Automated Insulin Delivery Systems in Pediatric Type 1 Diabetes: A Narrative Review.

This narrative review assesses the use of automated insulin delivery (AID) systems in managing persons with type 1 diabetes (PWD) in the pediatric population. It outlines current research, the differences between various AID systems currently on the market and the challenges faced, and discusses potential opportunities for further advancements within this field. Furthermore, the narrative review includes various expert opinions on how different AID systems can be used in the event of challenges with rapidly changing insulin requirements. These include examples, such as during illness with increased or decreased insulin requirements and during physical activity of different intensities or durations. Case descriptions give examples of scenarios with added user-initiated actions depending on the type of AID system used. The authors also discuss how another AID system could have been used in these situations.

Effects, Safety, and Treatment Experience of Advanced Hybrid Closed-Loop Systems in Clinical Practice Among Adults Living With Type 1 Diabetes.

BACKGROUND: There are few studies providing a more comprehensive picture of advanced hybrid closed-loop (AHCL) systems in clinical practice. The aim was to evaluate the effects of the AHCL systems, Tandem® t: slim X2™ with Control IQ™, and MiniMed™ 780G, on glucose control, safety, treatment satisfaction, and practical barriers for individuals with type 1 diabetes. METHOD: One hundred forty-two randomly selected adults with type 1 diabetes at six diabetes outpatient clinics in Sweden at any time treated with either the Tandem Control IQ (TCIQ) or the MiniMed 780G system were included. Glycated hemoglobin A1c (HbA1c) and glucose metrics were evaluated. Treatment satisfaction and practical barriers were examined via questionnaires. RESULTS: Mean age was 42 years, median follow-up was 1.7 years, 58 (40.8%) were females, 65% used the TCIQ system. Glycated hemoglobin A1c was reduced by 0.6% (6.8 mmol/mol; 95% confidence interval [CI] = 0.5-0.8% [5.3-8.2 mmol/mol]; P < .001), from 7.3% to 6.7% (57-50 mmol/mol). Time in range (TIR) increased with 14.5% from 57.0% to 71.5% (95% CI = 12.2%-16.9%; P < .001). Time below range (TBR) (<70 mg/dL, <3.9 mmol/L) decreased from 3.8% to 1.6% (P < .001). The standard deviation of glucose values was reduced from 61 to 51 mg/dL (3.4-2.9 mmol/L, P < .001) and the coefficient of variation from 35% to 33% (P < .001). Treatment satisfaction increased, score 14.8 on the Diabetes Treatment Satisfaction Questionnaire (DTSQ) (change version ranging from -18 to 18, P < .001). Four severe hypoglycemia events were detected and no cases of ketoacidosis. Skin problems were experienced by 32.4% of the study population. CONCLUSIONS: Advanced hybrid closed-loop systems improve glucose control with a reasonable safety profile and high treatment satisfaction. Skin problems are common adverse events.

Diabetes Technology Meeting 2023.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 1 to November 4, 2023. Meeting topics included digital health; metrics of glycemia; the integration of glucose and insulin data into the electronic health record; technologies for insulin pumps, blood glucose monitors, and continuous glucose monitors; diabetes drugs and analytes; skin physiology; regulation of diabetes devices and drugs; and data science, artificial intelligence, and machine learning. A live demonstration of a personalized carbohydrate dispenser for people with diabetes was presented.

Diabetic retinopathy among the elderly with type 2 diabetes: A Nationwide longitudinal registry study.

PURPOSE: To investigate the prevalence, incidence and risk factors of DR in elderly people living with type 2 diabetes. METHODS: Individuals >80 years, in the Swedish National Diabetes Register (NDR) between 2008 and 2017, were included. Prevalence and incidence were calculated and stratified by age. Estimates were assessed by longitudinal binary logistic regression models. RESULTS: One hundred forty-one thousand, one hundred fifty-eight individuals with type 2 diabetes were included, median age 83 years, 53.3% females and with a median HbA1c 52 mmol/mol. The DR prevalence was stable at 336.2 cases/1000 patients in 2008 (95% CI, 330.2-342.3), with no significant changes during the 10-year period. Crude DR incidence rate: 88.5 cases/1000 patient years (95% CI, 87.6-89.4). The incidence rate was lower at higher ages. The effect of age on incident DR varied by sex, with females having an increasingly higher risk than males from 83 years of age, OR 1.25 (1.11-1.42) at age 90 years. The risk of incident DR with longer diabetes duration increased more rapidly at worse glycaemic control. CONCLUSION: The growing population of elderly with type 2 diabetes shows a stable proportion of DR and proposes an increased need for DR screening and eye care. Established risk factors for DR, such as diabetes duration and level of glycaemic control, are also important in the elderly; however, age and sex should be considered.

