key: cord-0996878-fp1dbhyh
authors: Dutta, Siddhartha; Kumar, Tarun; Singh, Surjit; Ambwani, Sneha; Charan, Jaykaran; Varthya, Shoban B.
title: Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors: A systematic review and quantitative analysis
date: 2022-03-10
journal: J Family Med Prim Care
DOI: 10.4103/jfmpc.jfmpc_644_21
sha: 35252a9f3bcd835a1bda7dce5ef8fbfa60daadcc
doc_id: 996878
cord_uid: fp1dbhyh

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) rarely cause euglycemic diabetic ketoacidosis (euDKA) in diabetic patients. The aim was to identify demographic, clinical, and predisposing factors for euDKA from published case reports. METHODS: A systematic review of published case reports of euDKA in patients receiving SGLT2 inhibitors and meta-analysis of clinical trials to quantify the risk ratio (RR) of DKA in patients receiving SGLT2 inhibitors. PubMed and EMBASE databases were searched for the case reports of and clinical trials from January 2010 to August 2020. Studies published in English language were included and other languages were excluded. Data related to patients’ demography, clinical presentation, drug and dose of SGLT2 inhibitors, and concomitant medication were extracted. Incidence of diabetic ketoacidosis (DKA) extracted from clinical trials. Data related to demographic, clinical, and other parameters presented as ratios and proportions and incidence of DKA in RR using Review Manager 5.3. RESULTS: Forty-seven of 160 reports with an aggregate of 77 patients were included in the analysis. The majority of the patients were females (67.53%), with T2DM and with gastrointestinal symptoms (58%). Surgery was the most common precipitating factor (n/N = 15/77). Canagliflozin (n/N = 34/77) was the commonest SGLT2 inhibitor reported along with metformin as the concomitant medication (63.6%). The pooled RR of DKA was 3.70 (95%CI 2.58, 5.29) and I(2) = 0%. CONCLUSION: euDKA is commonly seen in middle-aged female, T2DM patients taking SGLT2 inhibitors along with metformin. The risk of DKA in patients receiving SGLT2 inhibitors increases by 3.7 times than the other medication.

Diabetes mellitus (DM) is a chronic metabolic disorder associated with either deficiency of insulin called Type 1 diabetes mellitus (T1DM) or resistance to insulin action known as Type 2 diabetes mellitus (T2DM). T2DM is more common in adults and accounts for around 90% of all diabetes cases. [1] The sodium-glucose cotransporter 2 (SGLT2) inhibitors are one of the latest classes of antihyperglycemic medications and are currently highly recommended for the treatment of T2DM because of its multidimensional benefits on the cardiovascular system and renal system. [2, 3] SGLT2 inhibitors (SGLT2i) act on the proximal tubular epithelium by inhibiting the reabsorption of glucose from the glomerular filtrate to the blood. [4] Glycosuria with SGLT2i usually results in a reduction of body weight and associated osmotic diuresis ends up in reducing the blood pressure; hence, they are quite beneficial in obese or overweight patients and hypertension with T2DM. [5] The cardiovascular benefits of empagliflozin are reported in "EMPA-REG Outcome trial," which further makes these drugs a preferred choice for physicians. The cardiovascular benefits are due to the production of ketone bodies by SGLT2i, and its energy efficiency improves cardiovascular and renal functions. [6, 7] With this evidence and insulin-independent mode of action, SGLT2i is a suitable class of drug for both T2DM and T1DM patients. [8, 9] In view of such a broad clinical utility of SGLT2i in diabetes, it is crucial to keep a track of their associated adverse events (AEs). Usually, these agents have a low tendency to cause hypoglycemia, still, because of glycosuria, there are chances of genital and urinary tract infections (UTI) and occasional orthostatic hypotension due to mild dehydration. [10] In addition to the usual AEs, the US Food and Drug Administration (FDA) in May 2015, based on the 20 cases of diabetic ketoacidosis (DKA), published a warning with potential increased risk of DKA associated with the use of SGLT2i in both T2DM and T1DM patients. [11] Later by June 2015, the European Medicines Agency also spotted 147 cases of DKA in patients on treatment with SGLT2i. [12] Large trials like "DECLARE-TIMI 58 study" and "CREDENCE trial" have shown an increased probability of DKA with SGLT2i as compared to placebo. [13, 14] The cases of SGLT2i-associated DKA were atypical in presentation as the glucose levels were mildly elevated (<200 mg/dL), hence can be called euglycemic diabetic ketoacidosis (euDKA). [10, 15, 16] The DKA is an emergency condition and is common in T1DM but is rare in T2DM. However, with the usage of SGLT2i in T2DM, the incidence of DKA is seen increasing. [10, 16] Being a life-threatening condition, early diagnosis and treatment are crucial for a better prognosis of the patient, but euglycemia in euDKA poses a great challenge in diagnosing the underlying DKA; hence, high clinical intuition is needed for diagnosis. [17] Diabetes being a very prevalent noncommunicable disorder in the Indian population and with the evolution of SGLT-2 inhibitors in the therapy of DM, they are being currently used effectively and in the future might turn out to be a very commonly used drug by physicians. As the majority of the population in India lies in rural areas and inaccessibility of superspecialists physicians in the community, a major chunk of the diabetic patients is being treated by primary care and community physicians. [3] Hence, it is crucial for them to have an idea of euDKA associated with SGLT2i, which will help to manage the cases in a better way. In this article, we systematically reviewed published case reports and case series of euDKA, to understand the demographic characteristics, clinical presentation, precipitating factors, and predisposed drug and its dose relationship with euDKA with SGLT2i.

