Thiamine as adjunctive therapy for diabetic ketoacidosis (DKAT) trial protocol and statistical analysis plan: a prospective, single-centre, double-blind, randomised, placebo-controlled clinical trial in the USA.

INTRODUCTION: Diabetic ketoacidosis (DKA) is a potentially life-threatening diabetic complication. Despite the high prevalence of DKA and the substantial associated healthcare burden, limited research on strategies to improve outcomes currently exists.Thiamine (vitamin B1) is a cofactor of pyruvate dehydrogenase, which plays a key role in aerobic glucose metabolism. Thiamine deficiency is common in patients with DKA, resulting in a shift to anaerobic metabolism and hyperlactatemia, which can prolong and complicate recovery. Therefore, we hypothesise that thiamine administration will improve aerobic metabolism and lead to faster resolution of acidemia in patients with DKA. METHODS AND ANALYSIS: In this single centre, double-blind, randomised, placebo-controlled, parallel group interventional trial, 100 patients admitted to the hospital with DKA will be randomised to receive either intravenous thiamine (200 mg in 50 mL 0.9% saline) or placebo (0.9% saline identical in appearance and volume) two times per day for 2 days. The primary outcome will be the change in bicarbonate level over 24 hours as compared between the two treatment groups. Additional secondary outcomes include the change over time in anion gap, lactate levels, oxygen consumption by circulating mononuclear cells, intensive care unit and hospital length-of-stay and hospital resource usage when comparing the two study arms. ETHICS AND DISSEMINATION: This trial was approved by the Committee on Clinical Investigations, the institutional review board of Beth Israel Deaconess Medical Center (protocol number 2018P000475). Findings will be disseminated through peer-reviewed publications and professional conference presentations. TRIAL REGISTRATION NUMBER: NCT03717896; clinicaltrials.gov.

Acute Diabetes Complications After Transition to a Value-Based Medication Benefit.

Importance: The association of value-based medication benefits with diabetes health outcomes is uncertain. Objective: To assess the association of a preventive drug list (PDL) value-based medication benefit with acute, preventable diabetes complications. Design, Setting, and Participants: This cohort study used a controlled interrupted time series design and analyzed data from a large, national, commercial health plan from January 1, 2004, through June 30, 2017, for patients with diabetes aged 12 to 64 years enrolled through employers that adopted PDLs (intervention group) and matched and weighted members with diabetes whose employers did not adopt PDLs (control group). All participants were continuously enrolled and analyzed for 1 year before and after the index date. Subgroup analysis assessed patients with diabetes living in lower-income and higher-income neighborhoods. Data analysis was performed between August 19, 2020, and December 1, 2023. Exposure: At the index date, intervention group members experienced employer-mandated enrollment in a PDL benefit that was added to their follow-up year health plan. This benefit reduced out-of-pocket costs for common cardiometabolic drugs, including noninsulin antidiabetic agents and insulin. Matched control group members continued to have cardiometabolic medications subject to deductibles or co-payments at follow-up. Main Outcomes and Measures: The primary outcome was acute, preventable diabetes complications (eg, bacterial infections, neurovascular events, acute coronary disease, and diabetic ketoacidosis) measured as complication days per 1000 members per year. Intermediate measures included the proportion of days covered by and higher use (mean of 1 or more 30-day fills per month) of antidiabetic agents. Results: The study 10 588 patients in the intervention group (55.2% male; mean [SD] age, 51.1 [10.1] years) and 690 075 patients in the control group (55.2% male; mean [SD] age, 51.1 [10.1] years) after matching and weighting. From baseline to follow-up, the proportion of days covered by noninsulin antidiabetic agents increased by 4.7% (95% CI, 3.2%-6.2%) in the PDL group and by 7.3% (95% CI, 5.1%-9.5%) among PDL members from lower-income areas compared with controls. Higher use of noninsulin antidiabetic agents increased by 11.3% (95% CI, 8.2%-14.5%) in the PDL group and by 15.2% (95% CI, 10.6%-19.8%) among members of the PDL group from lower-income areas compared with controls. The PDL group experienced an 8.4% relative reduction in complication days (95% CI, -13.9% to -2.8%; absolute reduction, -20.2 [95% CI, -34.3 to -6.2] per 1000 members per year) compared with controls from baseline to follow-up, while PDL members residing in lower-income areas had a 10.2% relative reduction (95% CI, -17.4% to -3.0%; absolute, -26.1 [95% CI, -45.8 to -6.5] per 1000 members per year). Conclusions and Relevance: In this cohort study, acute, preventable diabetes complication days decreased by 8.4% in the overall PDL group and by 10.2% among PDL members from lower-income areas compared with the control group. The results may support a strategy of incentivizing adoption of targeted cost-sharing reductions among commercially insured patients with diabetes and lower income to enhance health outcomes.