The Determination of Diabetes Utilities, Costs, and Effects Model: A Cost-Utility Tool Using Patient-Level Microsimulation to Evaluate Sensor-Based Glucose Monitoring Systems in Type 1 and Type 2 Diabetes: Comparative Validation.

OBJECTIVES: To assess the accuracy and validity of the Determination of Diabetes Utilities, Costs, and Effects (DEDUCE) model, a Microsoft-Excel-based tool for evaluating diabetes interventions for type 1 and type 2 diabetes. METHODS: The DEDUCE model is a patient-level microsimulation, with complications predicted based on the Sheffield and Risk Equations for Complications Of type 2 diabetes models for type 1 and type 2 diabetes, respectively. For this tool to be useful, it must be validated to ensure that its complication predictions are accurate. Internal, external, and cross-validation was assessed by populating the DEDUCE model with the baseline characteristics and treatment effects reported in clinical trials used in the Fourth, Fifth, and Ninth Mount Hood Diabetes Challenges. Results from the DEDUCE model were evaluated against clinical results and previously validated models via mean absolute percentage error or percentage error. RESULTS: The DEDUCE model performed favorably, predicting key outcomes, including cardiovascular disease in type 1 diabetes and all-cause mortality in type 2 diabetes. The model performed well against other models. In the Mount Hood 9 Challenge comparison, error was below the mean reported from comparator models for several outcomes, particularly for hazard ratios. CONCLUSIONS: The DEDUCE model predicts diabetes-related complications from trials and studies well when compared with previously validated models. The model may serve as a useful tool for evaluating the cost-effectiveness of diabetes technologies.

Automated Insulin Delivery for Pregnant Women With Type 1 Diabetes: Where do we stand?

Automated insulin delivery (AID) systems mimic an artificial pancreas via a predictive algorithm integrated with continuous glucose monitoring (CGM) and an insulin pump, thereby providing AID. Outside of pregnancy, AID has led to a paradigm shift in the management of people with type 1 diabetes (T1D), leading to improvements in glycemic control with lower risk for hypoglycemia and improved quality of life. As the use of AID in clinical practice is increasing, the number of women of reproductive age becoming pregnant while using AID is also expected to increase. The requirement for lower glucose targets than outside of pregnancy and for frequent adjustments of insulin doses during pregnancy may impact the effectiveness and safety of AID when using algorithms for non-pregnant populations with T1D. Currently, the CamAPS® FX is the only AID approved for use in pregnancy. A recent randomized controlled trial (RCT) with CamAPS® FX demonstrated a 10% increase in time in range in a pregnant population with T1D and a baseline glycated hemoglobin (HbA1c) ≥ 48 mmol/mol (6.5%). Off-label use of AID not approved for pregnancy are currently also being evaluated in ongoing RCTs. More evidence is needed on the impact of AID on maternal and neonatal outcomes. We review the current evidence on the use of AID in pregnancy and provide an overview of the completed and ongoing RCTs evaluating AID in pregnancy. In addition, we discuss the advantages and challenges of the use of current AID in pregnancy and future directions for research.

Comparator Data Characteristics and Testing Procedures for the Clinical Performance Evaluation of Continuous Glucose Monitoring Systems.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems.

A narrative commentary about interoperability in medical devices and data used in diabetes therapy from an academic EU/UK/US perspective.

People living with diabetes have many medical devices available to assist with disease management. A critical aspect that must be considered is how systems for continuous glucose monitoring and insulin pumps communicate with each other and how the data generated by these devices can be downloaded, integrated, presented and used. Not only is interoperability associated with practical challenges, but also devices must adhere to all aspects of regulatory and legal frameworks. Key issues around interoperability in terms of data ownership, privacy and the limitations of interoperability include where the responsibility/liability for device and data interoperability lies and the need for standard data-sharing protocols to allow the seamless integration of data from different sources. There is a need for standardised protocols for the open and transparent handling of data and secure integration of data into electronic health records. Here, we discuss the current status of interoperability in medical devices and data used in diabetes therapy, as well as regulatory and legal issues surrounding both device and data interoperability, focusing on Europe (including the UK) and the USA. We also discuss a potential future landscape in which a clear and transparent framework for interoperability and data handling also fulfils the needs of people living with diabetes and healthcare professionals.

