Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase ketoacidosis risk, limiting their use in type 1 diabetes. To better understand the pathophysiology of SGLT2 inhibitor-mediated ketoacidosis, we measured blood glucose, capillary blood and plasma β-hydroxybutyrate (BOHB) and breath acetone (BrACE) during supervised insulin withdrawal in adults with type 1 diabetes with and without dapagliflozin treatment.

Twenty adults with type 1 diabetes underwent supervised insulin withdrawal twice in a randomized crossover design: during usual care and after treatment with dapagliflozin (10 mg daily for 2 weeks plus the test day). After insulin withdrawal, capillary blood glucose, BOHB and BrACE measurements were obtained at least hourly until stopping rules were met (>8 h elapsed, symptoms of ketosis, glucose >400 mg/dL, BOHB >4 mmol/L or participant request).

The peak BOHB and BrACE values achieved during supervised insulin withdrawal were both greater with dapagliflozin than with usual care. Throughout the insulin withdrawal study, dapagliflozin treatment was associated with significantly greater BOHB and BrACE concentrations. The proportions of participants reaching BOHB >1.5 mmol/L and >2.5 mmol/L during supervised insulin withdrawal were greater in the dapagliflozin arm. Blood glucose reached a lower peak in the dapagliflozin arm.

In adults with type 1 diabetes undergoing supervised insulin withdrawal, dapagliflozin treatment compared to usual care was associated with greater blood and breath ketone concentrations in the absence of significant hyperglycaemia.

Euglycemic diabetic ketoacidosis (EuDKA) is a potentially life-threatening complication associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors. Its subtle presentation, often lacking the hallmark of marked hyperglycemia, can lead to delayed recognition and treatment. We present the case of a 53-year-old female with type 2 diabetes mellitus who developed EuDKA following the abrupt discontinuation of long-term insulin therapy and transition to an SGLT2 inhibitor. Her vague symptoms and near-normal glucose levels concealed the severity of her condition, delaying the diagnosis. Once identified, she was managed with intravenous insulin, dextrose-containing fluids, and potassium replacement, resulting in resolution of acidosis and normalization of serum ketones. This case focuses on the diagnostic challenges posed by euglycemic DKA and highlights the importance of considering it in patients with SGLT2 inhibitors, even without significant hyperglycemia. It also emphasizes the need for careful clinical judgment when adjusting diabetic regimens and calls for more structured prescribing guidelines as these agents gain broader use.

Blood ketone monitoring is commonly used in the management of diabetic ketoacidosis (DKA). However, bedside ketone meters have limited availability in hospitals. This study aimed to clarify the correlation between blood ketones and blood gas analysis (BGA) in the treatment of DKA and thereby identify parameters that can be used as surrogates for blood ketones.

This retrospective observational study included patients with DKA admitted to the JA Toride General Medical Center between November 2021 and March 2024. Multiple regression analysis was performed using blood ketone levels as the objective variable and BGA indices as explanatory variables. Additionally, the study evaluated 1) the time course of ketone levels and BGA indices during the DKA treatment and 2) the correlation between ketone levels and the BGA indices.

Sixteen patients were enrolled. Multiple regression analysis showed that the corrected anion gap (cAG), defined as the anion gap minus lactate concentration, was a significant predictor of blood ketones. Among pH, HCO3 -, and cAG, only cAG had significant regression coefficients (-0.061 [95% confidence interval (CI): -3.49 to 1.98], -0.233 [-0.156 to 0.0118], 0.636 [0.129 to 0.246], respectively; coefficient of determination: 0.765). The correlation coefficient between cAG and blood ketone levels was high (0.9694).

cAG levels strongly correlate with blood ketone concentrations and may serve as a surrogate marker for blood ketones in the management of DKA. Because measurements of the anion gap and lactate concentrations are inexpensive and widely available in most medical facilities, cAG is a promising indicator for DKA management.

This narrative review aims to explore the literature on advancements in diabetes management within long-term care facilities (LTCFs). Managing chronic diseases like diabetes in LTCFs is particularly challenging due to the dynamic nature of these environments and the significant changes they have undergone over the past decade. Various factors, including rising care costs and government regulations, influence the quality-of-care residents receive in these settings.

Many diabetes medications have not been extensively studied in LTCFs, and high-risk medications such as sulfonylureas and sliding scale insulin are still in use, potentially increasing the risk of morbidity and mortality among residents. Additionally, the adoption of diabetes technologies, such as continuous glucose monitors (CGMs) and insulin pumps, remains limited in LTCFs. Despite the high prevalence of diabetes, significant research gaps persist. Diabetes technologies have the potential to greatly improve diabetes management and outcomes for residents. However, more research is needed to evaluate their efficacy and safety in long-term care settings. Furthermore, there is a pressing need to address the gap in staff training on the use of these technologies. Closing these research gaps is essential for developing evidence-based guidelines and improving the quality of diabetes care in LTCFs.

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have shown benefits in managing heart failure, renal insufficiency and type 2 diabetes, but euglycemic ketoacidosis, while rare, has been reported in several patients on those medications. Therefore, their potential for inducing ketoacidosis, even in the presence of normal glucose levels, requires careful monitoring. We describe the case of a 78-year-old woman with type 2 diabetes treated with the SGLT-2 inhibitor dapagliflozin and the biguanide metformin, who presented after several days of reduced food and fluid intake due to nausea and diarrhoea to the emergency department. A few hours after admission to the medical ward with a working diagnosis of infectious gastroenteritis her condition deteriorated, and mottling served as an early sign of life-threatening euglycemic ketoacidosis. The mottling score increased in parallel with the National Early Warning Score (NEWS). She was treated with intravenous fluids, continuous insulin therapy and supportive measures, resulting in rapid clinical improvement. This report highlights the importance of early recognition to prevent serious complications and underscores that mottling might be a valuable early sign in addition to classical tools such as the NEWS. Although rare, euglycemic ketoacidosis can be precipitated by factors such as starvation, dehydration or infections in patients taking SGLT-2 inhibitors. The risk might be higher in individuals on SGLT-2 inhibitors and metformin. Timely intervention and metabolic correction are essential for improving outcomes in these patients, particularly when they present with atypical symptoms.