This review was synthesized by following a prespecified study protocol (unpublished) and reported by following the guidelines of the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" statement.

To identify the case reports and case series on SGLT2i-associated euDKA, we systematically screened the PubMed/Medline and EMBASE database published up to Aug 2, 2020 for medical literature. The articles were screened by using the search string "(Euglycemic Diabetic Ketoacidosis) AND (Sglt2 Inhibitor)." Second, to identify the events of DKA we screened the PubMed and Embase for clinical trials using the string "(Diabetic ketoacidosis) AND (Sglt2 inhibitors) AND (placebo)."

The prospective or retrospective descriptive case reports and case series of euDKA after treatment with SGLT2 inhibitors were included. The articles published in a language other than English and full text not available/accessible were excluded. Second, the clinical trials with SGLT2i were selected to assess the events of DKA in the drug group as compared to the placebo. All the potentially relevant articles were screened in two stages for the final eligibility. Initially, the abstracts of the selected articles were screened independently by two reviewers (TK, SD). Later, the full-text articles that met the inclusion criteria were extracted and independently reviewed.

From the included case reports and case series, we extracted information like study characteristics, including author name, publication year, study type, number of patients, patient demographics (e.g., age and gender), details of SGLT2i (type and dose), and concomitant medicines. The events of DKA with the SGLT2i as compared to placebo were assessed from the included published clinical trials. The data was collated, disagreements were discussed, and differences were resolved between review authors. Grades of Recommendations, Assessment, Development, and Evaluations (GRADE) Pro GDT guidelines were used for grading the main outcome as per the GRADE recommendation. Online software was used for analysis. [18] Observed data were combined with Review Manager 5 (RevMan) Version 5.3. (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). [19] Age is presented as mean and SD, sex, and ethnicity along with clinical presentation and precipitating factors presented in proportions. The incidence of DKA is summarized as a risk ratio (RR) with 95% CI. Heterogeneity was assessed based on the calculated I 2 (the proportion of total variability explained by heterogeneity), estimated using the restricted maximum likelihood-based method. We set predecided criteria for significant heterogeneity as I 2 >40%, and the analysis was done using a fixed-effect model even if heterogeneity is greater than 40% in the most pooled analysis, as heterogeneity was not taken care of by the random effect model. The reason for heterogeneity was assessed and explained and for high heterogeneity; inconsistency was downgraded for quality evidence in GRADE Pro analysis. To assess the publication bias, funnel plot assessment was applied.

