SGLT2 Inhibitor–Associated Euglycemic Diabetic Ketoacidosis (EDKA) in Hematologic Malignancy Patients: A Case Series

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

Sodium-glucose co-transporter 2 inhibitors for heart failure: clinical trial efficacy and clinical practice effectiveness.

Funding Acknowledgements Type of funding sources: None. Background The sodium-glucose cotransporter 2 inhibitor (SGLT2i) medications have proven mortality and morbidity benefit for patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (HF) over the previous decade leading to a rapid expansion of societal guideline recommendations and US FDA indications. With this rapid expansion of SGLT2i indications and prescribing, it is essential that we understand the safety and adverse effects of this drug class. Diabetic ketoacidosis (DKA) is a life-threatening adverse effect of the SGLT2i that has been described in post-marketing reports, prompting an FDA warning. The clinical characteristics of patients with T2DM and HF who develop SGLT2i associated DKA are lacking. Purpose To describe the clinical characteristics of patients with T2DM and chronic HF prescribed SGLT2i who develop DKA. Methods Data was collected retrospectively with Penn State Health TriNetX Local, a web-based tool for healthcare system research population queries, between January 1, 2013-December 31, 2020. Patients with T2DM and chronic HF who were prescribed empagliflozin, canagliflozin or dapagliflozin and subsequently developed DKA were eligible for inclusion. Patients with type 1 diabetes mellitus were excluded. Patient health records were reviewed to confirm SGLT2i use at the time of DKA hospitalization. Baseline characteristics, clinical features and outcome data of hospitalized patients were collected. Results Four unique patient records were identified. Mean age was 59.8 years, BMI 30.5 kg/m2, HbA1c 10.6%. Two patients had baseline heart failure mid-range ejection fraction and two patients had heart failure preserved ejection fraction. All patients were baseline NYHA class II, ACC/AHA stage C. Three patients were on a baseline diuretic, two were on ACE/ARB, two were on beta blocker, three were on metformin, two were on pioglitazone and none were on insulin. Two patients were on baseline empagliflozin 10 mg daily and two were on canagliflozin 100 mg daily. Two patients were on SGLT2i for less than 1 month prior to presentation. Three patients presented with SGLT2i associated DKA and one with euglycemic DKA. None of the patients presented with decompensated congestive HF. Three patients presented with concomitant acute medical conditions; Fournier’s gangrene, asthma exacerbation and alcoholic hepatitis. One patient developed acute stress induced cardiomyopathy while hospitalized. Another patient suffered cardiac arrest secondary to acidosis. Average duration of insulin infusion was 60 hours before resolution of DKA. All of the patients recovered. Conclusions In this single center study, we presented four unique cases of SGLT2i associated DKA in patients with T2DM and chronic HF. Diagnosis can be challenging as concomitant acute medical conditions and/or euglycemia can mask underlying DKA. Early diagnosis and management of SGLT2i associated DKA is important as this condition is life-threatening.

Background: Diabetic ketoacidosis (DKA) is defined by metabolic acidosis, ketosis and hyperglycemia. It is considered to be a consequence of significant insulin deficiency and/or insulin resistance and is usually precipitated by the presence of hyperglucagonemia or other counterregulatory hormones. In patients on oral sodium-glucose cotransporter 2 (SGLT2) inhibitors, decreased carbohydrate availability through renal glucose excretion can cause serum glucose levels to be lower than what is normally seen (< 200 mg/dL) in DKA cases, masking the diagnosis. This phenomenon is termed euglycemic DKA (EuDKA). Existing evidence suggests that EuDKA in the setting of SGLT2 inhibitor use is rare and occurs mostly in patients with type I diabetes mellitus (T1D) and seldom in type 2 diabetes mellitus (T2D). Most published reports of EuDKA in patients with T2D describe patients on SGLT2 inhibitors with clear inciting events such as decreased insulin doses, surgery, or severe acute illness. To our knowledge, none have reported EuDKA precipitated by ertugliflozin. This is also the first report of EuDKA of a patient in the United States with T2D initiating SGLT-2 inhibitor use while on a low carbohydrate diet. Clinical Case: A 53-year-old female with a history of poorly controlled T2D was admitted to the hospital with EuDKA within seven days of starting ertugliflozin and alogliptin. Patient admitted to strict adherence to a low-carbohydrate diet for one week prior to admission. On admission, the patient was afebrile. Initial labs showed blood glucose 104 mg/dL, serum bicarbonate 8 mmol/L, anion gap 22, pH 7.100, beta-hydroxybutyrate 66.94 ng/mL (0.20-2.81), and a hemoglobin A1c of 11.2%. Urinalysis revealed glucosuria ≥500 mg/dL, ketonuria 80 mg/dL, hyaline cast 20/lpf, no nitrites or leukocyte esterase, WBC 1/hpf. Flu PCR negative. WBC count was 17.4 x10e3/uL initially, though all CBC cell lines decreased with fluid administration. CXR was negative for acute pulmonary disease. All oral T2D agents were held and our patient was initiated on a DKA protocol based on ADA guidelines. Her EuDKA subsequently resolved with successful transition to a weight-based basal-bolus insulin regimen. Conclusions: There are no published case reports identifying patients with T2D developing euglycemic DKA precipitated only by a low carbohydrate diet and ertugliflozin initiation. We hypothesize that our patient’s ketogenic diet lowered the threshold for a euglycemic ketoacid crisis resulting directly from the new addition of the SGLT2 inhibitor in the setting of pre-existing glucose toxicity. In patients considering, starting and being maintained on ertugliflozin or other SGLT2 inhibitors, the importance of effective, early and frequent dietary counseling with close follow-up cannot be overstated. Further, this report of EuDKA in a patient starting ertugliflozin supports that EuDKA is an SGLT2 inhibitor class risk.