Outcomes associated with a variable rate insulin infusion diabetic ketoacidosis protocol.

AIMS: To relate adverse events with glucose correction rates in diabetic ketoacidosis (DKA) using variable rate intravenous insulin-infusions (VRIII). METHODS: Retrospective, observational study in adults with DKA who received insulin infusions between 2012 and 2017 at St Vincent's Hospital, Melbourne. Early correction of hyperglycaemia (<10 mmol/L) was evaluated for association with hypoglycaemia (<4.0 mmol/L), hypokalaemia (potassium <3.3 mmol/L) and clinical outcomes via regression analysis. RESULTS: The study involved 97 patients, with 93 % having type 1 diabetes. The mean age was 38 years, 47 % were women and 35 % were admitted to intensive care. Hypoglycaemia rates during 12 and 24 h of treatment were 6.2 % and 8.2 %, respectively with 58 % of patients recording their first BGL <10 mmol/L within 12 h and 88 % within 24 h. Ketone clearance time averaged at 15.6 h. Hyperglycaemia correction rates to <10 mmol/L were not different in those with/without hypoglycaemia at 12/24 h, in multivariate analysis including admission BGL. Hypokalaemia occurred in 40.2 % of patients and was associated with lower pH but not BGL correction rates. CONCLUSION: The VRIII protocol achieved early hyperglycaemia correction and ketoacidosis reversal with low hypoglycaemia risk. However, high hypokalaemia rates suggest the need for aggressive potassium replacement, especially in markedly acidotic patients.

Phenotype and predictors of insulin independence in adults presenting with diabetic ketoacidosis: a prospective cohort study.

AIMS/HYPOTHESIS: The aim of this work was to describe the phenotype of adults presenting with a first episode of diabetic ketoacidosis (DKA) in Cape Town, South Africa, and identify predictors of insulin independence at 12 and 60 months after presentation. METHODS: A prospective, descriptive cohort study of all individuals, 18 years or older, presenting for the first time with DKA to four public-sector hospitals of the Groote Schuur Academic Health Complex was performed. Clinical, biochemical and laboratory data including GAD antibody and C-peptide status were collected at baseline. Insulin was systematically weaned and stopped in individuals who achieved normoglycaemia within the months after DKA. Individuals were followed for 12 months and then annually until 5 years after initial presentation with ketoacidosis. RESULTS: Eighty-eight individuals newly diagnosed with diabetes when presenting with DKA were included and followed for 5 years. The mean ± SD age was 35±10 years and the median (IQR) BMI at diagnosis was 28.5 (23.3-33.4) kg/m2. Overall, 46% were insulin independent 12 months after diagnosis and 26% remained insulin independent 5 years after presentation. Forty-one participants (47%) tested negative for anti-GAD and anti-IA-2 antibodies and had C-peptide levels >0.3 nmol/l; in this group, 68% were insulin independent at 12 months and 37% at 5 years after diagnosis. The presence of acanthosis nigricans was strongly associated with insulin independence (OR 27.1 [95% CI 7.2, 102.2]; p<0.001); a positive antibody status was associated with a lower likelihood of insulin independence at 12 months (OR 0.10 [95% CI 0.03, 0.36]; p<0.001). On multivariable analysis only acanthosis (OR 11.5 [95% CI 2.5, 53.2]; p=0.004) was predictive of insulin independence 5 years after diagnosis. CONCLUSIONS/INTERPRETATION: The predominant phenotype of adults presenting with a first episode of DKA in Cape Town, South Africa, was that of ketosis-prone type 2 diabetes. These individuals presented with obesity, acanthosis nigricans, negative antibodies and normal C-peptide and could potentially be weaned off insulin at follow-up. Classic type 1 diabetes (lower weight, antibody positivity, low or unrecordable C-peptide levels and long-term insulin dependence) was less common. The simple clinical sign of acanthosis nigricans is a strong predictor of insulin independence at 12 months and 5 years after initial presentation.

