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Background: Immune checkpoint inhibitors (ICIs) are becoming more frequently used in the treatment of many types of malignant cancers by disinhibiting T-cell activation, which promotes the destruction of cancer cells. This disinhibition can also result in autoimmune conditions, like endocrinopathies., Case: We report a case of a 78-year-old male patient with malignant mesothelioma treated with combination ICI therapy who presented with diabetic ketoacidosis (DKA) with no history of diabetes mellitus or hyperglycemia. The patient was admitted to the intensive care unit and treated with intravenous (IV) fluid repletion and IV insulin for DKA. The patient was diagnosed with new-onset type 1 diabetes mellitus (T1DM) induced by ICI therapy., Discussion: Approximately 75% of patients diagnosed with ICI-induced T1DM initially present with DKA. This, along with the rapid onset of hyperglycemia in this patient, suggests current guidelines for monitoring blood glucose are inadequate. Current guidelines recommend monitoring blood glucose at the following times: baseline, at the initiation of each cycle for 12 weeks, and then every 3-6 weeks thereafter. We propose the following schedule for monitoring blood glucose in patients receiving ICI therapy: baseline, twice weekly for the first six cycles, and then once weekly thereafter. This proposed update is supported by our patient's rapid onset of hyperglycemia and other case reports and reviews showing that most patients with this diagnosis have an initial presentation of DKA. Detecting hyperglycemia and starting treatment early is important in the prevention of acute complications from uncontrolled T1DM, like DKA., Conclusion: This case adds to the existing body of literature and provides support for more frequent monitoring of blood glucose in patients receiving ICI therapy. Blood glucose monitoring is a simple, reliable, low risk, and inexpensive laboratory test that should be used in patients receiving ICI therapy to ensure prompt diagnosis and treatment of T1DM., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Immune checkpoint inhibitors (ICIs) have radically altered cancer treatment, but immune toxicities called immune-related adverse events (irAEs), particularly endocrine toxicities, such as acute-onset diabetes and thyroid dysfunction, pose challenges. Although most irAEs have mild-to-moderate severity, failure to diagnose and treat them promptly can result in life-threatening complications. This report presents the case of a 50-year-old woman who developed ICI-induced diabetes mellitus (ICI-DM) during sintilimab treatment for advanced cervical carcinoma. The patient experienced repeated episodes of diabetic ketoacidosis (DKA) and subclinical hypothyroidism. Unlike the case of patients with typical type 1 diabetes mellitus (T1DM), our patient tested negative for β cell autoantibodies and progressed rapidly. Prompt recognition and insulin treatment are crucial for helping patients overcome such crises. Eventually, sintilimab was discontinued, and chemotherapy was initiated. This case report contributes to our understanding of ICI-DM. The significance of monitoring thyroid function and blood glucose levels before initiating ICI treatment to identify irAEs early and effectively manage them are important considerations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Cai and Feng.)

Background: There is a growing trend to include non-randomised studies of interventions (NRSIs) in rare events meta-analyses of randomised controlled trials (RCTs) to complement the evidence from the latter. An important consideration when combining RCTs and NRSIs is how to address potential bias and down-weighting of NRSIs in the pooled estimates. The aim of this study is to explore the use of a power prior approach in a Bayesian framework for integrating RCTs and NRSIs to assess the effect of rare events., Methods: We proposed a method of specifying the down-weighting factor based on judgments of the relative magnitude (no information, and low, moderate, serious and critical risk of bias) of the overall risk of bias for each NRSI using the ROBINS-I tool. The methods were illustrated using two meta-analyses, with particular interest in the risk of diabetic ketoacidosis (DKA) in patients using sodium/glucose cotransporter-2 (SGLT-2) inhibitors compared with active comparators, and the association between low-dose methotrexate exposure and melanoma., Results: No significant results were observed for these two analyses when the data from RCTs only were pooled (risk of DKA: OR = 0.82, 95% confidence interval (CI): 0.25-2.69; risk of melanoma: OR = 1.94, 95%CI: 0.72-5.27). When RCTs and NRSIs were directly combined without distinction in the same meta-analysis, both meta-analyses showed significant results (risk of DKA: OR = 1.50, 95%CI: 1.11-2.03; risk of melanoma: OR = 1.16, 95%CI: 1.08-1.24). Using Bayesian analysis to account for NRSI bias, there was a 90% probability of an increased risk of DKA in users receiving SGLT-2 inhibitors and an 91% probability of an increased risk of melanoma in patients using low-dose methotrexate., Conclusions: Our study showed that including NRSIs in a meta-analysis of RCTs for rare events could increase the certainty and comprehensiveness of the evidence. The estimates obtained from NRSIs are generally considered to be biased, and the possible influence of NRSIs on the certainty of the combined evidence needs to be carefully investigated., (© 2024. The Author(s).)

