surgery under general anaesthesia. METHODS AND ANALYSIS This multicentre, prospective, observational study will recruit 750 adult Japanese patients with diabetes who are receiving SGLT2 inhibitors and undergoing surgery under general anaesthesia. Urine samples will be collected on postoperative days 0, 1, 2 and 3. Blood gas analysis will be performed when urine ketone positivity is detected. The incidence of postoperative ketoacidosis will be identified based on urine ketone positivity and a blood pH of ≤7.3. The study will also collect data to identify risk factors for SAPKA. ETHICS AND DISSEMINATION The study protocol has been approved by the ethics committee of Kyorin University (approval number: 785, 26 October 2020) and local ethical approval will be required at each participating centre. Study findings will be submitted to peer-reviewed journals and abstracts will be submitted to relevant national and international meetings. TRIAL REGISTRATION NUMBER UMIN000042795.
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Affiliation(s)
| | | | - Toshiya Shiga
- Anesthesiology, International University of Health and Welfare Ichikawa Hospital, Ichikawa, Japan
| | - Yudai Iwasaki
- Anesthesiology and Perioperative Medicine, Tohoku University, Sendai, Japan
| | - Kanae Karita
- Hygiene and Public Health, Kyorin University, Mitaka, Japan
| | - Kazuki Yasuda
- Diabetes, Endocrinology and Metabolism, Kyorin University, Mitaka, Japan
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25
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Menghoum N, Oriot P, Hermans MP. Clinical and biochemical characteristics and analysis of risk factors for euglycaemic diabetic ketoacidosis in type 2 diabetic individuals treated with SGLT2 inhibitors: A review of 72 cases over a 4.5-year period. Diabetes Metab Syndr 2021; 15:102275. [PMID: 34562870 DOI: 10.1016/j.dsx.2021.102275] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS To study euglycemic diabetic ketoacidosis (euDKA) outcomes associated with sodium-glucose co-transporter 2 inhibitors (SGLT2is) METHODS: Review of 72 euDKA cases in T2DM between September 2015 and January 2020 (PUBMED). RESULTS euDKA could occur at any time during SGLT2is treatment, with nausea, abdominal pain and vomiting as main symptoms. Hyperglycemia did not correlate with pH and β-hydroxybutyrates. Low pH and high β-hydroxybutyrates were significantly associated with euDKA. In biguanides users, acidosis was unrelated to lactic acidosis. euDKA occurred during fasting, surgery, acute infection, insulin deprivation (endogenous or exogenous). CONCLUSIONS These data support avoidance of euDKA risk states in SGLT2i users.
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Affiliation(s)
- N Menghoum
- Department of Internal Medicine, Mouscron Hospital Center, Avenue de Fécamp 49, 7700, Mouscron, Belgium; Pole of Cardiovascular Research, Institute of Experimental and Clinical Research, Catholic University of Louvain, 1200, Brussels, Belgium
| | - P Oriot
- Department of Internal Medicine, Mouscron Hospital Center, Avenue de Fécamp 49, 7700, Mouscron, Belgium; Department of Diabetology, Mouscron Hospital Centre, Avenue de Fécamp 49, 7700, Mouscron, Belgium.
| | - M P Hermans
- Endocrinology & Nutrition Unit, Cliniques Universitaires St-Luc, and Pole of Cardiovascular Research, Institute of Experimental and Clinical Research, Catholic University of Louvain, Avenue Hippocrate 55, 1200, Brussels, Belgium
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26
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Fralick M, Schneeweiss S, Redelmeier DA, Razak F, Gomes T, Patorno E. Comparative effectiveness and safety of sodium-glucose cotransporter-2 inhibitors versus metformin in patients with type 2 diabetes: An observational study using data from routine care. Diabetes Obes Metab 2021; 23:2320-2328. [PMID: 34169619 DOI: 10.1111/dom.14474] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/03/2021] [Accepted: 06/18/2021] [Indexed: 12/28/2022]
Abstract
AIM To assess the effectiveness and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in treatment-naïve patients compared with metformin. PARTICIPANTS AND METHODS We conducted a cohort study of US adults with type 2 diabetes mellitus who had not filled a prescription for a diabetes medication in the preceding year. We then identified patients who newly filled a prescription for an SGLT2 inhibitor or metformin between 2013 and 2018. The primary outcome was a composite of heart failure, myocardial infarction or stroke. Safety outcomes included hypoglycaemia, diabetic ketoacidosis, genital infection, lactic acidosis and acute kidney injury. After 1:1 propensity-score (PS) matching, proportional hazards models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS We identified 9964 individuals newly prescribed an SGLT2 inhibitor who were PS-matched to 9964 individuals newly prescribed metformin. The mean age was 54 years, 52% were women, and the duration of follow-up was 213 days for metformin and 147 days for SGLT2 inhibitors. The primary outcome occurred in 54 patients (7.2 events per 1000 person-years) who received an SGLT2 inhibitor, compared to 84 patients (8.5 per 1000 person-years) who received metformin (HR 0.82, 95% CI 0.58, 1.15). Similar results (HR 0.87, 95% CI 0.69, 1.09) were observed in an analysis with longer follow-up (ie, approximately 600 days). The rates of genital infection (HR 2.28, 95% CI 1.87, 2.78) and diabetic ketoacidosis (HR 1.58, 95% CI 0.92, 2.70) were higher for patients prescribed an SGLT2 inhibitor compared to metformin, while the rates of acute kidney injury (HR 0.94, 95% CI 0.60, 1.47) or hypoglycaemia (HR 0.83, 95% CI 0.48, 1.42) were not. CONCLUSIONS We observed a numerically lower rate of short-/mid-term cardiovascular events for patients newly prescribed an SGLT2 inhibitor compared to metformin, albeit with wide CIs that include the possibility of a null effect. SGLT2 inhibitors were associated with a higher rate of genital infection and diabetic ketoacidosis. Larger cohort studies and long-term clinical trials powered to assess cardiovascular events are necessary to understand the risk-benefit profile of SGLT2 inhibitors as first-line therapy for adults with type 2 diabetes mellitus.
