SGLT2 inhibitor-induced euglycaemic diabetic ketoacidosis in a diabetic patient managed in primary care

Ka-man Lau 劉嘉雯, Catherine XR Chen 陳曉瑞

HK Pract 2026;48:25-28

Summary

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been increasingly used for treatment of patients with Type 2 Diabetes Mellitus (T2DM) due to their cardiovascular and renal protective benefits. However, adverse effects have also been reported with concerns about euglycaemic diabetic ketoacidosis (eDKA) and severe urinary tract infection (UTI). We present a patient with a history of T2DM, hypertension, hyperlipidaemia, and benign prostate hypertrophy, who was put on SGLT2i due to suboptimal diabetic control, and later suffered from a UTI and SGLT2i-induced eDKA resulting in hospitalisation.

摘要

鈉-葡萄糖協同轉運蛋白2抑製劑(SGLT2i)因其對於心血管和腎臟保護作用而越來越多用於2型糖尿病(T2DM)患者。但其不良反應也有報告，主要是對正常血糖值的糖尿病酮症酸中毒(eDKA)和嚴重的尿路感染的關注。我們呈報了一位病人，他有T2DM、高血壓、高血脂症和良性前列腺肥大病史，由於糖尿病控制不佳而接受SGLT2i治療，後來因尿路感染和SGLT2i誘導的eDKA而住院治療。

Introduction

Type 2 diabetes mellitus (T2DM) is one of the most common conditions encountered in primary care. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new group of oral hypoglycaemic agents for T2DM management, which have found increasingly widespread use in primary care due to their cardiovascular and renal benefits.

As SGLT2i exerts its glucose-lowering effect by preventing the reabsorption of filtered glucose and therefore promoting urinary glucose excretion¹, one of the potential side effects of SGLT2i is urinary tract infection (UTI) and volume depletion. In 2015, the Food and Drug Administration (FDA) added a warning that SGLT2i might increase the risk of diabetic ketoacidosis (DKA) regardless of the presenting blood glucose levels.² As primary care physicians have been managing large numbers of T2DM patients in our daily practice, it is crucial for us to understand the risks and benefits of SGLT2i use and strive to provide optimal patient care. Herewith, we present a case of UTI complicated euglycaemic DKA (eDKA) in a T2DM patient treated with SGLT2i in primary care with its important learning points.

Case Presentation

A 76-year-old gentleman, Mr. Leung, who is a non-smoker and non-drinker, had regular follow-ups at a Family Medicine Clinic (FMC) of the Hospital Authority of Hong Kong for the management of his T2DM, hypertension, hyperlipidaemia, and benign prostate hypertrophy (BPH). There was no history of recurrent UTI in the past 5 years. He was put on metformin 1000mg twice daily, gliclazide 160mg twice daily, amlodipine 2.5mg daily, simvastatin 10mg nocte, and terazosin 2mg at bedtime. An annual diabetic complication assessment done in 11/2021 revealed that his glycaemic control was suboptimal with haemoglobin A1c (HbA1c) at 8.3%. Because of his overall high cardiovascular risk, dapagliflozin (SGLT2i) 10mg daily was added to his existing regimen in 12/2021.

5 months after commencing the use of dapagliflozin, Mr. Leung suffered from severe nausea, vomiting, and abdominal pain for 2 days and was admitted into the hospital medical ward on 21/04/2022. Otherwise, there was no fever, or urinary symptoms such as haematuria and dysuria, diarrhoea, chest pain, or shortness of breath. Physical examination showed a normal temperature of 36.7°C, blood pressure of 161/85mmHg, and a pulse of 83 per minute. His mucous membranes were dry with decreased skin turgor. Abdominal examination revealed mild tenderness over the periumbilical region with no peritoneal signs, and the costovertebral angle was non-tender.

Investigations revealed a total WBC of 24.8x10⁹/ L with neutrophilia, serum creatinine 90mmol/L, serum sodium 129mmol/L, and random glucose 10 mmol/L. Arterial blood gas showed metabolic acidosis with an elevated anion gap (pH 7.27, bicarbonate 14mEq/L, anion gap 13mEq/L), β-hydroxybutyrate 3 mol/L and lactate 1.5 mol/L. Urinalysis was positive for ketonic bodies. Urine culture showed Citrobacter infection. Blood culture and stool culture were unremarkable. Bedside abdominal ultrasound revealed no hydronephrosis or abnormal echogenicity of the renal parenchyma, and the hepatobiliary system was unremarkable.