Rationale: Glucagon-like peptide-1 is an endogenous incretin that plays an active role in weight loss and hypoglycemia. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), which has been approved for the treatment of patients with type 2 diabetes (T2D). GLP-1RAs can increase insulin secretion and inhibit glucagon release, thereby leading to a decrease in blood glucose levels within the body. Specifically, GLP-1RAs control postprandial blood glucose levels by inhibiting hepatic glucose production and delaying gastric emptying. However, attention should be given to gastrointestinal adverse reactions. There are currently a few cases of GLP-1RA causing diabetic ketoacidosis (DKA)., Patient Concerns: The following report details the case of a 50-year-old Chinese female who has been living with diabetes for 12 years. Initially diagnosed with T2D, she was subsequently identified as a patient with latent autoimmune diabetes in adults (LADA) following treatment. The patient presented severe nausea, vomiting, and fatigue 1 day after injecting dulaglutide 1 time and discontinuing insulin therapy. She was diagnosed with severe DKA in the emergency department., Diagnoses: LADA and DKA., Interventions: Changed from dulaglutide to insulin therapy., Outcomes: After discontinuing dulaglutide and switching to insulin for blood glucose reduction, the patient's DKA was corrected, and blood glucose levels returned to normal., Lessons: This case suggests that clinicians should be alert to patients with severe DKA in cases of severe gastrointestinal adverse reactions after the use of GLP-1RAs. In addition, in most countries, GLP-1RAs are administered to patients with T2D, but we should consider the use of GLP-1RAs in patients with type 1 diabetes and LADA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Sodium glucose co-transporter-2 inhibitors (SGLT-2i) are increasingly being used among hospitalized patients. Our objective was to assess the risk of diabetic ketoacidosis (DKA) among hospitalized patients receiving an SGLT-2i., Research Design and Methods: We conducted a multicentre cohort study of patients hospitalized at 19 hospitals. We included patients over 18 years of age who received an SGLT-2i or a dipeptidyl peptidase-4 inhibitor (DPP-4i) in hospital. The primary outcome was the risk of DKA during their hospitalization., Results: 61,517 patients received a DPP-4i and 11,061 received an SGLT-2i. The risk of inpatient DKA was 0.07 % (N = 41 events) among adults who received a DPP-4i and 0.18 % (N = 20 events) among adults who received an SGLT-2i; adjusted odds ratio of 3.30 (95 % CI: 1.85-5.72)., Conclusions: In hospitalized patients, the absolute risk of DKA was 0.2 %, which corresponded to a three-fold higher relative risk., Competing Interests: Declaration of competing interest MF was a consultant for ProofDx, a start-up company creating point of care diagnostic tests for COVID-19 using CRISPR. MF is an advisor for SIGNAL1, a start-up company deploying machine learned models to improve inpatient care. MF has been paid for medicolegal cases unrelated to the content of this study. FR is a provincial clinical lead for quality improvement at Ontario Health (as a part-time salaried employee). This research was undertaken, in part, with funding from the Canada Research Chairs Program. AV is a part-time employee of Ontario Health and is supported by the Temerty Professorship of AI Research and Education in Medicine at the University of Toronto., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Immunotherapy has a crucial role in the current treatment of multiple malignancies. Albeit described as rare, new onset autoimmune diabetes is a potentially life-threatening complication of programmed cell death-1 (PD-1) inhibitors, such as pembrolizumab, and its predisposing factors and pathological mechanism are yet to be clarified., Case Report: We present a case of a 72-year-old man with a high-grade bladder carcinoma undergoing pembrolizumab treatment. He had no personal or family history of diabetes mellitus but was diagnosed with primary hypothyroidism four months after starting pembrolizumab. Two years after starting pembrolizumab, he presented in the emergency department due to abdominal pain, anorexia, polydipsia, polyuria and vomiting over the preceding five days and he met criteria for severe diabetic ketoacidosis (DKA). Three days prior to his admission, he had received prednisolone therapy for suspected hypersensitivity related to a contrast-enhanced imaging that he performed., Management & Outcome: Prompt treatment for DKA was started, with transition to insulin basal-bolus therapy after DKA resolution, with progressive glycaemic stabilization. Further investigation revealed low C-peptide levels (0.07 ng/dL, with a fasting blood glucose of 288 mg/dL), HbA1c 9.2% and positive anti-IA2 antibodies, which allowed the diagnosis of new-onset autoimmune diabetes. Pembrolizumab was transiently suspended, and the patient resumed treatment after glycaemic profile optimization under multiple daily insulin administrations two months later., Discussion: This case highlights the importance of clinical suspicion and glycaemic monitoring as an integral part of treatment protocols in patients on pembrolizumab and other immune checkpoint inhibitors. Additional research and investigation into the underlying mechanisms of this condition are necessary to identify potential screening tests for individuals at higher risk of developing DM and to guide the implementation of management and preventive strategies for ketoacidosis complication., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims/hypothesis: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis., Methods: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013-2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument., Results: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA 1c reduction was similar between SGLT2i and DPP4i (-0.3 mmol/mol [-1.6, 1.1], -0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (-4 mmol/mol [4.8, -3.1], -0.4% [-0.4, -0.3])., Conclusions/interpretation: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes., (© 2024. The Author(s).)

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

Aims: To assess the comparative cardiovascular and renal effectiveness and safety of empagliflozin vs. dapagliflozin among patients with type 2 diabetes in routine clinical practice., Methods and Results: Cohort study using data from nationwide registers in Sweden, Denmark, and Norway, from June 2014 to June 2021 included 141 065 new users of empagliflozin and 58 306 new users of dapagliflozin. Coprimary outcomes were major cardiovascular events (myocardial infarction, stroke, and cardiovascular death), heart failure (hospitalization or death because of heart failure) and serious renal events (renal replacement therapy, hospitalization for renal events, and death from renal causes). Secondary outcomes were the individual components of the primary outcomes, any cause death, and diabetic ketoacidosis. Use of empagliflozin vs. dapagliflozin was associated with similar risk of major cardiovascular events [adjusted incidence rate: 15.9 vs. 15.8 events per 1000 person-years; HR 1.02, (95% confidence interval 0.97-1.08)], heart failure [6.5 vs. 6.3 events per 1000 person-years; HR 1.05 (0.97-1.14)] and serious renal events [3.7 vs. 4.1 events per 1000 person-years; HR 0.97 (0.87-1.07)]. In secondary outcome analyses, the HRs for use of empagliflozin vs. dapagliflozin were 1.00 (0.93-1.07) for myocardial infarction, 1.03 (0.95-1.12) for stroke, 1.01 (0.92-1.13) for cardiovascular death, 1.06 (1.00-1.11) for any cause death, 0.77 (0.60-0.99) for renal replacement therapy, 1.20 (0.75-1.93) for renal death, 1.01 (0.90-1.12) for hospitalization for renal events and 1.12 (0.94-1.33) for diabetic ketoacidosis., Conclusion: Use of empagliflozin and dapagliflozin was associated with similar risk of cardiovascular and renal outcomes, mortality, and diabetic ketoacidosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients., Methods: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO 3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis., Results: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%)., Conclusions: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases., (© 2024. The Author(s).)

Backgrounds: The prescription of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been increasing due to their additional benefits, including weight loss, cardioprotection and renoprotection. Accordingly, there are concerns about the potential rise in severe adverse drug reactions (ADRs), such as urinary tract infections, diabetic ketoacidosis, volume depletion, and hypoglycemia. The Society has announced recommendations on the proper use of SGLT2 inhibitors. We aimed to elucidate the recent occurrence of severe ADRs which need discontinuation of SGLT2 inhibitors or hospitalization., Methods: In this retrospective cohort study, we identified 391 diabetic patients who were prescribed SGLT2 inhibitors upon admission to our hospital between April 2017 and March 2023. Of these, 68 patients who discontinued SGLT2 inhibitors for reasons other than ADRs were excluded. Patients were classified into the 2017 group and the 2020 group based on the treatment period of SGLT2 inhibitors, and the occurrence of ADRs and patient backgrounds were compared between the two groups., Results: A total of 323 eligible patients were identified. Discontinuations of SGLT2 inhibitors decreased in the 2020 group ( p < 0.05). However, discontinuations due to frailty increased ( p < 0.05). Hospitalization due to ADRs, specifically those due to urinary tract infections, diabetic ketoacidosis, or volume depletion, did not specifically decrease ( p = 0.273)., Conclusions: This study indicated that there has been some improvement in the awareness of the proper use of SGLT2 inhibitors and there is still a need to continue enlightenment activities.

BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used to improve the prognosis of patients with diabetes, heart failure, or chronic kidney disease. The use of SGLT2 inhibitors in patients without diabetes is expected to increase. Diabetic ketoacidosis is a severe complication of SGLT2 inhibitors in patients with diabetes. People without diabetes are thought to be less likely to develop ketoacidosis, and reports of SGLT2 inhibitor-induced ketoacidosis are uncommon in people without diabetes. CASE REPORT Herein, we describe a case of ketoacidosis in an 83-year-old Japanese woman without diabetes who was administered SGLT2 inhibitors for heart failure (ejection fraction: approximately 30%). Two weeks prior to admission, she had suffered a vertebral fracture and rib fracture due to a fall, which was followed by anorexia, but she continued to take SGLT2 inhibitors. On admission, blood test results revealed a blood glucose level of 124 mg/dL, hemoglobin A1C level of 5.9%, pH of 7.329, HCO₃⁻ concentration of 14.3 mmol/L, and a ß-hydroxybutyrate concentration of 5150 μmol/L, leading to a diagnosis of euglycemic ketoacidosis. The patient's C-peptide level was consistent with the blood glucose levels on admission, indicating that she had adequate insulin secretion. The patient was treated only with glucose administration without insulin and was discharged after discontinuation of the SGLT2 inhibitor. CONCLUSIONS This case illustrates that patients with or without diabetes may develop SGLT2 inhibitor-related ketoacidosis after several days of inadequate food intake; therefore, patients should be informed of this risk.

Competing Interests: Declaration of competing interest Dr. Vanneman receives $3,000 annually in patent royalties for novel cancer immunotherapy.

Objective: To describe reported cases of prolonged or relapsed ketoacidosis (KA) in adults with type 2 diabetes receiving treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors., Methods: We performed a search of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and medical literature, to identify our case series and to characterize cases of prolonged KA, relapsed KA, or persistent ketonemia, persistent ketonuria and/or persistent glucosuria in adults receiving SGLT2 inhibitors., Results: The FDA identified 29 unique cases of prolonged or relapsed KA, as well as related terms persistent ketonemia, persistent ketonuria, and persistent glucosuria, in patients receiving SGLT2 inhibitors through July 26, 2022. The patients ranged in age from 26 to 85 years. Treatment duration of KA ranged from 3 to 20 days. There were 7 cases of relapsed KA when insulin was reduced or transitioned to subcutaneous route. Arterial pH value was 7.0 or below in 4 patients, and the median pH was 7.1. Associated factors for prolonged or relapsed KA included surgery, decreased caloric intake, and ketogenic/carbohydrate restricted diet. A total of 62% of the patients were taking 3 or more glycemic control medications including the SGLT2 inhibitor. All patients with sufficient follow-up information recovered., Conclusion: Although KA is a well-known risk associated with SGLT2 inhibitors, this case series demonstrated the potential for prolonged or recurrent KA events with serious outcomes. These cases informed updates to FDA's prescribing information to inform prescribers of this risk., Competing Interests: Disclosure The views expressed are those of the authors and do not necessarily represent the position of, nor imply endorsement from, the U.S. Food and Drug Administration or the U.S. Government. The authors have no multiplicity of interest to disclose., (Published by Elsevier Inc.)

Background: Alpelisib is a PI3K inhibitor indicated with fulvestrant for treatment of advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated breast cancer. In the phase III SOLAR-1 trial, grade 3/4 hyperglycemic events were reported in 36.6% of patients receiving alpelisib-fulvestrant compared to 0.7% receiving placebo-fulvestrant. As case reports of diabetic ketoacidosis (DKA) have been associated with alpelisib use, the goal of this study was to characterize the FAERS reported cases of this severe adverse effect., Methods: A retrospective disproportionality analysis was performed using the FAERS database by calculating the reporting odds ratio (ROR) of DKA events with alpelisib from 2019 to 2022. A PubMed literature review of case reports characterizing alpelisib-induced DKA was performed., Results: Pharmacovigilance database analysis revealed significance in reporting among 87 DKA cases with alpelisib (ROR 9.84, 95% confidence interval 7.3-13.2), including hospitalization and death as reported outcomes. Review of 11 published case reports reveals median onset of DKA at 14 days with successful rechallenge possible., Conclusion: Significant association with reporting exists between DKA and alpelisib exposure. We observed similar median time to onset of hyperglycemia between our analysis compared to that reported in SOLAR-1. Considering early onset of this toxicity, it is imperative that patients be closely monitored when initiating alpelisib. Addition of a preemptive antihyperglycemic or escalation in those previously on antihyperglycemic medications is beneficial in decreasing the severity of hyperglycemia with alpelisib. Further study investigating risk factors is warranted to better elucidate which patients require preemptive therapy., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: No studies have reported the long-term outcomes of initiating sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with estimated glomerular filtration rates less than 20 mL/min/1.73 m 2 to predialysis., Objective: To compare the risk for dialysis, cardiovascular events, and death between SGLT2i users and nonusers in patients with type 2 diabetes (T2D) and stage 5 chronic kidney disease (CKD)., Design: Target trial emulation study., Setting: Taiwan's National Health Insurance Research Database (NHIRD)., Participants: By applying sequential target trial emulation principle, 23 854 SGLT2i users and 23 892 SGLT2i nonusers were selected from the NHIRD for patients with T2D and stage 5 CKD from 1 May 2016 to 31 October 2021., Measurements: Conditional Cox proportional hazards models were used to compare the risks for dialysis, hospitalization for heart failure, acute myocardial infarction (AMI), diabetic ketoacidosis (DKA), acute kidney injury (AKI), and all-cause mortality between SGLT2i users and nonusers., Results: In the intention-to-treat model, compared with no SGLT2i use, SGLT2i use was associated with lower risks for dialysis (hazard ratio [HR], 0.34 [95% CI, 0.27 to 0.43]), hospitalization for heart failure (HR, 0.80 [CI, 0.73 to 0.86]), AMI (HR, 0.61 [CI, 0.52 to 0.73]), DKA (HR, 0.78 [CI, 0.71 to 0.85]), and AKI (HR, 0.80 [CI, 0.70 to 0.90]), but there was no difference in the risk for all-cause mortality (HR, 1.11 [CI, 0.99 to 1.24]). The Kaplan-Meier curves and subgroup analyses also showed that initiation of an SGLT2i in stage 5 CKD was associated with a lower risk for long-term dialysis than no SGLT2i use., Limitation: This result may not apply to patients without T2D., Conclusion: This emulated target trial showed that SGLT2i use was associated with a lower risk for dialysis, cardiovascular events, DKA, and AKI than no SGLT2i use in patients with T2D and stage 5 CKD., Primary Funding Source: National Health Research Institutes, Taiwan., Competing Interests: Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1874.