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Affiliation(s)
- Michael Fralick
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Sinai Health, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- ICES in Ontario, Toronto, Ontario, Canada
| | - Sebastian Schneeweiss
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | | | - Fahad Razak
- St Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada
| | - Tara Gomes
- ICES in Ontario, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada
| | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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27
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Kapila V, Topf J. Sodium-Glucose Co-transporter 2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis After Bariatric Surgery: A Case and Literature Review. Cureus 2021; 13:e17093. [PMID: 34527480 PMCID: PMC8432437 DOI: 10.7759/cureus.17093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2021] [Indexed: 12/26/2022] Open
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce cardiovascular, kidney, and overall mortality. SGLT2i are also associated with a rare adverse event, euglycemic diabetic ketoacidosis (EDKA). This report describes a case of EDKA one day after bariatric surgery in a 51-year-old female with type 2 diabetes mellitus managed with the SGLT2i, canagliflozin. She was following a ketogenic diet for three weeks prior to surgery. The patient made a steady recovery with rapid anion gap closure followed by prolonged non-anion gap metabolic acidosis. Her medical record was tagged with a life-threatening reaction to SGLT2i. The risk of EDKA from SGLT2i may be increased by a low carbohydrate diet or postoperative status. Our case was complicated by hypokalemia, exemplifying the need for aggressive electrolyte management. Further guidance is needed to manage risk factors provoking EDKA and the use of SGLT2i therapy after an episode of EDKA.
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Affiliation(s)
- Vaishali Kapila
- Medicine, Central Michigan University College of Medicine, Mt. Pleasant, USA
| | - Joel Topf
- Nephrology, Ascension St. John Hospital, Detroit, USA.,Nephrology, Oakland University William Beaumont School of Medicine, Rochester, USA
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28
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Identifying Risk Factors for Diabetic Ketoacidosis Associated with SGLT2 Inhibitors: a Nationwide Cohort Study in the USA. J Gen Intern Med 2021; 36:2601-2607. [PMID: 33564942 PMCID: PMC8390572 DOI: 10.1007/s11606-020-06561-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 12/22/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Sodium glucose co-transporter-2 inhibitors (SGLT2) are commonly prescribed to patients with type 2 diabetes mellitus, but can increase the risk of diabetic ketoacidosis. Identifying patients prone to diabetic ketoacidosis may help mitigate this risk. METHODS We conducted a population-based cohort study of adults initiating SGLT2 inhibitor use from 2013 through 2017. The primary objective was to identify potential predictors of diabetic ketoacidosis. Two machine-learning methods were applied to model high-dimensional pre-exposure data: gradient boosted trees and least absolute shrinkage and selection operator (LASSO) regression. We rank ordered the variables produced from LASSO by the size of their estimated coefficient (largest to smallest). With gradient boosted trees, a relative importance measure for each variable is provided rather than a coefficient. The "top variables" were identified after reviewing the distributions of the effect estimates from LASSO and gradient boosted trees to identify where there was a substantial decrease in variable importance. The identified predictors were then assessed in a logistic regression model and reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS We identified 111,442 adults who started SGLT2 inhibitor use. The mean age was 57 years, 44% were female, the mean hemoglobin A1C was 8.7%, and the mean creatinine was 0.89 mg/dL. During a mean follow-up of 180 days, 192 patients (0.2%, i.e., 2 per 1000) were diagnosed and hospitalized with diabetic ketoacidosis (DKA) and 475 (0.4%, i.e., 4 per 1000) were diagnosed in either an inpatient or outpatient setting. Using gradient boosted trees, the strongest predictors were prior DKA, baseline hemoglobin A1C level, baseline creatinine level, use of medications for dementia, and baseline bicarbonate level. Using LASSO regression not including laboratory test results due to missing data, the strongest predictors were prior DKA, digoxin use, use of medications for dementia, and recent hypoglycemia. The logistic regression model incorporating the variables identified from gradient boosted trees and LASSO regression suggested the following pre-exposure characteristics had the strongest association with a hospitalization for DKA: use of dementia medications (OR = 7.76, 95% CI 2.60, 23.1), prior intracranial hemorrhage (OR = 11.5, 95% CI 1.46, 91.1), a prior diagnosis of hypoglycemia (OR = 5.41, 95% CI 1.92,15.3), prior DKA (OR = 2.45, 95% CI 0.33, 18.0), digoxin use (OR = 4.00, 95% CI 1.21, 13.2), a baseline hemoglobin A1C above 10% (OR = 3.14, 95% CI 1.95, 5.06), and baseline bicarbonate below 18 mmol/L (OR 5.09, 95% CI 1.58, 16.4). CONCLUSION Diabetic ketoacidosis affected approximately 2 per 1000 patients starting to use an SGLT2 inhibitor. We identified both anticipated, e.g., low baseline serum bicarbonate, and unanticipated, e.g., digoxin, dementia medications, risk factors for SGLT2 inhibitor-induced DKA.
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29
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Fookeerah P, Law H, Ali F, Chatten K, Kim C, Cheung NW. An audit of the effect of SGLT2 inhibitor cessation in a pre-admission clinic before and after Australian Diabetes Society guidelines. Intern Med J 2021; 51:980-983. [PMID: 34155765 DOI: 10.1111/imj.15366] [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: 08/18/2020] [Revised: 02/16/2021] [Accepted: 02/16/2021] [Indexed: 11/30/2022]
Abstract
Perioperative ketoacidosis is an important adverse event related to the use of sodium glucose co-transporter 2 inhibitor (SGLT2i). We compared perioperative outcomes in patients on SGLT2i, before and after protocolised pre-operative cessation of the drug. There were no cases of clinically detected diabetic ketoacidosis in the 96 patients included in the study. Withdrawal of SGLT2i did not appear to alter significantly pre-operative glycaemia.
