Euglycemic diabetic ketoacidosis (EDKA) is a type of DKA whose incidence has increased in recent years because of the widespread use of sodium-glucose transport protein 2 inhibitors in diabetes treatment. However, the concomitant occurrence of a thyroid storm is uncommon, easily misdiagnosed and missed, and has a high risk of death. This report described the case of a 46-year-old woman with type 2 diabetes mellitus who used a sodium-glucose transport protein 2 inhibitor to manage her blood glucose levels. Before undergoing hysteroscopic surgery for a uterine mass, she developed EDKA and thyroid storm after experiencing nausea, vomiting, and a high fever with persistent tachycardia. This report summarizes and analyzes the clinical characteristics, diagnosis, and treatment process and outcomes to accumulate clinical experience and improve clinicians' understanding of this acute and life-threatening disease. Timely and appropriate treatment may help reduce the incidence of morbidity and mortality associated with EDKA and thyroid storm.

To evaluate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) with diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) patients across different subgroups, we searched randomized controlled trials (RCTs) comparing SGLT2i with the control groups among T2DM patients and including DKA as a safety outcome. Pooled risk ratios (RRs) were calculated using random or fixed-effects models, as appropriate. An inverse-variance-weighted Mendelian randomization (MR) analysis was performed to estimate the genetic correlation. Twenty-two trials involving 80,235 patients were included. SGLT2i increased the risk of DKA compared to the control groups (RR 2.32, 95% CI 1.64-3.27). The risk was significantly increased in patients with higher HbA1c levels (> 7.9%) (RR 2.24, 95% CI 1.59-3.14), but not in those with lower HbA1c levels (≤ 7.9%) (RR 1.05, 95% CI 0.49-2.26; interaction P = 0.034). SGLT2i increased DKA risk in chronic kidney disease (CKD) (RR 2.70, 95% CI 1.55-4.71) and high atherosclerotic cardiovascular disease (ASCVD) risk trials (RR 2.46, 95% CI 1.47-4.11) but not significantly in heart failure (HF) trials (RR 1.23, 95% CI 0.51-2.96). Moreover, in the HF trials, SGLT2i consistently did not increase the risk of DKA in any clinical subgroups. Nevertheless, MR analysis still confirmed a genetic association between SGLT2i and the risk of DKA among overall T2DM patients. SGLT2i may increase the risk of DKA in T2DM patients, particularly in patients with higher levels of HbA1c and those with comorbid CKD or at high-risk ASCVD. However, the increased risk was not significant in patients with HF.

Case reports and small retrospective studies have suggested that there is an increased risk of postoperative euglycemic ketoacidosis (eKA) and acute kidney injury (AKI) among patients using sodium-glucose cotransporter 2 inhibitors (SGLT2i) preoperatively. However, there has not been a representative assessment of the risks of these agents among patients undergoing surgery.

To evaluate the risk of postoperative eKA, AKI, and mortality within 30 days after surgery among preoperative long-term SGLT2i users compared with nonusers.

This is a multicenter, propensity-matched, retrospective case-control study from the Veterans Affairs Health Care System (VAHCS) National Registry performed from January 1, 2014, to December 31, 2022. Adult patients using SGLT2i preoperatively who underwent inpatient surgical procedures were compared with a 1:5 matched control group using propensity score matching, including the patient's demographic characteristics, comorbidities, and surgical characteristics. Data analysis was performed from June 2023 to August 2024.

Long-term use of SGLT2i, defined as having more than 3 fills of outpatient prescription or less than a 180-day gap of the last fill according to the VAHCS pharmacy registries.

The primary outcome was the rate of postoperative eKA among SGLT2i users vs control patients. Secondary outcomes included postoperative AKI and 30-day mortality after surgery.

Among 462 968 patients undergoing surgery, 7448 SGLT2i users (mean [SD] age, 67.7 [8.1] years; 7204 [96.7%] male) and 455 520 nonusers (mean [SD] age, 65.8 [11.0] years; 424 785 [93.3%] male) were identified. After propensity score matching, 7439 patients were identified as SGLT2i users and compared with 33 489 control patients. SGLT2i use was associated with an increased risk of eKA (odds ratio [OR], 1.11; 95% CI, 1.05-1.17) but reduced risks of perioperative AKI (OR, 0.69; 95% CI, 0.62-0.78) and 30-day mortality (OR, 0.70; 95% CI, 0.55-0.88). The mortality rate 30 days after surgery was 1.1% among SGLT2i users vs 1.6% among control patients. The median hospital length of stay among the patients presenting with eKA increased by 3 days (median [IQR], 6 [3-10] days for those with eKA vs 3 [2-6] days for those without eKA).

Patients treated with SGLT2i had a small but significantly higher risk of postoperative eKA but lower risks of postoperative AKI and 30-day mortality.

