{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:26:32Z","timestamp":1793139992735,"version":"4.5.0"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["CJASN"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:p>\n                    Sodium-glucose cotransporter-2 (SGLT2) inhibitors are drugs designed to lower plasma glucose concentration by inhibiting Na\n                    <jats:sup>+<\/jats:sup>\n                    -glucose\u2013coupled transport in the proximal tubule. Clinical trials demonstrate these drugs have favorable effects on cardiovascular outcomes to include slowing the progression of CKD. Although most patients tolerate these drugs, a potential complication is development of ketoacidosis, often with a normal or only a minimally elevated plasma glucose concentration. Inhibition of sodium-glucose cotransporter-2 in the proximal tubule alters kidney ATP turnover so that filtered ketoacids are preferentially excreted as Na\n                    <jats:sup>+<\/jats:sup>\n                    or K\n                    <jats:sup>+<\/jats:sup>\n                    salts, leading to indirect loss of bicarbonate from the body and systemic acidosis under conditions of increased ketogenesis. Risk factors include reductions in insulin dose, increased insulin demand, metabolic stress, low carbohydrate intake, women, and latent autoimmune diabetes of adulthood. The lack of hyperglycemia and nonspecific symptoms of ketoacidosis can lead to delays in diagnosis. Treatment strategies and various precautions are discussed that can decrease the likelihood of this complication.\n                  <\/jats:p>","DOI":"10.2215\/cjn.17621120","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T12:31:43Z","timestamp":1612873903000},"page":"1284-1291","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":120,"title":["Euglycemic Ketoacidosis as a Complication of SGLT2 Inhibitor Therapy"],"prefix":"10.2215","volume":"16","author":[{"given":"Biff F.","family":"Palmer","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah J.","family":"Clegg","sequence":"additional","affiliation":[{"name":"Associate Dean for Research, College of Nursing and Health Professionals, Drexel University, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,8]]},"reference":[{"key":"B1-20241015","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N Engl J Med"},{"key":"B2-20241015","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in patients with heart failure and reduced ejection fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N Engl J Med"},{"key":"B3-20241015","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and renal outcomes with empagliflozin in heart failure","volume":"383","author":"Packer","year":"2020","journal-title":"N Engl J Med"},{"key":"B4-20241015","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","article-title":"Canagliflozin and renal outcomes in type 2 diabetes and nephropathy","volume":"380","author":"Perkovic","year":"2019","journal-title":"N Engl J Med"},{"key":"B5-20241015","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in patients with chronic kidney disease","volume":"383","author":"Heerspink","year":"2020","journal-title":"N Engl J Med"},{"key":"B7-20241015","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/dom.13012","article-title":"Sodium-glucose co-transporter-2 inhibitors and diabetic ketoacidosis: An updated review of the literature","volume":"20","author":"Bonora","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"B8-20241015","doi-asserted-by":"crossref","first-page":"532","DOI":"10.2337\/dc15-1995","article-title":"Diabetic ketoacidosis with canagliflozin, a sodium\u2010glucose cotransporter 2 inhibitor, in patients with type 1 diabetes","volume":"39","author":"Peters","year":"2016","journal-title":"Diabetes Care"},{"key":"B9-20241015","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.2337\/dc18-1087","article-title":"Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: The DEPICT\u20101 52\u2010week study","volume":"41","author":"Dandona","year":"2018","journal-title":"Diabetes Care"},{"key":"B11-20241015","doi-asserted-by":"crossref","first-page":"e2924","DOI":"10.1002\/dmrr.2924","article-title":"Ketoacidosis associated with SGLT2 inhibitor treatment: Analysis of FAERS data","volume":"33","author":"Blau","year":"2017","journal-title":"Diabetes Metab Res Rev"},{"key":"B12-20241015","doi-asserted-by":"crossref","first-page":"417","DOI":"10.7326\/M20-0289","article-title":"Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic ketoacidosis: A multicenter cohort study","volume":"173","author":"Douros","year":"2020","journal-title":"Ann Intern