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Affiliation(s)
- Prishila Fookeerah
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Henry Law
- Department of Anaesthesia and Perioperative Medicine, Westmead Hospital, Sydney, New South Wales, Australia
| | - Farheen Ali
- Department of Anaesthesia and Perioperative Medicine, Westmead Hospital, Sydney, New South Wales, Australia
| | - Katherine Chatten
- Department of Anaesthesia and Perioperative Medicine, Westmead Hospital, Sydney, New South Wales, Australia
| | - Claire Kim
- Department of Anaesthesia and Perioperative Medicine, Westmead Hospital, Sydney, New South Wales, Australia
| | - Ngai Wah Cheung
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, New South Wales, Australia.,Faculty of Medicine, The University of Sydney, Sydney, New South Wales, Australia
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30
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Araki E, Mathieu C, Shiraiwa T, Maeda H, Ikeda H, Thoren F, Arya N, Asano M, Iqbal N. Long-term (52-week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT-2 study. Diabetes Obes Metab 2021; 23:1496-1504. [PMID: 33620762 PMCID: PMC8251623 DOI: 10.1111/dom.14362] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 02/09/2021] [Accepted: 02/16/2021] [Indexed: 12/24/2022]
Abstract
AIM To examine the long-term efficacy and safety of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT-2 study. MATERIALS AND METHODS Patients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24-week, double-blind period followed by a 28-week, single-blind extension phase. RESULTS From baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of -0.58% and -0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo. CONCLUSIONS Efficacy and safety results from the Japanese subpopulation of the DEPICT-2 study were generally consistent with those from the overall population, indicating that long-term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.
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Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Chantal Mathieu
- Clinical and Experimental EndocrinologyUniversity of LeuvenLeuvenBelgium
| | | | | | | | | | - Niki Arya
- Biopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
| | | | - Nayyar Iqbal
- Biopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
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31
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Cavka L, Bencak Ferko U, Pitz N, Trpkovski Z, Lainscak M. Sodium-glucose cotransporter 2 inhibitor-induced euglycaemic diabetic ketoacidosis in heart failure with preserved ejection fraction. ESC Heart Fail 2021; 8:2631-2636. [PMID: 34102028 PMCID: PMC8318418 DOI: 10.1002/ehf2.13452] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/17/2021] [Accepted: 05/21/2021] [Indexed: 12/13/2022] Open
Abstract
The number of patients receiving sodium-glucose cotransporter 2 inhibitors (SGLT2is), especially those with heart failure, is increasing worldwide. SGLT2is control glycaemia by triggering glycosuria with simultaneous facilitation of a more ketogenic metabolic profile. Patients therefore are more prone to develop euglycaemic diabetic ketoacidosis (euDKA), an entity largely unknown beyond diabetes care professionals. We present a heart failure with preserved ejection fraction (HFpEF) patient with known Type 2 diabetes. He was treated with dapagliflozin and presented acutely with dyspnoea, hyperglycaemia, and ketoacidosis. After standard treatment for diabetic ketoacidosis, hyperglycaemia was corrected, while metabolic ketoacidosis persisted, and thus, euDKA was suspected. With adequate therapy, the patient recovered completely and was discharged without any sequelae. To the best of our knowledge, our case is the first to describe SGLT2i-induced euDKA in HFpEF patients. Regarding no previous reports of euDKA in heart failure with reduced ejection fraction, our report is highly relevant for ongoing SGLT2i trials in HFpEF and clinical practice in general.
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Affiliation(s)
- Luka Cavka
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška cesta 2, Ljubljana, 1000, Slovenia.,Department of Oncology, University Medical Center Maribor, Maribor, Slovenia.,Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia
| | - Urska Bencak Ferko
- Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia
| | - Natasa Pitz
- Division for Diabetes, General Hospital Murska Sobota, Murska Sobota, Slovenia
| | - Zoranco Trpkovski
- Division for Diabetes, General Hospital Murska Sobota, Murska Sobota, Slovenia
| | - Mitja Lainscak
- Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia.,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
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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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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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Abstract
The dual pandemics of coronavirus disease-19 (COVID-19) and diabetes among patients are associated with 2- to 3-times higher intensive care admissions and higher mortality rates. Whether sheltering at home, quarantined with a positive COVID-19 test, or hospitalized, the person living with diabetes needs special considerations for successful management. Having diabetes and being COVID-19-positive increases the risk of poor outcomes and death. Providers need to give anticipatory pharmacologic guidance to patients with diabetes during COVID-19 lockdown. Patients with diabetes need to be more observant than others and to use self-protective actions. This review (1) discusses the clinical observations of COVID-19, diabetes and underlying mechanisms, (2) describes special considerations in caring for patients with diabetes in a COVID-19 environment, and (3) reviews clinical implications for the health care provider. This review highlights current evidenced-based knowledge. Additional research regarding clinical management is warranted.
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Puls HA, Haas NL, Franklin BJ, Theyyunni N, Harvey CE. Euglycemic diabetic ketoacidosis associated with SGLT2i use: Case series. Am J Emerg Med 2021; 44:11-13. [PMID: 33571749 DOI: 10.1016/j.ajem.2021.01.033] [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: 11/29/2020] [Revised: 01/09/2021] [Accepted: 01/12/2021] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION Euglycemic diabetic ketoacidosis (EuDKA) associated with Sodium-Glucose Cotransporter-2 inhibitor (SGLT2i) use has been described but remains poorly understood. Data on Emergency Department (ED) presentation, resource utilization, and safety outcomes for these patients are lacking. We report a case series of patients diagnosed with EuDKA in the ED. METHODS An electronic medical record search identified adult patients presenting to a large tertiary ED with EuDKA. They were screened for concurrent use of SGLT2i. Clinical presentation, resource utilization, safety, and disposition data were collected and described. RESULTS Five patients were included for analysis. Median age [range] was 57 [43-73] years. Presenting symptoms included nausea, vomiting, fatigue, and altered mental status. Initial results included: serum glucose 191 mg/dL [176-215], venous pH 7.01 [6.95-7.30], serum HCO3 8 mEq/L [6-13], anion gap 27 [26-31], serum beta-hydroxybutyrate 9.9 mmol/L [9.2-12.3], and urine ketones 150 [150-150]. Patients remained on an insulin infusion for 18.77 h [11.25-56.48]. There were zero episodes of hypoglycemia and one episode of hypokalemia while on insulin infusion. Time to resolution of metabolic acidosis was 23.82 h [15.45-24.77]. DISCUSSION We report a case series of ED patients with EuDKA associated with SGLT2i use, and describe presentation characteristics, resource utilization, and safety outcomes. Emergency physicians should be aware of the association between SGLT2i use and EuDKA. An appropriate work-up should be pursued for patients taking an SGLT2i who present with symptoms suggestive of DKA, including nausea, vomiting, malaise, and altered mental status, or are noted to have an unexplained elevated anion gap metabolic acidosis.