Rates of diabetic ketoacidosis with empagliflozin use during hospitalization for acute heart failure.

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

Intravenous Insulin in Hypertriglyceridemic Pancreatitis.

Hypertriglyceridemia is a rare but significant cause of pancreatitis in children. Hypertriglyceridemic pancreatitis is often correlated with more severity and complications like pancreatic necrosis. Therefore, proper management and prevention of further episodes is essential. The authors report a case of a child with hypertriglyceridemic pancreatitis who was managed with intravenous insulin. According to various case reports and case series, intravenous insulin has been found to be effective in hypertriglyceridemic pancreatitis in adults. Few case reports in children also have mentioned use of intravenous insulin in diabetic ketoacidosis with hypertriglyceridemia. The authors found intravenous insulin to be highly effective in management of pancreatitis due to severe hypertriglyceridemia in the present child.

Comparison of insulin infusion protocols for management of canine and feline diabetic ketoacidosis.

OBJECTIVE: Describe the use of fixed-rate intravenous insulin infusions (FRIs) in cats and dogs with diabetic ketoacidosis (DKA) and determine if this is associated with faster resolution of ketosis compared to variable-rate intravenous insulin infusions (VRIs). Secondary objectives were to evaluate complication rates, length of hospitalization (LOH), and survival to discharge (STD). DESIGN: Randomized clinical trial (January 2019 to July 2020). SETTING: University veterinary teaching hospital and private referral hospital. ANIMALS: Dogs and cats with DKA and venous pH <7.3, blood glucose concentration >11 mmol/L (198 mg/dL), and ß-hydroxybutyrate (BHB) concentration >3 mmol/L were eligible for inclusion. Patients were randomly assigned to receive either FRI or VRI. INTERVENTIONS: Neutral (regular) insulin was administered IV as an FRI or VRI. For FRI, the rate was maintained at 0.01 IU/kg/h. For VRI, the dose was adjusted according to blood glucose concentration. MEASUREMENTS AND RESULTS: Sixteen cats and 20 dogs were enrolled. Population characteristics, mean insulin infusion rate, time to resolution of ketosis (BHB <0.6 mmol/L), complications, LOH, and STD were evaluated. In cats, overall resolution of ketosis was low (9/16 [56.3%]), limiting comparison of protocols. In dogs, resolution of ketosis was high (19/20 dogs [95.0%]) but the time to resolution in the FRI group was not different than that in the VRI group (P = 0.89), despite a 25% higher average insulin infusion rate in the FRI group (P = 0.04). The incidence of complications was low and did not differ between protocols. In cats, LOH and STD did not differ between protocols. All cats that died (5/16) did so within 78 hours and none had resolution of ketosis. Dogs receiving FRI had a shorter LOH (P = 0.01) but STD did not differ between protocols. Six dogs (30.0%) did not survive to hospital discharge but all had resolution of ketosis. CONCLUSIONS: FRIs can be used in veterinary species but may not hasten resolution of ketosis.

Clinically Approved Monoclonal Antibodies-based Immunotherapy: Association With Glycemic Control and Impact Role of Clinical Pharmacist for Cancer Patient Care.