Background: The purpose of this systematic review and meta-analysis was to evaluate the common clinical adverse events associated with sodium/glucose cotransporter-2 inhibitor (SGLT2i) use compared to placebo in patients with chronic kidney disease (CKD) with or without type 2 diabetes., Methods: Twelve articles were chosen via a systematic search of the PubMed, Embase, and Cochrane Library databases. We screened for randomised placebo-controlled trials. The main clinical adverse events included diabetes ketoacidosis (DKA), amputation, and volume depletion. We performed heterogeneity testing and assessment of publication bias., Results: In all, 65 600 patients were included in the analysis. Compared to placebo, SGLT2i may increase the risk of DKA and volume depletion in patients with CKD with or without type 2 diabetes. For DKA, compared with placebo, the combined effect of SGLT2i was OR 2.03 (95% CI: 1.28 to 3.23 I 2 : 2.3%, P: 0.420). For volume depletion, compared with placebo, the combined effect of SGLT2i was OR 1.24 (95% CI: 1.13 to 1.37 I 2 : 0.0%, P: 0.484). For the risk of amputation, despite low heterogeneity for amputation, the forest plot indicated no statistical significance, and thus it cannot be concluded that SGLT2i increases the risk of amputation. Compared with placebo, the combined effect of SGLT2i was OR 1.10 (95% CI: 0.94 to 1.29 I 2 : 0.0%, P: 0.642)., Conclusion: The use of SGLT2i may increase the risk of DKA and volume depletion in patients with chronic renal insufficiency with or without type 2 diabetes.

Aim: To estimate risks of diabetic ketoacidosis (DKA), acute liver injury (ALI), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infection (UTI) and genital infection (GI) among patients with type 2 diabetes initiating empagliflozin versus those initiating a dipeptidyl peptidase-4 (DPP-4) inhibitor., Materials and Methods: In this large multinational, observational, new-user cohort study in UK, Danish and US healthcare data sources, patients initiated empagliflozin or a DPP-4 inhibitor between August 2014 and August 2019, were aged ≥18 years, and had ≥12 months' continuous health plan enrolment. Incidence rates by exposure and incidence rate ratios, adjusted for propensity-score deciles, were calculated., Results: In total, 64 599 empagliflozin initiators and 203 315 DPP-4 inhibitor initiators were included. There was an increased risk [pooled adjusted incidence rate ratios (95% confidence interval)] of DKA [2.19 (1.74-2.76)] and decreased risks of ALI [0.77 (0.50-1.19) in patients without predisposing conditions of liver disease; 0.70 (0.56-0.88) in all patients] and AKI [0.54 (0.41-0.73)]. In the UK data, there was an increased risk of GI [males: 4.04 (3.46-4.71); females: 3.24 (2.81-3.74)] and decreased risks of CKD [0.53 (0.43-0.65)] and severe complications of UTI [0.51 (0.37-0.72)]. The results were generally consistent in subgroup and sensitivity analyses., Conclusions: Compared with DDP-4 inhibitor use, empagliflozin use was associated with increased risks of DKA and GI and decreased risks of ALI, AKI, CKD and severe complications of UTI. These associations are consistent with previous studies and known class effects of sodium-glucose cotransporter 2 inhibitors, including renoprotective effects and beneficial effects on alanine aminotransferase levels., (© 2024 Research Triangle Institute d/b/a RTI Health Solutions. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

SGLT2i can induce euglycemic diabetic ketoacidosis (eDKA) in conditions with relative insulin deficiency, such as infections, surgery, or fasting state. In comparison with classical DKA, eDKA typically presents with lower blood glucose levels and more diffuse symptoms like tiredness, tachypnea, nausea and abdominal pain. The diagnosis is commonly delayed, and signs are often attributed to other factors. Early diagnosis and prevention are critical due to the risk of lethal outcome or prolonged hospital stay. Generous screening for ketonemia in risk situations allows identification of eDKA. To minimize the risk, we propose that SGLT2i should be discontinued 3-4 days before surgery (1-2 weeks prior to bariatric surgery) and during infections, acute disease, or poor oral intake. Postoperative slow infusion of low-dose insulin may prevent eDKA if SGLT2i could not be stopped in time or in prolonged fasting state. In this overview, the pathogenesis behind eDKA is discussed.