Mottling can serve as an early clinical indicator of euglycemic ketoacidosis (EKA) in patients treated with sodium-glucose co-transporter-2 (SGLT-2) inhibitors, even in the absence of circulatory shock, highlighting the importance of timely detection and intervention.Factors such as starvation, dehydration or infections can precipitate EKA in patients using SGLT-2 inhibitors, emphasising the need for careful monitoring in at-risk populations.Discontinuation of SGLT-2 inhibitors, rapid metabolic correction using fluids and insulin and avoidance of unnecessary antibiotics are essential for effective management and recovery from EKA.

Euglycemic diabetic ketoacidosis is a rare but serious adverse effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors. They are a newer class of oral hypoglycemic drugs commonly prescribed for managing patients with diabetes mellitus.

We present a case of a woman in her 60s with type 2 diabetes mellitus hospitalized for operation of pancreatic body tumor who developed dapagliflozin-associated euglycemic diabetic ketoacidosis despite having stopped the medication before operation. She underwent laparoscopic distal pancreatectomy and occurred euglycemic diabetic ketoacidosis during post-operative period.

Surgical stress, acute postoperative illness, and decreased carbohydrate intake are postulated to be contributing factors to the development of ketosis in this patient, while near-normal glucose levels initially suggested non-diabetic ketoacidosis physiology and led to delayed diagnosis and treatment. Patients with type 2 diabetes mellitus may develop diabetic ketoacidosis during states of relative insulinopenia, most frequently from inadequate medication or intercurrent illness. During periods of carbohydrate deficiency, volume depletion, and up-regulation of counter-regulatory stress hormones, SGLT2 inhibitor therapy can promote lipolysis and ketogenesis while maintaining euglycemia.

Clinical considerations to ensure safe SGLT2 inhibitor therapy include appropriate holding parameters, timely diagnosis of euglycemic diabetic ketoacidosis, and recognition that the pharmacologic effects of SGLT2 inhibitor treatment may persist beyond several half-lives of elimination.

SGLT-2 inhibitors (SGLT-2i) are linked to a higher risk of diabetic ketoacidosis (DKA). However, it is still unclear whether the severity of SGLT-2i associated DKA is higher. This is a retrospective cohort study with patients admitted for DKA at a tertiary hospital (2013-2024). Patients were matched by propensity score for age, sex, diabetes duration, type, and ischemic heart disease. ICU admission risk and clinical severity were compared between SGLT-2i users and controls. The matched sample included 105 subjects (35 SGLT-2i users, 70 controls). The average age was 63.1 ± 15.4 years, and 40 (38.1%) patients were women. ICU admission was higher in the treatment group (65.7% versus 24.6%, p < 0.001). A conditional logistic regression showed higher risk of ICU admission in the treatment group (odds ratio 12.7, 95% confidence interval 1.9-84.3, p = 0.009) after adjusting for confounding factors. The treatment group exhibited less favorable blood gas results (pH 7.10 ± 0.17 vs 7.18 ± 0.16, p = 0.024) and shorter symptom duration (2 [1-3] vs 3 [2-7] days, p < 0.002). No significant differences were found in diabetes type, ketonemia, creatinine, or DKA precipitating factors. DKA in patients with diabetes treated with SGLT-2i is associated with more severe acidosis with quicker onset, leading to higher risk of ICU admission compared to patients not receiving this treatment. We recommend temporary discontinuation of SGLT-2i during any acute event until resolution, regardless of diabetes type or the patient's glycemic control.

Euglycemic diabetic ketoacidosis (EuDKA) is a rare but serious complication of sodium-glucose cotransporter 2 (SGLT2) inhibitors, characterized by metabolic acidosis with near-normal blood glucose levels, making it challenging to diagnose. This case report describes a 49-year-old male with stage 4 chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) on an SGLT2 inhibitor and metformin who developed EuDKA and lactic acidosis following an upper respiratory infection. Despite discontinuation of the medications and intravenous fluid resuscitation, severe metabolic acidosis persisted. Early initiation of hemodialysis led to rapid correction of acidemia, hyperkalemia, and improvement in renal function. This case highlights the importance of early recognition of SGLT2 inhibitor-associated EuDKA, particularly when complicated by lactic acidosis, and emphasizes the potential role of hemodialysis in managing refractory metabolic acidosis to prevent further clinical deterioration, even with modest hyperglycemia.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is), commonly known as flozins, have garnered attention not only for their glucose-lowering effects in type 2 diabetes mellitus (T2DM) but also for their cardioprotective properties. This review examines the mechanisms underlying the anti-fibrotic effects of SGLT2is, with a focus on key clinical trials and preclinical models. SGLT2is, mainly empagliflozin and dapagliflozin, have demonstrated significant reductions in heart failure-related hospitalizations, cardiovascular death, and fibrosis markers, independent of their glucose-lowering effects. The cardioprotective benefits appear to stem from direct actions on cardiac tissues, modulation of inflammatory responses, and improvements in metabolic parameters. In animal models of heart failure, SGLT2is were demonstrated to reduce cardiac fibrosis through mechanisms involving AMPK activation, reduced oxidative stress, and inhibition of pro-fibrotic pathways, not only through the inhibition of SGLT2 present on cardiac cells but also by targeting several other molecular targets. These findings confirm their efficacy in the treatment of heart failure and align with evidence from human trials, supporting the potential involvement of multiple pathways in mediating cardiac fibrosis. These results also provide a promising basis for clinical trials specifically targeting pathways shared with SGLT2is.