SGLT2 Inhibitors: Mind the Gap

Raising awareness of the link between sodium glucose co-transporter 2 inhibitors and euglycaemic diabetic ketoacidosis – an important perioperative consideration

Euglycemic diabetic ketoacidosis (DKA) (glucose <250milligrams per deciliter (mg/dL) has increased in recognition since introduction of sodium-glucose co-transporter 2 (SGLT2) inhibitors but remains challenging to diagnose and manage without the hyperglycemia that is otherwise central to diagnosing DKA, and with increased risk for hypoglycemia with insulin use. Our objective was to compare key resource utilization and safety outcomes between patients with euglycemic and hyperglycemic DKA from the same period. This is a retrospective review of adult emergency department patients in DKA at an academic medical center. Patients were included if they were >18years old, met criteria for DKA on initial laboratories (pH ≤7.30, serum bicarbonate ≤18millimoles per liter [mmol/L], anion gap ≥10), and were managed via a standardized DKA order set. Patients were divided into euglycemic (<250milligrams per deciliter [mg/dL]) vs hyperglycemic (≥250mg/dL) cohorts by presenting glucose. We extracted and analyzed patient demographics, resource utilization, and safety outcomes. Etiologies of euglycemia were obtained by manual chart review. For comparisons between groups we used independent-group t-tests for continuous variables and chi-squared tests for binary variables, with alpha 0.05. We identified 629 patients with DKA: 44 euglycemic and 585 hyperglycemic. Euglycemic patients had milder DKA on presentation (higher pH and bicarbonate, lower anion gap; P < 0.05) and lower initial glucose (195 vs 561mg/dL, P < 0.001) and potassium (4.3 vs 5.3mmol/L, P < 0.001). Etiologies of euglycemia were insulin use prior to arrival (57%), poor oral intake with baseline insulin use (29%), and SGLT2 inhibitor use (14%). Mean time on insulin infusion was shorter for those with euglycemic DKA: 13.5 vs 19.4 hours, P = 0.003. Mean times to first bicarbonate >18mmol/L and first long-acting insulin were similar. Incidence of hypoglycemia (<70mg/dL) while on insulin infusion was significantly higher for those with euglycemic DKA (18.2 vs 4.8%, P = 0.02); incidence of hypokalemia (<3.3mmol/L) was 27.3 vs 19.1% (P = 0.23). Compared to hyperglycemic DKA patients managed in the same protocolized fashion, euglycemic DKA patients were on insulin infusions 5.9 hours less, yet experienced hypoglycemia over three times more frequently. Future work can investigate treatment strategies for euglycemic DKA to minimize adverse events, especially iatrogenic hypoglycemia.