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Affiliation(s)
- Henrique A Puls
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Nathan L Haas
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Emergency Medicine, Division of Critical Care, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI, USA
| | | | - Nik Theyyunni
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI, USA
| | - Carrie E Harvey
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Emergency Medicine, Division of Critical Care, University of Michigan, Ann Arbor, MI, USA
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Alyammahi SK, Abdin SM, Alhamad DW, Elgendy SM, Altell AT, Omar HA. The dynamic association between COVID-19 and chronic disorders: An updated insight into prevalence, mechanisms and therapeutic modalities. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 87:104647. [PMID: 33264669 PMCID: PMC7700729 DOI: 10.1016/j.meegid.2020.104647] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/27/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023]
Abstract
The devastating pandemic of coronavirus disease 2019 (COVID-19) has caused thousands of deaths and left millions of restless patients suffering from its complications. Increasing data indicate that the disease presents in a severe form in patients with pre-existing chronic conditions like cardiovascular diseases, diabetes, respiratory system diseases, and renal diseases. This denotes that these patients are more susceptible to COVID-19 and have higher mortality rates compared to patients with no comorbid conditions. Several factors can explain the heightened susceptibility and fatal presentation of COVID-19 in these patients, for example, the enhanced expression of the angiotensin-converting enzyme-2 (ACE2) in specific organs, cytokine storm, and drug interactions contribute to the increased morbidity and mortality. Adding to the findings that individuals with pre-existing conditions may be more susceptible to COVID-19, it has also been shown that COVID-19 can induce chronic diseases in previously healthy patients. Therefore, understanding the interlinked relationship between COVID-19 and chronic diseases helps in optimizing the management of susceptible patients. This review comprehensively described the molecular mechanisms that contribute to worse COVID-19 prognosis in patients with pre-existing comorbidities such as diabetes, cardiovascular diseases, respiratory diseases, gastrointestinal and renal diseases, blood disorders, autoimmune diseases, and finally, obesity. It also focused on how COVID-19 could, in some cases, lead to chronic conditions as a result of long-term multi-organ damage. Lastly, this work carefully discussed the tailored management plans for each specific patient population, aiming to achieve the best therapeutic outcome with minimum complications.
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Affiliation(s)
- Shatha K Alyammahi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Shifaa M Abdin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Dima W Alhamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Sara M Elgendy
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Amani T Altell
- School of Public Health and Health Sciences, University of Massachusetts, Amherst 01002, United States of America
| | - Hany A Omar
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.
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Lindsay PJ, Gibson LE, Bittner EA, Berg S, Chang MG. Sodium-glucose cotransporter-2 (SGLT2) inhibitor-induced euglycemic diabetic ketoacidosis complicating the perioperative management of a patient with type 2 diabetes mellitus (T2DM) and Fournier's gangrene: A case report. Int J Surg Case Rep 2020; 77:463-466. [PMID: 33395826 PMCID: PMC7695895 DOI: 10.1016/j.ijscr.2020.11.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/04/2020] [Accepted: 11/08/2020] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Sodium glucose cotransporter-2 inhibitors (SGLT2) are an increasingly administered class of medication used to lower blood glucose levels in patients with type 2 diabetes mellitus. Diabetic ketoacidosis (DKA) and Fournier's gangrene are rare, but potentially catastrophic side effects of SGLT2 inhibitors. This manuscript reports a case of both DKA and Fournier's gangrene in the context of SGLT2 inhibitor use. PRESENTATION OF CASE A 51-year-old morbidly obese man with hypertension and poorly controlled Type 2 Diabetes Mellitus presented to the emergency department with a clinical presentation consistent with Fournier's gangrene. He was promptly taken to the operating room by the urology team where he had extensive debridement of the perineum and abdomen. Intra-operatively he was found to have DKA, which was managed appropriately. The acidosis and Fournier's gangrene were deemed a likely side effect of SGLT2 inhibitor use. After a thirty-day hospital admission, the patient was discharged to a rehabilitation facility where he is progressing well. His SGLT2 inhibitor was discontinued upon admission to hospital. DISCUSSION Perioperative providers should have a high index of suspicion for diabetic ketoacidosis (DKA) and Fournier's gangrene in patients prescribed SGLT2 inhibitors. Prompt treatment of DKA through correction of underlying triggers, aggressive fluid resuscitation, insulin to close the anion gap, and appropriate potassium repletion is vital to optimize patient outcomes. CONCLUSION The use of SGLT2 inhibitors among surgical populations is increasing. This case highlights the importance of being aware of the mechanism and side effects of SGLT2 inhibitors, and the management of DKA.