This case highlights a rare yet severe presentation of euglycemic diabetic ketoacidosis (DKA) in a male in his mid-eighties with type 2 diabetes mellitus managed on SGLT-2 inhibitors. Despite nearly normal blood glucose levels, he developed profound metabolic acidosis and elevated ketones, necessitating emergency intervention. Initial treatment with intravenous fluids and insulin led to temporary stabilization. Still, progressive metabolic derangement and multi-organ dysfunction resulted in a transition to palliative care, ultimately leading to his demise. This case underscores the need for heightened clinical awareness, early diagnosis, and cautious use of SGLT-2 inhibitors, particularly in elderly patients with multiple comorbidities.

Diabetic ketoacidosis is a common endocrine emergency. A subset of patients present with euglycemic diabetic ketoacidosis, which may be diagnosed late due to its rarity and relatively lower blood glucose levels. Pregnancy is associated with euglycemic diabetic ketoacidosis, which can lead to maternal and fetal demise without prompt treatment. The objective of this case report is to describe a patient with type 1 diabetes mellitus who developed euglycemic diabetic ketoacidosis on insulin pump therapy during pregnancy.

A 30-year-old pregnant patient at 33 weeks of gestation with type 1 diabetes mellitus on continuous subcutaneous insulin infusion presented to the emergency department with vomiting. Her serum bicarbonate of 9 mmol/L was accompanied by serum glucose of 130 mg/dL, moderate blood ketones, and urine ketones 80 mg/dL (large). She was treated with intravenous insulin infusion without complications to herself or the fetus.

Pregnancy is a common background for euglycemic diabetic ketoacidosis and can lead to maternal and fetal demise if not addressed early. Despite insulin resistance in pregnancy, a relatively low blood glucose is maintained by increased glycogen storage and increased fetoplacental uptake. Altered acid-base physiology in pregnancy may also increase the propensity for euglycemic diabetic ketoacidosis.

Diabetic ketoacidosis can present in pregnancy with euglycemia, and a high index of suspicion is needed by both patients and health care teams. There are a few reports on this phenomenon in a pregnant patient using an insulin pump. Early identification and treatment are important to prevent maternal and fetal complications.

Sodium-Glucose Co-transporter-1/2 (SGLT1/2) inhibitors (also called glifozins) are a class of glucose-decreasing drugs in adults with Type 2 Diabetes (T2D). SGLT2 inhibitors diminish sodium and glucose reabsorption in the renal proximal convoluted tubule. Recent clinical trials have revealed that SGLT2 inhibitors might be beneficial for treating diseases other than diabetes, including chronic renal disease and Heart Failure (HF). Currently, SGLT2 inhibitors are recommended not only for the glycemic management of T2D but also for cardiovascular protection. SGLT2 inhibitors have become one of the foundational drugs for HF with reduced Ejection Fraction (HFrEF) treatment and the first medications with proven prognostic benefit in HF with preserved Ejection Fraction (HFpEF). At present, 11 SGLT1/2 inhibitors have been approved for clinical use in different countries. Beyond their anti-hyperglycemic effect, these inhibitors have shown clear cardio- and nephroprotective properties. A growing body of research studies suggests that SGLT1/2 inhibitors may provide potential clinical benefits in metabolic as well as oncological, hematological, and neurological disorders.

To examine the effects of insulin-adjunctive therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes.

In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods.

Average glucose and percent time with glucose in range (70-180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy.

Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now widely used for treating type 2 diabetes mellitus (T2DM) and obesity. We examined their association with acetonemic vomiting, especially when given to patients with low body weight, in hopes of achieving early recognition of this complication which is potentially life-threatening if not dealt with appropriately.

Cases identified incidentally are described and discussed referring to prior reports.

We managed two episodes of acetonemic vomiting, associated with GLP-1 RA use, affecting type 2 diabetes patients with low body weight. The absence of significant abnormalities in regularly tested laboratory data or imaging workup findings in these patients made it difficult to diagnose and recognize the emergent nature of the problem.

GLP1-RAs have the potential to induce acetonemic vomiting when prescribed to patients with diabetes, especially those with low body weight. Although it is a potentially life-threatening disorder, acetonemic vomiting is not common in adults, making accurate diagnosis challenging. It is important that clinicians not hesitate to administer a dextrose-containing intravenous bolus, with insulin if necessary, to maintain normal glucose levels and thereby prevent progression to severe outcomes including death.

SGLT2 (Sodium-Glucose Co-transporter 2) inhibitors, also known as gliflozin class, are a novel family of oral drugs being used to treat type 2 diabetes. SGLT2 inhibitors can work alone or in conjunction with other medications. This class includes five drugs, including canagliflozin, ertugliflozin, sotagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors inhibit the SGLT2 cotransporter in the proximal tubules of the kidney, reducing glucose and sodium reabsorption. It promotes the elimination of sugar in urine (diabetes mellitus) and lowers blood sugar levels. SGLT2 inhibitors also have pleiotropic effects on cardiac and renal function, broadening their therapeutic applications in heart failure. Despite the clinical benefits, regulators have placed secondary warnings in product information since the medications first hit the market. SGLT2 inhibitors, in particular, have had a significant impact on a variety of risk factors. This can lead to hypoglycaemia, urinary tract infections, diabetic ketoacidosis, lower limb amputation, and fractures. Although some of these events are uncommon, they can lead to severe and deadly consequences; therefore, patients must be closely monitored. In general, SLGT2 inhibitors are an efficient diabetes treatment with strong cardiovascular and renal protection and a favourable safety overview. This review sought to summarise the safety overview of commercially available SGLT2 inhibitors.