The overall quality of evidence for each of the outcomes was assessed using GRADEpro GDT (guideline development tool) software based on the principles of GRADE. [19] Risk of bias, the directness of evidence, consistency and precision of results, risk of publication bias, magnitude of the effect, dose-response gradient, and influence of residual plausible confounding were assessed for grading the overall quality of evidence for individual outcomes. The final overall GRADE may be high, moderate, low, or very low. The online version of GRADE pro GDT software was accessed from the site: https://gradepro.org/. [20] Ethical permission

The systematic review was synthesized from the data already published in open access and no direct contact with the patients was done; hence, ethical permission was not required.

Our systematic search of the PubMed and EMBASE database resulted in an initial number of 160 potentially relevant articles. After removing seven duplicates, 153 articles were taken for the systematic review. Of 153 articles, 45 were review, 16 were communications, 19 were conference abstracts, 8 were research articles, 4 were book chapters, and five articles were not accessible hence excluded. Applying the inclusion/exclusion criteria on 52 full-text documents, five other language articles were excluded. Finally, 47 articles were included for the synthesis of this review. The details are illustrated in [ Figure 1 ]. In 42 case reports and 5 case series, we got 77 patients with a mean age of 51.31 years (SD = 15.25). Basic characteristics of individual case reports and case series of euDKA with SGLT-2i are summarized in [ Table 1 ]. The majority of the patients reported were females (67.5%, n = 52). The majority of the reports did not mention (n/N = 62/77) the ethnicity still among mentioned, Asians (46.6%, n = 7) was the most common. Among the disease distribution, T2DM was most prevalent, followed by T2DM with cardiovascular diseases like hypertension, coronary artery diseases, arrhythmia, etc., T1DM, T2DM with oncological disorders like benign or malignant cancers, T2DM with other endocrine disorders like hypothyroidism, etc., T2DM with renal dysfunction like acute or chronic kidney disease, etc., T2DM with multiple sclerosis, T1DM with other endocrine disorders like hypothyroidism, etc., and others which include multiple diseases and comorbidities [ Table 2 ].

The presenting complaints were mentioned in 45 of 77 patients of all the case reports. The commonest presenting complaints of euDKA (58%, n = 45) were nausea, vomiting, abdominal pain, malaise, and sometimes shortness of breath. The prevalent precipitating factor for DKA was surgery as about 33% of patients developed DKA in their postsurgical period. Other precipitating factors of DKA were associated with UTI, cardiovascular irregularities, acute gastroenteritis, etc.

Canagliflozin (44%, n = 34) was the commonest SGLT-2i reported in the selected studies followed by Dapagliflozin (27%, n = 21) and Empagliflozin (25%, n = 19). A dose-dependent increase in the number of cases of DKA was observed with all the three SGLT2i [ Figure 2 ]. Among the concomitant medications used along with SGLT2i, metformin was the commonest, followed by Insulin, Dipeptidyl peptidase-4 (DPP-4) i, sulfonylureas along with vitamin B12, vitamin C, vitamin D, and multivitamins [ Table 3 ]. Contd...

Sixteen studies comprising a total of 31,256 patients (18, 956 in the SGLT2i group and 12,300 in the placebo group) were included for pooling the RR for DKA. [6, [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] The pooled RR was 3.70 (95% CI 2.58, 5.29). I 2 was 0% and the test overall effect was significant (P < 0.00001) [ Figure 3 ]. High-quality evidence as per GRADE Pro analysis is shown in Table 3 ]. Publication bias was low as the funnel plot of 16 studies is symmetrical around the effect estimate [ Figure 4 ].