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Affiliation(s)
- Patrick J Lindsay
- Department of Anesthesia Critical Care and Pain, Massachusetts General Hospital, Boston, MA, USA.
| | - Lauren E Gibson
- Department of Anesthesia Critical Care and Pain, Massachusetts General Hospital, Boston, MA, USA
| | - Edward A Bittner
- Department of Anesthesia Critical Care and Pain, Massachusetts General Hospital, Boston, MA, USA
| | - Sheri Berg
- Department of Anesthesia Critical Care and Pain, Massachusetts General Hospital, Boston, MA, USA
| | - Marvin G Chang
- Department of Anesthesia Critical Care and Pain, Massachusetts General Hospital, Boston, MA, USA
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Meyer EJ, Mignone E, Hade A, Thiruvenkatarajan V, Bryant RV, Jesudason D. Periprocedural Euglycemic Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter 2 Inhibitor Therapy During Colonoscopy. Diabetes Care 2020; 43:e181-e184. [PMID: 32943440 PMCID: PMC7576412 DOI: 10.2337/dc20-1244] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 07/30/2020] [Indexed: 02/03/2023]
Affiliation(s)
- Emily J Meyer
- Department of Endocrinology and Diabetes, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia .,Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Edward Mignone
- Department of Endocrinology and Diabetes, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia
| | - Anthony Hade
- Department of Anaesthesia and Perioperative Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Venkatesan Thiruvenkatarajan
- Department of Anaesthesia, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.,Discipline of Acute Care Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Robert V Bryant
- Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,Department of Gastroenterology, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia
| | - David Jesudason
- Department of Endocrinology and Diabetes, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.,Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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COVID-19-associated euglycemic diabetic ketoacidosis in a patient with type 2 diabetes on SGLT2 inhibitor: a case report. Diabetol Int 2020; 12:313-316. [PMID: 33133998 PMCID: PMC7592186 DOI: 10.1007/s13340-020-00473-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/15/2020] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus (DM) patients are at high risk for the development of severe COVID-19. Euglycemic diabetic ketoacidosis (eu-DKA) is a rare life-threatening complication associated with the use of SGLT2 inhibitor that may be unnoticed, particularly in a pandemic setting, due to the absence of significant hyperglycemia, delaying its treatment. In this report, we describe a case of a 56-year-old patient who presented an elevated anion gap metabolic acidosis during a SARS-CoV-2 infection and was diagnosed with SGLT2-associated euglycemic diabetic ketoacidosis. COVID-19 may increase patients’ insulin demand, present gastrointestinal symptoms, and increase the production of ketone bodies. This situation can be worsened in susceptible diabetic patients on SLGT2 inhibitors, due to the persistent glycosuria, which can cause volume depletion. Recently some authors recommended that insulin-deficient patients or those using SGLT2 inhibitors should monitor for ketosis using available home testing kits in case of infections and should discontinue the medication in case of COVID-19. Given the increased use of this drug class in the management of type 2 DM patients due to its reduction of cardiovascular risk, we set out to emphasize the importance for the medical community to consider the possibility of eu-DKA on SARS-CoV-2-infected patients using SLGT2 inhibitors, so physicians can provide these patients with appropriate therapy promptly.
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Abstract
Sodium-glucose co-transporter 2 inhibitors are oral glucose-lowering drugs that increase the urinary excretion of glucose. In patients with type 2 diabetes and cardiovascular disease they reduce all-cause mortality, cardiac mortality, rates of hospitalisation for heart failure and the progression of renal disease There are adverse effects related to the mechanism of action. These include polyuria and intravascular volume depletion from osmotic diuresis, and genitourinary infections from glycosuria. Ketoacidosis is a rare adverse effect The glucose-lowering efficacy of sodium-glucose co-transporter 2 inhibitors decreases with increasing renal impairment
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Affiliation(s)
- Thomas Chesterman
- Southern Adelaide Diabetes and Endocrine Service, South Australia Health.,College of Medicine and Public Health, Flinders University.,Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University.,Adelaide
| | - Tilenka Rj Thynne
- Southern Adelaide Diabetes and Endocrine Service, South Australia Health.,College of Medicine and Public Health, Flinders University.,Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University.,Adelaide
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Milder TY, Stocker SL, Day RO, Greenfield JR. Potential Safety Issues with Use of Sodium-Glucose Cotransporter 2 Inhibitors, Particularly in People with Type 2 Diabetes and Chronic Kidney Disease. Drug Saf 2020; 43:1211-1221. [PMID: 33095409 PMCID: PMC7582030 DOI: 10.1007/s40264-020-01010-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2020] [Indexed: 12/31/2022]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a major advance in the fields of diabetology, nephrology, and cardiology. The cardiovascular and renal benefits of SGLT2 inhibitors are likely largely independent of their glycaemic effects, and this understanding is central to the use of these agents in the high-risk population of people with type 2 diabetes and chronic kidney disease. There are a number of potential safety issues associated with the use of SGLT2 inhibitors. These include the rare but serious risks of diabetic ketoacidosis and necrotising fasciitis of the perineum. The data regarding a possibly increased risk of lower limb amputation and fracture with SGLT2 inhibitor therapy are conflicting. This article aims to explore the potential safety issues associated with the use of SGLT2 inhibitors, with a particular focus on the safety of these drugs in people with type 2 diabetes and chronic kidney disease. We discuss strategies that clinicians can implement to minimise the risk of adverse effects including diabetic ketoacidosis and volume depletion. Risk mitigation strategies with respect to SGLT2 inhibitor-associated diabetic ketoacidosis are of particular importance during the current coronavirus disease 2019 (COVID-19) pandemic.
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Affiliation(s)
- Tamara Y Milder
- Department of Diabetes and Endocrinology, St. Vincent's Hospital, Sydney, Australia.,Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia.,Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, Australia.,St. Vincent's Clinical School, University of NSW, Sydney, Australia
| | - Sophie L Stocker
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia.,St. Vincent's Clinical School, University of NSW, Sydney, Australia
| | - Richard O Day
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia.,St. Vincent's Clinical School, University of NSW, Sydney, Australia
| | - Jerry R Greenfield
- Department of Diabetes and Endocrinology, St. Vincent's Hospital, Sydney, Australia. .,Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, Australia. .,St. Vincent's Clinical School, University of NSW, Sydney, Australia.
