Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are highly selective, effective, and generally well-tolerated antihyperglycemic agents targeting the SGLT-2 transmembrane protein. Despite being primarily registered for diabetes treatment, due to their cardiorenal protective properties, SGLT-2 inhibitors caused a paradigm shift in the treatment of other diseases on the cardiorenal spectrum, becoming a fundamental part of heart failure and chronic kidney disease management. With their rapidly increasing use, there are also increased reports of a rare, often under-recognised and potentially deadly side effect, SGLT-2-inhibitor-induced euglycemic diabetic ketoacidosis (EDKA). The primary pathophysiological process behind its multifactorial aetiology comprises glucosuria and osmotic diuresis, which produce a significant carbohydrate deficit, leading to an increase in the glucagon-insulin ratio, thus resulting in accelerated ketogenesis. Although EDKA has a similar clinical presentation as diabetic ketoacidosis (DKA), the absence of the high glucose levels typically expected for DKA and the presence of urine ketone reabsorption contribute to a significant delay in its recognition and timely diagnosis. Given the broad use of SGLT-2 inhibitors, increased awareness, early recognition, and prompt identification of precipitating factors are essential. In this narrative review, we comprehensively explore the pathophysiological mechanisms of SGLT-2-inhibitor-induced EDKA, analyse its clinical manifestation, and identify the most common triggers for its development. We also discuss EDKA management and preventive strategies.

Acute pancreatitis is a common and potentially life-threatening condition. It is characterized by inflammation of the pancreas, most often leading to elevated levels of pancreatic enzymes in the blood. In a subset of patients, however, conventional biomarker levels may remain within the reference range. Such instances have the potential to create a diagnostic challenge for healthcare professionals and can lead to misdiagnosis or delayed treatment. This article presents the intriguing clinical scenario of acute pancreatitis with normal amylase and lipase, discusses factors that may lead to normoenzymatic presentation, and reminds clinicians of the diagnostic criteria for acute pancreatitis, which does not necessarily require elevated pancreatic enzymes.

Diabetic ketoacidosis (DKA) is a severe complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis, and ketosis. We present a challenging case of euglycemic DKA secondary to fasting and urinary tract infection with acute renal failure in a 50-year-old woman. Despite normal random blood sugar levels, the patient exhibited clinical signs of DKA, leading to further investigation. High anion gap metabolic acidosis with hyperkalemia and abnormal renal function tests were identified. After hemodialysis, serum ketones were found to be highly positive, confirming the diagnosis. Prompt management led to a complete clinical and laboratory resolution. This case underscores the importance of considering DKA in patients with suggestive symptoms, even with normal blood sugar levels.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, integral in type 2 diabetes mellitus (T2DM) management, are not without risks, with reported adverse effects including euglycemic diabetic ketoacidosis (EDKA). We present a case of a 75-year-old female with T2DM on canagliflozin, who developed altered mental status (AMS), nausea, vomiting, and hypotension. The laboratory results revealed ketoacidosis, elevated troponins, and Takotsubo cardiomyopathy (TC), prompting the cessation of canagliflozin. This paradoxical EDKA case underscores the necessity for cautious prescribing. Additionally, our discussion delves into the risk factors, mechanisms, and epidemiology of EDKA associated with SGLT2 inhibitors (SGLT2i), emphasizing the importance of individualized medicine and shared decision-making in their use, despite their proven cardiovascular benefits.

Euglycemic diabetic ketoacidosis (EDKA) is an uncommon subtype of diabetic ketoacidosis (DKA) which presents with similar laboratory findings to classic DKA with the exception of blood glucose levels being under 250 mg/dl. EDKA has several etiologies including pregnancy, starvation and the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2). SGLT-2 inhibitors such as empagliflozin and dapagliflozin are increasing in popularity due to their positive benefits for patients with diabetes mellitus and cardiac disease. EDKA is underdiagnosed as it presents with blood sugar levels lower than expected in classic DKA. This case report describes a well-controlled type 2 diabetic patient prescribed an SGLT-2 inhibitor who developed EDKA after undergoing coronary angiography for acute heart failure.

Euglycemic diabetic ketoacidosis (eDKA) has emerged as an adverse event associated with sodium-glucose transporter-2 inhibitors (SGLT2i). We present two consecutive cases of SGLT2i-induced eDKA, both manifested as life-threatening coronary vasospastic angina (VSA). Case 1: A 64-year-old male overweight patient with type 2 diabetes (BMI 28.2 kg/m2), treated with dapagliflozin 5 mg daily for 6 months and a restricted diet for 2 months, experienced loss of consciousness following severe chest pain while driving, resulting in a traffic accident: plasma glucose, 163 mg/dL; urine ketones, (+++); bicarbonate (HCO3-), 13.2 mmol/L; and total ketone body, 1539 µmol/L. Coronary angiography (CAG) performed on day 5 revealed diffusely spastic coronary arteries with 90% stenosis in the right coronary artery, leading to the diagnosis of VSA in the presence of coronary atherosclerosis. Case 2: A 63-year-old male patient with type 2 diabetes (BMI 22.2 kg/m2) experienced severe chest discomfort and faintness following 2 months of chest pain while on dapagliflozin 10 mg daily for 1 year: plasma glucose, 112 mg/dL; urine ketones, (+++); HCO3-, 15.3 mmol/L; and total ketone body, 10,883 µmol/L. CAG performed on day 10 revealed no organic stenosis but diffusely spastic coronary arteries in response to coronary ergonovine infusion, confirming the diagnosis of VSA. SGLT2i has the potential to inhibit acetylcholine and butyrylcholine esterase activities, leading to reduced scavenging of acetylcholine and possible induction of coronary vasospasm. These cases highlight the association between life-threatening VSA and SGLT2i-induced eDKA.