Med"},{"key":"B13-20241015","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12245-019-0240-0","article-title":"Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: A case report and review of the literature","volume":"12","author":"Diaz-Ramos","year":"2019","journal-title":"Int J Emerg Med"},{"key":"B14-20241015","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1007\/s00125-018-4656-5","article-title":"Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2","volume":"61","author":"Ghezzi","year":"2018","journal-title":"Diabetologia"},{"key":"B15-20241015","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.cmet.2014.03.005","article-title":"Glucagon regulates hepatic kisspeptin to impair insulin secretion","volume":"19","author":"Song","year":"2014","journal-title":"Cell Metab"},{"key":"B16-20241015","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.2337\/dc15-2688","article-title":"Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes","volume":"39","author":"Daniele","year":"2016","journal-title":"Diabetes Care"},{"key":"B17-20241015","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.2337\/dc15-1380","article-title":"Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors","volume":"38","author":"Rosenstock","year":"2015","journal-title":"Diabetes Care"},{"key":"B18-20241015","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1210\/jc.2011-2260","article-title":"Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin","volume":"97","author":"Bolinder","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B19-20241015","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ebiom.2017.05.028","article-title":"SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice","volume":"20","author":"Xu","year":"2017","journal-title":"EBioMedicine"},{"key":"B20-20241015","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1172\/JCI72227","article-title":"Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients","volume":"124","author":"Ferrannini","year":"2014","journal-title":"J Clin Invest"},{"key":"B21-20241015","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.2337\/db15-1356","article-title":"Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes","volume":"65","author":"Ferrannini","year":"2016","journal-title":"Diabetes"},{"key":"B22-20241015","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/jcph.1030","article-title":"Model-based evaluation of proximal sodium reabsorption through SGLT2 in health and diabetes and the effect of inhibition with canagliflozin","volume":"58","author":"Brady","year":"2018","journal-title":"J Clin Pharmacol"},{"key":"B23-20241015","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1007\/s00125-018-4669-0","article-title":"The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure","volume":"61","author":"Thomas","year":"2018","journal-title":"Diabetologia"},{"key":"B24-20241015","doi-asserted-by":"crossref","first-page":"5335","DOI":"10.1074\/jbc.M117.779520","article-title":"SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice","volume":"292","author":"Wang","year":"2017","journal-title":"J Biol Chem"},{"key":"B25-20241015","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1038\/ki.2010.509","article-title":"Glucose handling by the kidney","volume":"120","author":"Mather","year":"2011","journal-title":"Kidney Int Suppl"},{"key":"B26-20241015","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2017.04.011","article-title":"Sodium-glucose co-transporters and their inhibition: Clinical physiology","volume":"26","author":"Ferrannini","year":"2017","journal-title":"Cell Metab"},{"key":"B27-20241015","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1681\/ASN.2013060588","article-title":"Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+\/H+ exchanger isoform 3 activity in the renal proximal tubule","volume":"25","author":"Pessoa","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"B28-20241015","doi-asserted-by":"crossref","first-page":"F712","DOI":"10.1152\/ajprenal.00264.2020","article-title":"A role for tubular Na+\/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin","volume":"319","author":"Onishi","year":"2020","journal-title":"Am J Physiol Renal Physiol"},{"key":"B29-20241015","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/dmr.5610050402","article-title":"Renal and hepatic aspects of ketoacidosis: A quantitative analysis based on energy turnover","volume":"5","author":"Halperin","year":"1989","journal-title":"Diabetes Metab Rev"},{"key":"B30-20241015","first-page":"F607","article-title":"Regulation of the maximum rate of renal ammoniagenesis in the acidotic dog","volume":"248","author":"Halperin","year":"1985","journal-title":"Am