Around 9 million people live with diabetes mellitus (DM) in Germany. Around 500,000 new cases are documented every year. In addition, it must be assumed that there are at least 2 million unreported cases. The proportion of patients with type 2 DM is by far the highest and it is currently estimated that around 340,000 adults and 32,000 children are affected by type 1 DM [1]. People with diabetes have an increased mortality rate; however, this has decreased in recent years, particularly due to a reduction in cardiovascular mortality. "New" antidiabetic drugs have certainly played a relevant role in this. Various studies have shown that sodium-glucose Cotransporter 2 inhibitors (SGLT2 inhibitors) in particular but also glucagon-like peptide‑1 receptor agonists (GLP1-RA), have a significant benefit in patients with heart failure [2-5]. Surprisingly, this effect was also detectable in patients without DM [6]. Thus, the group of people who are treated with an SGLT2 inhibitor or a GLP1-RA has been expanded to include people who suffer from heart failure not associated with diabetes. This applies both to patients with reduced left ventricular systolic function (heart failure with reduced ejection fraction, HFrEF) and with preserved or mildly reduced systolic function (heart failure with preserved/mildly reduced ejection fraction, HFpEF/HFmrEF) [7]. In Germany heart failure is the most common diagnosis for hospitalization (40.6 cases/10,000 insurance years) and diseases of the cardiovascular system are the most common cause of death [8]. The increased risk of morbidity and mortality is also reflected in the perioperative setting.In addition to the risks posed by DM itself or associated diseases, the treatment with antidiabetic drugs can also lead to perioperative complications. This article focuses on the drug-related risks of the "new" antidiabetic drugs and draws conclusions regarding the management of anesthesia. The potentially life-threatening euglycemic diabetic ketoacidosis (eDKA) can be a perioperative side effect of SGLT2 inhibitors; however, the diagnosis is associated with hurdles. The GLP1-RAs are also increasingly being prescribed as they reduce cardiovascular risk and make weight loss much easier. GLP1-RAs delay gastric emptying, which potentially results in an increased risk of aspiration. In particular, if other risk factors for aspiration exist, patients should not be considered fasting, if the recommended break in GLP1‑RA intake has not been followed.

To describe the medical management of euglycemic diabetic ketoacidosis (EDKA) after two administrations of dapagliflozin in a cat with congenital diabetes mellitus undergoing insulin therapy.

A 2-year-old neutered female domestic shorthair cat with a prior presumptive diagnosis of congenital diabetes mellitus was followed for 20 months. After several adjustments to insulin therapy, the cat was relatively stable on high doses of insulin glargine (8.3 IU/kg, SC, q 12 h) with persistent hyperglycemia. Due to concerns regarding the impact of chronic hyperglycemia in a young cat, treatment was started with dapagliflozin (10 mg/cat, PO, q 24 h). A reduced dose of insulin glargine (1.3 IU/kg, SC, q 12 h) was administered concurrently to minimize the risk of ketoacidosis. Forty-eight hours after the second dapagliflozin administration, the cat was admitted for lethargy, hyporexia, and vomiting. Bloodwork was consistent with ketoacidosis and hypokalemia. During initial treatment for diabetic ketoacidosis, the cat developed hypophosphatemia, hyperbilirubinemia, and increased liver enzyme activities, with normal interstitial glucose values despite cessation of dapagliflozin. Management consisted of 7.5% glucose supplementation, a constant rate infusion of short-acting insulin, and correction of electrolyte and acid-base derangements. Improvement was seen within 12 h of starting this protocol. The cat was discharged after 9 days of hospitalization. Sixteen days after the discontinuation of dapagliflozin, the cat's interstitial glucose concentration, liver enzyme activities, and serum bilirubin concentration returned to pretreatment values.

With the introduction of sodium-glucose linked cotransporter 2 inhibitors, clinicians should be aware of EDKA and its management. This case report describes how the treatment of EDKA in cats, similar to treatment in people, may require proactive, aggressive glucose supplementation, treatment with short-acting soluble insulin, and vigilant electrolyte and acid-base monitoring. It also showcases the possibility of dapagliflozin having effect days beyond drug cessation.

Prolonged hyperglycemia caused by type 2 diabetes mellitus (T2DM) can lead to liver injury and disrupt the community of the gut microbiota that pose significant risks to human health. As a food rich in a variety of active ingredients, Zingiber striolatum (Z. striolatum) exhibits hypoglycemic and hypolipidemic effects. However, the regulatory influence of Z. striolatum ethanol extract (ZSE) on the gut microbiota of T2DM mice or its potential relationship with T2DM pathology remains unexplored.

After a one-week acclimation period, 12 mice were randomly selected as the normal group. The remaining 48 mice were employed T2DM model, and then randomly assigned to four groups: the model group, a low-dose ZSE group (ZSE-L, 100 mg/kg/day), a high-dose ZSE group (ZSE-H, 300 mg/kg/day), and a positive control group treated with metformin hydrochloride (MET, 100 mg/kg/day).