Diabetes is a complex global healthcare burden involving multiple organ systems with its prevalence on the rise. SGLT2 inhibitors enhance glucose excretion. The objective of our literature review was to determine the association between cutaneous adverse drug reactions (CADRs) and the use of SGLT2 inhibitors. We collected data on CADRs related to the use of SGLT2 inhibitors from all available published articles and studied their details to understand the patterns of their association. PubMed, Cochrane, Google, and Embase were searched for relevant articles. A total of 37 papers were included and studied. Most articles were case reports followed by pharmacovigilance studies, case series, and reviews. The cutaneous findings ranged from benign eruptions to severe reactions. The available literature suggests a strong link between the use of SGLT2 inhibitors and Fournier's gangrene/necrotizing fasciitis. T2DM patients using SGLT2 inhibitors have also developed fixed drug eruptions, drug-induced pruritus, and Sweet syndrome/acute febrile neutrophilic dermatosis, among other skin lesions. We found that SGLT2 inhibitors present a risk of developing CADRs. Raising awareness among healthcare providers regarding CADRs to SGLT2 inhibitors can reduce complications, minimize hospitalizations, and improve patient care in the vulnerable population of diabetes patients.

Diabetes mellitus (DM) is a chronic disease associated with numerous complications, including cardiovascular diseases, nephropathy, and neuropathy. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, a class of novel antidiabetic agents, have demonstrated promising therapeutic effects beyond glycemic control, with potential benefits extending to the cardiovascular and renal systems. Recently, research has increasingly focused on exploring the potential role of SGLT-2 inhibitors in preventing dementia. The aim of this review is to summarize the current research suggesting that SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, may have neuroprotective effects that reduce dementia risk and improve cognitive function in type 2 diabetes patients. These benefits are likely due to better glycemic control, reduced oxidative stress, and less advanced glycation end-product (AGE) formation, all linked to neurodegeneration. Despite these promising findings, existing studies are limited by small sample sizes and short follow-up durations, which may not adequately capture long-term outcomes. To establish more robust evidence, larger-scale, long-term randomized controlled trials (RCTs) involving diverse populations are needed. These studies should involve diverse populations and focus on understanding the mechanisms behind the neuroprotective effects. Addressing these limitations will provide clearer guidelines for using SGLT-2 inhibitors in dementia prevention and management. This will help improve therapeutic strategies for cognitive health in diabetic patients.

Euglycemic diabetic ketoacidosis is a rare metabolic derangement seen in both type 1 and type 2 diabetes. Initially characterized decades ago, the prevalence of euglycemic diabetic ketoacidosis has increased in recent years following the introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors. Here, we present a case of euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors.

Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have demonstrated efficacy in reducing cardiovascular events and potentially improving kidney function in diabetic patients. This investigation analyzes the TriNetX database to assess the efficacy of SGLT-2i in diabetic kidney transplant recipients (KTR) concerning all-cause mortality, major adverse cardiac events (MACE), and major adverse kidney events (MAKE). The study includes type 2 diabetic patients over 18 who underwent kidney transplants between June 1, 2015, and June 1, 2023, with a focus on SGLT-2i use within the first three months post-transplant. After propensity score matching, the study compares 1970 SGLT-2i users with matched non-users. With a median follow-up of 3.4 years, SGLT-2i users showed significantly lower rates of all-cause mortality (adjusted hazard ratio [aHR]: 0.32), MACE (aHR: 0.48), and MAKE (aHR: 0.52). These findings indicate that SGLT-2i significantly reduces mortality and adverse events in diabetic KTR, underscoring its potential to improve post-transplant outcomes.

One of the notable adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor is diabetic ketoacidosis (DKA) often characterized by euglycemia. In this retrospective review of patients with DKA from 2015 to 2023, 21 cases of SGLT2 inhibitorassociated DKA were identified. Twelve (57.1%) exhibited euglycemic DKA (euDKA) while nine (42.9%) had hyperglycemic DKA (hyDKA). More than 90% of these cases were patients with type 2 diabetes mellitus. Despite similar age, sex, body mass index, and diabetes duration, individuals with hyDKA showed poorer glycemic control and lower C-peptide levels compared with euDKA. Renal impairment and acidosis were worse in the hyDKA group, requiring hemodialysis in two patients. Approximately one-half of hyDKA patients had concurrent hyperosmolar hyperglycemic state. Common symptoms included nausea, vomiting, general weakness, and dyspnea. Seizure was the initial manifestation of DKA in two cases. Infection and volume depletion were major contributors, while carbohydrate restriction and inadequate insulin treatment also contributed to SGLT2 inhibitor-associated DKA. Despite their beneficial effects, clinicians should be vigilant for SGLT2 inhibitor risk associated with DKA.

Medication management in the perioperative period is a critical part of the decision-making prior to surgery. While randomized trial levels of evidence in this space are scant, retrospective data and expert consensus provide practical guidance for these decisions. Clinicians must understand risks and benefits of withholding versus continuing medications, stop medications based on pharmacokinetics and effect on primary disease and surgical risk, and resume medications after surgery in a timely manner. Knowing alternate routes of medication administration can help keep chronic disease processes stable through surgery.

Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are increasingly being used among hospitalized patients. Our objective was to assess the risk of diabetic ketoacidosis (DKA) among hospitalized patients receiving an SGLT-2i.

We conducted a multicentre cohort study of patients hospitalized at 19 hospitals. We included patients over 18 years of age who received an SGLT-2i or a dipeptidyl peptidase-4 inhibitor (DPP-4i) in hospital. The primary outcome was the risk of DKA during their hospitalization.

61,517 patients received a DPP-4i and 11,061 received an SGLT-2i. The risk of inpatient DKA was 0.07 % (N = 41 events) among adults who received a DPP-4i and 0.18 % (N = 20 events) among adults who received an SGLT-2i; adjusted odds ratio of 3.30 (95 % CI: 1.85-5.72).

In hospitalized patients, the absolute risk of DKA was 0.2 %, which corresponded to a three-fold higher relative risk.

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1-3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.