The overall risk of bias was recorded as low in all the included studies. The weighted summary plot of ROB is shown in [ Figure 5 ].

SGLT2 inhibitors are emerging as a preferred drug because of its effectiveness in decreasing glycated hemoglobin levels along with weight loss, increasing peripheral insulin sensitivity, and preventing cardiovascular comorbidities in diabetic patients. [83] In addition, SGLT2i have a potentially beneficial role in decreasing morbidity and mortality in patients with congestive heart failure. [77] There are two different classes of SGLT transporters in the proximal convoluted tubule of the nephron, classified as SGLT-1 and SGLT-2. SGLT-2 itself reabsorbs nearly 90% of total filtered glucose into the nephron. SGLT2i decreases the renal threshold drastically, causes osmotic diuresis, and reduces plasma glucose concentration. [84] Blau et al. [85] observed that the risk of DKA is seven times more in diabetic patients taking the SGLT2i than the patient taking DPP-4 inhibitors. Though reported by Blau et al., the incidence of euDKA still not clear maybe because of its rare occurrence, underreporting as well as due to underdiagnosis. The reason for euDKA and precipitating factors in DM patients still needs comprehensive research.

Recent FDA warning about euDKA associated with SGLT2i raised concern to understand the patient profile and presentation symptoms for risk evaluation in patients taking SGLT2i. [7] In this review, we studied patient demographic characteristics, clinical presentation, precipitating factors, and predisposed drug and its dose, from the published reports to enable treating physicians for early diagnosis and treatment of euDKA and prevent the potential adverse outcome.

In this review, we observed that half of the patients had T2DM without any comorbidities and about 1 in 5 patients had T2DM with cardiovascular disease, and 1 in 10 patients had T1DM. The majority of patients were middle age diabetic females (66%), maybe because of lower body mass index and poor glycogen stores. [51] The clinical presentation in these patients is similar to traditional symptoms of DKA, which include nausea, vomiting, abdominal pain, shortness of breath, etc. We also observed that diabetic patients during the postoperative period or patients with cardiovascular comorbidities prone to euDKA. This observation helps clinicians or treating physicians to create awareness among As I2=0%, hence low heterogeneity. b As CI does not include one and overall information size is adequate; therefore, the outcome is precise. c As RR is greater than 2, it is regarded as large effect the patients and instruct them to report the clinician, in case they experience such symptoms. In the case of patients in postoperative care need to be screened for euDKA to avoid complications as a result of ketoacidosis. Infections were one of the precipitating factors for euDKA which was supported by the multicenteric cohort study done by Ata et al. [86] Treating community or primary care physicians also needs to be aware of these symptoms and high-risk individuals to avoid misdiagnosis or underdiagnosis. These symptoms and precipitating agents were similar to previously published articles. [83, 87, 88] We observed that patients taking canagliflozin more prone to euDKA than dapagliflozin and empagliflozin. A multicenteric cohort study conducted by Ata et al. [86] also reported canagliflozin as the commonest SGLT-2 inhibitor causing euDKA. The reason for this difference may be because canagliflozin was the earliest drug approved under this class and it has been used by physicians for a longer duration than other drugs resulting in publishing more case reports. [7] We also observed the doseresponse relationship with all three drugs as the incidence of euDKA proportionately increases as the dose of the drug was increased. This pattern may be because of the excessive release of glucagon in diabetic patients. [89] Wibawa et al. in their recent case reported euDKA with the use of empagliflozin. [90] We also conducted a meta-analysis of randomized controlled trials, to see the overall events of DKA in patients taking SGLT2i compared to either active drug or placebo. Our findings show that patients taking SGLT2i are at the risk of experiencing DKA is about 2.58 to 5.29 times higher than the control group. This meta-analysis gives additional strength to our analysis in reinforcing the evidence showing that SGLT2i causes DKA including euDKA in both type 1 and type 2 diabetic patients. Blau et al. [85] showed that the risk of DKA is around 7-fold The current pandemic of COVID-19 has infected a large population around the world and people with comorbidities like DM are more prone to develop a severe form of the disease. [91, 92] Recently, the cases of euDKA have also been seen in the COVID-19 patients and the probability might increase in COVID-19 because of the viral infection and its associated complications. [93, 94] Vitale et al. [95] in their case series also reported cases of T2DM with no previous history of DKA and on SGLT-2 inhibitors presented with euDKA.

