Euglycemic Diabetic Ketoacidosis: Clinical Suspicion and Diagnosis

Abstract

With the introduction of sodium-glucose cotransporter inhibitors, the incidence and awareness of euglycemic DKA have been increasing. This condition is a distinct subset of DKA without marked hyperglycemia. It can arise in various clinical settings, present with non-specific symptoms, and is thus prone to underdiagnosis. A set of circumstances (SGLT2i users during major stress, pregnancy with diabetes), clinical findings (non-specific GI symptoms, lassitude), and biochemical changes (ketonemia and metabolic acidosis) are consistent findings in the majority of cases of euglycemic DKA. Awareness that diabetic ketoacidosis can occur with normoglycemia, and leveraging the use of blood ketone tests, including meter kits, will significantly improve the diagnosis of euglycemic DKA.

Plain Language Summary

Diabetic Ketoacidosis Without High Blood Glucose. A Review

Diabetic ketoacidosis (DKA) is a serious and life-threatening complication of diabetes. It usually happens when the body does not have enough insulin, causing high blood sugar levels and a buildup of dangerous acids called “ketones” in the blood. Because DKA is traditionally known for causing very high blood sugar, doctors and patients often rely on high glucose readings to suspect it. However, there is a specific type of DKA called “euglycemic DKA” where patients have dangerous acid buildup but normal or near-normal blood sugar levels. This review explains that relying solely on blood sugar tests can lead to missed or delayed diagnoses, which can be fatal. This condition is becoming more common due to the widespread use of certain diabetes medications (known as SGLT2 inhibitors) and can also occur during pregnancy, major surgery, or severe illness. In these situations, patients may feel nauseous, tired, or short of breath, but because their blood sugar looks normal, the seriousness of their condition is often overlooked. This article highlights the importance of checking for ketones using a simple blood test or urine strip in any patient with diabetes who feels unwell, even if their blood sugar is not high. We recommend that patients taking SGLT2 inhibitors and pregnant women with diabetes be extra vigilant. Raising awareness that “normal blood sugar does not mean no DKA” can help ensure patients get the life-saving treatment they need faster.

Introduction

Diabetes mellitus leads to various health-related complications, mostly chronic complications, and a few acute crises such as diabetic ketoacidosis. Diabetic ketoacidosis (DKA) mostly occurs in type 1 diabetes patients and presents with characteristically high blood glucose levels. However, it can also occur in patients with type 2 diabetes, sometimes without significant hyperglycemia. Previously, the diagnosis of DKA required the biochemical triad of hyperglycemia (blood glucose level ⩾ 250 mg/dl), ketonemia, and metabolic acidosis. ¹ However, recognizing that DKA can occur with lower plasma glucose levels, hyperglycemia criteria have been redefined. A 2024 joint consensus by the American and European authorities redefined the hyperglycemia threshold to ⩾200 mg/dl (11.1 mmol/l) or any glucose level in individuals with prior diabetes. DKA is now diagnosed in individuals with a blood glucose concentration ⩾ 200 mg/dl, or in those with known diabetes (regardless of presenting blood glucose), when significant ketosis (a blood beta-hydroxybutyrate concentration ⩾ 3.0 mmol/l or urine ketones ⩾2+) and metabolic acidosis (bicarbonate < 18.0 mmol/l and/or venous pH < 7.3) are present. ²