Associations of bolus insulin injection frequency and smart pen engagement with glycaemic control in people living with type 1 diabetes.

AIM: To evaluate whether both bolus insulin injection frequency and smart pen engagement were associated with changes in glycaemic control, using real-world data from adults with type 1 diabetes (T1D). MATERIALS AND METHODS: Adults using a smart pen (NovoPen 6) to administer bolus insulin (fast-acting insulin aspart or insulin aspart) alongside continuous glucose monitoring were eligible for inclusion. Smart pen engagement was characterized by number of days with pen data uploads over the previous 14 days. Glycaemic control was evaluated by analysing glucose metrics. RESULTS: Overall, data from 1194 individuals were analysed. The number of daily bolus injections was significantly associated with time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]; P < 0.0001). Individuals administering, on average, three daily bolus insulin injections had an estimated 11% chance of achieving >70% TIR. The probability of achieving >70% TIR increased with the mean number of daily bolus injections. However, the percentage of TIR was lower on days when individuals administered higher-than-average numbers of injections. The observed mean number of daily bolus injections administered across the study population was lower than the optimal number required to reach glycaemic targets (4.8 injections vs. 6-8 injections). Smart pen engagement was significantly associated with improved TIR. CONCLUSIONS: Glycaemic control was associated with daily bolus insulin injection frequency and smart pen engagement. A treatment regimen combining an optimal bolus injection strategy, and effective smart pen engagement, may improve glycaemic control among adults with T1D.

A European Cost-Utility Analysis of the MiniMed™ 780G Advanced Hybrid Closed-Loop System Versus Intermittently Scanned Continuous Glucose Monitoring with Multiple Daily Insulin Injections in People Living with Type 1 Diabetes.

Background: Advanced hybrid closed-loop (AHCL) automated insulin delivery systems are the most effective therapy in terms of assisting people with type 1 diabetes (T1D) to achieve glycemic targets; however, the cost can represent a barrier to uptake. In this study, a cost-utility analysis of the MiniMed™ 780G AHCL system (MM780G) versus intermittently scanned continuous glucose monitoring (is-CGM) plus multiple daily insulin injections (MDI) in people with T1D not achieving glycemic goals was performed across six European countries. Methods: Clinical input data were sourced from the ADAPT trial. Assuming a baseline HbA1c of 9.04%, HbA1c reductions of 1.54% for AHCL and 0.2% for is-CGM+MDI were modeled. The analyses were performed from a payer perspective over a time horizon of 40 years and an annual discount rate of 3% was applied. Results: Across all countries, the use of AHCL was projected to result in an incremental gain in quality-adjusted life expectancy of >2 quality-adjusted life years (QALYs) versus is-CGM+MDI. Lifetime direct costs were higher with AHCL resulting in incremental cost-utility ratios for AHCL versus is-CGM+MDI ranging from EUR 11,765 per QALY gained in Austria to EUR 43,963 per QALY gained in Italy. Conclusions: For people with T1D managed with is-CGM+MDI not achieving glycemic targets, initiation of the MM780G system was projected to improve long-term clinical outcomes; however, due to differences in health care costs between countries, the health economic outcomes differed. In all included countries, AHCL is likely to be cost-effective relative to is-CGM+MDI for people not achieving glycemic goals with is-CGM+MDI. The ADAPT trial is registered with ClinicalTrials.gov, NCT04235504.

Clinical Performance Evaluation of Continuous Glucose Monitoring Systems: A Scoping Review and Recommendations for Reporting.

The use of different approaches for design and results presentation of studies for the clinical performance evaluation of continuous glucose monitoring (CGM) systems has long been recognized as a major challenge in comparing their results. However, a comprehensive characterization of the variability in study designs is currently unavailable. This article presents a scoping review of clinical CGM performance evaluations published between 2002 and 2022. Specifically, this review quantifies the prevalence of numerous options associated with various aspects of study design, including subject population, comparator (reference) method selection, testing procedures, and statistical accuracy evaluation. We found that there is a large variability in nearly all of those aspects and, in particular, in the characteristics of the comparator measurements. Furthermore, these characteristics as well as other crucial aspects of study design are often not reported in sufficient detail to allow an informed interpretation of study results. We therefore provide recommendations for reporting the general study design, CGM system use, comparator measurement approach, testing procedures, and data analysis/statistical performance evaluation. Additionally, this review aims to serve as a foundation for the development of a standardized CGM performance evaluation procedure, thereby supporting the goals and objectives of the Working Group on CGM established by the Scientific Division of the International Federation of Clinical Chemistry and Laboratory Medicine.