Diabetic ketoacidosis (DKA) is a life-threatening condition among diabetic patients characterized by metabolic anion gap (AG) acidosis of arterial pH <7.30, glucose >250 mg/dL, and positive ketones. The triggers for DKA can be infection, surgery, and, in reported cases, intraparenchymal hemorrhage (IPH). In rare cases of DKA, despite being in active ketoacidosis, glucose levels may be within normal or accepted range. Such a condition is called euglycemic DKA. It has been recently recognized in association with the use of sodium glucose co-transporter-2 (SGLT-2) inhibitors in the treatment of type 2 diabetes.

An 83-year-old male taking an SGLT-2 inhibitor (empagliflozin) for type 2 diabetes presented with an IPH. His laboratory studies revealed an elevated AG acidosis, an elevated beta hydroxybutyrate, and serum glucose levels within the acceptable range. Urine studies revealed elevated ketones and glucose. The diagnosis of euglycemic DKA was made, and the patient was treated with insulin and glucose infusions.

Like hyperglycemic ketoacidosis, euglycemic DKA requires prompt recognition and immediate aggressive medical therapy, but the diagnosis can be challenging, and the treatment using insulin in the setting of a normal glucose can be counterintuitive. Euglycemic DKA can often be missed in the setting of blood glucose not being elevated. Prompt recognition and treatment are critical for successful management.

Our bodies have adaptive mechanisms to fasting, in which glycogen stored in the liver and muscle protein are broken down, but also lipid mobilisation is triggered. As a result, glycerol and fatty acids are released into the bloodstream, increasing the production of ketone bodies in liver. However, there are limited studies on the incidence of perioperative urinary ketosis, the intraoperative blood glucose changes and metabolic acidosis after fasting for surgery in non-diabetic adult patients.

We conducted a retrospective cohort study involving 1831 patients undergoing gynecologic surgery under general anesthesia from January to December 2022. Ketosis was assessed using a postoperative urine test, while blood glucose levels and acid-base status were collected from intraoperative arterial blood gas analyses.

Of 1535 patients who underwent postoperative urinalysis, 912 (59.4%) patients had ketonuria. Patients with ketonuria were younger, had lower body mass index, and had fewer comorbidities than those without ketonuria. After adjustments, younger age, higher body mass index and surgery starting late afternoon were significant risk factors for postoperative ketonuria. Of the 929 patients assessed with intraoperative arterial blood gas analyses, 29.0% showed metabolic acidosis. Multivariable logistic regression revealed that perioperative ketonuria and prolonged surgery significantly increased the risk for moderate-to-severe metabolic acidosis.

Perioperative urinary ketosis and intraoperative metabolic acidosis are common in patients undergoing gynecologic surgery, even with short-term preoperative fasting. The risks are notably higher in younger patients with lower body mass index. Optimization of preoperative fasting strategies including implementation of oral carbohydrate loading should be considered for reducing perioperative metabolic derangement due to ketosis.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated efficacy in slowing the progression of chronic kidney disease (CKD), managing conditions such as congestive heart failure (CHF), and reducing cardiovascular and overall mortality in patients with type 2 diabetes mellitus (T2DM). However, their use is associated with complications, including euglycemic diabetic ketoacidosis (euDKA), genital fungal infections, and urinary tract infections (UTIs). Although rare, complications like euDKA can lead to serious consequences if not promptly addressed, as illustrated by this case report of a 90-year-old man with ischemic cardiomyopathy and type 2 diabetes who developed both euDKA and a UTI while on SGLT2 inhibitor therapy. Early identification of euDKA from SGLT2 inhibitor usage prompted cessation of the SGLT2 inhibitor and administration of insulin infusion, ultimately resolving the life-threatening condition.

Patients suffering from acromegaly and Cushing's Disease (CD) face the risk of several clinical complications. The onset of diabetes mellitus (DM) is among the most important: exposure to elevated growth hormone or cortisol levels is associated with insulin resistance (IR). DM contributes to increasing cardiovascular risk for these subjects, which is higher compared to healthy individuals. Hyperglycemia may also be caused by pasireotide, a second-generation somatostatin receptor ligand (SRLs), currently used for the treatment of these diseases. Accordingly, with 2014 medical expert recommendations, the management of hyperglycemia in patients with CD and treated with pasireotide is based on lifestyle changes, metformin, DPP-4 inhibitors (DPP-4i) and, subsequently, GLP-1 Receptor Agonists (GLP-1 RAs). There is no position for SGLT2-inhibitors (SGLT2-i). However, a very recent experts' consensus regarding the management of pasireotide-induced hyperglycemia in patients with acromegaly suggests the use of GLP-1 RAs as first line treatment (in suitable patients) and the use of SGLT2-i as second line treatment in patients with high cardiovascular risk or renal disease. As a matter of fact, beyond the hypoglycemic effect of GLP1-RAs and SGLT2-i, there is increasing evidence regarding their role in the reduction of cardiovascular risk, commonly very high in acromegaly and CD and often tough to improve despite biochemical remission. So, an increasing use of GLP1-RAs and SGLT2-i to control hyperglycemia is desirable in these diseases. Obviously, all of that must be done with due attention in order to minimize the occurrence of adverse events. For this reason, large studies are needed to analyze the presence of potential limitations.

To describe reported cases of prolonged or relapsed ketoacidosis (KA) in adults with type 2 diabetes receiving treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

We performed a search of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and medical literature, to identify our case series and to characterize cases of prolonged KA, relapsed KA, or persistent ketonemia, persistent ketonuria and/or persistent glucosuria in adults receiving SGLT2 inhibitors.