PURPOSE: Compared with more conventional, nonspecific therapy options, such as radiotherapy and chemotherapy, monoclonal antibodies (mAbs) constitute a crucial approach of cancer treatment. Multiple autoimmune diseases have been observed during treatment with mAb medications, including autoimmune diabetes mellitus (DM). This study provides a narrative review of clinically approved mAbs in cancer treatment and focuses on the development of hyperglycemia and DM arising from using these therapies. Furthermore, it highlights the critical role of oncology clinical pharmacists in the management of autoimmune DM and patient care while using these medications in an oncology setting. METHODS: An extensive literature search was conducted using various sources of electronic databases, such as Scopus, Embase, Web of Science, and PubMed, and search engines, such as Google Scholar, for studies on mAb classification, types, mechanisms of action, pharmacokinetic properties, current clinical applications, and the associated common adverse effects with significant recommendations for patient care in an oncology setting, along with focusing on the proposed mechanisms and clinical studies that reported the association of DM after the use of these therapies. FINDINGS: There are 4 types (murine, chimeric, humanized, and human) and 3 classes (unconjugated, conjugated, and bispecific) of mAbs with several mechanisms of action that can destroy cancer cells, including preventing tumor cell survival cascades, inhibiting tumor growth by interfering with tumor angiogenesis, evading programmed cell death, and bypassing immune checkpoints. However, multiple endocrinopathies, autoimmune diseases, and complications were reported from the use of these medications, including the development of autoimmune DM and diabetic ketoacidosis. These autoimmune disorders were reported most with the use of immune checkpoint inhibitors, including inhibitors of the programmed cell death protein 1 (nivolumab and pembrolizumab), its ligand (atezolizumab, avelumab, and durvalumab), and cytotoxic T-lymphocyte-associated protein 4 (ipilimumab). IMPLICATIONS: mAbs are considered important approaches for the treatment of many cancer types. However, a high incidence of hyperglycemia, type 1 DM, and diabetic ketoacidosis is observed with the use of these medications, particularly immune checkpoint inhibitors. It is important for oncologic clinical pharmacists to be involved in addressing these autoimmune disorders from the use of these immunotherapies via the provision of patient education, medication adherence support, close monitoring, and follow-up, which will lead to better health-related outcomes and improved patient quality of life.

Perioperative Management of Patients Receiving Sodium-Glucose Cotransporter 2 Inhibitors: Development of a Clinical Guideline at a Large Academic Medical Center.

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.

Real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes in Spain: The Dapa-ON multicenter retrospective study.

OBJECTIVE: To assess real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes mellitus (T1DM). METHODS: We conducted a multicenter retrospective study in Spain including data from 250 people living with T1DM receiving dapagliflozin as add-on therapy to insulin (80.8 % on-label use). The number of diabetic ketoacidosis (DKA) events was calculated over a 12-month follow-up (primary outcome). Changes in body weight, HbA1c, total daily insulin dose, and continuous glucose monitoring (CGM) metrics from baseline (at dapagliflozin prescription) to 12 months were also evaluated. RESULTS: A total of five DKA events (2.4 % [95 % CI 0.3;4.5] were reported in patients with a 12-month follow-up, n = 207): two events related to insulin pump malfunction, two events related to concomitant illnesses, and one event related to insulin dose omission. DKA events were more frequent among insulin pump users than among participants on multiple daily injections (7.7 % versus 1.2 %). Four of the reported DKA events occurred within the first six months after initiation of dapagliflozin. No deaths or persistent sequelae due to DKA were reported. No severe hypoglycemia episodes were reported. Significant reductions in mean body weight (-3.3 kg), HbA1c (-0.6 %), and total daily insulin dose (-8.6 %), P < 0.001, were observed 12 months after dapagliflozin prescription. Significant improvements in TIR (+9.3 %), TAR (-7.2 %), TBR (-2.5 %), and coefficient of variation (-5.1 %), P < 0.001, were also observed in the subgroup of patients with available CGM data. Finally, an improvement in urinary albumin-to-creatinine ratio (UACR) was found among participants with UACR ≥ 30 mg/g at baseline (median decrease of 99 mg/g in UACR, P = 0.001). CONCLUSION: The use of dapagliflozin in people living with T1DM has an appropriate safety profile after careful selection of participants and implementation of strategies to reduce the risk of DKA (i.e., prescribed according to the recommendations of the European Medicines Agency), and also leads to clinical improvements in this population.

Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition.

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.