A diagnosis of SGLT2i-induced eDKA precipitated by UTI was made; therefore, dapagliflozin was stopped immediately. Mr. Leung was treated with intravenous fluid resuscitation, intravenous amoxicillin/clavulanate, insulin infusion, as well as withholding of all other oral hypoglycaemic agents. Later, his appetite gradually improved, and he recovered after two weeks of treatment. On discharge, all oral hypoglycaemic agents were stopped, and the patient was given regular protaphane injection of 26 units before breakfast and 12 units before dinner for his T2DM management.

Discussion

Although studies have confirmed the renal protective effects of SGLT2i, cases of genital infection, UTI, and even severe UTI have been reported among patients treated with dapagliflozin³ and empagliflozin.⁴ Moreover, the US FDA adverse reporting database showed 19 cases of SGLT2i use in T2DM where UTI preceded the development of urosepsis and pyelonephritis. Therefore, the FDA added a warning of severe UTI as an adverse effect of SGLT2i. However, randomised clinical trials and a meta-analysis did not find a significantly increased risk of UTIs in patients treated with SGLT2i compared to placebo or other oral hypoglycaemic agents.⁵ It is also still unclear about the risk of UTIs in higher-risk populations including people with structural or functional urinary tract abnormalities. Lower urinary tract symptoms (LUTS) in male diabetic patients are common, which may be due to BPH or autonomic neuropathy. A case series reported that SGLT2i may exacerbate LUTS because of increased urine output.⁶ A case report also highlighted that SGLT2i use may increase the risk of UTIs in male patients with bladder outlet obstruction³, but currently, no large study is available to demonstrate any association between them. Therefore, SGLT2i may not be appropriate for patients with a history of recurrent UTIs. Physicians may also consider withholding SGLT2i in patients with significant UTIs (e.g. pyelonephritis, prostatitis, urosepsis, prolonged clinical course) and consider its cessation if the patient develops recurrent UTIs.⁷ For the management of SGLT2i-associated UTIs, discontinuation of the drug with antibiotic management is vital to prevent life-threatening complications. In our case, Mr. Leung did not have any urinary symptoms, nor any signs suggestive of urosepsis or pyelonephritis, but he did have persistent vomiting with decreased oral intake which might be due to an underlying UTI. Moreover, he had a history of BPH, which may also make him more prone to the development of UTIs. After stopping dapagliflozin and the administration of antibiotics, Mr. Leung’s UTI was quickly controlled. Besides pharmacological management, it is crucial to ensure adequate glycaemic control in diabetes patients and to encourage them to drink sufficient water and to empty their bladders entirely during voiding.

DKA is a life-threatening condition characterised by the presence of hyperglycaemia, metabolic acidosis (pH<=7.3, bicarbonate <=15mmol/L, anion gap >12mmol/L), and ketonemia/ketonuria. It usually occurs when there is absolute or relative insulin deficiency to prevent ketosis or when there are excess counter regulatory hormones such as glucagon, cortisol, and catecholamines.⁸ However, hyperglycaemia, although commonly present in patients with DKA, may not always be present. Such a condition is termed eDKA, i.e., DKA when blood glucose is less than 14mmol/L. The absence of hyperglycaemia in eDKA has posed a great challenge to primary care doctors in establishing a clinical diagnosis. Clinical presentations of eDKA are similar to those of hyperglycaemic DKA but more insidious and non-specific, with nausea, vomiting, abdominal pain, shortness of breath, or generalised malaise. Severe dehydration and metabolic acidosis can lead to shock, respiratory failure, or coma.⁹ For such patients, a screening test with spot urine for ketone helps make the diagnosis in the primary care setting. In our case, Mr. Leung was diagnosed with eDKA based on the typical laboratory findings of metabolic acidosis with the presence of ketonaemia and a relatively normal random glucose level. The dehydration and poor oral intake induced by the UTI may have contributed to the development of DKA. After stopping the SGLT2i, together with aggressive hydration, the use of insulin, and treatment of his UTI, Mr. Leung’s eDKA significantly improved after two weeks.