The FDA identified 29 unique cases of prolonged or relapsed KA, as well as related terms persistent ketonemia, persistent ketonuria, and persistent glucosuria, in patients receiving SGLT2 inhibitors through July 26, 2022. The patients ranged in age from 26 to 85 years. Treatment duration of KA ranged from 3 to 20 days. There were 7 cases of relapsed KA when insulin was reduced or transitioned to subcutaneous route. Arterial pH value was 7.0 or below in 4 patients, and the median pH was 7.1. Associated factors for prolonged or relapsed KA included surgery, decreased caloric intake, and ketogenic/carbohydrate restricted diet. A total of 62% of the patients were taking 3 or more glycemic control medications including the SGLT2 inhibitor. All patients with sufficient follow-up information recovered.

Although KA is a well-known risk associated with SGLT2 inhibitors, this case series demonstrated the potential for prolonged or recurrent KA events with serious outcomes. These cases informed updates to FDA's prescribing information to inform prescribers of this risk.

Diabetic ketoacidosis (DKA) is an acute, life-threatening metabolic complication of diabetes classically associated with hyperglycemia, metabolic acidosis, and ketosis. Though relatively uncommon, patients can also develop DKA with relative euglycemia, further complicating diagnosis. Here, we describe the case of a patient who presented with intractable vomiting secondary to diabetic gastroparesis. He was euglycemic, non-acidemic, and serum bicarbonate was within normal limits. However, labs were significant for ketonuria, an elevated anion gap, and an elevated beta-hydroxybutyrate. Given the high concern for euglycemic DKA in the setting of a competing primary metabolic alkalosis, he was transferred to the intensive care unit for intravenous insulin infusion and fluid resuscitation with significant clinical improvement and normalization of laboratory results. This serves as an important reminder that DKA can be masked by euglycemia as well as additional metabolic derangements, and should be suspected in any diabetic patient with an anion gap and/or ketosis.

Dapagliflozin possesses the capacity to cure a wide range of diseases, however, there are many adverse events (AEs) that have not yet been acknowledged or recorded.

Safety assessment of dapagliflozin based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to explore differences between the reported AEs to provide a overview of the safety profile of dapagliflozin.

We extracted data from the United States FAERS database, including from the fourth quarter of 2012 to the third quarter of 2023. Reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric average (EBGM) were used to evaluate the relationship between dapagliflozin and its associated AEs.

A total of 13,593,946 case reports were gathered from the Food and Drug Administration Adverse Event Reporting System database for this investigation. Among these, there were 44,506 episodes of adverse events that were associated with dapagliflozin. Included in the analysis were 341 preferred words and 2 system organ classes that showed statistical significance according to all four methods simultaneously. The system organ classes encompassed illnesses related to metabolism and nutrition, as well as problems affecting the renal and urinary systems. PT levels were screened for adverse drug reaction signals including scrotal gangrene, scrotal cellulitis, perineal cellulitis, diabetic ketoacidosis, and pancreatitis.

The majority of our findings aligned with the specification, however, certain novel indicators of AEs such as acute pancreatitis were not accounted for. The analysis of the AE signals may provide support for clinical monitoring and risk identification of dapagliflozin. Due to the inherent limitations of FAERS data, well-designed studies are required to demonstrate the safety of dapagliflozin.

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.

Despite improvements in glucose monitoring technologies, insulin formulations and insulin delivery systems, too many patients with type 1 diabetes (T1D) continue to struggle to meet their glycemic goals. As a result, they suffer from high rates of microvascular and macrovascular disease. Titration of insulin therapy, while essential to the care of these patients, is often limited by undesirable side effects of hypoglycemia and weight gain. Sodium-glucose cotransporter (SGLT) inhibitors have been proposed as a potential adjunctive therapy to insulin that may offset some of these effects, while simultaneously enabling patients with T1D to potentially reap the cardiovascular and renal benefits afforded by these agents in those with type 2 diabetes. This review summarizes and contextualizes the clinical trial data that has emerged with these agents in this specific population.

A clinical review based on current literature was generated by the authors.

This review summarizes the data from several clinical trial programs investigating the use of SGLT inhibitors in T1D, describing the potential benefits and the ketosis-related adverse events of these agents (including euglycemic DKA), along with a discussion of possible mitigation strategies to reduce this risk.

Although theoretically SGLT inhibitors have the potential to improve metabolic, cardiovascular, and renal outcomes in patients with T1D, the risks of diabetic ketoacidosis currently represent an important limitation to the widespread use of these agents. If treatment is undertaken, caution must be taken, with implementation of effective mitigation strategies being essential.

To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus.

After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period.

Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001).

Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.

An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.

To evaluate the safety and performance of an implantable near-infrared (NIR) spectroscopy sensor for multi-metabolite monitoring of glucose, ketones, lactate, and ethanol.

This is an early feasibility study (GLOW, NCT04782934) including 7 participants (4 with type 1 diabetes (T1D), 3 healthy volunteers) in whom the YANG NIR spectroscopy sensor (Indigo) was implanted for 28 days. Metabolic challenges were used to vary glucose levels (40-400 mg/dL, 2.2-22.2 mmol/L) and/or induce increases in ketones (ketone drink, up to 3.5 mM), lactate (exercise bike, up to 13 mM) and ethanol (4-8 alcoholic beverages, 40-80g). NIR spectra for glucose, ketones, lactate, and ethanol levels analyzed with partial least squares regression were compared with blood values for glucose (Biosen EKF), ketones and lactate (GlucoMen LX Plus), and breath ethanol levels (ACE II Breathalyzer). The effect of potential confounders on glucose measurements (paracetamol, aspartame, acetylsalicylic acid, ibuprofen, sorbitol, caffeine, fructose, vitamin C) was investigated in T1D participants.

The implanted YANG sensor was safe and well tolerated and did not cause any infectious or wound healing complications. Six out 7 sensors remained fully operational over the entire study period. Glucose measurements were sufficiently accurate (overall mean absolute (relative) difference MARD of 7.4%, MAD 8.8 mg/dl) without significant impact of confounders. MAD values were 0.12 mM for ketones, 0.16 mM for lactate, and 0.18 mM for ethanol.