Euglycemic diabetic ketoacidosis (EuDKA) is a subset of DKA in which an individual with diabetes presents with euglycemia (blood glucose level < 200 mg/dl), significant ketosis, and metabolic acidosis.^{3 -5} The term euglycemic DKA was first introduced in 1973 by Munro et al, who found that among 211 patients with DKA, 17.5% had a glucose concentration below 300 mg/dl at presentation, and 7.5% had glucose levels below 200 mg/dl. ⁶ In subsequent decades, there was an infrequent mention of euDKA until the mid-2010s.^6,7 After 2015, with the launch of SGLT2 (sodium-glucose co-transporter 2) inhibitors for type 2 diabetes, euDKA, an unremembered subset of DKA, resurfaced. Within a year of SGLT2-inhibitors entering the market, the U.S. Food and Drug Administration issued an alert paper highlighting their association with DKA. ⁸ In view of the benefits outweighing the amount of risk, subsequent trials popularized the use of SGLT2i in the management of type 2 diabetes mellitus, heart failure, and kidney diseases. ⁵ SGLT2i block SGLT2 receptors in nephrons, reducing glucose reabsorption, increasing glucose excretion, and lowering blood glucose levels. A SGLT2i also increases the production and utilization of ketones in the body (and myocardium), which is 1 of the postulations for improved heart function in patients with heart failure, regardless of whether they have diabetes. ⁹ Due to the interplay of multiple factors, SGLT2i increases the risk of ketoacidosis, including euglycemic DKA. ⁵ Regardless of the cause, euDKA occurs due to a state of carbohydrate deficiency in the background of insulin deficiency and excess counter-regulatory hormones.^3,4

In this review, we report common triggers, early clinical symptoms, and biochemical changes in patients with euDKA. We performed literature search in MEDLINE, EMBASE, and the Cochrane Library with keywords including “euglycemic diabetic ketoacidosis,” “SGLT2 inhibitors,” and “ketoacidosis.” We also reviewed reference lists from relevant publications. We prioritized high-quality evidence, including randomized controlled trials, meta-analyses, and clinical guidelines, as well as illustrative case reports that highlighted distinct and relevant information about euDKA. The selected literature was synthesized to provide a narrative overview of the clinical features and diagnostic approach to euDKA.

When to Suspect Euglycemic DKA

Non-specific clinical symptoms and normal blood glucose levels can mislead clinicians, diverting their differential diagnoses from diabetic ketoacidosis. Therefore, the diagnosis of euglycemic DKA requires a high level of suspicion. A combination of certain distinct circumstances, clinical symptoms, and biochemical abnormalities is common among patients with euDKA.

Circumstances

Patients with Diabetes on Insulin Therapy

Before the advent of SGLT2i, most reported cases of euglycemic DKA belonged to this category.^{6,7,10 -12} When an insulin-dependent patient with diabetic is subjected to a triggering factor for DKA and is fasting or starving while continuing insulin treatment, euDKA may develop.^{13 -16} Pre-hospital self-administration of insulin by the patient for the symptoms of suspected DKA can lead to reduced glucose levels at the time of presentation.^4,12

Patients with Diabetes on SGLT2i

SGLT2i -associated diabetic ketoacidosis (DKA) is more likely to occur in patients with type 1 diabetes, although it can also occur in patients with type 2 diabetes.^8,17,18 Most of the time, DKA is precipitated by a recognizable factor, but it occasionally occurs spontaneously.^2,19 Infections, surgical stress, myocardial infarction, acute pancreatitis, and acute trauma are common acute stressors reported to trigger ketoacidosis in these patients.^{19 -21} A review of 169 patients with euDKA among SGLT2i users (primarily type 2 diabetes) found acute infection to be the precipitating factor in 37.9%, followed by perioperative use of this drug during major surgeries (24.3%). ²⁰ Low carbohydrate intake, dehydration due to illness or prolonged fasting, alcohol abuse,^{20,22 -24} and adoption of a ketogenic diet (with the intention of weight loss)^25,26 are other important precipitants among these patients. It seems that patients with type 2 diabetes with a longer history of diabetes, poorer disease control, lower BMI, and reduced β-cell function reserve are more likely to develop SGLT2i-associated DKA. ²⁷

In patients with severe pancreatic insulin deficiency (type 1 diabetes, latent autoimmune diabetes in adults, history of pancreatitis, or pancreatic surgery), off-label or erroneous use of SGLT2i has been significantly associated with the development of euDKA.^8,18,28,29 Among insulin-dependent patients, sudden omission or incorrect adjustment of the insulin dose while adding or continuing SGLT2i is a frequently reported precipitating factor.^{29 -31} The risk of ketoacidosis appears unrelated to the duration of SGLT2i use, with cases of euDKA reported after just 1 day of therapy and others after several months.^20,32 Additionally, patients may remain at risk of ketoacidosis for days after SGLT2i discontinuation, likely due to the residual effects of the drug on glucose handling. ³³