The pathophysiology of euDKA in patients receiving SGLT 2 inhibitors remains unclear, but there are multiple hypotheses explained to understand the mechanism of euDKA. The most popular hypothesis was that SGLT2 inhibitors increase glucagon secretion by binding to alpha cells of pancreatic islets and causing gluconeogenesis. Simultaneously, it decreases in blood glucose by hastening its renal execration from the plasma. A decrease in blood glucose cause decreased insulin secretion from islets which results in excess ketone body formation. [90] In addition to the above mechanism, it was observed that in type 1 diabetic patients, the decreased daily requirement of insulin causes increased lipolysis in adipose tissue and increased ketone body synthesis in the liver. [90] In addition, increased reabsorption of ketone bodies from the kidney due to positive electrochemical gradient generation by inhibition of SGLT 2 transporter. [96] Bonner C et al. [89] observed that treatment with dapagliflozin in mice resulted in inhibition of Solute Carrier Family 5 (Sodium/Glucose Cotransporter), Member 2 (SLC5A2) on pancreatic alpha cells thereby increasing glucagon. Also, increased glucagon gene expression results in increased glucagon synthesis leading to increased hepatic gluconeogenesis and excess fatty acid degradation leading to excess production of ketone bodies.

We did a comprehensive systematic review describing the data on demographic, clinical characteristics of euDKA in patients taking SGLT2 inhibitors and the dose-dependent relationship between euDKA and SGLT 2 inhibitors. There are chances of missing out on case reports published in local languages as we included only case reports published in the English language. We analyzed symptomatic reported cases. Case reports are good for generating hypotheses, but the potential risk of bias due to lack of external validity cannot be ruled out.

The overall quality of the systematic review is high as the incidence of DKA has a high quality of evidence. This evidence suggests that further research is very unlikely to have an important impact on our confidence in the estimate and change the estimate.

• DM is a prevalent noncommunicable disease in India.

• SGLT-2 inhibitor is a crucial class of novel antidiabetic drugs in view of their additive cardiovascular benefits. • euDKA in case of diabetic ketoacidosis without hyperglycemia and is rarely seen with use with SGLT-2 inhibitors. • Type-2 DM patients with a long history and inadequate control of blood glucose seem to be more prone to develop euDKA • The cause of euDKA with SGLT-2 inhibitors might be an increase in glucagon secretion, excess ketone body formation, and increased reabsorption of ketone bodies from the kidney. • The symptoms of euDKA are lesser as compared to classical DKA; therefore, early detection of this potential complication might be a challenging task.

should have a high level of suspicion to diagnose the condition early and treat it as normal glucose levels in these patients mask the diagnosis of DKA.

Systematic review of euDKA and the incidence of DKA with SGLT-2 inhibitors were performed, to assist the endocrinologists and primary care physicians in getting aware of these complications. This helps in the prevention, early diagnosis, and 

Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants

Pharmacologic management of type 2 diabetes: 2016 interim update

SGLT-2 inhibitors: An evidence-based perspective

Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes

Renal sodium-glucose transport: Role in diabetes mellitus and potential clinical implications

Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes

SGLT2 inhibitors: A systematic review of diabetic ketoacidosis and related risk factors in the primary literature

Sodium-glucose cotransporter 2 inhibition in type 1 diabetes: Simultaneous glucose lowering and renal protection?