EUGLYCEMIC DIABETIC KETOACIDOSIS SECONDARY TO EMPAGLIFLOZIN USE

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to acute exacerbations, cardiovascular disease, and premature death. To compare the risk of COPD exacerbation, cardiovascular diseases, and mortality between sodium-glucose cotransporter-2 (SGLT-2) inhibitor use and no use in patients with type 2 diabetes mellitus (T2DM) and COPD. The study included 299,168 patients diagnosed with T2DM and COPD in the National Health Insurance Research Database from January 1, 2009, to December 31, 2020. Cox proportional hazards models were used to examine the relative hazard of major adverse cardiovascular events, hospitalization for COPD, noninvasive positive pressure ventilation (NIPPV), invasive mechanical ventilation, lung cancer, and mortality between SGLT-2 inhibitor users and nonusers. We used propensity score matching to select 1288 pairs of SGLT-2 inhibitor users and nonusers. In the matched cohorts, SGLT-2 inhibitor use was associated with a significantly lower risk of mortality (aHR 0.64, 95% CI 0.43-0.95), NIPPV (aHR 0.48, 95% CI 0.27-0.87), and hospitalization for COPD (aHR 0.82, 95% CI 0.69-0.98) than SGLT-2 inhibitor non-use. Subgroup and dose-response analyses showed that SGLT-2 inhibitor use was associated with a significantly lower risk of mortality, NIPPV, and hospitalization for COPD (p<0.05) than no use of SGLT-2 inhibitors. This population-based cohort study showed that SGLT-2 inhibitors use was associated with a lower risk of COPD exacerbations, ventilator support, and mortality than non- SGLT-2 inhibitors use in patients with T2DM and COPD. SGLT-2 inhibitors may have a role in treating patients with COPD and diabetes.

On top of improving glycemic control, sodium-glucose cotransporter-2 inhibitors have been shown to reduce cardiovascular mortality &amp; heart failure hospitalization. Sodium-glucose cotransporter-2 inhibitors have also been gaining momentum as effective reno-protective agents. Recent evidences have shown that sodium-glucose cotransporter-2 inhibitors are transforming the management of heart failure and chronic kidney disease in patients without type 2 diabetes mellitus. In view of the cardioprotective and reno-protective outcomes, as well as the potential benefits that outweigh adverse effects, it is no doubt that there will be continued increased use of sodium-glucose cotransporter-2 inhibitors. However, with use of sodium-glucose cotransporter-2 inhibitors comes risk of adverse effects, in particular diabetic ketoacidosis. Although uncommon, diabetic ketoacidosis is a potentially life-threatening acute metabolic complication. Diabetic ketoacidosis developing during sodium-glucose cotransporter-2 inhibitors use can present with normal blood glucose concentrations (euglycemia). This atypical presentation can delay diagnosis and hence, treatment. It is therefore crucial for dental practitioners to be cognizant of the increased risk of euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors use, especially during periods of reduced oral intake, such as in patients with odontogenic infection. Euglycemic diabetic ketoacidosis is a diagnosis of exclusion and should be considered as a differential in an ill patient on sodium-glucose cotransporter-2 inhibitors, despite normal blood glucose or absent urine ketones. We report a case of starvation ketosis in a patient with well-controlled type 2 diabetes mellitus, after excisional biopsy of right cervical lymph node and extractions of two lower right molars. Although the patient did not develop euglycemic diabetic ketoacidosis peri-operatively, it was an important diagnosis to exclude considering his high-risk profile of developing euglycemic diabetic ketoacidosis and the potential sequelae of missing the diagnosis.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are emerging as an important therapy not only for type 2 diabetes (T2DM), but also for heart disease and kidney disease. As these medicines gain acceptance, the number of hospitalized patients receiving them is likely to rise. During clinical trials, SGLT2 inhibitors were noted to have a potential risk for diabetic ketoacidosis (DKA), particularly DKA with relatively normal blood glucose levels, ‘euglycemic DKA’. Similar to DKA that is not associated with SGLT2 inhibitors, most of these events seem to be related to acute illnesses or other changes in a patient’s medications or self-management circumstances. This creates a need among hospital providers to create strategies to prevent DKA in their hospitalized patient and guidance on monitoring and treating euglycemic DKA. Our combined experience concerning this phenomenon has given a great deal of insight into this problem and the knowledge needed to improve patient care, by augmenting patient education, inpatient surveillance, and early treatment for euglycemic DKA.