J Physiol"},{"key":"B31-20241015","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1056\/NEJMra1503102","article-title":"Electrolyte and acid-base disturbances in patients with diabetes mellitus [published correction appears in N Engl J Med 381: 1598, 2019 10.1056\/NEJMx190026]","volume":"373","author":"Palmer","year":"2015","journal-title":"N Engl J Med"},{"key":"B32-20241015","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1056\/NEJMra1704724","article-title":"Electrolyte disturbances in patients with chronic alcohol-use disorder","volume":"377","author":"Palmer","year":"2017","journal-title":"N Engl J Med"},{"key":"B33-20241015","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fmed.2020.00065","article-title":"Defective mitochondrial fatty acid oxidation and lipotoxicity in kidney diseases","volume":"7","author":"Jang","year":"2020","journal-title":"Front Med (Lausanne)"},{"key":"B34-20241015","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nm.3762","article-title":"Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development","volume":"21","author":"Kang","year":"2015","journal-title":"Nat Med"},{"key":"B35-20241015","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41419-020-2544-7","article-title":"Sodium-glucose cotransporter 2 inhibition suppresses HIF-1\u03b1-mediated metabolic switch from lipid oxidation to glycolysis in kidney tubule cells of diabetic mice","volume":"11","author":"Cai","year":"2020","journal-title":"Cell Death Dis"},{"key":"B36-20241015","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1152\/ajplegacy.1976.231.3.880","article-title":"Effect of fatty acids on renal ammoniagenesis in in vivo and in vitro studies","volume":"231","author":"Vinay","year":"1976","journal-title":"Am J Physiol"},{"key":"B37-20241015","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0026-0495(75)90004-9","article-title":"Renal conservation of ketone bodies during starvation","volume":"24","author":"Sapir","year":"1975","journal-title":"Metabolism"},{"key":"B38-20241015","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0300-595X(83)80046-2","article-title":"Ketosis of starvation: A revisit and new perspectives","volume":"12","author":"Owen","year":"1983","journal-title":"Clin Endocrinol Metab"},{"key":"B39-20241015","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/0026-0495(86)90241-6","article-title":"Effect of hyperketonemia on renal ammonia excretion in man","volume":"35","author":"Desir","year":"1986","journal-title":"Metabolism"},{"key":"B40-20241015","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1172\/JCI108057","article-title":"Effect of ketone infusions on amino acid and nitrogen metabolism in man","volume":"55","author":"Sherwin","year":"1975","journal-title":"J Clin Invest"},{"key":"B41-20241015","first-page":"F420","article-title":"Cellular mechanisms of the antiammoniagenic effect of ketone bodies in the dog","volume":"239","author":"Lemieux","year":"1980","journal-title":"Am J Physiol"},{"key":"B42-20241015","doi-asserted-by":"crossref","first-page":"771","DOI":"10.2337\/dc16-2724","article-title":"Renal handling of ketones in response to sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes","volume":"40","author":"Ferrannini","year":"2017","journal-title":"Diabetes Care"},{"key":"B43-20241015","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ejphar.2014.01.040","article-title":"SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats","volume":"727","author":"Yokono","year":"2014","journal-title":"Eur J Pharmacol"},{"key":"B44-20241015","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.2337\/dc18-0623","article-title":"Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 24-week results from a randomized controlled trial","volume":"41","author":"Mathieu","year":"2018","journal-title":"Diabetes Care"},{"key":"B45-20241015","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.2337\/dc18-1749","article-title":"Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: The EASE trials","volume":"41","author":"Rosenstock","year":"2018","journal-title":"Diabetes Care"},{"key":"B46-20241015","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1056\/NEJMoa1708337","article-title":"Effects of sotagliflozin added to insulin in patients with type 1 diabetes","volume":"377","author":"Garg","year":"2017","journal-title":"N Engl J Med"},{"key":"B47-20241015","doi-asserted-by":"crossref","first-page":"991","DOI":"10.2337\/dci19-0008","article-title":"SGLT inhibitors for type 1 diabetes: Proceed with extreme caution","volume":"42","author":"Wolfsdorf","year":"2019","journal-title":"Diabetes