After a 4-week intervention, the results revealed that ZSE significantly ameliorated fasting blood glucose (FBG), area under the curve of oral glucose tolerance test (AUC of OGTT) and glycated serum protein (GSP) in T2DM mice. Moreover, the high-dose (ZSE-H) treatment increased the relative abundance of beneficial bacteria such as Faecalibaculum, while reducing harmful bacteria such as Bilophila, thereby alleviating insulin resistance. Additionally, ZSE-H demonstrated superior efficacy over low-dose (ZSE-L) in improving FBG, AUC of OGTT, and other hypoglycemic parameters. Predictive analysis of the correlation between gut microbiota and hypoglycemic parameters identified Dubosiella, Bacillus, and Mailhella as potential microbial biomarkers for further investigation into the pathogenesis of T2DM.

ZSE plays a pivotal role in mitigating hyperglycemia in T2DM mice through the modulation of intestinal microbiota communities.

Sodium-glucose cotransporter-2(SGLT-2) inhibitors are a newer class of antidiabetic drugs with the increased risk of euglycemic diabetic ketoacidosis(EuDKA). Encephalopathy is a rare but life-threatening event of EuDKA. Due to paradoxically normal or slightly elevated serum glucose levels, it's easy to be mimicked by cerebral infarction, structural brain damage, thus leading to delayed diagnosis and causing seriously irreversible brain injury.

We report severe EuDKA with metabolic encephalopathy secondary to dapagliflozin in a type 2 diabetes mellitus(T2DM) patient.A 72-year-old female was found unconscious 70 minutes ago.Laboratory evaluation revealed a severe metabolic acidosis with an elevated anion gap, and ketones were elevated in the blood and positive in the urine. The patient was eventually diagnosed with metabolic encephalopathy associated with EuDKA and managed accordingly.

Metabolic encephalopathy is a rare but life-threatening complication of EuDKA caused by SGLT-2 inhibitors, the imaging features are similar to those of other metabolic encephalopathy such as poisoning and hypoxia. The precise pathogenesis of encephalopathy in EuDKA remains poorly understood, potentially resulting from the toxic consequences of electrolyte disturbances, ketosis, and acidosis.Testing the level of ketones is essential for unconscious patients who are taking SGLT-2 inhibitors.

Diabetic ketoacidosis (DKA) is a serious complication in patients treated with sodium-glucose co-transporter 2 inhibitors (SGLT2i). The aim of this study was to investigate the relationship between SGLT2i and the risk of DKA, and to identify high-risk groups and characteristics that should be emphasised.

A retrospective case series study was conducted to collect medical records of inpatients diagnosed with DKA and using SGLT2i before the onset of the disease from September 2022 to September 2023 in a tertiary hospital in Shanghai. Cases that met the inclusion criteria were retrieved through the electronic medical record system. Information was collected to compare the risk of DKA in patients with different characteristics.

A total of 21 patients (12 men and 9 women) met the criteria for SGLT2i-associated DKA. The mean diabetes duration was 10.4 years, with 47.6% (10/21) of patients diagnosed with euglycaemic DKA. The drug treatment regimen most commonly used was the combination of SGLT2i and metformin, representing 52.4% (11/21) of cases. The most common clinical symptoms were nausea, vomiting, abdominal pain and malaise. Common predisposing factors were acute infections, acute pancreatitis (predominantly hyperlipidaemic type), dietary inappropriateness, acute cardiovascular and cerebrovascular events and surgery. 71.4% of patients (15/21) had multiple risk factors.

The use of SGLT2i in diabetic patients is associated with an increased risk of DKA, particularly in the presence of predisposing factors such as infection. Furthermore, long diabetes duration, decreased pancreatic β-cell function and the combined use of metformin may also contribute to the risk of DKA in patients treated with SGLT2i. The findings of this study provide valuable insights for better identification and management of DKA risks associated with SGLT2i in clinical practice.

To examine the efficacy and safety of Curalin, as a supplement to anti-diabetic drugs (ADD).

135 patients were enrolled in the study. Among them, 109, ages 18-85 years, with HA1c 7.5-10 % under treatment with ADD were randomized 1:1 to receive Curalin supplement or placebo. The primary efficacy endpoint was the change in HbA1c after 3 months. The secondary endpoint was a decrease in HbA1c by more than 0.5 % and by more than 1 %. The exploratory endpoints included the Diabetes Treatment Satisfaction Questionnaire (DTSQ), clinical and laboratory results.

After 3 months, the mean reduction in HbA1c was 1.30 % (SD = 0.79) in the Curalin group compared to 0.10 % (SD = 0.70) in the placebo group (P < 0.0001). A decrease in HbA1c of ≥ 0.5 % was observed in 90.0 % of Curalin patients versus 19.0 % of placebo patients (P < 0.0001). HbA1c reduction of ≥ 1 % occurred in 64.0 % of Curalin patients and 11.9 % of placebo patients (P < 0.0001). Curalin patients reported higher satisfaction (DTSQ) with no severe adverse events.

Curalin treatment significantly reduced HbA1c over a period of 3 months and was well-tolerated.

