Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Dialysis and Cardiovascular Disease in Patients With Stage 5 Chronic Kidney Disease.

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 m2 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.

Hyperglycaemic crises in adults with diabetes: a consensus report.

The American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), Joint British Diabetes Societies for Inpatient Care (JBDS), American Association of Clinical Endocrinology (AACE) and Diabetes Technology Society (DTS) convened a panel of internists and diabetologists to update the ADA consensus statement on hyperglycaemic crises in adults with diabetes, published in 2001 and last updated in 2009. The objective of this consensus report is to provide up-to-date knowledge about the epidemiology, pathophysiology, clinical presentation, and recommendations for the diagnosis, treatment and prevention of diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) in adults. A systematic examination of publications since 2009 informed new recommendations. The target audience is the full spectrum of diabetes healthcare professionals and individuals with diabetes.

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.

Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach.

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, HbA1c 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.

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease.

BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).

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.

Adverse effects of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a systematic review and meta-analysis.

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.

Fluid therapy in diabetic ketoacidosis.

PURPOSE OF REVIEW: To evaluate recent evidence (2021-2023) on fluid therapy in diabetic ketoacidosis. Key evidence gaps which require generation of new evidence are discussed. RECENT FINDINGS: Balanced crystalloid solutions, compared to the commonly recommended and used 0.9% sodium chloride solution (saline), may result in better outcomes for patients with diabetic ketoacidosis, including faster resolution of acidosis, less hyperchloremia and shorter hospital length of stay. Upcoming results from randomized trials may provide definitive evidence on the use of balanced crystalloid solutions in diabetic ketoacidosis. Evidence remains scarce or conflicting for the use of "two-bag" compared to conventional "one-bag" fluid, and rates of fluid administration, especially for adult patients. In children, concerns about cerebral oedema from faster fluid administration rates have not been demonstrated in cohort studies nor randomized trials. SUMMARY: Fluid therapy is a key aspect of diabetic ketoacidosis management, with important evidence gaps persisting for several aspects of management despite recent evidence.

Fluid resuscitation with balanced electrolyte solutions results in faster resolution of diabetic ketoacidosis than with 0.9% saline in adults - A systematic review and meta-analysis.

Fluid resuscitation during diabetic ketoacidosis (DKA) is most frequently performed with 0.9% saline despite its high chloride and sodium concentration. Balanced Electrolyte Solutions (BES) may prove a more physiological alternative, but convincing evidence is missing. We aimed to compare the efficacy of 0.9% saline to BES in DKA management. MEDLINE, Cochrane Library, and Embase databases were searched for relevant studies using predefined keywords (from inception to 27 November 2021). Relevant studies were those in which 0.9% saline (Saline-group) was compared to BES (BES-group) in adults admitted with DKA. Two reviewers independently extracted data and assessed the risk of bias. The primary outcome was time to DKA resolution (defined by each study individually), while the main secondary outcomes were changes in laboratory values, duration of insulin infusion, and mortality. We included seven randomized controlled trials and three observational studies with 1006 participants. The primary outcome was reported for 316 patients, and we found that BES resolves DKA faster than 0.9% saline with a mean difference (MD) of -5.36 [95% CI: -10.46, -0.26] hours. Post-resuscitation chloride (MD: -4.26 [-6.97, -1.54] mmoL/L) and sodium (MD: -1.38 [-2.14, -0.62] mmoL/L) levels were significantly lower. In contrast, levels of post-resuscitation bicarbonate (MD: 1.82 [0.75, 2.89] mmoL/L) were significantly elevated in the BES-group compared to the Saline-group. There was no statistically significant difference between the groups regarding the duration of parenteral insulin administration (MD: 0.16 [-3.03, 3.35] hours) or mortality (OR: -0.67 [0.12, 3.68]). Studies showed some concern or a high risk of bias, and the level of evidence for most outcomes was low. This meta-analysis indicates that the use of BES resolves DKA faster than 0.9% saline. Therefore, DKA guidelines should consider BES instead of 0.9% saline as the first choice during fluid resuscitation.