Rationale: Prader-Willi syndrome (PWS) is a genetic disorder affecting multiple systems. Approximately one-quarter of PWS patients will develop diabetes. Given the uncontrolled hyperphagia and resultant severe obesity in these patients, their glycemic management poses a significant challenge., Case Report: We present the clinical profile of a male patient diagnosed with both PWS and diabetes. Previous administration of the sodium-glucose co-transporter 2 (SGLT-2) inhibitor Canagliflozin resulted in improved glycemic control and weight management. But at the age of 25, the patient was hospitalized due to worsened glycemic control and the detection of ketonuria. After thorough examination and clinical observation, we discovered that the patient ketonuria was associated with enhanced lipid metabolism related to Canagliflozin. After excluding the risk of SGLT-2 inhibitor-induced euglycemic diabetic ketoacidosis, adjustments of the hypoglycemic regimen, building upon prior treatment, were recommended for the patient., Conclusion: It is important to note that among patients with both PWS and diabetes, the utilization of SGLT-2 inhibitors can lead to the emergence of ketonuria due to increased lipolysis. Therefore, any decision to discontinue SGLT-2 inhibitors should undergo thorough evaluation., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: As a newly approved immune checkpoint inhibitor in China, serplulimab has been widely used in the immunotherapy of tumors. However, the immune-related adverse events of immune checkpoint inhibitors should not be ignored. Although immune checkpoint inhibitor-induced type 1 diabetes mellitus is a rare complication, it may cause diabetic ketoacidosis and endanger the lives of patients., Case Presentation: This case report describes a 55-year-old male of Han nationality from China diagnosed with small-cell lung cancer with multiple metastases who experienced an adverse event of type 1 diabetes mellitus 68 weeks after receiving serplulimab therapy. The patient presented with typical symptoms of diabetic ketoacidosis, including severe thirst, nausea, vomiting, deep respirations, and stupor. Despite the absence of diabetes-related autoantibodies, the patient had extremely low levels of insulin and C-peptide release. Other potential causes of diabetes were ruled out, confirming the condition as serplulimab-induced immune checkpoint inhibitor-induced type 1 diabetes mellitus. After aggressive treatment to correct diabetic ketoacidosis, the patient's blood glucose levels stabilized and symptoms of diabetes improved significantly, although long-term insulin maintenance therapy was necessary., Conclusion: This case highlights a rare, late-onset adverse event of immune checkpoint inhibitor-induced type 1 diabetes mellitus that may be overlooked during treatment with serplulimab. The monitoring of blood glucose levels and early signs and symptoms of diabetes cannot be relaxed at the late stage of treatment, even if patients do not have elevated blood glucose levels before and during the middle stage of treatment., (© 2023. The Author(s).)

Objective: Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in older or frail individuals remains unclear., Methods: We searched PubMed, Scopus, Web of Science, Cochrane CENTRA and Google Scholar and selected randomised controlled trials and observational studies comparing SGLT2Is versus placebo/other glucose-lowering agent for people with frailty or older individuals (>65 years) with T2D and heart failure (HF). Extracted data on the change in HbA1c % and safety outcomes were pooled in a random-effects meta-analysis model., Results: We included data from 20 studies (22 reports; N = 77,083 patients). SGLT2Is did not significantly reduce HbA1c level (mean difference -0.13, 95%CI: -0.41 to 0.14). SGLT2Is were associated with a significant reduction in the risk of all-cause mortality (risk ratio (RR) 0.81, 95%CI: -0.69 to 0.95), cardiac death (RR 0.80, 95%CI: -0.94 to 0.69) and hospitalisation for heart failure (HHF) (RR 0.69, 95%CI: 0.59-0.81). However, SGLT2Is did not demonstrate significant effect in reducing in the risk of macrovascular events (acute coronary syndrome or cerebral vascular occlusion), renal progression/composite renal endpoint, acute kidney injury, worsening HF, atrial fibrillation or diabetic ketoacidosis., Conclusions: In older or frail patients with T2D and HF, SGLT2Is are consistently linked with a decrease in total mortality and the overall burden of cardiovascular (CV) events, including HHF events and cardiac death, but not protective for macrovascular death or renal events. Adverse events were more difficult to quantify but the risk of diabetic ketoacidosis or acute kidney injury was not significantly increase., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Objective: Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) remain significant risks with intensive insulin therapy. While these adverse event (AE) rates are generally very low in advanced hybrid closed-loop (AHCL) clinical studies, prospectively collected real-world AE rates are lacking. Research Design and Methods: The Control-IQ Observational (CLIO) study was a single-arm, prospective, longitudinal, postmarket surveillance study of individuals with type 1 diabetes (T1D) age 6 years and older who began the use of t:slim X2 insulin pump with Control-IQ technology in the real-world outpatient setting. AEs were reported monthly over 12 months and were compared to historical data from the T1D Exchange. Patient-reported outcomes were assessed quarterly. All study visits were virtual. Results: Three thousand one hundred fifty-seven participants enrolled from August 2020 through March 2022. Two thousand nine hundred ninety-eight participants completed through 12 months. SH rates were significantly lower than historic rates for children (9.31 vs. 19.31 events/100 patient years, d  = 0.29, P  < 0.01) and adults (9.77 vs. 29.49 events/100 patient years, d  = 0.53, P  < 0.01). DKA rates were also significantly lower in both groups. Lower observed rates of AEs occurred independent of baseline hemoglobin A1c or prior insulin delivery method. Time in range 70-180 mg/dL was 70.1% (61.0-78.8) for adults, 61.2% (52.4-70.5) for age 6-13, 60.9% (50.1-71.8) for age 14-17, and 67.3% (57.4-76.9) overall. Reduction in diabetes burden was consistently reported. Conclusions: SH and DKA rates were lower for users of t:slim X2 with Control-IQ technology compared to historical data for both adults and children. Real-world use of this AHCL system proved safe and effective in this virtual study design. The study was registered at clinicaltrials.gov (NCT04503174).

Sirolimus (mammalian target of rapamycin inhibitor) is a potent immunosuppressive agent, used in patients receiving hematopoietic stem cell transplant (HSCT) for Graft vs Host disease prophylaxis. Compared to calcineurin inhibitors, sirolimus has no neurotoxicity or nephrotoxicity, but sirolimus causes dose-dependent thrombocytopenia, leukopenia, delayed wound healing, hyperlipidemia, and hypertriglyceridemia. Here we report a case of acute pancreatitis and diabetic ketoacidosis in a patient with sickle cell disease post haploidentical family donor HSCT which was managed conservatively without plasmapheresis. Based on our review of the literature, this is the first reported case of developing acute pancreatitis as an adverse effect of sirolimus-induced hypertriglyceridemia leading to diabetic ketoacidosis in a recipient of HSCT., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are increasingly used in cancer treatments. As experience in the use of immunotherapy increases, more is known about its safety profile and immune-mediated adverse effects. Among them is diabetic ketoacidosis (DKA), a rare but serious fatal complication of treatment. In this paper we describe the cases of three patients who presented with episodes of DKA during treatment with ICIs, two of which manifested with fulminant forms, leading to an acute course with initially normal glycosylated hemoglobin values. In addition, we conducted a review of the literature on DKA associated with ICIs in order to highlight the importance of noticing these potentially fatal complications and promptly establishing appropriate therapy.