To achieve a consensus on optimal blood pressure (BP) targets for older adults remains challenging, necessitating a trade-off between cardiovascular benefits and the risk of impaired organ perfusion. Evidence suggests that age and frailty have a minimal influence on the cardiovascular benefits of intensive BP control in community-dwelling elderly. Nonetheless, an increased incidence of acute kidney injury with intensive BP control has been observed in octogenarians. Therefore, it is recommended to maintain systolic BP below 130 mmHg for hypertensive patients aged 65-80 years. If well-tolerated, a systolic BP target below 120 mmHg can be recommended for patients with chronic kidney disease (CKD). However, no conclusive evidence supports a stringent BP target for patients aged 80 years and older. The selection of antihypertensive medications for elderly patients requires consideration of their cardiovascular condition and potential contraindications. Combination therapy may be necessary to achieve the desired BP target. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the primary choices for patients with CKD. Newer generation mineralocorticoid receptor antagonists may further reduce the risk of cardiovascular or renal events in this population. In conclusion, managing hypertension in elderly patients requires a personalized approach that balances cardiovascular benefits with potential risks, considering individual health profiles and tolerability.

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.

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.

Diabetic cardiomyopathy (DCM) is a condition characterized by myocardial dysfunction that occurs in individuals with diabetes, in the absence of coronary artery disease, valve disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. It is considered a significant and consequential complication of diabetes in the field of cardiovascular medicine. The primary pathological manifestations include myocardial hypertrophy, myocardial fibrosis, and impaired ventricular function, which can lead to widespread myocardial necrosis. Ultimately, this can progress to the development of heart failure, arrhythmias, and cardiogenic shock, with severe cases even resulting in sudden cardiac death. Despite several decades of both fundamental and clinical research conducted globally, there are currently no specific targeted therapies available for DCM in clinical practice, and the incidence and mortality rates of heart failure remain persistently high. Thus, this article provides an overview of the current treatment modalities and novel techniques pertaining to DCM, aiming to offer valuable insights and support to researchers dedicated to investigating this complex condition.

Euglycemic diabetic ketoacidosis (EDKA) though rare is a life-threatening complication of sodium-glucose cotransporter 2 (SGLT2) inhibitors. With their increasing use in the management of type 2 diabetes mellitus (T2DM) due to long-term beneficial effects, the incidence of this complication is on the rise. We report a case of a 58-year-old lady with a history of T2DM on multiple anti-diabetes medications including dapagliflozin for one year, who during intercurrent illness developed EDKA. Her blood sugar on admission was 203 mg/dL, and arterial blood gas showed high anion-gap metabolic acidosis (HAGMA) with ketonuria and ketonemia (blood beta-hydroxybutyric (BOHB) acid level: 5.4 mmol/L). Low carbohydrate intake, dehydration resulting from repeated vomiting, and skipping the previous two days' dose of insulin could have precipitated this condition. She was treated with intravenous fluids, insulin, 5% dextrose infusion, and potassium supplements with complete resolution of acidosis after about 90 hours. This case signifies the importance of awareness of the link between the use of SGLT2 inhibitors and EDKA and early recognition of this complication to reduce morbidity and mortality. Furthermore, it also emphasizes the need for clinicians to educate their patients taking these drugs to stop them during the intercurrent illness to prevent them from developing EDKA.

Retrospective observational study. Setting. Inpatients at two teaching hospitals in Queensland, Australia. Primary Outcome Measure(s). The number of patients meeting the Joint British Diabetes Society (JBDS) and American Association of Clinical Endocrinology/American College of Endocrinology (AACE/ACE) diagnostic criteria for DKA. Patients were divided into two groups by treatment with SGLT2i at the time of diagnosis. Participants. Adult patients (>18 years old) with type 2 diabetes diagnosed with DKA from April 2015 to January 2022. Patients without type 2 diabetes were excluded.

One hundred and sixty-five patients were included in this study-comprising 94 patients in the SGLT2i cohort and 70 in the non-SGLT2i cohort. A significantly smaller proportion of patients in the SGLT2i vs. non-SGLT2i cohorts met both JBDS (56% vs. 72%, p = 0.035) and AACE/ACE (63% vs. 82%, p = 0.009) criteria for diagnosis of DKA.

Patients with type 2 diabetes treated with SGLT2i may be more likely to be diagnosed with DKA despite not meeting the criteria. Despite recent adjustments to account the physiological effects of SGLT2i, significant variation in criteria between major society guidelines presents ongoing challenges to clinicians. The proportion of patients diagnosed using both JDBS and AACE/ACE were comparable, suggesting a reasonable degree of agreement.

Healthcare resource utilization (HCRU) and healthcare costs are important factors to consider when selecting appropriate treatment for type 2 diabetes mellitus. We compared the HCRU and healthcare costs of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with type 2 diabetes mellitus in Japan.

This was a Japanese retrospective cohort study conducted using the JMDC Claims Database (January 1, 2015-December 31, 2021). Patients newly treated with an SGLT2i (31,872 patients) or a DPP4i (73,279 patients) were matched 1:1, using propensity score, after excluding patients without continuous SGLT2i or DPP4i prescriptions after the index date. HCRU and healthcare costs were compared between the treatment groups in the full cohort and subcohorts/subgroups of different baseline characteristics, including body mass index (BMI).