Indeed, a systematic review reported that SGLT2i use has demonstrated a 2.5-fold increased risk of DKA in a dose-dependent manner.¹⁰ Furthermore, evidence has shown that prior DKA, high HbA1c levels, infection, and starvation due to illness or fasting or excessive alcohol consumption were risk factors associated with SGLT2i-induced eDKA.¹¹ To prevent the occurrence of these important complications, SGLT2i use should be withheld when patients have an acute illness or are fasting, and three days before any major surgical procedures. Family physicians should be on high alert for the symptoms and signs of eDKA, withholding SGLT2i use immediately, performing point-of-care urine test for ketones in suspected cases, and referring positive cases to the hospital for further investigation.

Conclusion

SGLT2i is a promising agent and has been widely used among diabetes patients managed in primary care. Beyond glycaemic control, SGLT2i is also demonstrated to have beneficial effects on renal and cardiovascular outcomes. On the other hand, studies have shown that the use of SGLT2i is associated with an increased risk of eDKA. Therefore, ensuring that SGLT2i therapy is limited to carefully selected patients who will gain the greatest overall benefit, as well as identifying the risk factors or precipitating factors at the time of initiation and throughout therapy are important preventive measures to minimise the occurrence of eDKA. Staying on high alert for the symptoms and signs of eDKA, immediate discontinuation of SGLT2i use and promptly conducting point-of-care urine tests for ketones in suspected cases, before referring positive cases to the hospital for further investigation and monitoring can help reduce the mortality of this life-threatening condition.

References

1. Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose cotransporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73-79. doi:10.1097/MED.0000000000000311
2. Food and Drug Administration (2015) FDA drug safety communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. http://fda.gov. Accessed Feb 20, 2022.
3. Hall V, Kwong J, Johnson D, et al. Caution advised with dapagliflozin in the setting of male urinary tract outlet obstruction. BMJ Case Rep. 2017;2017:bcr2017219335. Published 2017 May 22. doi:10.1136/bcr-2017-219335
4. Brock GM, Lane SM, Roosevelt TS. Emphysematous cystitis and urinary retention in a male patient with diabetes mellitus type 2 treated with empagliflozin. AACE Clin Case Rep. 2022;8(4):163-165. doi: 10.1016/J.AACE.2022.04.002
5. Wiegley N, So PN. Sodium-Glucose Cotransporter 2 Inhibitors and Urinary Tract Infection: Is There Room for Real Concern?. Kidney360. 2022;3(11) :1991-1993. Published 2022 Sep 12. doi:10.34067/KID.0005722022
6. Chilelli NC, Bax G, Bonaldo G, et al. Lower urinary tract symptoms (LUTS) in males with type 2 diabetes recently treated with SGLT2 inhibitors—overlooked and overwhelming? A retrospective case series. Endocrine. 2018;59(3):690-693. doi:10.1007/s12020-017-1301-x
7. Zala A, Maple-Brown LJ, Shaw JE, et al. Current evidence and practical guidance for the use of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes. Aust J Gen Pract. 2021;50(4):225-230. doi:10.31128/AJGP-05-20-5432
8. Puttanna A and Padinjakara R. Diabetic ketoacidosis in type 2 diabetes mellitus. Pract Diab, 2014; 31(4): 155–158. https://doi.org/10.1002/pdi.1852
9. Rawla P, Vellipuram AR, Bandaru SS, et al. Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep. 2017;2017:17-0081. Published 2017 Sep 4. doi:10.1530/EDM-17-0081
10. Colacci M, Fralick J, Odutayo A, et al. Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Diabetic Ketoacidosis Among Adults With Type 2 Diabetes: A Systematic Review and Meta-Analysis. Can J Diabetes. 2022;46(1):10-15.e2. doi:10.1016/j.jcjd.2021.04.006
11. Fralick M, Redelmeier DA, Patorno E, et al. Identifying Risk Factors for Diabetic Ketoacidosis Associated with SGLT2 Inhibitors: a Nationwide Cohort Study in the USA. J Gen Intern Med. 2021;36(9):2601-2607. doi:10.1007/s11606-020-06561-z