Clinical care advice for monitoring of islet autoantibody positive individuals with presymptomatic type 1 diabetes.

BACKGROUND/AIM: Type 1 diabetes is an autoimmune disease that involves the development of autoantibodies against pancreatic islet beta-cell antigens, preceding clinical diagnosis by a period of preclinical disease activity. As screening activity to identify autoantibody-positive individuals increases, a rise in presymptomatic type 1 diabetes individuals seeking medical attention is expected. Current guidance on how to monitor these individuals in a safe but minimally invasive way is limited. This article aims to provide clinical guidance for monitoring individuals with presymptomatic type 1 diabetes to reduce the risk of diabetic ketoacidosis (DKA) at diagnosis. METHODS: Expert consensus was obtained from members of the Fr1da, GPPAD, and INNODIA consortia, three European diabetes research groups. The guidance covers both specialist and primary care follow-up strategies. RESULTS: The guidance outlines recommended monitoring approaches based on age, disease stage and clinical setting. Individuals with presymptomatic type 1 diabetes are best followed up in specialist care. For stage 1, biannual assessments of random plasma glucose and HbA1c are suggested for children, while annual assessments are recommended for adolescents and adults. For stage 2, 3-monthly clinic visits with additional home monitoring are advised. The value of repeat OGTT in stage 1 and the use of continuous glucose monitoring in stage 2 are discussed. Primary care is encouraged to monitor individuals who decline specialist care, following the guidance presented. CONCLUSIONS: As type 1 diabetes screening programs become more prevalent, effective monitoring strategies are essential to mitigate the risk of complications such as DKA. This guidance serves as a valuable resource for clinicians, providing practical recommendations tailored to an individual's age and disease stage, both within specialist and primary care settings.

Fulminant type 1 diabetes: Focusing on triggering factors.

Fulminant type 1 diabetes (FT1D) is a novel type of type 1 diabetes that is caused by extremely rapid destruction of the pancreatic ß cells. Early diagnosis or prediction of FT1D is critical for the prevention or timely treatment of diabetes ketoacidosis, which can be life-threatening. Understanding its triggers or promoting factors plays an important role in the prevention and treatment of FT1D. In this review, we summarised the various triggering factors of FT1D, including susceptibility genes, immunological factors (cellular and humoural immunity), immune checkpoint inhibitor therapies, drug reactions with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome, pregnancy, viral infections, and vaccine inoculation. This review provides the basis for future research into the pathogenetic mechanisms that regulate FT1D development and progression to further improve the prognosis and clinical management of patients with FT1D.

One third of cases of new-onset diabetic ketosis in adults are associated with ketosis-prone type 2 diabetes-A systematic review and meta-analysis.

AIMS: Ketosis-prone type 2 diabetes was defined by the World Health Organization in 2019. According to the literature, the diagnosis is based on the presence of ketosis, islet autoantibody negativity and preserved insulin secretion. Our meta-analysis assessed the prevalence and clinical characteristics of ketosis-prone type 2 diabetes among patients hospitalised with diabetic ketoacidosis (DKA) or ketosis. METHODS: The systematic search was performed in five main databases as of 15 October 2021 without restrictions. We calculated the pooled prevalence of ketosis-prone type 2 diabetes (exposed group) within the diabetic population under examination, patients with ketoacidosis or ketosis, to identify the clinical characteristics, and we compared it to type 1 diabetes (the comparator group). The random effects model provided pooled estimates as prevalence, odds ratio and mean difference (MD) with 95% confidence intervals. RESULTS: Eleven articles were eligible for meta-analysis, thus incorporating 2010 patients of various ethnic backgrounds. Among patients presenting with DKA or ketosis at the onset of diabetes, 35% (95% CI: 24%-49%) had ketosis-prone type 2 diabetes. These patients were older (MD = 11.55 years; 95% CI: 5.5-17.6) and had a significantly higher body mass index (BMI) (MD = 5.48 kg/m2 ; 95% CI: 3.25-7.72) than those with type 1 diabetes. CONCLUSIONS: Ketosis-prone type 2 diabetes accounts for one third of DKA or ketosis at the onset of diabetes in adults. These patients are characterised by islet autoantibody negativity and preserved insulin secretion. They are older and have a higher BMI compared with type 1 diabetes. C-peptide and diabetes-related autoantibody measurement is essential to identify this subgroup among patients with ketosis at the onset of diabetes.