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Hill NE, Oliver NS. Evolving type 1 diabetes in distinguishing between type 1 and type 2 diabetes. BMJ 2020; 370:m3772. [PMID: 32994191 DOI: 10.1136/bmj.m3772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- N E Hill
- Imperial College Healthcare NHS Trust, Charing Cross Hospital, London W6 8RF, UK
| | - N S Oliver
- Imperial College Healthcare NHS Trust, Charing Cross Hospital, London W6 8RF, UK
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Katulanda P, Dissanayake HA, Ranathunga I, Ratnasamy V, Wijewickrama PSA, Yogendranathan N, Gamage KKK, de Silva NL, Sumanatilleke M, Somasundaram NP, Matthews DR. Prevention and management of COVID-19 among patients with diabetes: an appraisal of the literature. Diabetologia 2020; 63:1440-1452. [PMID: 32405783 PMCID: PMC7220850 DOI: 10.1007/s00125-020-05164-x] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 04/20/2020] [Indexed: 12/15/2022]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has emerged as one of the greatest challenges faced by humankind in the recent past. People with diabetes and related comorbidities are at increased risk of its complications and of COVID-19-related death. Older age, multi-morbidity, hyperglycaemia, cardiac injury and severe inflammatory response are predictors of poor outcome. The complex interplay between COVID-19, diabetes and the effects of related therapies is being explored. Most patients experience a mild illness with COVID-19, while people with diabetes are at increased risk of severe disease. Optimising glycaemic control and adopting measures to prevent disease spread are critical aspects. The management of mild disease is supportive, while very many immunomodulatory and antiviral therapies are being investigated for the treatment of severe disease. Several of these agents have specific considerations for use in people with diabetes. Since mass population lockdowns are considered a key step in controlling disease spread, it follows that, in addition to the direct vulnerability to severe COVID-19, people with diabetes can be affected by limited access to healthcare, insulin, other medications and blood glucose monitoring equipment. Measures to prevent disease spread at the individual and community level are the key to mitigating the rapidly escalating pandemic, while agents for chemoprophylaxis and vaccines are being explored. People with diabetes should be recognised as a vulnerable group for complicated disease and are at risk during times of disturbed social systems. Strategies are needed to safeguard the health of patients with diabetes during the pandemic. This review summarises the current knowledge and perceived challenges for prevention and management of COVID-19 in people with diabetes.
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Affiliation(s)
- Prasad Katulanda
- University Medical Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka.
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, 25, Kynsey Road, Colombo, 00800, Sri Lanka.
- Harris Manchester College, University of Oxford, Oxford, UK.
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, OX3 7LE, UK.
| | | | - Ishara Ranathunga
- Diabetes and Endocrine Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka
| | - Vithiya Ratnasamy
- Diabetes and Endocrine Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka
| | | | | | - Kavinga K K Gamage
- Diabetes and Endocrine Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka
| | - Nipun L de Silva
- Diabetes and Endocrine Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka
- Department of Clinical Sciences, Faculty of Medicine, General Sir John Kotelawala Defence University, Colombo, Sri Lanka
| | | | - Noel P Somasundaram
- Diabetes and Endocrine Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka
| | - David R Matthews
- Harris Manchester College, University of Oxford, Oxford, UK.
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, OX3 7LE, UK.
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Fleming N, Hamblin PS, Story D, Ekinci EI. Evolving Evidence of Diabetic Ketoacidosis in Patients Taking Sodium-Glucose Cotransporter 2 Inhibitors. J Clin Endocrinol Metab 2020; 105:5821255. [PMID: 32302001 DOI: 10.1210/clinem/dgaa200] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 04/15/2020] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as an important class of blood glucose-lowering medications, due to cardiovascular, metabolic, and renal benefits. However, there is a small but significant risk of diabetic ketoacidosis (DKA) associated with their use. METHODS A literature search was conducted in Ovid MEDLINE and Embase to July 2019 using variants on the key search terms sodium-glucose cotransporter 2, diabetic ketoacidosis, and type 2 diabetes. A broad spectrum of evidence was incorporated to facilitate a comprehensive narrative review. Further sources were identified through hand searching of reference lists. DISCUSSION Although cardiovascular outcome trials demonstrated mixed evidence of SGLT2i associated DKA, increasing evidence from case reports and cohort studies has identified an increased risk. SGLT2i use is associated with a ketotic state caused by an increased glucagon:insulin ratio and stimulated by factors including stress-induced hormonal changes, insufficient insulin, decreased glucose, increased ketone resorption, and hypovolemia. Atypical presentations of DKA with lower-than-expected blood glucose levels are possible with SGLT2i use, so clinical and biochemical monitoring is vital for early identification and management. DKA risk is particularly increased with precipitating factors, therefore optimization of risk factors is vital. Recommendations for perioperative and sick day management of patients taking SGLT2i have been suggested based on available evidence. CONCLUSION SGLT2i are an excellent class of drug in the physician's toolkit for managing type 2 diabetes. However, both clinicians and patients must be aware of the potential for DKA and the need for increased monitoring, both clinically and biochemically, when potential precipitating factors are present. In acutely unwell patients, these medications should be withheld to reduce the risk of DKA.
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Affiliation(s)
- Nicola Fleming
- Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| | - Peter Shane Hamblin
- Department of Endocrinology & Diabetes, Western Health, Melbourne, Victoria, Australia
- Department of Medicine - Western Precinct, University of Melbourne, St Albans, Victoria, Australia
| | - David Story
- Centre for Integrated Critical Care, University of Melbourne, Parkville, Victoria, Australia
- Department of Anaesthesia, Austin Health, Heidelberg, Australia
| | - Elif I Ekinci
- Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
- Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
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Beware Ketoacidosis with SGLT2 Inhibitors in Latent Autoimmune Diabetes of the Adult. Am J Med 2020; 133:e422-e424. [PMID: 31923401 DOI: 10.1016/j.amjmed.2019.12.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/11/2019] [Accepted: 12/21/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sodium-glucose co-transporter-2 (SGLT2) inhibitors are increasingly used for the treatment of type 2 diabetes, but have been associated with ketoacidosis. METHODS/RESULTS We report a case series of three patients with latent autoimmune diabetes of the adult who presented with ketoacidosis, including one case with normal blood glucose levels, in the context of SGLT2 inhibitor use. CONCLUSIONS Sodium-glucose co-transporter-2 inhibitors should be used with caution and close clinical monitoring in patients with latent autoimmune diabetes of the adult. A clinical risk score permits targeted autoantibody testing and should be undertaken prior to commencement of SGLT2 inhibitors or cessation of insulin.