Ketoacidosis is a serious complication of diabetes that only occurs in cases of absolute or severe relative insulin deficiency. This condition is rare in type 2 diabetes. The use of gliflozin during intense physiological stress associated with fasting can lead to the development of ketoacidosis without severe hyperglycaemia. The diagnosis of this normoglycaemic or euglycaemic diabetic ketoacidosis in the context of type 2 diabetes may be challenging. The treatment of metabolic acidosis cannot rely solely on symptomatic measures such as bicarbonate infusion. The demonstration of metabolic acidosis necessitates the search for an etiological diagnosis. The calculation of the anion gap is the cornerstone of the pathophysiological diagnosis of metabolic acidosis. In the context of diabetes, the occurrence of metabolic acidosis of unknown etiology requires its calculation and systematic measurement of ketones, even in the absence of severe hyperglycaemia. Only the etiological treatment of diabetic ketoacidosis, which is insulin therapy, allows for the lasting restoration of acid-base balance. Normoglycaemic ketoacidosis induced by the use of gliflozin during intense physiological stress associated with fasting should therefore be a recognized situation by healthcare providers.

Purpose: Teprotumumab for thyroid eye disease has a known hyperglycemic adverse effect through its impact on the insulin-like growth factor-1 receptor. While most cases are mild and easily managed by adjusting diabetes medications, it appears some patients have a more dramatic response. The purpose of this case report is to highlight an example of rapidly declining glycemic control and diabetic ketoacidosis (DKA) in a patient with newly diagnosed diabetes after starting teprotumumab for thyroid eye disease., Methods: This was a single-patient case report assessing a severe episode of hyperglycemia leading to new-onset diabetes. The case report was approved by Atrium Health Wake Forest Baptist's IRB committee. The patient was closely monitored by a pharmacist-led pharmacotherapy clinic after initial diagnosis and periodically since then to adjust therapy and assess glucose and hemoglobin A1c (HbA1c) trends., Results: After the acute episode of DKA was managed inpatient, the patient was discharged with insulin outpatient, but this was ultimately weaned off, and the patient's glucose and HbA1c are stable on metformin alone. This patient decided to not continue teprotumumab due to extensive side effects including but not limited to severe hyperglycemia., Conclusion: While additional research is needed as to the cause of severe hyperglycemia in select patients, providers should consider proactively monitoring glucose throughout treatment with teprotumumab by ensuring that patients have baseline labs and labs at every visit and access to a glucometer with education for its use., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Ketoacidosis induced by sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment has been consistently observed in clinical practice in patients with type 2 diabetes despite minimal indication from the landmark cardiovascular outcome trials. It has been postulated that individuals without diabetes will not develop this complication due to an adequate insulin secretory capacity, which will protect against significant ketone formation. Cardiovascular outcome trials examining SGLT2i use in individuals with heart failure but not diabetes have not reported ketoacidosis., Research Design and Methods: We describe the first two case reports of severe nondiabetic ketoacidosis after initiation of an SGLT2i for the treatment of heart failure with reduced ejection fraction, and we describe the management strategies employed and implication for the pathophysiology of SGLT2i-associated ketoacidosis., Results: Each individual presented with ketoacidosis triggered by reduced oral nutrition intake. For both individuals, ketoacidosis resolved with intravenous glucose administration, encouragement of consumption of oral glucose-containing fluid, and minimal insulin administration., Conclusions: These two cases demonstrate that SGLT2i-associated ketoacidosis is possible in individuals without diabetes., (© 2023 by the American Diabetes Association.)

Purpose: Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition., Methods: We conducted a single-center retrospective review of adults initiating the PI3K inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes., Results: We identified 103 patients meeting eligibility criteria with median follow-up of 92 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -46 mg/dL (95% CI - 77 to - 15) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 48 DKA cases per 100 patient-years (95% CI 6, 171); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 15 (95% CI 2, 53); alpelisib only, 4 (95% CI 0.1, 22)., Conclusions: SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: 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., Objective: This review evaluated observational studies to inform the prevalence of SGLT2-inhibitor-associated DKA compared with other antihyperglycemic agents., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Disclosure The authors declare no conflict of interest., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Sodium-glucose cotransoporter-2 inhibitors (SGLT-2Is) improve prognosis in heart failure (HF) patients both with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, these drugs can have some side effects. To estimate the relative risk of side effects in HF patients treated with SGLT-2Is irrespective from left ventricular EF and setting (chronic and non-chronic HF). Five randomized controlled trials (RCTs) enrolling patients with HFrEF, 4 RCTs enrolling non-chronic HF, and 3 RCTs enrolling HFpEF were included. Among side effects, urinary infection, genital infection, acute kidney injury, diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations were considered in the analysis. Overall, 24,055 patients were included in the analysis: 9020 (38%) patients with HFrEF, 12,562 (52%) with HFpEF, and 2473 (10%) with non-chronic HF. There were no differences between SGLT-2Is and placebo in the risk to develop diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations. HFrEF patients treated with SGLT-2Is had a significant reduction of acute kidney injury (RR = 0.54 (95% CI 0.33-0.87), p = 0.011), whereas no differences have been reported in the HFpEF group (RR = 0.94 (95% CI 0.83-1.07), p = 0.348) and non-chronic HF setting (RR = 0.79 (95% CI 0.55-1.15), p = 0.214). A higher risk to develop genital infection (overall 2.57 (95% CI 1.82-3.63), p < 0.001) was found among patients treated with SGLT-2Is irrespective from EF (HFrEF: RR = 1.96 (95% CI 1.17-3.29), p = 0.011; HFpEF: RR = 3.04 (95% CI 1.88-4.90), p < 0.001). The risk to develop urinary infections was increased among SGLT-2I users in the overall population (RR = 1.13 (95% CI 1.00-1.28), p = 0.046) and in the HFpEF setting (RR = 1.19 (95% CI 1.02-1.38), p = 0.029), whereas no differences have been reported in HFrEF (RR = 1.05 (95% CI 0.81-1.36), p = 0.725) and in non-chronic HF setting (RR = 1.04 (95% CI 0.75-1.46), p = 0.806). SGLT-2Is increase the risk of urinary and genital infections in HF patients. In HFpEF patients, the treatment increases the risk of urinary infections compared to placebo, whereas SGLT-2Is reduce the risk of acute kidney disease in patients with HFrEF., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is limited evidence on the safety of sodium-glucose co-transporter-2 inhibitor (SGLT2i) use in the real world of China. We conducted this two-center, retrospective study to assess the incidence rate and risk factors of Dapagliflozin-associated DK/DKA among patients with type 2 diabetes mellitus (T2DM) in China., Research Design and Methods: Patients with T2DM treated with Dapagliflozin in Shanghai General Hospital were included in this retrospective analysis. Univariate and multivariate logistic regression was performed, and odds ratio (OR) and 95% confidence interval (CI) were calculated to identify the influencing factors associated with the occurrence of DK/DKA., Results: A total of 1985 T2DM patients received Dapagliflozin for the first time were included. The prevalence of DK and DKA was 2.47% and 0.35%, respectively. Multivariate logistic regression identified age <45 years [OR = 2.99, 95% CI (1.45-6.17)], concomitant use of Acarbose [OR = 2.18, 95% CI (1.06-3.38)], Metformin [OR = 1.84, 95% CI (1.01-3.38)], and Insulin [OR = 1.93, 95% CI (1.02-3.66)] as participating factors for DK/DKA. The 1:4 matched subset sensitivity analysis further confirmed the risk factors of Dapagliflozin-associated DK/DKA., Conclusions: Age less than 45 years, concomitant use of Acarbose and insulin were risk factors for Dapagliflozin-associated DK/DKA. Clinicians should watch out for high-risk features among patients with SGLT2i prescription.