After matching, patient characteristics were well balanced (17,767 patients each). Patients receiving an SGLT2i vs those receiving a DPP4i had significantly lower numbers of hospitalizations per person per month (PPPM) and outpatient visits PPPM, and had shorter lengths of stay per hospitalization. Healthcare costs, including all-cause overall healthcare costs PPPM and all-cause hospitalization costs PPPM, were generally lower in patients receiving an SGLT2i than those receiving a DPP4i. Similar results were observed among patients with a higher BMI but not among patients with a lower BMI.

SGLT2i were associated with lower HCRU and healthcare costs than DPP4i, suggesting economic benefits with SGLT2i vs DPP4i in type 2 diabetes mellitus management.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) use is associated with an increased risk of diabetic ketoacidosis (DKA). The clinical data regarding the use of SGLT2i and its potential side effects in oncology patients is limited. We are retrospectively reporting four oncology patients with type 2 diabetes mellitus using SGLT2i who were admitted with DKA. The mean age of the patients was 61.25 years, and male to female ratio was 1:1. The duration of type 2 diabetes ranged from 10 to 20 years (mean 15.75 years) and the types of SGLT2i used were empagliflozin 25 mg and dapagliflozin 10 mg. The types of malignancy in our case series included squamous cell carcinoma of the cheek, ovarian cancer, and two patients had laryngeal carcinoma (squamous cell carcinoma). Diabetic ketoacidosis was diagnosed in three patients following chemotherapy or concurrent chemo-radiotherapy. Poor oral intake and infections were the main risk factors in our patients. Mean blood glucose level, anion gap, and bicarbonate level were 11.7 mmol/l, 32.25, and 5 mmol/l, respectively. The majority had moderate DKA based on pH (mean 7.13). The hospital course was complicated by acute kidney injury (n=4), infections (n=4) (urinary tract infections, and pneumonia), and three patients required critical care. The mean length of hospitalization was 19.2 days and no mortality was reported among our patients. SGLT2i-related DKA is an emerging complication recognized in oncology patients. Some of the risk factors for this complication are starvation, poor oral intake, and infection which are quite prevalent in oncology patients. Temporary holding of SGLT2i medication during this period might have a potential preventive role.

Garlic (Allium sativum L.) is a popular spice that is widely used for food and medicinal purposes and has shown potential effects on diabetic kidney disease (DKD). Nevertheless, systematic preclinical studies are still lacking. In this meta-analysis and systematic review, we evaluated the role and potential mechanisms of action of garlic and its derived components in animal models of DKD. We searched eight databases for relevant studies from the establishment of the databases to December 2022 and updated in April 2023 before the completion of this review. A total of 24 trials were included in the meta-analysis. It provided preliminary evidence that supplementing with garlic could improve the indicators of renal function (BUN, Scr, 24 h urine volume, proteinuria, and KI) and metabolic disorders (BG, insulin, and body weight). Meanwhile, the beneficial effects of garlic and its components in DKD could be related to alleviating oxidative stress, suppressing inflammatory reactions, delaying renal fibrosis, and improving glucose metabolism. Furthermore, time-dose interval analysis exhibited relatively greater effectiveness when garlic products were supplied at doses of 500 mg kg-1 with interventions lasting 8-10 weeks, and garlic components were administered at doses of 45-150 mg kg-1 with interventions lasting 4-10 weeks. This meta-analysis and systematic review highlights for the first time the therapeutic potential of garlic supplementation in animal models of DKD and offers a more thorough evaluation of its effects and mechanisms to establish an evidence-based basis for designing future clinical trials.

The U.S. Food and Drug Administration (FDA) revised the labels of sodium-glucose transporter 2 (SGLT2) inhibitors in December 2015 to inform users regarding the risk of diabetic ketoacidosis (DKA). As more drugs of this class are approved and their indications are expanded, this serious adverse effect has been increasingly reported.

This review evaluated observational studies to inform the prevalence of SGLT2-inhibitor-associated DKA compared with other antihyperglycemic agents.

A systematic review was conducted in PubMed and EMBASE until 19 July 2022 (PROSPERO: CRD42022385425). We included published retrospective cohort active comparator/new user (ACNU) and prevalent new user studies assessing SGLT2-inhibitor-associated DKA prevalence in adult patients with type 2 diabetes mellitus (T2DM) against active comparators. We excluded studies which lacked 1:1 propensity score matching. The JBI Checklist for Cohort Studies guided the risk-of-bias assessments. Meta-analysis was conducted based on the inverse variance method in R software.

Sixteen studies with a sample of 2,956,100 nonunique patients met the inclusion criteria. Most studies were conducted in North America (n = 9) and adopted the ACNU design (n = 15). Meta-analysis of 14 studies identified 33% higher DKA risk associated with SGLT2 inhibitors (HR = 1.33, 95% CI: 1.14-1.55, P < 0.01). Meta-regression analysis identified the study location (P = 0.02), analysis principle (P < 0.001), exclusion of chronic comorbidities (P = 0.007), and canagliflozin (P = 0.04) as significant moderator variables.