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Chawla R, Madhu SV, Makkar BM, Ghosh S, Saboo B, Kalra S, On behalf of RSSDI-ESI Consensus
Group. RSSDI-ESI Clinical Practice Recommendations for the Management
of Type 2 Diabetes Mellitus 2020. Int J Diabetes Dev Ctries 2020. [PMCID: PMC7371966 DOI: 10.1007/s13410-020-00819-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Rajeev Chawla
- North Delhi Diabetes Centre Rohini, New Delhi, India
| | - S. V. Madhu
- Centre for Diabetes, Endocrinology & Metabolism, UCMS-GTB Hospital, Delhi, India
| | - B. M. Makkar
- Dr Makkar’s Diabetes & Obesity Centre Paschim Vihar, New Delhi, India
| | - Sujoy Ghosh
- Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal India
| | - Banshi Saboo
- DiaCare - A Complete Diabetes Care Centre, Ahmedabad, India
| | - Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, Haryana India
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Matsubayashi Y, Yoshida A, Suganami H, Osawa T, Furukawa K, Suzuki H, Fujihara K, Tanaka S, Kaku K, Sone H. Association of increased hepatic insulin clearance and change in serum triglycerides or β-hydroxybutyrate concentration via the sodium/glucose-cotransporter 2 inhibitor tofogliflozin. Diabetes Obes Metab 2020; 22:947-956. [PMID: 31984623 PMCID: PMC7318197 DOI: 10.1111/dom.13980] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/14/2020] [Accepted: 01/19/2020] [Indexed: 12/25/2022]
Abstract
AIMS Obesity and hepatic fat accumulation diminish hepatic insulin clearance, which can cause hyperinsulinaemia. Sodium/glucose-cotransporter 2 inhibitors (SGLT2-is) improve insulin resistance and hyperinsulinaemia by weight loss via increased urinary glucose excretion in type 2 diabetes. However, there are few reports of the influence of SGLT2-is on hepatic insulin clearance. We examined the impact of an SGLT2-i on hepatic insulin clearance and explored the clinical influence associated with changes in hepatic insulin clearance via an SGLT2-i and the mechanism of the effects of SGLT2-i. MATERIALS AND METHODS Data were analysed from 419 patients with type 2 diabetes controlled by diet and exercise. Patients received a placebo or the SGLT2-i tofogliflozin (TOFO) (placebo: n = 56; TOFO: n = 363) orally once daily for ≥24 weeks. Hepatic insulin clearance was calculated from the ratio of areas under the curve (AUC) of C-peptide and insulin levels derived from oral meal tolerance test data (C-peptide AUC0-120 min /insulin AUC0-120 min : HICCIR ). The correlation of HICCIR via the SGLT2-i with other clinical variables was analysed using multivariate analysis. RESULTS HICCIR was significantly increased via TOFO at week 24. Furthermore, with TOFO insulin and triglyceride (TG) levels were significantly reduced (P < 0.001) and β-hydroxybutyrate (BHB) was significantly elevated (P < 0.001). Changes in HICCIR were significantly correlated with changes in TG and BHB via TOFO. CONCLUSIONS Increased HICCIR was significantly associated with reduced TG via TOFO and contributed to the greater increase in BHB compared with placebo in addition to the correction of hyperinsulinaemia.
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Affiliation(s)
- Yasuhiro Matsubayashi
- Department of Hematology, Endocrinology and Metabolism, Faculty of MedicineNiigata UniversityNiigataJapan
| | - Akihiro Yoshida
- Department of Hematology, Endocrinology and Metabolism, Faculty of MedicineNiigata UniversityNiigataJapan
- Kowa Company, LtdTokyoJapan
| | | | - Taeko Osawa
- Department of Hematology, Endocrinology and Metabolism, Faculty of MedicineNiigata UniversityNiigataJapan
| | - Kazuo Furukawa
- Department of Hematology, Endocrinology and Metabolism, Faculty of MedicineNiigata UniversityNiigataJapan
| | - Hiroshi Suzuki
- Department of Hematology, Endocrinology and Metabolism, Faculty of MedicineNiigata UniversityNiigataJapan
| | - Kazuya Fujihara
- Department of Hematology, Endocrinology and Metabolism, Faculty of MedicineNiigata UniversityNiigataJapan
| | - Shiro Tanaka
- Department of Clinical Biostatistics, Graduate School of MedicineKyoto UniversityJapan
| | | | - Hirohito Sone
- Department of Hematology, Endocrinology and Metabolism, Faculty of MedicineNiigata UniversityNiigataJapan
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Lee IH, Ahn DJ. Dapagliflozin-associated euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus: A case report. Medicine (Baltimore) 2020; 99:e20228. [PMID: 32481295 PMCID: PMC7249933 DOI: 10.1097/md.0000000000020228] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
RATIONALE Rare cases of euglycemic diabetic ketoacidosis (eu-DKA) have been reported after the administration of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. No reports have described eu-DKA complicated by hypernatremia due to SGLT-2 inhibitors. PATIENT CONCERNS A 76-year-old woman with a 40-year history of type 2 diabetes mellitus (DM), for which metformin (1000 mg/day) and dapagliflozin (10 mg/day) were prescribed, presented with malaise, fever, and oliguria. On presentation, her white blood cell count (11,800/μL), serum creatinine (3.2 mg/dL), and C-reactive protein (54 mg/L) were abnormal. Bilateral pyeloureteritis and diffuse paralytic ileus were present. She received intravenous antibiotics and total parenteral nutrition, and was asked to fast. Her renal function and ileus briefly improved. Oral hypoglycemic agents, metformin and dapagliflozin, along with enteral feeding were reinstituted on day 3 of hospitalization. However, on day 6 of hospitalization, the patient developed an altered state of consciousness including confusion, lethargy, and stupor. Several laboratory abnormalities suggestive of ketoacidosis with euglycemia were noted. DIAGNOSES The patient was diagnosed with eu-DKA accompanied by severe hypernatremia (corrected serum Na concentration, 163 mEq/L) and hypokalemia following dapagliflozin re-administration. INTERVENTIONS The patient was treated with indicated intravenous fluid therapy. Dapagliflozin use was discontinued. OUTCOMES The patient's mental status and laboratory findings improved gradually, and she was discharged on maintenance doses of insulin and metformin on day 14 of hospitalization. LESSONS Acute illnesses such as diffuse paralytic ileus and urinary tract infection, and dietary restrictions or fasting in patients with DM can be considered potential predisposing factors for SGLT-2 inhibitor-associated eu-DKA. For patients with diabetes in the setting of acute morbidity, timely resumption of the SGLT-2 inhibitor therapy should be carefully determined. In addition, eu-DKA due to SGLT-2 inhibitor use may be accompanied by electrolyte disturbances such as hypernatremia and hypokalemia.