Patients with Diabetes During Perioperative Stress

Perioperative stress (low-calorie intake, surgical stress, and intravascular volume depletion) significantly increases the risk of DKA in patients with diabetes.^{34 -36} Inappropriate reduction or omission of insulin dose in perioperative patients is another important precipitant. ³⁴ The use of the SGLT2i for up to 3 days before a major surgical procedure has been associated with the occurrence of euDKA.^34,35,37 This includes patients on SGLT2i who underwent urgent or emergency procedures without prophylactic discontinuation of this drug. A review of 42 patients found that the presentation time for perioperative euDKA ranged from a few hours to several weeks postoperatively, with most cases occurring between 3 and 10 days. ³⁴ There have also been reported of intraoperative manifestations of euDKA.^38,39 A significantly higher incidence of SGLT2i-induced euDKA has been reported in perioperative bariatric and cardiac surgery patients.^34,35,40,41 In the absence of SGLT2i prescriptions, cases of diabetes complicated by euDKA following bariatric ⁴² and pancreatic surgeries ³⁶ have also been reported. The perioperative euDKA may initially present as simply as malaise, vomiting, difficulty breathing, tachycardia, or abdominal pain.^4,34,43,44 Occasionally, it may present as refractory acidemia, ⁴⁵ delirium,^46,47 severe cases like shock requiring inotropes. ⁴⁷

Pregnancy with Diabetes

Diabetic ketoacidosis can develop in both those who develop diabetes during pregnancy and in diabetics who become pregnant. During pregnancy, DKA often occurs at lower glucose levels, and euDKA is also a well-recognized phenomenon.^11,48,49 Some studies have claimed that up to 30% to 50% of DKAs in pregnancy might occur without significant hyperglycemia.^49,50 EuDKA is more common in pregnancies with pre-existing type 1 diabetes than in those with type 2 diabetes or gestational diabetes. ⁴⁹ It typically occurs during the third trimester, with common precipitants, including low calorie intake or fasting, infections, and improper insulin dose adjustments.^10,11,49 Recurrence of euDKA within the same pregnancy and in subsequent pregnancies has also been documented. ⁴⁹

Others

In the medical literature, most cases of euglycemic diabetic ketoacidosis (euDKA) have been observed under the aforementioned conditions. However, it has been infrequently reported that individuals with type 1 diabetes and severe insulin deficiency and carbohydrate deprivation may develop euDKA.^23,51,52 Reports of euDKA with the use of GLP1 (glucagon-like peptide-1) agonists in insulin-dependent individuals with diabetes^53,54 either alone or in combination with SGLT2i ⁵⁵ have been documented. Some case reports have suggested that severe hypertriglyceridemia may result in spurious low blood glucose levels, leading to pseudoeuglycemia. When accompanied by DKA, it can manifest as pseudonormoglycemic DKA.^55,56 Cocaine intoxication,^57,58 glycogen storage disorders, and liver cirrhosis have also been reported as predisposing factors of euDKA. ⁴

Clinical Features

There are no significant differences in the clinical characteristics between hyperglycemic and euglycemic DKA. ²¹ Commonly reported symptoms include nausea, vomiting, abdominal discomfort, generalized weakness, difficulty in breathing, and altered mental status. The clinical signs often observed are tachypnea, tachycardia, a fruity odor on the breath, Kussmaul breathing, and dehydration.^{4,22,40,49,56,59} None of these symptoms alone are definitive for ketoacidosis. However, the mental status (alert, drowsy, stuporous, or comatose) can help classify the severity of DKA. ² The symptoms in euDKA are milder than those in hyperglycemic DKA, yet clinical consequences might be grievous due to delayed or misdiagnosis.^5,59

The clinical symptoms may result from metabolic derangements associated with ketoacidosis or could be related to the underlying factor that triggered ketoacidosis. Ketone body production leads to metabolic acidosis, which causes respiratory compensation, resulting in dyspnea and symptoms, such as nausea, vomiting, and anorexia. ⁴ Additionally, nausea, vomiting, lassitude, and abdominal discomfort are common in various infections and other DKA precipitators. Due to the nonspecific and mild nature of symptoms, the presence of risk factors (discussed above) and even subtle signs should prompt thorough biochemical evaluation. ²⁰

Biochemical Manifestations

Biochemical abnormalities in euDKA are largely similar to those in hyperglycemic DKA, except for the presence of normal blood glucose levels in euDKA. The key biochemical features of euDKA can be summarized as follows: euglycemia in diabetics with ketosis and metabolic acidosis.