Despite limitations related to heterogeneity, generalizability, and misclassification, the results of this study show that SGLT2 inhibitors increase the prevalence of DKA among adult T2DM patients in the real world. The findings supplement evidence from randomized controlled trials (RCTs) and call for continued vigilance.

The use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) is increasing rapidly for patients with diabetes, heart failure, and chronic kidney disease. These medications can cause euglycemic diabetic ketoacidosis in the perioperative period, and the Food and Drug Administration recently updated their recommendations that they be held for at least 3-to-4 days preoperatively. There is a paucity of guidelines for the perioperative management of patients taking SGLT2i who present for emergent surgery or elective surgery having not held the medications per Food and Drug Administration guidelines. At the University of Pennsylvania, a multidisciplinary team from the Departments of Anesthesiology, Endocrinology, and Pharmacy has developed comprehensive guidelines detailing preoperative, intraoperative, and postoperative management for patients using these medications. In this article, the authors present these guidelines and discuss challenges encountered while implementing them at a large academic medical center with satellite hospitals and surgery centers with varying resources and patient populations.

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

The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are available for individuals with type 1 diabetes, but appropriate use is recommended to prevent ketosis or ketoacidosis. This study aimed to evaluate the risk of ketosis in people with type 1 diabetes, focusing on the relationship between nutritional assessment, glycaemic status, c-peptide immunoreactivity (CPR) index and body composition.

In total, 46 Japanese patients with type 1 diabetes were included, and dietary assessment from food photographs and ketone levels were evaluated before and after taking SGLT2is. The effect of diet on morning ketone levels was also investigated.

All patients had an increase in mean ketone concentrations after taking SGLT2is (before 0.12 ± 0.06 mmol/L, after 0.23 ± 0.16 mmol/L). A significant negative correlation was found between average morning ketone levels and age (r = -0.514, p < .001) and the CPR index (r = -0.523, p = .038) after taking SGLT2is. Using a mixed-effects model based on the results before starting the inhibitors, it was noted that both patient-to-patient and age, or patient-to-patient and capacity of insulin secretion, influenced the ketone levels. Multiple regression analysis showed that factors associated with the risk of increasing ketone levels after taking SGLT2is were younger age (β = -0.504, p = .003) and a low ratio of basal to bolus insulin (β = -0.420, p = .005).

When administering SGLT2is to patients with a low CPR index or younger patients with type 1 diabetes, adequate instructions to prevent ketosis should be given.

Diabetes Mellitus Type 2 (T2D) is an emerging health burden in the USand worldwide, impacting approximately 15% of Americans. Current front-line therapeutics for T2D patients include sulfonylureas that act to reduce A1C and/or fasting blood glucose levels, or Metformin that antagonizes the action of glucagon to reduce hepatic glucose production. Next generation glucomodulatory therapeutics target members of the high-affinity glucose transporter Sodium-Glucose-Linked-Transporter (SGLT) family. SGLT1 is primarily expressed in intestinal epithelium, whose inhibition reduces dietary glucose uptake, whilst SGLT2 is highly expressed in kidney - regulating glucose reabsorption. A number of SGLT2 inhibitors are FDA approved whilst SGLT1 and dual SGLT1 & 2 inhibitor are currently in clinical trials. Here, we discuss and compare SGLT2, SGLT1, and dual inhibitors' biochemical mechanism and physiological effects.

Euglycemic diabetic ketoacidosis (DKA) is a rare, but clinically important, presentation that can lead to significant morbidity and mortality in patients with diabetes mellitus. It has been associated with multiple etiologies, including sodium-glucose cotransport-2 (SGLT2) inhibitor use. This case report details the presentation of a 28-year-old male patient who was recently diagnosed with non-ST elevated myocardial infarction (NSTEMI) status post-percutaneous coronary intervention (PCI) to left anterior descending (LAD) and type 2 diabetes mellitus (T2DM) and discharged on a new medical regiment that included an SGLT2 inhibitor. The patient presented five days later with dyspnea, nausea, and vomiting. On initial evaluation, he had tachycardia and hypertension. Lab work revealed hyperkalemia, metabolic anion gap acidosis, and the presence of ketones and glucose in the urine, which led to the diagnosis of euglycemic DKA. The patient was started on intravenous (IV) insulin, bicarbonate, and D5 ½ normal saline (NS) and required five days of continuous treatment for the anion gap to close. Considering studies have shown that SGLT2 inhibitors are associated with euglycemic DKA, it is proposed that the use of an SGLT2 inhibitor in this newly diagnosed, post-PCI patient led to the development of euglycemic DKA. DKA most commonly resolves within 24 hours of treatment; however, our patient did not recover until after 120 hours of treatment. Recent studies have suggested that SGLT2-inhibitor euglycemic DKA may be associated with longer recovery time; however, there is still a need to further research the consistency of these findings and quantify the estimated duration of treatment across populations. There is also a need for investigation into how co-morbid factors, such as a recent NSTEMI and PCI, may affect recovery times or predispose patients who are taking SGLT2-inhibitors to develop euglycemic DKA as SGLT2 inhibitors are being more widely prescribed. This case report highlights the importance of creating more detailed and evidence-based guidelines for prescribing SGLT2 inhibitors for patients with diabetes and encourages more research into the expected duration of treatment for patients with SGLT2-induced euglycemic DKA and factors that may affect it.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are commonly prescribed to manage patients with diabetes mellitus. These agents may rarely lead to the development of euglycemic diabetic ketoacidosis (EDKA), which may complicate the disease course of these patients.