Competing Interests: Competing interests: None declared.

Rationale: The increasing use of immune checkpoint inhibitors (ICIs) for treating malignant tumors result in the concomitant rise of immune-related adverse events (irAEs). This case report may provide useful insight to understanding the etiology of ICI-induced hypophysitis, a severe irAE leading to potentially fatal secondary adrenal insufficiency., Patient Concerns: An 81-year-old Japanese man was hospitalized for diabetic ketoacidosis following 4 courses of ICI combination therapy with nivolumab and ipilimumab for metastatic renal cell carcinoma., Diagnosis: Insulin secretion was depleted, leading to diagnosis of fulminant type 1 diabetes. Adrenocorticotropic hormone (ACTH) and cortisol levels were very high (60.8 pmol/L and 1575 nmol/L, respectively) upon admission. ACTH and cortisol returned to normal ranges on the 2nd day. On the 8th day, an ACTH loading test showed intact cortisol response (peak value 519 nmol/L). However, on the 14th day, there was a sharp decrease in ACTH and cortisol levels (10.5 pmol/L and 47 nmol/L, respectively) accompanied by fatigue and a drop in blood pressure to 97/63 mm Hg. As secondary adrenal insufficiency was suspected, hydrocortisone replacement was initiated. An ACTH loading test on the 17th day revealed low cortisol peak (peak value 232 nmol/L), indicating sudden disruption of adrenal function. Magnetic resonance imaging showed no abnormal findings and there was no other pituitary hormone deficiency. These findings, along with the patient clinical course, suggest that secondary adrenal insufficiency was caused by acute ACTH producing cell destruction as an irAE associated with ICI therapy., Interventions: The patient hyperglycemia and ketoacidosis were treated using extracellular fluid and insulin therapy. After development of adrenal insufficiency, hydrocortisone 20 mg was started, and the patient symptoms improved., Outcomes: He was continued on insulin therapy, hydrocortisone, and reinitiated nivolumab., Lessons: This case provides a detailed course of the fulminant onset of ACTH deficiency during ICI administration, emphasizing the importance of close monitoring., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with diabetic kidney disease (DKD) is still controversial. This study aimed to analyze the safety of SGLT2 inhibitors in elderly patients with type 2 diabetes mellitus (T2DM) and DKD. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to March 2023. Randomized controlled trials (RCTs) were included. Data including patient characteristics and interesting outcomes were extracted, and the dichotomous data and continuous variables were evaluated using risk ratio (RR) with 95% confidence intervals (CIs) and mean difference (MD) with 95% CIs, respectively. A total of 14 RCTs with 59874 participants were finally included. There were 38,252 males (63.9%) and 21,622 females (36.1%). The patients' mean age was > 64.6 years. SGLT2 inhibitors could delay the further decline of estimated glomerular filtration rate (eGFR) when eGFR ≥ 60 ml/min/1.73m 2 (MD: 2.36; 95%CI [1.15-3.57]). SGLT2 inhibitors in elderly patients with eGFR < 60 ml/min/1.73m 2 (RR: 0.86; 95%CI [0.67-1.11]) may have a relatively increased risk of acute kidney injury compared to eGFR ≥ 60 ml/min/1.73m 2 . SGLT2 inhibitors increased the incidence of genital mycotic infections (RR: 3.47; 95%CI [2.97-4.04]) and diabetic ketoacidosis (RR: 2.25; 95%CI [1.57-3.24]). Except for genital mycotic infections and diabetic ketoacidosis, other adverse reactions were few, indicating that SGLT2 inhibitors are relatively safe for elderly patients with T2DM and DKD. Safety and renoprotection may be diminished when SGLT2 inhibitors are used in elderly patients with eGFR < 60 ml/min/1.73m 2 .