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.
OBJECTIVE: 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.
CONCLUSIONS: 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.

Euglycemic diabetic ketoacidosis (euDKA) is a rare but deadly complication of sodium-glucose cotransport-2 (SGLT-2) inhibitors. Primarily indicated for the treatment of Type 2 Diabetes Mellitus, the incidence of euDKA is expected to rise as SGLT-2 inhibitors become a mainstay therapy for diabetics with heart failure. Diagnosis of euDKA can be difficult given the presence of normoglycemia and is especially challenging among geriatric patients that are complicated by additional comorbidities. We present a case of an elderly male with multiple comorbidities who presented for dehydration and altered mentation from a nursing home facility. Laboratory investigations showed signs of acute renal failure, uremia, electrolyte abnormalities, and severe metabolic acidosis due to high levels of plasma beta-hydroxybutyrate. He was admitted to the medical intensive care unit (ICU) for further management. A presumptive diagnosis of euDKA was strongly suspected due to his laboratory data and medication reconciliation which revealed the recent initiation of empagliflozin. The patient was promptly started on a standardized treatment protocol for DKA with continuous infusion of regular insulin with strict glucose monitoring, along with intravenous fluids, and a small dose of sodium bicarbonate infusion as per current standard guidelines. With the rapid improvement in symptoms and metabolic derangements, the diagnosis was confirmed. Geriatric patients from nursing home facilities are a high-risk cohort who if not properly cared for by nursing staff can develop dehydration, malnutrition and worsening frailty including sarcopenia that exposes them to increased risk of medication side effects, such as euDKA. Clinicians should consider euDKA in their differential diagnosis in elderly patients with overt or relative insulinopenia who are receiving SGLT-2 inhibitors when presenting with acute changes in health and mentation.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been implemented in treating diabetic patients for the past 10 years. Euglycemic diabetic ketoacidosis (euDKA) can be a life-threatening complication in diabetic patients. The authors report a severe euDKA with lactic acidosis in a type 2 diabetes mellitus (T2DM) patient. This report highlights the importance of the early detection and treatment of EuDKA to avoid complications.
UNASSIGNED: Forty-four-year-old female with T2DM had multiple visits to the emergency department with recurrent diarrhoea and vomiting. On her third visit, she presented with shortness of breath and tachypnoea, found to have severe metabolic acidosis with euglycemia. She was admitted to ICU with euDKA secondary to SGLT2i and was managed accordingly.
UNASSIGNED: The association between SGLT2i and euDKA in T2DM is controversial. SGLT2i leads to euDKA by stimulating lipolysis and ketogenesis in the setting of volume depletion, carbohydrate deficiency, and upregulation of counter-regulatory stress hormones. EuDKA can be life-threatening, especially if not diagnosed and managed properly. The treatment protocol is similar to hyperglycaemic diabetic ketoacidosis. Our case has been reported in line with the CARE criteria.34.
UNASSIGNED: SGLT2i benefits in diabetic patients outweigh the risks. Clinicians are advised to counsel diabetic patients maintained on SGLT2 and educate them regarding holding the medication in the setting of acute illness, volume depletion, decreased oral intake, and surgery. In addition, there should be a high index of suspicion for patients presenting with metabolic acidosis in the background of SGLT2i use to provide early diagnosis and management.

Metformin-associated lactic acidosis is a well-known metformin treatment complication; however, the development of euglycemic diabetic ketoacidosis (euDKA) has rarely been reported. Here we report a case of lactic acidosis and euDKA after metformin overdose. A 57-year-old female patient was transferred to our hospital with severe metabolic acidosis and acute kidney injury. She had type 2 diabetes mellitus and was on oral antidiabetic therapy of vildagliptin metformin hydrochloride daily. On the admission day, she had committed suicide by overdosing 50 tablets of vildagliptin metformin hydrochloride, which was equivalent to 25,000 mg of metformin and 2500 mg of vildagliptin. She had severe lactic acidosis 5 h after overdosing. However, after 34 h of overdosing, serum lactate levels decreased while serum anion gap levels increased. She received single hemodialysis treatment. Serum total ketone bodies, β-hydroxybutyrate acetoacetic acid, and acetone were increased even after hemodialysis treatment. Her blood glucose levels have never exceeded 250 mg/dL since admission. Therefore, we considered that the cause of metabolic acidosis in this patient was not only lactic acidosis but also euDKA. The causes of euDKA in our patient might be hepatic production of ketone bodies due to metformin overdose in addition to type 2 diabetes mellitus, starvation, infection, and stressful physical conditions such as vomiting and diarrhea. We propose that not only lactic acidosis but also ketoacidosis is one of the important pathological conditions in patients with metformin overdose.