To analyze the demographic profile, predisposing factors, symptomology, clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series.

We performed a systematic search of PubMed, Science Direct, Google Scholar and Reference Citation Analysis databases using the terms "canagliflozin" OR "empagliflozin" OR "dapagliflozin" OR "SGLT2 inhibitors" OR "Sodium-glucose cotransporter-2" AND "euglycemia" OR "euglycemic diabetic ketoacidosis" OR "metabolic acidosis". The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported EDKA secondary to SGLT2i. Furthermore, the data were filtered from the literature published in the English language and on adults (> 18 years). We excluded: (1) Conference abstracts; and (2) Case reports or series which did not have individual biochemical data. All the case reports and case series were evaluated. The data extracted included patient demographics, clinical symptomatology, clinical interventions, intensive care unit course, need for organ support and outcomes.

Overall, 108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included. The majority of patients were females (54.4%, n = 92), and the commonly reported symptoms were gastrointestinal (nausea/vomiting 65.1%, abdominal pain 37.3%) and respiratory (breathlessness 30.8%). One hundred and forty-nine (88.2%) patients had underlying type II diabetes, and the most commonly involved SGLT-2 inhibitor reported was empagliflozin (46.8%). A triggering factor was reported in most patients (78.7%), the commonest being acute severe infection (37.9%), which included patients with sepsis, coronavirus disease 2019, other viral illnesses, and acute pancreatitis. 61.5% were reported to require intensive unit care, but only a minority of patients required organ support in the form of invasive mechanical ventilation (13%), vasopressors (6.5%) or renal replacement therapy (5.9%). The overall mortality rate was only 2.4%.

Patients on SGLT2i may rarely develop EDKA, especially in the presence of certain predisposing factors, including severe acute infections and following major surgery. The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels, which may make the diagnosis challenging. Outcomes of EDKA are good if recognized early and corrective actions are taken. Hence, physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management.

Bariatric/metabolic surgery and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are becoming increasingly popular for the management of overweight/obese patients with type 2 diabetes mellitus (T2DM). Consequently, the chance that a patient undergoing bariatric/metabolic surgery is also treated with an SGLT2i would be rather common in clinical practice. Both risks and benefits have been reported. On the one hand, several cases of euglycemic diabetic ketoacidosis have been reported within the few days/weeks after bariatric/metabolic surgery. The causes are diverse but a drastic reduction in caloric (carbohydrate) intake most probably plays a crucial role. Thus, SGLT2is should be stopped a few days (and even more if a pre-operative restricted diet is prescribed to reduce liver volume) before the intervention and reintroduced only when the caloric (carbohydrate) intake is sufficient. On the other hand, SGLT2is may exert a favorable effect to reduce the risk of postprandial hypoglycemia, a complication reported among patients who have been treated with bariatric/metabolic surgery. An increased hepatic glucose production and a reduced production of interleukin-1β have been proposed as possible underlying mechanisms for this protective effect. Finally, whether SGLT2is could prolong diabetes remission following surgery and improve the prognosis of patients with T2DM who benefit from bariatric/metabolic surgery remains to be investigated.

Euglycemic diabetic ketoacidosis (euDKA) is a rare but life-threatening adverse effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors. We present a case of delayed euDKA seven days after cure of acute pancreatitis and discharge from the hospital of a 51-year-old man with type 2 diabetes mellitus (T2DM) managed with a combination of antidiabetic medications, including the SGLT2 inhibitor dapagliflozin. Prior acute pancreatitis was postulated to be a contributing factor to the development of SGLT2 inhibitor-associated euDKA in this patient discharged from the hospital. The patient was managed accordingly and improved clinically while his oral hypoglycemic agents were stopped. The risk of euDKA from SGLT2 inhibitor therapy may be increased by some stress factors (eg, infection, surgery, acute illness, low-carbohydrate diet, excessive alcohol intake). As these SGLT2 inhibitors become a popular therapeutic strategy for the management of hyperglycemia in T2DM, clinicians should be aware that acute illnesses such as pancreatitis in patients with T2DM can be potential predisposing factors for the development of SGLT2 inhibitor-associated euDKA.

Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an antihyperglycemic agent, metformin also has a plethora of pleiotropic effects on various systems and processes. It acts majorly by activating AMPK (Adenosine Monophosphate-Activated Protein Kinase) in the cells and reducing glucose output from the liver. It also decreases advanced glycation end products and reactive oxygen species production in the endothelium apart from regulating the glucose and lipid metabolism in the cardiomyocytes, hence minimizing the cardiovascular risks. Its anticancer, antiproliferative and apoptosis-inducing effects on malignant cells might prove instrumental in the malignancy of organs like the breast, kidney, brain, ovary, lung, and endometrium. Preclinical studies have also shown some evidence of metformin's neuroprotective role in Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Metformin exerts its pleiotropic effects through varied pathways of intracellular signalling and exact mechanism in the majority of them remains yet to be clearly defined. This article has extensively reviewed the therapeutic benefits of metformin and the details of its mechanism for a molecule of boon in various conditions like diabetes, prediabetes, obesity, polycystic ovarian disease, metabolic derangement in HIV, various cancers and aging.

Although sodium-glucose cotransporter-2 (SGLT2) inhibitors have risen in popularity for managing heart failure (HF) and chronic kidney disease (CKD), little guidance is available for the management of patients with an overlap of HF and CKD.

Following a brief review of the cardiorenal effects of SGLT2 inhibitors, this narrative review focused on the published clinical evidence pertaining to the cardiovascular and renal efficacy of SGLT2 inhibitors in patients with HF and CKD, including both randomized controlled trials and real-world observational studies. Real-world considerations of using SGLT2 inhibitors in these patients were also reviewed.

Although no randomized controlled trial has specifically studied the use of SGLT2 inhibitors in patients with HF and CKD, evidence from existing trials is largely sufficient to demonstrate that SGLT2 inhibitors are efficacious in these patients, in whom these agents should be initiated early to maximally slow declines in renal function. Further studies should focus on better guiding the timing of initiating SGLT2 inhibitors, improving these agents' cost-effectiveness, and bettering equity of access to these agents. Further areas of study may include the prognostic implications of SGLT2 inhibitors-induced changes in biomarker levels (e.g. natriuretic peptides), and the potentials of SGLT1 inhibition.

Euglycemic diabetic ketoacidosis (euDKA) is an uncommon condition, which is characterized by an elevated anion gap metabolic acidosis with ketonemia/ketonuria, in the presence of normal blood glucose levels. Common risk factors for the development of this condition include pregnancy, prolonged fasting, acute pancreatitis, and bariatric surgery. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been identified as a rare cause of euDKA. A recent literature review on PubMed found only 86 case reports of euDKA secondary to SGLT inhibitors published in the medical literature up to December 2022. Here, we present the case of a 43-year-old man who was taking empagliflozin, an SGLT-2 inhibitor. The patient was found to have euDKA, which was likely an adverse effect of his medication.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic mediations found to also reduce cardiovascular morbidity and mortality and hospitalization for heart failure. Positive results from the EMPEROR-Preserved (empagliflozin) and PRESERVED-HF (dapagliflozin) studies led to recommendations for SGLT2 inhibitors in HFpEF within major international heart failure guidelines. However, studies of ipragliflozin and luseogliflozin, agents approved outside the United States (U.S.), reported different outcomes relative to pivotal trials and failed to realize benefits in the HFpEF population. Varying definitions of HFpEF and outcomes studied complicate the interpretation of study results. SGLT2 inhibitors may cause common adverse events (genital mycotic infections, volume depletion) in addition to rare but severe sequela, including euglycemic diabetic ketoacidosis, Fournier's gangrene, and lower limb amputation. While evidence of CV benefits grows, SGLT2 inhibitor prescribing has lagged, particularly among patients without diabetes. In the U.S., high cost and administrative hurdles may contribute to decreased patient and clinician uptake of this drug class. Future trial results and clinical experience with SGLT2 inhibitors may lead to expanded use and greater uptake among patients with heart failure.

(1) Background. We aimed to assess long-term efficacy and safety in inadequately controlled type 2 diabetes (T2DM) of two SGLT-2 inhibitors: empagliflozin (Empa) and dapagliflozin (Dapa), combined with metformin, other oral antidiabetics or insulin, according to the protocols in Romania. (2) Methods. The data of 100 patients treated for T2DM with associated dyslipidemia and/or cardiovascular diseases at the University Hospital and Consultmed Medical Center in Iasi were retrospectively reviewed (2017-2021). In total, 48 patients had received dapagliflozin (10 mg with oral antidiabetics or insulin) and 52 patients received empagliflozin (10 mg /25 mg with oral antidiabetics). (3) Results. In both groups, the lowering of BMI was significant: Dapa group (32.04 ± 4.49 vs. 31.40 ± 4.18 kg/m2; p = 0.006), and Empa group (34.16 ± 5.08 vs. 33.17 ± 4.99 kg/m2; p = 0.002). Blood sugar average levels decreased significantly (170 vs. 136 mg/dL; p = 0.001 for Dapa; 163 vs. 140 mg/dL; p = 0.002 for Empa) and also average levels of HbA1c (7.90% vs. 7.51%; p = 0,01 for Dapa; 7.72% vs. 7.35%; p = 0.004 for Empa). (4) Conclusions. Better results in all variables were observed in younger male patients with a shorter duration of diabetes and threshold BMI levels of 34.1, treated with SGLT2, and more significantly with Empa.