• Euglycemia: blood glucose levels < 200 mg/dl.

• Ketosis: A β-hydroxybutyrate concentration ⩾ 3 mmol/l in the blood is a defining characteristic. Significant ketonuria and urine ketone levels ⩾2+ can also be used as indicators.

• Metabolic acidosis: Defined as a bicarbonate concentration < 18.0 mmol/l and/or venous pH < 7.3. ²

In DKA, insulin deficiency leads to lipolysis and ketogenesis, resulting in ketoacid accumulation. Because ketoacids are unmeasured anions, their accumulation causes elevated anion-gap metabolic acidosis. Metabolic acidosis and insulin deficiency cause potassium to shift from the intracellular to the extracellular space, whereas extracorporeal losses (osmotic diuresis and vomiting) contribute to the depletion of potassium ions from the body. Due to the combined transcellular shift and loss of potassium from the body, serum potassium levels may appear normal or near normal despite total-body potassium depletion. ⁴⁸

Identifying the precipitating factors is crucial for managing current episodes and preventing future events. While infection is a common trigger, evidence of mild leukocytosis alone is insufficient, as it may result from hemoconcentration or stress. ⁴ Though high anion gap metabolic acidosis is characteristic of diabetic ketoacidosis, mixed acid-base disorders can arise from severe dyselectrolytemia and compensatory alkalosis. ² Urinary ketone (acetoacetate) measurement does not reflect the degree of ketonemia (β-hydroxybutyrate levels). Since β-hydroxybutyrate is subsequently converted to acetoacetate and later excreted in the urine, urine ketone testing may underestimate early DKA. Furthermore, in the setting of SGLT2i use, urine ketones may be reabsorbed, leading to false negative results. Therefore, β-hydroxybutyrate measurement should be preferred over urine ketone testing, whenever possible.^1,2

Approach to Differential Diagnosis

First, in any clinically suspected case of diabetic ketoacidosis (DKA), a normal blood glucose level should not exclude this diagnosis. Second, all patients on a SGLT2i presenting with an acute serious illness should be considered at risk of developing ketoacidosis. Although DKA is a laboratory-based diagnosis, thorough medical history and clinical examination remain crucial. Common causes of euglycemic ketoacidosis include euglycemic DKA, starvation ketoacidosis, alcoholic ketoacidosis, ketosis during pregnancy (due to accelerated starvation, hyperemesis), and SGLT2i-related non-diabetic euglycemic ketoacidosis.^56,61 EuDKA could be considered in the individuals with diabetes only after ruling out other potential causes of euglycemic ketoacidosis. ⁴⁸ Starvation ketosis is typically identified based on a clinical history of prolonged starvation, with serum bicarbonate levels usually remaining above 18 mEq/l (rarely < 18 mEq/l). Patients with alcoholic ketoacidosis (AKA) are typically chronic alcohol users, often presenting in a dehydrated state after 1 to 3 days of reduced oral intake following binge drinking. ⁶¹ Similar to DKA, β-hydroxybutyrate is the main ketoacid in AKA, but the elevated NADH/NAD⁺ ratio raises the β-hydroxybutyrate-to-acetoacetate ratio to 8:1 compared to 3:1 in DKA. In cases involving unidentified individuals unable to provide their medical history, a high HbA1c level may suggest the possibility of DKA, whereas low or negative plasma alcohol concentrations do not rule out AKA.^60,61 Acidosis from starvation or AKA typically resolves with rehydration using dextrose-containing intravenous fluids, whereas euDKA requires additional exogenous insulin. ⁵⁸