Objective: Diabetic ketoacidosis (DKA) is a serious life-threatening condition and can be associated with antipsychotic medication. Asian patients with diabetes exhibit less insulin resistance than Caucasians; however, all previous studies concerning antipsychotic-related DKA have been conducted in Western populations. We analyzed the rank order of the association of antipsychotic agents for schizophrenia with DKA using the Japanese Adverse Drug Event Report database, a spontaneous reporting system database., Methods: We performed a retrospective pharmacovigilance disproportionality analysis using adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and March 2021. The study population comprised 7435 patients with schizophrenia, and the total number of antipsychotic-related DKA reports was 55., Results: Among the 55 cases of DKA in patients with schizophrenia, 6% (3/55) patients died after DKA. The signals of DKA were reported after treatment with olanzapine, with a significant adjusted reporting odds ratio (95% CI) of 3.26 (1.87-5.66). In 1399 olanzapine treatment cases, multivariable logistic regression analysis using a forward selection method showed that being male (adjusted RORs 2.72 (1.07-6.90)) was associated with the onset of DKA., Conclusion: Our study revealed that treatment with olanzapine was associated with the development of DKA among patients with schizophrenia. The results also clarified that male patients were at higher risk for DKA among patients treated with olanzapine. The application of these data will aid in risk monitoring and management that may reduce the occurrence of antipsychotic-related DKA in treatment for schizophrenia., Competing Interests: Declaration of Competing Interest Kazutaka Shimoda has received research support from Novartis Pharma, Dainippon Sumitomo Pharma, Astellas Pharma, Meiji Seika Pharma, Eisai, Pfizer, Otsuka Pharmaceutical, Daiichi Sankyo, and Takeda Pharmaceutical and honoraria from Eisai, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Meiji Seika Pharma, Janssen Pharmaceutical, Shionogi, Dainippon Sumitomo Pharma, Daiichi Sankyo, and Pfizer. The other authors report no conflicts of interest related to this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Patients undergoing insulin-based therapy for type 1 diabetes often experience poor glycemic control characterized by significant fluctuations. This study was undertaken to analyze the effect of sodium-glucose cotransporter 2 inhibitors (SGLT2Is), as an adjunct to insulin, on time in range (TIR) and glycemic variability in patients with type 1 diabetes, using continuous glucose monitoring (CGM). In addition, we examined which type of SGLT2I yielded a superior effect compared to others., Methods: We conducted a comprehensive search of PubMed, EMBASE, the Cochrane Library, Web of Science, and clinical trial registry websites, retrieving all eligible randomized clinical trials (RCTs) published up until February 2023. We analyzed the mean TIR, mean amplitude of glucose excursions (MAGE), mean daily glucose (MDG), diabetic ketoacidosis (DKA), standard deviation (SD), total insulin dose, and severe hypoglycemia to evaluate the efficacy and safety of SGLT2Is. A random-effects model was also employed., Results: This study encompassed 15 RCTs. The meta-analysis revealed that the use of SGLT2Is as an adjuvant therapy to insulin led to a significant increase in TIR (MD = 10.78, 95%CI = 9.33-12.23, I 2  = 42 %, P < 0.00001) and a decrease in SD (MD = -0.38, 95%CI = -0.50 to -0.26, I 2  = 0 %, P < 0.00001), MAGE (MD = -0.92, 95%CI = -1.17 to -0.67, I 2  = 19 %, P < 0.00001), MDG(MD = -1.01, 95%CI = -1.32 to -0.70, I 2  = 48 %, P < 0.00001), and total insulin dose (MD = -5.81, 95%CI = -7.81 to -3.82, I 2  = 32 %, P < 0.00001). No significant increase was observed in the rate of severe hypoglycemia (RR = 1.04, 95 % CI = 0.76-1.43, P = 0.80). However, SGLT2I therapy was associated with increased DKA occurrence (RR = 2.79, 95 % CI = 1.42-5.48; P = 0.003, I 2  = 16 %). In addition, the subgroup analyses based on the type of SGLT2Is revealed that dapagliflozin might exhibit greater efficacy compared to other SGLT2Is across most outcomes., Conclusions: SGLT2Is exhibited a positive effect on improving blood glucose level fluctuations. Subgroup analysis showed that dapagliflozin appeared to have more advantages. However, giving due consideration to preventing adverse effects, particularly DKA, is paramount., Registration: Prospero CRD42023408276., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Aim: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are particularly effective in preventing adverse outcomes of heart failure and chronic kidney disease, which are highly prevalent in the elderly. Here, we aimed to access the safety of SGLT2i in elderly patients with type 2 diabetes., Materials and Methods: We performed a meta-analysis of randomized controlled trials (RCTs) reporting safety outcomes of the elderly (≥65 years) patients with type 2 diabetes, randomized to an SGLT2i or placebo. We recorded the incidence of acute kidney injury, volume depletion, genital tract infections, urinary tract infections, bone fractures, amputations, diabetic ketoacidosis, hypoglycaemia and drug discontinuation, by group of treatment., Results: Of the 130 RCTs screened, only six reported data on elderly patients. In total, 19 986 patients were included. The SGLT2i discontinuation rate was approximately 20%. The risk of acute kidney injury was significantly lower among SGLT2i users compared with placebo [risk ratio (RR) 0.73; 95% CI 0.62-0.87]. SGLT2i were associated with a six-fold increased risk of genital tract infections (RR 6.55; 95% CI 2.09-20.5). The rate of amputations was increased only among canagliflozin users (RR 1.94, 95% CI 1.25-3). The risk of fractures, urinary tract infection, volume depletion, hypoglycaemia and diabetic ketoacidosis was similar between SGLT2i and placebo., Conclusions: SGLT2is were well tolerated in the elderly. However, older patients are underrepresented in most RCTs and a call for action is need to favour clinical trials reporting safety outcomes stratified by age., (© 2023 John Wiley & Sons Ltd.)

Background: In youth with type 1 diabetes (T1D), high haemoglobin A1c (HbA1c) levels are associated with an increased risk for diabetic ketoacidosis (DKA)., Aims: This study examined whether daily school-supervised basal insulin injections were feasible and if they reduced the risk of morning ketosis in children and adolescents with high HbA1c levels. We hypothesized that supervised glargine and degludec would reduce the risk of ketosis and that the prolonged action of degludec would protect from ketosis after consecutive days of unsupervised injections., Materials & Methods: After a 2-4-week run-in, youth (10-18 years, HbA1c ≥ 8.5%) managing T1D with injections were randomized to school-supervised administration of degludec or glargine for 4 months. School nurses observed daily blood β-hydroxybutyrate (BHB) and glucose checks. During COVID closures, the research team supervised procedures remotely., Results: Data from 28 youth (age 14.3 ± 2.3 years, HbA1c 11.4 ± 1.9%, 64% F) were analysed. School-supervised injections of both basal insulins for 1-4 days progressively lowered the percent of participants with elevated BHB. The percent of participants with elevated BHB (≥0.6 mmol/L) after 2 days of unsupervised basal insulin doses at home was greater in the glargine than degludec group but had a high p-value (17.2% vs. 9.0%, p = 0.3). HbA1c was unchanged in both groups., Discussion: In youth with T1D at high risk for DKA, daily supervised long-acting insulin administration decreased the probability of elevated ketone levels on subsequent school days, regardless of basal insulin type. A larger sample size may have demonstrated that the longer action profile of degludec would offer additional protection from ketosis during days of not attending school., Conclusion: Engaging school-based caregivers in management of youth with T1D on injected insulin may decrease clinically significant ketosis and minimize acute complications of diabetes., (© 2023 Diabetes UK.)