The first implantable multi-biomarker sensor was shown to be well tolerated and produce accurate measurements of glucose, ketones, lactate, and ethanol.

Clinical trial identifier: NCT04782934.

Ketone bodies are an energy substrate produced by the liver and used during states of low carbohydrate availability, such as fasting or prolonged exercise. High ketone concentrations can be present with insulin insufficiency and are a key finding in diabetic ketoacidosis (DKA). During states of insulin deficiency, lipolysis increases and a flood of circulating free fatty acids is converted in the liver into ketone bodies-mainly beta-hydroxybutyrate and acetoacetate. During DKA, beta-hydroxybutyrate is the predominant ketone in blood. As DKA resolves, beta-hydroxybutyrate is oxidized to acetoacetate, which is the predominant ketone in the urine. Because of this lag, a urine ketone test might be increasing even as DKA is resolving. Point-of-care tests are available for self-testing of blood ketones and urine ketones through measurement of beta-hydroxybutyrate and acetoacetate and are cleared by the US Food and Drug Administration (FDA). Acetone forms through spontaneous decarboxylation of acetoacetate and can be measured in exhaled breath, but currently no device is FDA-cleared for this purpose. Recently, technology has been announced for measuring beta-hydroxybutyrate in interstitial fluid. Measurement of ketones can be helpful to assess compliance with low carbohydrate diets; assessment of acidosis associated with alcohol use, in conjunction with SGLT2 inhibitors and immune checkpoint inhibitor therapy, both of which can increase the risk of DKA; and to identify DKA due to insulin deficiency. This article reviews the challenges and shortcomings of ketone testing in diabetes treatment and summarizes emerging trends in the measurement of ketones in the blood, urine, breath, and interstitial fluid.

The increasing use of sodium glucose transporter 2 inhibitors (SGLT2i) for treating cardiovascular (CV) diseases and type 2 diabetes (T2D) is accompanied by a rise in euglycemic diabetic ketoacidosis occurrences in cardiac surgery patients. Patients undergoing cardiac surgery, due to their pre-existing CV disease which often requires SGLT2i prescriptions, face an increased risk of postoperative metabolic acidosis (MA) or ketoacidosis (KA) associated with SGLT2i, compounded by fasting and surgical stress. The primary aim of this study is to quantify the incidence of SGLT2i-related postoperative MA or KA and to identify related risk factors. We analyzed data retrospectively of 823 cardiac surgery patients, including 46 treated with SGLT2i from November 2019 to October 2022. Among 46 final cohorts treated preoperatively with SGLT2i, 29 (63%) developed postoperative metabolic complications. Of these 46 patients, stratified into two categories based on postoperative laboratory findings, risk factor analysis were conducted and compared. Analysis indicated a prescription duration over one week significantly elevated the risk of complications (Unadjusted OR, 11.7; p = 0.032*; Adjusted OR, 31.58; p = 0.014*). A subgroup analysis showed that a cardiopulmonary bypass duration of 60 min or less significantly raises the risk of SGLT2i-related postoperative MA in patients with a sufficient prescription duration. We omitted the term "diabetes" in describing complications related to SGLT2i, as these issues are not exclusive to T2D patients. Awareness of SGLT2i-related postoperative MA or KA can help clinicians distinguish between non-life-threatening conditions and severe causes, thereby preventing unnecessary tests and ensuring best practice.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels by reducing glucose reabsorption in the kidneys, which can lead to ketogenesis. Euglycemic diabetic ketoacidosis (DKA) is a rare but potentially life-threatening complication of SGLT2 inhibitors that can be triggered by trauma. However, the absence of significant hyperglycemia can delay its diagnosis and treatment, which may lead to detrimental consequences. Herein, we report a case of euglycemic DKA following traumatic brain injury in a patient with type 2 diabetes who was taking an SGLT2 inhibitor. Delayed recognition of euglycemic DKA in this case led to progressive metabolic deterioration. This report emphasizes the importance of promptly suspecting, diagnosing, and treating euglycemic DKA in patients with traumatic injuries who exhibit high anion-gap metabolic acidosis, ketonuria, and glucosuria-even if they do not have significant hyperglycemia.

We present a case of anion gap euglycemic diabetic ketoacidosis (EuDKA) in a patient with COVID-19 infection. Patients with diabetes mellitus are at increased risk of severe illness, and hyperglycaemia is associated with higher morbidity and mortality in patients infected with COVID-19.

A 76-year-old male with diabetes mellitus treated with SGLT2 inhibitor tested positive for COVID-19 infection on day 3 after his admission. In the emergency room he had a high anion gap metabolic acidosis and a blood glucose of 248 mg/dl. His urine tested strongly positive for ketones. A diagnosis of euglycemic diabetic ketoacidosis was made and he was treated with intravenous insulin and normal saline; his antidiabetic medications were stopped. His metabolic acidosis gradually resolved, and he was discharged.

Euglycemic diabetic ketoacidosis is a rare complication of COVID-19 infection. It is defined by the American Diabetes Association as the triad of anion gap metabolic acidosis with arterial pH <7.3, serum bicarbonate <18 mmol/l and ketonuria or ketonemia. It is a life-threatening complication which usually occurs in type 1 diabetes mellitus patients but may also occur in type 2 diabetes mellitus patients. As described earlier, it is associated with hyperglycaemia but if blood glucose is low or near normal but <250 mg/dl it is then named euglycemic diabetic ketoacidosis. Patients treated with SGLT2 inhibitors are at increased risk of euglycemic diabetic ketoacidosis.

COVID-19 infection precipitated euglycemic diabetic ketoacidosis in our patient. SGLT2 inhibitors must be stopped when this adverse reaction occurs. As their use increases, the risk of this adverse reaction is higher as well. Their prescription should be restricted to trained physicians who are able to educate their patients and treat them appropriately in situations that may arise.