When serum β-hydroxybutyrate is unavailable, the diagnosis of euglycemic DKA becomes more challenging. Although DKA is common, anion gap metabolic acidosis from any other causes can occur in patients with diabetes, such as glycols, oxyproline (pyroglutamic acid, the toxic metabolite of excessive acetaminophen), L-lactate (lactic acidosis), D-lactate (produced by gut bacteria), methanol (and other alcohols), aspirin, renal failure (uremic acidosis), and ketones (alcoholic and starvation ketosis) (remember them as “GOLD MARK”).^56,59,62 Following thorough history taking, clinical assessment, and routine investigations, it may further demand blood gas analysis, serum osmolarity, osmolality, osmolar gap, volatile screen, serum levels of ethanol, acetaminophen, lactate, d-lactate, and salicylic acid, urine toxicology panel, urinary crystals, etc. to narrow the differential diagnoses.^4,62 Also, perioperative euDKA is a great masquerader. Nausea, vomiting, abdominal can be easily overlooked at first as usual postoperative complications, but also secondary to underlying ketoacidosis. Hence, early suspicion in susceptible patients is necessary. Some guidelines recommend perioperative routine ketone measurement in the SGLT2i users undergoing surgical procedures. ⁶³

Discussion

The increasing incidence of euglycemic DKA has made it an increasingly common clinical concern. Up to 10% of DKA cases may present without remarkable hyperglycemia. ² Nonspecific symptoms, normal blood glucose, and occasional non-significant ketonuria (particularly in the early stages) waver clinicians’ suspicion of DKA. Recognizing that DKA can occur with normoglycemia and using blood ketone tests (including portable meter kits) will significantly improve the diagnosis of euDKA. Demonstrating significant ketonemia is a characteristic of DKA and helps narrow the differential diagnosis. We propose that a patient with euglycemic ketoacidosis be categorized as “diabetes with euglycemic ketoacidosis” or “non-diabetic euglycemic ketoacidosis” based on their diabetes status. Only after excluding other plausible causes of ketoacidosis in patients with diabetes should the condition be classified as euglycemic diabetic ketoacidosis, as depicted in Figure 1.

Figure 1.

Algorithm to identify cases of euglycemic diabetic ketoacidosis.

Diabetic ketoacidosis is an important complication of the SGLT2-inhibitors, an uncommon complication of anti-diabetic drugs. The use of SGLT2i has been associated with a 2.2-fold increase in the risk of DKA compared to that in non-users.^64,65 In a cohort of 9940 patients with type 2 diabetes on SGLT2i, the prevalence of DKA was 0.43%, with 0.25% euglycemic DKA and 0.18% hyperglycemic DKA. ¹⁹ The increased propensity for ketogenesis may have resulted from elevated glucagon secretion and a higher glucagon-insulin ratio.^18,22 The occurrence of ketoacidosis in individuals without diabetes taking SGLT2i when subjected to ketogenic stress has also been reported,^{66 -68} yet some researchers deny this entity. ⁶⁹ SGLT2i-induced DKA might be more protracted and prolonged than DKA in non-users.^{70 -73} The longer hospital stay and longer time for acidosis correction among euDKA patients has been attributed to later diagnosis, lower insulin infusion rates, presumably chosen to prevent hypoglycemia and probable a longer residual effect of SGLT2i on glucose handling in the body.^72,73 A metasummary of 169 euDKA cases reported a 2.4% mortality rate among these patients. ²⁰ Though no studies have compared the risk of euDKA among individual SGLT2i drugs, reports have suggested that canagliflozin may have the strongest association.^19,34

Perioperative SGLT2i use has been linked to postoperative ketosis in both patients with and without diabetes.^35,74 A retrospective review of 1307 patients on SGLT2i found that euglycemic DKA rates were lower in elective cases than in emergency procedures, likely due to proper preoperative cessation in the former group. ⁷⁴ Presently, the FDA recommends stopping canagliflozin, dapagliflozin, and empagliflozin at least 3 days before, and ertugliflozin at least 4 days before scheduled surgery. ⁷⁵ The perioperative use of SGLT2i in bariatric surgical patients, which requires extensive dietary modification perioperatively, and underlying insulin resistance might put patients at further risk of euDKA. ⁴⁰ Similarly, periprocedural SGLT2i-linked hyperketonemia and euDKA have also been reported around colonoscopy, where prolonged fasting and bowel preparation further compound the ketogenic milieu. ⁷⁶ This occurs commonly in emergent surgeries, and while not much may be done at the time of the procedure, close monitoring right after surgery may lead to early detection and treatment of euglycemic DKA, and therefore decrease the likelihood of subsequent complications. ⁴⁶