The effect of dehydration, hyperchloremia and volume of fluid resuscitation on acute kidney injury in children admitted to hospital with diabetic ketoacidosis.

BACKGROUND: Acute kidney injury (AKI) is a recognized comorbidity in pediatric diabetic ketoacidosis (DKA), although the exact etiology is unclear. The unique physiology of DKA makes dehydration assessments challenging, and these patients potentially receive excessive amounts of intravenous fluids (IVF). We hypothesized that dehydration is over-estimated in pediatric DKA, leading to over-administration of IVF and hyperchloremia that worsens AKI. METHODS: Retrospective cohort of all DKA inpatients at a tertiary pediatric hospital from 2014 to 2019. A total of 145 children were included; reasons for exclusion were pre-existing kidney disease or incomplete medical records. AKI was determined by change in creatinine during admission, and comparison to a calculated baseline value. Linear regression multivariable analysis was used to identify factors associated with AKI. True dehydration was calculated from patients' change in weight, as previously validated. Fluid over-resuscitation was defined as total fluids given above the true dehydration. RESULTS: A total of 19% of patients met KDIGO serum creatinine criteria for AKI on admission. Only 2% had AKI on hospital discharge. True dehydration and high serum urea levels were associated with high serum creatinine levels on admission (p = 0.042; p < 0.001, respectively). Fluid over-resuscitation and hyperchloremia were associated with delayed kidney recovery (p < 0.001). Severity of initial AKI was associated with cerebral edema (p = 0.018). CONCLUSIONS: Dehydration was associated with initial AKI in children with DKA. Persistent AKI and delay to recovery was associated with hyperchloremia and over-resuscitation with IVF, potentially modifiable clinical variables for earlier AKI recovery and reduction in long-term morbidity. This highlights the need to re-address fluid protocols in pediatric DKA.

A case of rapidly declining glycemic control and diabetic ketoacidosis in a newly diagnosed diabetes patient after starting teprotumumab for thyroid eye disease.

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.

Balanced crystalloids (RInger's lactate) versus normal Saline in adults with diabetic Ketoacidosis in the Emergency Department (BRISK-ED): a pilot randomised controlled trial.

BACKGROUND: Current diabetic ketoacidosis (DKA) treatment guidelines recommend using normal saline (NS); however, NS may delay DKA resolution by causing more hyperchloremic metabolic acidosis compared with balanced crystalloids. This study's objective was to determine the feasibility of a future multicentred randomised controlled trial (RCT) comparing intravenous Ringer's lactate (RL) with NS in managing ED patients with DKA. METHODS: We conducted a parallel-arm, triple-blind, pilot RCT of adults (≥18 years) with DKA at a Canadian academic tertiary care ED. The primary feasibility outcome was recruitment rate (target ≥41.3% of eligible participants over the 1-year study period); the primary efficacy outcome was time elapsed from ED presentation to DKA resolution. The superiority margin for a clinically significant difference was chosen to be a 40% time reduction to DKA resolution. We also assessed the need to break allocation concealment and loss to follow-up. Patients with clinical suspicion for DKA were screened for inclusion and enrolled patients were randomised 1:1 to receive RL or NS. Patients, clinicians and outcome assessors were blinded to allocation. RESULTS: We enrolled 52 (25 RL, 27 NS) of 60 eligible patients (86.7%), exceeding our target recruitment rate. There were more patients in the NS group with type 1 diabetes, and more patients in the RL group had an admission co-diagnosis in addition to DKA. For the 44 participants with confirmed laboratory evidence of resolution, median (IQR) time to DKA resolution for RL versus NS was 15.7 (10.4-18.8) and 12.7 (7.9-19.2) hours, respectively. There were no cases where blinding was broken, and there was no loss to follow-up. CONCLUSIONS: This pilot trial demonstrated our protocol's feasibility by exceeding our target recruitment rate. Our results may be used to inform future multicentre trials to compare the safety and efficacy of RL and NS in managing DKA in the ED. TRIAL REGISTRATION NUMBER: NCT04926740.

Effectiveness of interventions for emergency care of hypoglycaemia and diabetic ketoacidosis: A systematic review.