COVID-19 infected patients are at increased risk of developing diabetic ketoacidosis or euglycemic ketoacidosis when treated with SGLT-2 inhibitors.It is practical to discontinue the drug at the onset of any symptoms consistent with acute infection to prevent the development of euglycemic diabetic ketoacidosis.

Metabolic syndrome (MS) is associated with both cardiovascular and bladder dysfunction. Insulin resistance (IR) and central obesity, in particular, are the main risk factors. In these patients, vicious pathological cycles exacerbate abnormal carbohydrate metabolism and sustain an inflammatory state, with serious implications for both the heart and bladder. Ketone bodies serve as an alternative energy source in this context. They are considered a "super-fuel" because they generate adenosine triphosphate with less oxygen consumption per molecule, thus enhancing metabolic efficiency. Ketone bodies have a positive impact on all components of MS. They aid in weight loss and glycemic control, lower blood pressure, improve lipid profiles, and enhance endothelial function. Additionally, they possess direct anti-inflammatory, antioxidant, and vasodilatory properties. A shared key player in dysfunction of both the heart and bladder dysfunction is the formation of the NLRP3 inflammasome, which ketone bodies inhibit. Interventions that elevate ketone body levels-such as fasting, a ketogenic diet, ketone supplements, and sodium-glucose cotransporter 2 inhibitors-have been shown to directly affect cardiovascular outcomes and improve lower urinary tract symptoms derived from MS. This review explores the pathophysiological basis of the benefits of ketone bodies in cardiac and bladder dysfunction.

Familial renal glucosuria (FRG) is a hereditary disorder caused by variants in SLC5A2 encoding sodium-glucose cotransporter 2 (SGLT2). In this study, we aimed to characterize proximal tubule solute transport, glucagon secretion and the genotype-phenotype relationship in FRG patients.

We sequenced SLC5A2 and PDZK1IP1 in 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients. We built an open-source online calculator of RTG, evaluated the proximal tubule transport of amino acid, uric acid and phosphate, and explored glucagon secretion after glucose ingestion in FRG patients.

We identified 12 novel SLC5A2 variants (G484D, R564W, A212S, c.574+1G>C, W649*, S592Cfs*6, Q579*, Y339*, V39F, G491E, A464E and G360D) in our cohort and yielded 111 SLC5A2 variants from literature review. RTG in our cohort ranged from 1.0 to 9.2 mmol/L. Patients with two SLC5A2 variants had lower RTG (3.9 vs 6.2 mmol/L) and higher 24-h urinary glucose excretion (24hUG) than single-variant carriers (291.0 vs 40.0 mmol/1.73 m2). Patients with homozygous missense or in-frame indels had mean 24hUG of 457.2 mmol/1.73 m2, comparable to those with homozygous truncating variants (445.0 mmol/1.73 m2) and significantly more than those with homozygous splicing variants (196.6 mmol/1.73 m2). Patients with homozygous missense variants involving conservative residues (582.0 mmol/1.73 m2) had more 24hUG than those with variants at non-conservative residues (257.6 mmol/1.73 m2). Four out of 14 tested patients had mild aminoaciduria. The RTG of FRG patients had no significant correlation to phosphate reabsorption but a potential negative correlation to the fractional excretion of uric acid. Postprandial suppression of glucagon secretion was absent in most FRG patients.

We built a comprehensive map showing the impact of SLC5A2 variant type and variant location on glucosuria severity. Our results highlighted the role of key residues in maintaining the transport function of SGLT2 and the functional link between glucosuria and reabsorption of amino acid and uric acid in FRG patients.

There is concern that sodium-glucose cotransporter-2 inhibitors during hospitalization for acute heart failure (aHF) may precipitate diabetic ketoacidosis (DKA). A retrospective study of all hospitalization encounters for aHF defined by a primary HF International Classification of Diseases (ICD)-10 code in 15 Kaiser Permanente Southern California medical centers hospitalized between January 1, 2021 and August 31, 2023 was performed to describe rates of DKA with empagliflozin use. DKA was defined by the presence of either a DKA ICD-10 code or ketoacidosis lab criteria (bicarbonate <18 mmol/L and urine ketone 1+ or more or elevated serum beta-hydroxybutyrate within 12 h) during hospitalization. Among 21,630 hospital encounters (15,518 patients) for aHF, 1678 (8%) had empagliflozin use. There were 2 (0.1%) probable DKA cases in empagliflozin encounters and 15 (0.1%) in nonexposed encounters. These rates were similar when stratified by diabetes status and ejection fraction. Empagliflozin may be safe during aHF hospitalization.

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) are life-threatening complications of diabetes mellitus. Their clinical profiles have not been fully investigated.

A multicenter retrospective cohort study was conducted in 21 acute care hospitals in Japan. Patients included were adults aged 18 or older who had been hospitalized from January 1, 2012, to December 31, 2016 due to DKA or HHS. The data were extracted from patient medical records. A four-group comparison (mild DKA, moderate DKA, severe DKA, and HHS) was performed to evaluate outcomes.

A total of 771 patients including 545 patients with DKA and 226 patients with HHS were identified during the study period. The major precipitating factors of disease episodes were poor medication compliance, infectious diseases, and excessive drinking of sugar-sweetened beverages. The median hospital stay was 16 days [IQR 10-26 days]. The intensive care unit (ICU) admission rate was 44.4% (mean) and the rate at each hospital ranged from 0 to 100%. The in-hospital mortality rate was 2.8% in patients with DKA and 7.1% in the HHS group. No significant difference in mortality was seen among the three DKA groups.

The mortality rate of patients with DKA in Japan is similar to other studies, while that of HHS was lower. The ICU admission rate varied among institutions. There was no significant association between the severity of DKA and mortality in the study population.

This study is registered in the UMIN clinical Trial Registration System (UMIN000025393, Registered 23th December 2016).