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Affiliation(s)
- In Hee Lee
- Department of Internal Medicine, Daegu Catholic University School of Medicine
| | - Dong Jik Ahn
- Department of Internal Medicine, Hansung Union Internal Medicine Clinic and Dialysis Center, Daegu, Republic of Korea
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Westcott GP, Segal AR, Mitri J, Brown FM. Prolonged glucosuria and relapse of diabetic ketoacidosis related to SGLT2-inhibitor therapy. Endocrinol Diabetes Metab 2020; 3:e00117. [PMID: 32318635 PMCID: PMC7170458 DOI: 10.1002/edm2.117] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/02/2020] [Indexed: 01/07/2023] Open
Abstract
SGLT2 inhibitors (SGLT2i) are glucose-lowering medications which increase the renal threshold for glucose reabsorption and promote glucosuria. Treatment with these agents raises serum ketone levels, and cases of diabetic ketoacidosis (DKA) during therapy have been reported. The duration of glucosuria and inpatient course of SGLT2i-related DKA, however, is not well-characterized. We report 11 inpatient cases of SGLT2i-related DKA, including a subset of patients who experienced prolonged glucosuria and relapse of DKA during their hospitalization.
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Affiliation(s)
- Gregory P. Westcott
- Joslin Diabetes CenterBostonMassachusetts
- Beth Israel Deaconess Medical CenterBostonMassachusetts
| | - Alissa R. Segal
- Joslin Diabetes CenterBostonMassachusetts
- MCPHS UniversityBostonMassachusetts
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Araki E, Watada H, Uchigata Y, Tomonaga O, Fujii H, Ohashi H, Okabe T, Asano M, Thoren F, Kim H, Yajima T, Langkilde AM. Efficacy and safety of dapagliflozin in Japanese patients with inadequately controlled type 1 diabetes (DEPICT-5): 52-week results from a randomized, open-label, phase III clinical trial. Diabetes Obes Metab 2020; 22:540-548. [PMID: 31742898 PMCID: PMC7078973 DOI: 10.1111/dom.13922] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 11/10/2019] [Accepted: 11/14/2019] [Indexed: 12/16/2022]
Abstract
AIMS To investigate the safety and tolerability of 5 and 10 mg dapagliflozin added to insulin therapy over 52 weeks in Japanese patients with inadequately controlled type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS This randomized, open-label, parallel-group, multicentre phase III clinical trial was conducted from October 26, 2015 to June 15, 2017. The primary endpoint was the occurrence of adverse events such as hypoglycaemia and diabetic ketoacidosis. Secondary endpoints included changes in glycaemic parameters, total daily insulin dosage and body weight over time. The efficacy of dapagliflozin in patients stratified by body mass index (BMI) <25.0 and ≥25.0 kg/m2 was evaluated in a subgroup analysis. RESULTS In total, 151 patients received 5 mg (n = 76) or 10 mg (n = 75) dapagliflozin once daily for 52 weeks. Adverse events were observed in 88.2% and 73.3% of patients in the 5 and 10 mg dapagliflozin groups, respectively. Severe hypoglycaemia was reported in 2.6% (n = 2) and 6.7% (n = 5) of patients, and diabetic ketoacidosis in 2.6% (n = 2) and 1.3% (n = 1) of patients in the 5 and 10 mg dapagliflozin groups, respectively. The adjusted mean (95% confidence interval) changes in glycated haemoglobin at week 52 were -0.33% (-0.50, -0.15) and -0.36% (-0.53, -0.18) in the 5 and 10 mg dapagliflozin groups, respectively. There were no differences in efficacy parameters when stratified by BMI. CONCLUSIONS This study demonstrated the long-term safety and tolerability of dapagliflozin added to insulin therapy in Japanese patients with inadequately controlled T1DM.
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Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Hirotaka Watada
- Department of Metabolism and EndocrinologyJuntendo University Graduate School of MedicineTokyoJapan
| | - Yasuko Uchigata
- Diabetes Center, Tokyo Women's Medical University School of MedicineTokyoJapan
| | - Osamu Tomonaga
- Diabetes and Lifestyle Center, Tomonaga ClinicTokyoJapan
| | - Hitomi Fujii
- Internal Medicine, Tama‐center Mirai ClinicTokyoJapan
| | | | | | | | - Fredrik Thoren
- Global Medicine Development, AstraZeneca GothenburgMölndalSweden
| | - Hyosung Kim
- Research & Development, AstraZeneca K.K.OsakaJapan
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