AIM: This systematic review aims to provide evidence on effectiveness of interventions used in emergency care of hypoglycaemia and diabetic ketoacidosis (DKA). METHODOLOGY: This is a systematic review of randomized controlled trials and analytical studies. We selected studies based on eligibility criteria. The databases Medline, Cochrane library and Embase were searched from their inception till November 2, 2022, using search strategy. We used the term such as "diabetes mellitus", "treatment", "hypoglycaemia", "diabetic ketoacidosis", "low blood sugar", "high blood sugar" and Mesh terms like "disease management", "hypoglycaemia", "diabetic ketoacidosis", and "diabetes mellitus" to form search strategy. RESULTS: Hypoglycemia: Both 10 % dextrose (D10) and 50 % dextrose (D50) are effective options with similar hospital mortality D10 (4.7 %) and D50 (6.2 %). DKA: Low dose insulin is non-inferior to standard dose with time till resolution of DKA 16.5 (7.2) hours and 17.2 (7.7) hours (p value = 0.73) respectively. In children, subcutaneous insulin was associated with reduced ICU admissions and hospital readmissions (67.8 % to 27.9 %). Plasmalyte (PL) is noninferior to sodium chloride (SC), with ICU length of stay 49 h (IQR 23-72) and 55 h (IQR 41-80) respectively, hyperchloremia was associated with longer in-hospital length of stay and longer time to resolution of DKA. And potassium replacement at < 10 mmol/L was associated with higher mortality (n = 72). CONCLUSION: We conclude either of the 10 % or 50 % dextrose is effective for management of hypoglycaemia. For DKA subcutaneous insulin and intravenous insulin, chloride levels ≤ 109 mEq/L, potassium above 10 mmol/l, IV fluids like Plasmalyte and normal saline are effective.

Successful treatment of nivolumab and ipilimumab triggered type 1 diabetes by using sodium-glucose transporter 2 inhibitor: a case report and systematic review.

Objective: Checkpoint inhibitors (CPIs) can trigger complications related to the autoimmune process such as CPI-triggered diabetes mellitus. The typical treatment for CPI-triggered diabetes is insulin, but a detailed therapeutic method has not yet been established. To prevent severe symptoms and mortality of diabetic ketoacidosis in advanced-stage cancer patients, the establishment of effective treatment of CPI-triggered diabetes, other than insulin therapy, is required. Methods: We present a case of a 76-year-old man with CPI-triggered diabetes who was treated with nivolumab and ipilimumab for lung cancer. We also conducted a systematic review of 48 case reports of type 1 diabetes associated with nivolumab and ipilimumab therapy before June 2023. Results: The patient's hyperglycemia was not sufficiently controlled by insulin therapy, and after the remission of ketoacidosis, the addition of a sodium-glucose transporter (SGLT) 2 inhibitor, dapagliflozin, improved glycemic control. Most of the reported nivolumab/ipilimumab-induced type 1 diabetes was treatable with insulin, but very few cases required additional oral anti-diabetic agents to obtain good glucose control. Conclusion: Although SGLT2 inhibitors have been reported to have adverse effects on ketoacidosis, recent studies indicate that the occurrence of ketoacidosis is relatively rare. Considering the pathological mechanism of CPI-triggered diabetes, SGLT2 inhibitors could be an effective choice if they are administered while carefully monitoring the patient's ketoacidosis.

Treatment of a Severe Form of Euglycemic Ketoacidosis in a Patient Treated with SGLT-2 Inhibitors with the Aid of Somatostatin.

Currently, the use of SGLT2 inhibitors is becoming more widespread, both for their role in controlling diabetes, and for their pleiotropic effects on glomerular hyperfiltration and heart failure. Along with their positive effects, these drugs can lead to various complications, the most severe being euglycemic ketoacidosis. The clinical case we have reported precisely describes this potentially serious complication which occurred in a 47-year-old patient who had been on SGLT2 inhibitor therapy for 5 years. In the resolution of this case we used, in addition to standard therapy, the continuous infusion of somatostatin, resulting in a rapid resolution of ketoacidosis and an improvement in the clinical condition.