Care, control and complications of hospitalised patients with type 1 diabetes in China: A nationwide-based registry study.

AIMS: To evaluate the status quo of type 1 diabetes (T1D) management and characteristics of hospitalised patients with T1D in China through a nationwide multicentre registry study, the China Diabetes Type 1 Study (CD1S). MATERIALS AND METHODS: Clinical data from the electronic hospital records of all people with T1D were retrospectively collected in 13 tertiary hospitals across 7 regions of China from January 2016 to December 2021. Patients were defined as newly diagnosed who received a diagnosis of diabetes for less than 3 months. RESULTS: Among the 4993 people with T1D, the median age (range) at diagnosis was 23.0 (1.0-87.0) years and the median disease duration was 2.0 years. The median haemoglobin A1c (HbA1c) level was 10.7%. The prevalence of obesity, overweight, dyslipidemia, and hypertension were 2.5%, 10.8%, 62.5% and 25.9%, respectively. The incidence rate of diabetic ketoacidosis at disease onset was 41.1%, with the highest in children <10 years of age (50.6%). In patients not newly diagnosed, 60.7% were diagnosed with at least one chronic diabetic complication, with the highest proportion (45.3%) of diabetic peripheral neuropathy. Chronic complications were detected in 79.2% of people with T1D duration ≥10 years. CONCLUSIONS: In the most recent years, there were still unsatisfactory metabolic control and high incidence of diabetic ketoacidosis as well as chronic diabetic complications among inpatients with T1D in China. The ongoing CD1S prospective study aims to improve the quality of T1D management nationally.

Outcomes measured in studies assessing health systems interventions for type 1 diabetes management: A scoping review.

AIMS: Describe the outcomes reported in research on health systems interventions for type 1 diabetes management in comparison to the outcomes proposed by a core outcome set (COS) for this condition, an essential list of outcomes that studies should measure. METHODS: Systematic search of studies published between 2010 and 2021 reporting health systems interventions directed to improve the management of type 1 diabetes using PubMed, EMBASE and CENTRAL. Information on the outcomes was extracted and classified according to a COS: self-management, level of clinical engagement, perceived control over diabetes, diabetes-related quality of life, diabetes burden, diabetes ketoacidosis, severe hypoglycemia, and glycated hemoglobin (HbA1C). RESULTS: 187 studies were included. Most of the studies included either children (n = 82/187) or adults (n = 82/187) living with type 1 diabetes. The most common outcome measured was HbA1C (n = 149/187), followed by self-management (n = 105/187). While the least measured ones were diabetes ketoacidosis (n = 15/187), and clinical engagement (n = 0/187). None of the studies measured all the outcomes recommended in the COS. Additionally, different tools were found to be used in measuring the same outcome. CONCLUSIONS: This study provides a description of what researchers are measuring when assessing health systems interventions to improve type 1 diabetes management. In contrast to a COS, it was found that there is a predominance of clinical-based outcomes over patient-reported outcome measures.

Reasons for hospitalisation in youth with type 1 diabetes, 2010-2019.