POS-692 Euglycemic Diabetic Ketoacidosis Related to SGLT2 Inhibitor Use in Kidney Transplant Patient with Squamous Cell Carcinoma

Care gaps remain in modern health care despite the availability of robust, evidence-based medications. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated profound benefits in improving both cardiovascular and kidney outcomes in patients, the uptake of these medications remain suboptimal, and the causes have not been systematically explored. The purpose of this study was to use the Consolidated Framework for Implementation Research (CFIR) to describe the barriers and facilitators faced by clinicians in British Columbia, Canada, when prescribing an SGLT2 inhibitor. To achieve this, we conducted semistructured interviews using the CFIR with practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Semistructured interviews. British Columbia, Canada. Actively practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Twenty-one clinicians were interviewed using questions derived from the CFIR. The audio recordings were transcribed verbatim, and each transcription was individually analyzed in duplicate using thematic analysis. The analysis focused on identifying barriers and facilitators to using SGLT2 inhibitors in clinical practice and coded using the CFIR constructs. Once the transcriptions were coded, overarching themes were created. Five overarching themes were identified to the barriers and facilitators to using SGLT2 inhibitors: current perceptions and beliefs, clinician factors, patient factors, medication factors, and health care system factors. The current perceptions and beliefs were that SGLT2 inhibitors are efficacious and have distinct advantages over other agents but are underutilized in British Columbia. Clinician factors included varying levels of knowledge of and comfort in prescribing SGLT2 inhibitors, and patient factors included intolerable adverse events and additional pill burden, but many were enthusiastic about potential benefits. Multiple SGLT2 inhibitor related adverse events like mycotic infections and euglycemic diabetic ketoacidosis and the difficulty in obtaining reimbursement for these medications were also identified as a barrier to prescribing these medications. Facilitators for the use of SGLT2 inhibitors included consensus among colleagues, influential leaders, and peers in support of their use, and endorsement by national guidelines. The experience from the clinicians regarding costs and the reimbursement process is limited to British Columbia as each province has its own procedures. There may be responder bias as clinicians were approached through purposive sampling. This study highlights different themes to the barriers and facilitators of using SGLT2 inhibitors in British Columbia. The identification of these barriers provides a specific target for improvement, and the facilitators can be leveraged for the increased use of SGLT2 inhibitors. Efforts to address and optimize these barriers and facilitators in a systematic approach may lead to an increase in the use of these efficacious medications.

Euglycemic Diabetic ketoacidosis (DKA) is a rare complication in type II Diabetic patients who are taking sodiumglucose cotransporter-2 (SGLT-2) inhibitors. We present a case of euglycemic DKA in a type II diabetic patient taking SGLT-2 inhibitors with a positive Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) infection that was diagnosed early and treated with subcutaneous short-acting insulin. A 57-year-old man presented to our emergency department for sudden fall and dysarthria with a few days history of shortness of breath, fever and nausea. CT head at presentation showed segmental occlusion of right internal carotid artery(ICA). Nasal swab was positive with SARS-CoV2 PCR. Initial labs remarkable for bicarbonate of 17 meq/L, arterial pH 7.14 with an anion gap of 17 and PCO2 was 41. His serum blood glucose was 248mg/dl and lactate at 1.0 mmol/L. His past medical history was significant for type II diabetes (on Empagliflozin and Metformin) and extensive coronary artery disease with multiple stents, on dual anti-platelet therapy (DAPT). He underwent interventional radiology (IR) guided thrombectomy of right ICA and was admitted to ICU for post-stroke care. Due to aforementioned labs, we immediately checked his serum ketones which were elevated at 0.58mmol/L and the diagnosis of euglycemic-DKA secondary to SGLT-2 inhibitor use was made. Since the metabolic acidosis and ketonemia were still fairly in the early stages, we decided to manage it with subcutaneous short-acting insulin. The anion gap was closed within the next 12 hours. Euglycemic DKA is a known complication of SGLT-2 inhibitors with high morbidity and mortality. The reported incidence of euglycemic DKA with empagliflozin is 0.2 to 0.6 per 1,000 patient-years. Recently, a few case reports have been published sharing a correlation with SARS-CoV2 infection. This infection causes a state of profound inflammation and stress, making lab values in these patients widely deranged which can muddle the clinical picture. Since this infection also worsens the glycosuria seen with the use of SGLT-2 inhibitors, ICU physicians must pay close attention to this complication in diabetic patients. We propose that the incidence of developing euglycemic DKA with SGLT-2 inhibitor use may be higher in SARS-CoV2 infection and more research may prove a positive correlation between the two.

Identifying Barriers To SGLT2 Inhibitor Use In Eligible Patients With Heart Failure: A Real-world Experience From A Single Centre