“The Proof is in the Pudding”: Do SGLT2 Inhibitors Cause Diabetic Ketoacidosis?

Abstract

Abbreviations: DKA diabetic ketoacidosis EuDKA euglycemic diabetic ketoacidosis SGLT2i sodium-glucose cotransporter 2 inhibitors T2DM type 2 diabetes mellitus Abbreviations: DKA diabetic ketoacidosis EuDKA euglycemic diabetic ketoacidosis SGLT2i sodium-glucose cotransporter 2 inhibitors T2DM type 2 diabetes mellitus Euglycemic diabetic ketoacidosis (EuDKA) is “a known side effect” of sodium-glucose cotransporter 2 inhibitors (SGLT2i), or is it? It is difficult to argue that a complication observed a few days or weeks after starting a new drug is not a side effect. Sood et al (1.Sood M. Simon B. Ryan K.F. Zebrower M. Euglycemic diabetic ketoacidosis with SGLT2 inhibitor use in a patient on the Atkins diet: a unique presentation of a known side effect.Endocr Pract. 2018; 4: e104-e107Google Scholar) described a patient who developed EuDKA a few days after starting SGLT2i. The patient had “typical uncontrolled” type 2 diabetes mellitus (T2DM) for 16 years, with a body mass index of 33.8 kg/m2, on daily glipizide XL at 2.5 mg plus sitagliptin with metformin HCl at 100 to 1,000 mg daily, and a hemoglobin A1c level of 9.3% (78 mmol/mol). Glipizide was discontinued and canagliflozin was started. Four days later the patient presented to the emergency department with severe abdominal pain, blood glucose at 180 mg/dL, metabolic acidosis (arterial blood gas pH 7.26), bicarbonate level of 14 mmol/L (the reference range is 20 to 31 mmol/L), and beta-hydroxybutyrate of 75.5 mg/dL (the reference range is 0.20 to 2.80 mg/dL). The lactate and drug screen were normal as was a computed tomography scan of his abdomen and pelvis. The patient was diagnosed with dehydration, treated with intravenous fluids, and discharged after improvement of pain. At a follow-up visit 3 days later he was diagnosed with EuDKA, canagliflozin was discontinued, and insulin was started. Neither C-peptide nor islet cell antibodies were measured. The case was similar to other cases reported to the U.S. Food and Drug Administration which resulted in a safety communication and position statement on diabetic ketoacidosis (DKA) as a potential side effect of SGLT2i (2.Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis.Endocr Pract. 2016; 22 (et al): 753-762Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). The main suggested mechanisms included stimulating the release of glucagon and ketone reabsorption in the kidney (2.Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis.Endocr Pract. 2016; 22 (et al): 753-762Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). The incidence of DKA in clinical trials had been very low (about 0.07%) (2.Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis.Endocr Pract. 2016; 22 (et al): 753-762Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). The majority of cases were seen in patients with insulin deficiency, such as from type 1 diabetes mellitus, latent autoimmune diabetes of adults, or long-standing T2DM. Approximately 10% of patients with type 1 diabetes mellitus participating in SGLT2i clinical trials developed ketosis, and up to 6% experienced DKA (2.Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis.Endocr Pract. 2016; 22 (et al): 753-762Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Since Sood et al (1.Sood M. Simon B. Ryan K.F. Zebrower M. Euglycemic diabetic ketoacidosis with SGLT2 inhibitor use in a patient on the Atkins diet: a unique presentation of a known side effect.Endocr Pract. 2018; 4: e104-e107Google Scholar) did not measure C-peptide or islet cell antibodies, the possibility of type 1 diabetes mellitus could not be ruled out in their case. An observational study of clinical practices using a large insurance claims database found that SGLT2i were associated with approximately twice the risk of DKA compared to dipeptidyl peptidase 4 inhibitors, although cases of DKA leading to hospitalization were infrequent (3.Fralick M. Schneeweiss S. Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor.N Engl J Med. 2017; 376: 2300-2302Crossref PubMed Scopus (187) Google Scholar). A review of DKA cases reported to the Food and Drug Adminstration's Adverse Event Reporting System showed that SGLT2i were associated with an approximately 7-fold increase in developing DKA compared to dipeptidyl peptidase 4 inhibitors, and 71% had EuDKA (4.Blau J.E. Tella S.H. Taylor S.I. Rother K.I. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data.Diabetes Metab Res Rev. 2017; 33: 2924Crossref Scopus (110) Google Scholar). The accumulating experiences from ‘real’ practices point to the ‘real’ risk for DKA and EuDKA with SGLT2i, suggesting that physicians should be vigilant and also educate patients on incipient symptoms of DKA such as abdominal pain, nausea, vomiting, fatigue, and dyspnea. The American Association of Clinical Endocrinologists provided recommendations for the prevention of DKA (2.Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis.Endocr Pract. 2016; 22 (et al): 753-762Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). In brief, they recommended stopping the drug for “metabolic” stress (e.g. surgery, extreme exercise, etc.), remembering that SGLT2i action could persist for several days after stopping SGLT2i, avoiding excess alcohol and very-low carbohydrate or ketogenic diets, and tapering insulin slowly. Routine measurement of urine ketones was not recommended. Physicians should also remember that measuring blood ketones (like beta-hydroxybutyrate) and arterial blood pH were necessary tests for confirming DKA diagnosis (2.Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis.Endocr Pract. 2016; 22 (et al): 753-762Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). The presentation and resolution of Sood et al's case report (1.Sood M. Simon B. Ryan K.F. Zebrower M. Euglycemic diabetic ketoacidosis with SGLT2 inhibitor use in a patient on the Atkins diet: a unique presentation of a known side effect.Endocr Pract. 2018; 4: e104-e107Google Scholar) could be called “classical” DKA. The case is one among occasional patients with very poor control of T2DM who are started on SGLT2i, yet it has the distinguishing aspect of simultaneous use of the Atkins diet. The Atkins diet is ketogenic and can cause hyperketonemia. Ketogenic diets include very-low-energy diets and ketogenic low-carbohydrate diets such as the Atkins and Paleo diets. Ketone bodies per se are not harmful and ketogenic diets can be successful for appetite suppression, weight loss, treatment of epilepsy, and possibly as an adjunct to some cancer management programs (5.Yuen A.W.C. Walcutt I.A. Sander J.W. An acidosis-sparing ketogenic (ASK) diet to improve efficacy and reduce adverse effects in the treatment of refractory epilepsy.Epilepsy Behav. 2017; 74: 15-21Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Ketogenic diets, however, can promote higher intake of animal protein and dietary acid load potentially increasing the risks of DKA. On the other hand, alkaline diets like high intakes of vegetables and fruits have been proposed as beneficial in reducing morbidity and mortality from chronic diseases including obesity and T2DM (6.Schwalfenberg G.K. The alkaline diet: is there evidence that an alkaline pH diet benefits health?.J Environ Public Health. 2012; 2012 (727630)Crossref Scopus (101) Google Scholar). Conceptually, ketogenic diets can be modified to preserve their benefits while improving their benefit/risk ratio by measures that include monitoring animal protein intake and maximizing consumption of alkaline, mineral-rich, low-carbohydrate, green vegetables (5.Yuen A.W.C. Walcutt I.A. Sander J.W. An acidosis-sparing ketogenic (ASK) diet to improve efficacy and reduce adverse effects in the treatment of refractory epilepsy.Epilepsy Behav. 2017; 74: 15-21Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). There is, however, no proof to this “dietary pudding” yet and most likely the main factor leading to DKA in this case is use of SGLT2i. In conclusion, DKA can occasionally happen in patients with poorly controlled T2DM who are started on SGLT2i. SGLT2i are a valuable treatment for T2DM and even have additional, demonstrated benefits for cardiovascular conditions, and they can be safe and efficacious when properly used (2.Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis.Endocr Pract. 2016; 22 (et al): 753-762Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Similarly, low-calorie, ketogenic diets can be safe and efficacious for weight loss, and with appropriate monitoring can be used in patients with T2DM taking SGLT2i. The author has no multiplicity of interest to disclose.