AIMS: To determine the incidence of hospitalisation for all diagnoses among Australian youth with type 1 diabetes. METHODS: We linked Australians aged under 20 years with type 1 diabetes on the National Diabetes Services Scheme (n = 45,685) to hospital admission data from 2010 to 2019. We determined relative risks (RR) of hospitalisation among those with type 1 diabetes in the states of Victoria and Queensland (n = 21,898) compared to the general population for 2010-2017 using Poisson regression. RESULTS: Australian youth with type 1 diabetes had increased risk for almost all reasons for hospitalisation compared to the general population, especially infections such as anogenital herpesviral infections (RR 54.83, 95% CI 33.21-90.53), and mental health disorders including personality disorders (RR 9.70, 95% CI 8.02-11.72). Among those with type 1 diabetes, over 60% of hospitalisations were directly related to diabetes, almost half of which were for ketoacidosis. Approximately 15% of ketoacidosis admissions occurred within 3 months of diabetes diagnosis. One quarter of those with admissions for ketoacidosis were readmitted for ketoacidosis within 12 months. Residence in areas of high socio-economic disadvantage was an independent risk factor for admission and readmission for ketoacidosis. CONCLUSIONS: Youth with type 1 diabetes are susceptible to a wide range of complications. Clinicians should consider screening and prevention for conditions such as infections and mental health disorders. Targeted support and education around glycaemic management should be considered in those at high risk for ketoacidosis admission including those living in areas of high socio-economic disadvantage.

Modifiable factors to prevent severe hypoglycaemic and diabetic ketoacidosis presentations in people with type 1 diabetes.

AIMS: In tackling rising diabetes-related emergencies, the need to understand and address emergency service usage by people with type 1 diabetes is vital. This review aimed to quantify current trends in presentations for type 1 diabetes-related emergencies and identify public health strategies that reduce the frequency of diabetes-related emergencies and improve glycaemic management. METHODS: Medline (OVID), Cochrane and CINAHL were searched for studies published between 2000 and 2023, focusing on people with type 1 diabetes, severe hypoglycaemia and/or diabetic ketoacidosis, and ambulance and/or emergency department usage. There were 1313 papers identified, with 37 publications meeting review criteria. RESULTS: The incidence of type 1 diabetes-related emergencies varied from 2.4 to 14.6% over one year for hypoglycaemic episodes, and between 0.07 and 11.8 events per 100 person-years for hyperglycaemic episodes. Notably, our findings revealed that ongoing diabetes education and the integration of diabetes technology, such as continuous glucose monitoring and insulin pump therapy, significantly reduced the incidence of these emergencies. However, socio-economic disparities posed barriers to accessing these technologies, subsequently shifting the cost to emergency healthcare and highlighting the need for governments to consider subsidising these technologies as part of preventative measures. CONCLUSIONS: Improving access to continuous glucose monitoring and insulin pump therapy, in combination with ongoing diabetes education focusing on symptom recognition and early management, will reduce the incidence of diabetes-related emergencies. Concurrent research assessing emergency healthcare usage patterns during the implementation of such measures is essential to ensure these are cost-effective.

Ambulance clinician use of capillary blood ketone meters to improve emergency hyperglycaemia care: A stepped-wedged controlled, mixed-methods feasibility study.

AIM: To determine whether it was feasible, safe and acceptable for ambulance clinicians to use capillary blood ketone meters for 'high-risk' diabetic ketoacidosis (DKA) recognition and fluid initiation, to inform the need for a full-powered, multi-centre trial. METHODS: Adopting a stepped-wedge controlled design, participants with hyperglycaemia (capillary blood glucose >11.0 mmol/L) or diabetes and unwell were recruited. 'High-risk' DKA intervention participants (capillary blood ketones ≥3.0 mmol/L) received paramedic-led fluid therapy. Participant demographic and clinical data were collated from ambulance and hospital care records. Twenty ambulance and Emergency Department clinicians were interviewed to understand their hyperglycaemia and DKA care experiences. RESULTS: In this study, 388 participants were recruited (Control: n = 203; Intervention: n = 185). Most presented with hyperglycaemia, and incidence of type 1 and type 2 diabetes was 18.5% and 74.3%, respectively. Ketone meter use facilitated 'high-risk' DKA identification (control: 2.5%, n = 5; intervention: 6.5%, n = 12) and was associated with improved hospital pre-alerting. Ambulance clinicians appeared to have a high index of suspicion for hospital-diagnosed DKA participants. One third (33.3%; n = 3) of Control and almost half (45.5%; n = 5) of Intervention DKA participants received pre-hospital fluid therapy. Key interview themes included clinical assessment, ambulance DKA fluid therapy, clinical handovers; decision support tool; hospital DKA management; barriers to hospital DKA care. CONCLUSIONS: Ambulance capillary blood ketone meter use was deemed feasible, safe and acceptable. Opportunities for improved clinical decision making, support and safety-netting, as well as in-hospital DKA care, were recognised. As participant recruitment was below progression threshold, it is recommended that future-related research considers alternative trial designs. CLINICALTRIALS: gov: NCT04940897.