Up to 2% of pregnant women with pregestational diabetes develop diabetic ketoacidosis. ² Blunted acid-base buffering, relative insulin resistance, enhanced lipolysis, elevated free fatty acids, and ketogenesis increase the risk of DKA in pregnant women with diabetes. Meanwhile, reduced glycogenolysis, higher glucose utilization, glucosuria, and physiologic hemodilution may explain the lower blood glucose levels in DKA during pregnancy than in non-pregnant women with diabetes. ¹¹ Since maternal ketogenesis is accelerated during pregnancy, particularly in the third trimester, ketoacidosis occurs even during shorter periods of starvation and hyperemesis. DKA during pregnancy carries a higher risk of adverse outcomes in the fetus and mother.^5,77

Recognizing the risk of euDKA beyond the SGLT2i use is essential. Other notable risk populations include pregnant women with diabetes, insulin-dependent patients during acute stress or the perioperative period, and potentially those using GLP-1 agonists. While bedside measurement of capillary glucose using handheld glucometers is standard practice in emergency rooms, bedside ketone measurement remains underutilized. Though not diagnostic, high capillary ketone levels in high-risk populations would guide suspicion and investigation toward ketoacidosis even in the absence of significant hyperglycemia. A disparity exists in resource availability; whereas capillary ketone meters are frequently prescribed for home use in high-income countries, they remain uncommon in developing regions. Since point-of-care capillary ketone measurement is highly accurate for quantifying blood β-hydroxybutyrate levels and is superior to urine ketone testing, it should be prioritized for diagnosis and monitoring whenever possible.^2,78,79 Therefore, we advise that at-risk individuals with diabetes presenting with suggestive clinical features be evaluated using a reliable ketone meter, irrespective of their glucose levels.

For centuries, hyperglycemia (blood glucose > 250 mg/dl) has been a key component in diagnosing diabetic ketoacidosis. It has preoccupied clinicians’ minds that the absence of hyperglycemia has diverted their further workups away from the line of DKA. Presently, the reporting and incidence of euglycemic diabetic ketoacidosis (euDKA) are increasing; however, awareness of this condition among clinicians remains insufficient. ¹⁴ Though the detailed discussion of euDKA management is beyond the scope of this article; however, it is fundamentally the same principle as for hyperglycemic DKA (correction of dehydration and electrolyte deficit, insulin replacement, and avoidance of hypoglycemia). Current guidelines specifically suggest fixed-rate insulin infusion accompanied by the titration of dextrose-containing fluids to prevent hypoglycemia while clearing ketones.^2,73 Though the management of EuDKA is based on the same principles as for hyperglycemic DKA it may have worse outcomes due to late or missed diagnosis.^{2 -4} This also leads to the need for undue investigations and avoidable referrals. Although recent guidelines have considered this subset and have included it in the diagnostic criteria of DKA, there is still a lack of structured blueprints on when to suspect euDKA and how to deal with its differential diagnoses. We hope that this review will act to fill this gap and improve patient care and clinical practice. The graphical summary the manuscript has been depicted in Figure 2.

Figure 2.

Graphical summary.

Conclusion

Diabetic ketoacidosis associated with a SGLT2i use or pregnancy often presents with lower blood glucose levels than those typically observed in DKA. Euglycemic DKA closely resembles hyperglycemic DKA, both clinically and biochemically, with the key difference being normal blood glucose levels. Given the high risk of underdiagnosis, normoglycemia should not rule out the possibility of DKA in any clinically suspected patient. Awareness that DKA can occur with normoglycemia and leveraging the use of blood ketone tests, including meter kits, will significantly improve the diagnosis of euglycemic DKA.