The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: A systematic review and meta-analysis

Sodium-glucose cotransporter 2 inhibitors: An evidence-based practice approach to their use in the natural history of type 2 diabetes

FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections

Review of diabetes medicines called SGLT2 inhibitors started: Risk of diabetic ketoacidosis to be examined

Dapagliflozin and cardiovascular outcomes in type 2 diabetes

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

Euglycemic diabetic ketoacidosis

Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors

Euglycemic diabetic ketoacidosis: A diagnostic and therapeutic dilemma

GRADE handbook for grading quality of evidence and strength of recommendations

Copenhagen: The Nordic Cochrane Centre. The Cochrane Collaboration

The DKA that wasn't: A case of euglycemic diabetic ketoacidosis due to empagliflozin

Euglycemic diabetic ketoacidosis secondary to dapagliflozin use: A case report

Post-surgical euglycemic diabetic ketoacidosis in a patient

on empagliflozin in the intensive care unit

Two alcoholic liver cirrhosis patients developed diabetic ketoacidosis after SGLT2 inhibitors-prescription

Euglycemic diabetic ketoacidosis caused by dapagliflozin: A case report

Euglycemic diabetic ketoacidosis with canagliflozin: Not-so-sweet but avoidable complication of sodium-glucose cotransporter-2 inhibitor use

Cardiac arrest from acute myocardial infarction complicated with sodium-glucose cotransporter 2 inhibitor-associated ketoacidosis

Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: A case report and review of the literature

Insights into the recognition and management of SGLT2-inhibitor-associated ketoacidosis: It's not just euglycemic diabetic ketoacidosis

Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter type 2 inhibitors in patients with type 2 diabetes mellitus receiving oral therapy

Euglycemic diabetic ketoacidosis in concurrent very low-carbohydrate diet and sodium-glucose transporter-2 inhibitor use: A case report

Sudden-onset hypoglycemia following fluid replacement in a patient with dapagliflozin-induced diabetic ketoacidosis without prior insulin use: Case report

Euglycemic diabetic ketoacidosis caused by canagliflozin: A case report

A case of euglycemic diabetic keto acidosis

Dapagliflozin-induced late-onset euglycemic diabetic ketoacidosis

Euglycemic diabetic ketoacidosis in type 2 diabetes treated with a sodium-glucose cotransporter-2 inhibitor

Euglisemic diabetic ketoacidotic coma caused by dapagliflozin

Euglycemic diabetic ketoacidosis with prolonged glucosuria associated with the sodium-glucose cotransporter-2 canagliflozin

Euglycemic ketoacidosis with sodium-glucose cotransporter-2 inhibitor

high anion-gap metabolic acidosis in patients receiving SGLT-2 inhibitors for diabetes management

When guidelines fail: Euglycemic diabetic ketoacidosis after bariatric surgery in a patient taking a sodium-glucose cotransporter-2 inhibitor: A case report

Perioperative implications of sodium-glucose cotransporter-2 inhibitors: A case series of euglycemic diabetic ketoacidosis in three patients after cardiac surgery

Dapagliflozin-associated euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus: A case report

SGLT2-I in the hospital setting: Diabetic ketoacidosis and other benefits and concerns

Euglycemic diabetic ketoacidosis in the ICU: 3 Case reports and review of literature

Postoperative euglycemic diabetic ketoacidosis and encephalopathy related to SGLT-2 inhibitors: A case report and discussion of diabetes treatment and "sweet pee encephalopathy" in perioperative hospital management

Nephrology consultation for severe SGLT2 inhibitor-induced ketoacidosis in type 2 diabetes: Case report

Euglycemic diabetic ketoacidosis due to sodium-glucose cotransporter 2 inhibitor use in two patients undergoing pancreatectomy

Euglycemic diabetic ketoacidosis secondary to dapagliflozin in a patient with colon malignancy

Euglycemic ketosis in an adolescent with type 1 diabetes on insulin and dapaglifozin: Case report

Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium-glucose cotransporter 2 inhibition

patient with euglycemic diabetic ketoacidosis secondary to dapagliflozin

Prolonged acidosis is a feature of SGLT2i-induced euglycaemic diabetic ketoacidosis

Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: Case report and literature review

Euglycemic diabetic

Ketoacidosis with euglycemia in a patient with type 2 diabetes mellitus taking dapagliflozin: A case report

Euglycemic diabetic ketoacidosis associated with the use of a sodium-glucose cotransporter-2 inhibitor

Euglycemic diabetic ketoacidosis with persistent diuresis treated with canagliflozin

Protracted glycosuria after discontinuation of sodium-glucose cotransporter 2 inhibitors: Implications for weekly dosing and extended risk of euglycemic diabetes ketoacidosis

Challenges in the diagnosis of euglycemic diabetic ketoacidosis in a patient with multiple sclerosis taking a sodium-glucose cotransporter 2 inhibitor

Euglycemic diabetic ketoacidosis with elevated acetone in a patient taking a sodium-glucose cotransporter-2 (SGLT2) inhibitor

Euglycemic diabetic ketoacidosis in a 27 year-old female patient with type-1-diabetes treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin

Dapagliflozin-associated euglycemic diabetic ketoacidosis in a patient presenting with acute pancreatitis

Euglycemic diabetic ketoacidosis: The clinical concern of SGLT2 inhibitors

Sodium-glucose cotransporter-2 inhibitors induced eu-glycemic diabetic ketoacidosis: The first report in a type 2 diabetic (T2D) Taiwanese and literature review of possible pathophysiology and contributing factors

SGLT2 inhibitor-induced euglycemic diabetic ketoacidosis: A case report

Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: The North American inTandem1 study

insulin-requirement, glucose excretion and ss-hydroxybutyrate levels are not related to baseline HbA1c in youth with type 1 diabetes

Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: The DEPICT-1 52-week study

HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: The European inTandem2 study

Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: A randomized, double-blind, placebo-controlled pilot study

Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes

Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial

Dapagliflozin as additional treatment to liraglutide and insulin in patients with type 1 diabetes

Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 24-week results from a randomized controlled trial

Dapagliflozin in patients with heart failure and reduced ejection fraction

Short-term effects of dapagliflozin on insulin sensitivity, postprandial glucose excursion and ketogenesis in type 1 diabetes mellitus: A randomized, placebo-controlled, double blind, cross-over pilot study

Canagliflozin and cardiovascular and renal events in type 2 diabetes

Diabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes

Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: The EASE trials

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial

The effect of SGLT2 inhibitors on cardiovascular events and renal function

Ketoacidosis associated with SGLT2 inhibitor treatment: Analysis of

FAERS data

SGLT-2 inhibitors associated euglycemic and hyperglycemic DKA in a multicentric cohort

Diabetic ketoacidosis: A common debut of diabetes among African Americans with type 2 diabetes

Euglycemic diabetic ketoacidosis due to gastroparesis, A local experience

Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion

Euglycemic diabetic ketoacidosis associated with empagliflozin in patients hospitalized with acute pulmonary embolism

Household transmission of COVID-19: A cross-sectional study

Anticoagulants in Covid-19 therapy: An evidence-based review

Euglycemic diabetic ketoacidosis associated with empagliflozin use in the course of the SARS-Cov-2 pandemic

Euglycemic DKA (euDKA) as a presentation of COVID-19

Euglycemic diabetic ketoacidosis with COVID-19 infection in patients with type 2 diabetes taking SGLT2 inhibitors

SGLT2 inhibitors may predispose to ketoacidosis

Euglycemic diabetic ketoacidosis and sodium-glucose cotransporter-2 inhibitors: A focused review of pathophysiology, risk factors, and triggers

We are thankful for GRADEpro GDT site for allowing us to generate the grading of evidence and summary of findings table using their online software. Available from: gradepro.org.

Nil.

There are no conflicts of interest.