Care"},{"key":"B48-20241015","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1089\/dia.2017.0267","article-title":"Altered patterns of early metabolic decompensation in type 1 diabetes during treatment with a SGLT2 inhibitor: An insulin pump suspension study","volume":"19","author":"Patel","year":"2017","journal-title":"Diabetes Technol Ther"},{"key":"B49-20241015","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/phar.1881","article-title":"SGLT2 inhibitors: A systematic review of diabetic ketoacidosis and related risk factors in the primary literature","volume":"37","author":"Burke","year":"2017","journal-title":"Pharmacotherapy"},{"key":"B50-20241015","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.2337\/dc19-2579","article-title":"Metabolic effects of an SGLT2 inhibitor (Dapagliflozin) during a period of acute insulin withdrawal and development of ketoacidosis in people with type 1 diabetes","volume":"43","author":"Herring","year":"2020","journal-title":"Diabetes Care"},{"key":"B51-20241015","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1056\/NEJMra2010852","article-title":"Salicylate toxicity","volume":"382","author":"Palmer","year":"2020","journal-title":"N Engl J Med"},{"key":"B52-20241015","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s00125-017-4301-8","article-title":"SGLT2 inhibitors and diabetic ketoacidosis: Data from the FDA adverse event reporting system","volume":"60","author":"Fadini","year":"2017","journal-title":"Diabetologia"},{"key":"B53-20241015","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1017\/S0007114510004472","article-title":"Young women partition fatty acids towards ketone body production rather than VLDL-TAG synthesis, compared with young men","volume":"105","author":"Marinou","year":"2011","journal-title":"Br J Nutr"},{"key":"B54-20241015","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fendo.2015.00061","article-title":"Sexual dimorphism in glucose and lipid metabolism during fasting, hypoglycemia, and exercise","volume":"6","author":"Hedrington","year":"2015","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B55-20241015","first-page":"224","article-title":"Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man","volume":"85","author":"Davis","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"B56-20241015","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.mce.2014.11.029","article-title":"The sexual dimorphism of obesity","volume":"402","author":"Palmer","year":"2015","journal-title":"Mol Cell Endocrinol"},{"key":"B57-20241015","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.2337\/dc15-1251","article-title":"Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program","volume":"38","author":"Erondu","year":"2015","journal-title":"Diabetes Care"},{"key":"B58-20241015","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1080\/14740338.2020.1764532","article-title":"Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors: Epidemiology, pathophysiology, and treatment","volume":"19","author":"Sampani","year":"2020","journal-title":"Expert Opin Drug Saf"},{"key":"B59-20241015","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1053\/j.ajkd.2004.09.034","article-title":"Insulin resistance in patients with chronic kidney disease","volume":"45","author":"Kobayashi","year":"2005","journal-title":"Am J Kidney Dis"},{"key":"B60-20241015","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/s41467-019-08466-w","article-title":"Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats","volume":"10","author":"Perry","year":"2019","journal-title":"Nat Commun"},{"key":"B62-20241015","doi-asserted-by":"crossref","first-page":"112","DOI":"10.2337\/cd19-0035","article-title":"Sodium-glucose cotransporter 2 inhibitor-associated prolonged euglycemic diabetic ketoacidosis in type 2 diabetes: A case report and literature review","volume":"38","author":"Yehya","year":"2020","journal-title":"Clin Diabetes"},{"key":"B63-20241015","first-page":"e6089","article-title":"Dapagliflozin-induced late-onset euglycemic diabetic ketoacidosis","volume":"11","author":"Iqbal","year":"2019","journal-title":"Cureus"}],"container-title":["Clinical Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.2215\/CJN.17621120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:43:23Z","timestamp":1786369403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.2215\/CJN.17621120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8]]},"references-count":60,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.2215\/cjn.17621120","relation":{},"ISSN":["1555-9041","1555-905X"],"issn-type":[{"value":"1555-9041","type":"print"},{"value":"1555-905X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8]]}}}