Relative poverty is associated with increased risk of diabetic ketoacidosis at onset of type 1 diabetes in children. A Swedish national population-based study in 2014-2019.

AIMS: The aim of the study was to estimate the effect of household relative poverty on the risk of diabetic ketoacidosis at diagnosis of children with type 1 diabetes using an international standard measurement of relative poverty. METHODS: A national population-based retrospective study was conducted. The Swedish National Diabetes Register (NDR) was linked with data from Sweden's public statistical agency (Statistics Sweden). Children who were diagnosed with new-onset type 1 diabetes in the period of 2014-2019 were common identifiers. The definition of diabetic ketoacidosis was venous pH <7.30 or a serum bicarbonate level <18 mmol/L. The exposure variable was defined according to the standard definition of the persistent at-risk-of-poverty rate used by the statistical office of the European Union (Eurostat) and several other European public statistical agencies. Univariate and multi-variable analyses were used to calculate the effect of relative poverty on the risk of diabetic ketoacidosis. RESULTS: Children from households with relative poverty had a 41% higher risk of diabetic ketoacidosis (1.41, CI 1.12-1.77, p = 0.004) and more than double the risk of severe diabetic ketoacidosis (pH <7.10) (RR 2.10, CI 1.35-3.25, p = 0.001), as compared to children from households without relative poverty. CONCLUSIONS: Relative poverty significantly increases the risk of diabetic ketoacidosis at onset of type 1 diabetes in children, even in a high-income country with publicly reimbursed health care.

Protocol for the Australian Type 1 Diabetes National Screening Pilot: Assessing the feasibility and acceptability of three general population screening models in children.

AIM: One third of Australian children diagnosed with type 1 diabetes present with life-threatening diabetic ketoacidosis (DKA) at diagnosis. Screening for early-stage, presymptomatic type 1 diabetes, with ongoing follow-up, can substantially reduce this risk (<5% risk). Several screening models are being trialled internationally, without consensus on the optimal approach. This pilot study aims to assess three models for a routine, population-wide screening programme in Australia. METHODS: An implementation science-guided pilot study to evaluate the feasibility, acceptability and costs of three screening models in children will be conducted between July 2022 and June 2024. These models are as follows: (1) Genetic risk-stratified screening using newborn heel prick dried bloodspots, followed by autoantibody testing from 11 months of age; (2) genetic risk-stratified screening of infant (6-12 months) saliva followed by autoantibody testing from 10 months of age; and (3) autoantibody screening using capillary dried bloodspots collected from children aged 2, 6 or 10 years. Cohorts for each model will be recruited from targeted geographic areas across Australia involving ≥2 states per cohort, with a recruitment target of up to 3000 children per cohort (total up to 9000 children). The primary outcome is screening uptake for each cohort. Secondary outcomes include programme feasibility, costs, parental anxiety, risk perception, satisfaction, well-being and quality of life, and health professional attitudes and satisfaction. CONCLUSIONS: This pilot is the first direct comparison of three screening implementation models for general population screening. Findings will provide evidence to inform a potential national screening programme for Australian children. TRIAL REGISTRATION: ACTRN12622000381785.