Glimepiride Compared to Liraglutide Increases Plasma Levels of miR-206, miR-182-5p, and miR-766-3p in Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

BACKGRUOUND: Diabetes is a chronic disease with several long-term complications. Several glucose-lowering drugs are used to treat type 2 diabetes mellitus (T2DM), e.g., glimepiride and liraglutide, in which both having different modes of action. Circulating microRNAs (miRNAs) are suggested as potential biomarkers that are associated with the disease development and the effects of the treatment. In the current study we evaluated the effect of glimepiride, liraglutide on the expression of the circulating miRNAs. METHODS: The present study is a post hoc trial from a previously randomized control trial comparing liraglutide versus glimepiride both in combination with metformin in subjects with T2DM, and subclinical heart failure. miRNAs were determined in the subjects' serum samples with next generation sequencing. Expression patterns of the circulating miRNAs were analyzed using bioinformatic univariate and multivariate analyses (clinical trial registration: NCT01425580). RESULTS: Univariate analyses show that treatment with glimepiride altered expression of three miRNAs in patient serum, miR-206, miR-182-5p, and miR-766-3p. Both miR-182-5p and miR-766-3p were also picked up among the top contributing miRNAs with penalized regularised logistic regressions (Lasso). The highest-ranked miRNAs with respect to Lasso coefficients were miR-3960, miR-31-5p, miR-3613-3p, and miR-378a-3p. Liraglutide treatment did not significantly influence levels of circulating miRNAs. CONCLUSION: Present study indicates that glucose-lowering drugs differently affect the expression of circulating miRNAs in serum in individuals with T2DM. More studies are required to investigate possible mechanisms by which glimepiride is affecting the expression of circulating miRNAs.

Use of insulin pumps and closed-loop systems among people living with diabetes: A narrative review of clinical and cost-effectiveness to enable access to technology and meet the needs of payers.

The use of continuous subcutaneous insulin infusion (CSII) via insulin pumps is today considered standard of care for type 1 diabetes (T1D). Closed-loop systems combining continuous glucose monitoring with automated algorithm-driven insulin delivery have been shown to be safe and efficacious in randomized controlled trials and real-life studies in both paediatric and adult participants with T1D. Implementation of hybrid closed-loop (HCL) systems has shown incremental effectiveness, with further reduction of hypoglycaemia and hyperglycaemia. Although less extensively studied in type 2 diabetes (T2D), insulin pumps have demonstrated their effectiveness in glucose control, along with a reduction in need for insulin and a neutral effect on weight. Recent studies have also shown promising results with the use of HCL systems in T2D. Cost-effectiveness studies in both T1D and T2D have shown that pump use is cost-effective in several countries, leading to improvements in quality-adjusted life-years. Insulin pumps are currently reimbursed for T1D in many European countries, but in only a few for individuals with T2D. HCL systems are to be evaluated in future trials performed in T2D to compare their incremental efficacy and cost-effectiveness in comparison with available intensification tools which include multiple daily insulin injections, metformin, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. There is a need for updated guidelines for the use of CSII and HCL in individuals living with T2D based on the emerging evidence, with identification of and recommendations for the people who would benefit the most, which would eventually form a basis for reimbursement and health policies.

The association between type 2 diabetes and attention- deficit/hyperactivity disorder: A systematic review, meta-analysis, and population-based sibling study.

We conducted a systematic review and a meta-analysis to quantitatively summarize evidence on the association between attention-deficit/hyperactivity disorder (ADHD) and type 2 diabetes (T2D). Moreover, a register-based sibling study was conducted to simultaneously control for confounding factors. A systematic search identified four eligible observational studies (N = 5738,287). The meta-analysis showed that individuals with ADHD have a more than doubled risk of T2D when considering adjusted estimates (OR=2.29 [1.48-3.55], d=0.46). Results from the register-based Swedish data showed a significant association between ADHD and T2D (HR=2.35 [2.14-2.58]), with substance use disorder, depression, and anxiety being the main drivers of the association, and cardiovascular and familiar risk playing a smaller role. While results from the meta-analysis provide evidence for an increased risk of T2D in individuals with ADHD, the register-based analyses show that the association between ADHD and T2D is largely explained by psychiatric comorbidities. Pending further evidence of causal association, our findings suggest that early identification and treatment of ADHD comorbidities might greatly reduce the risk of developing T2D in individuals with ADHD.

Burden of established cardiovascular disease in people with type 2 diabetes and matched controls: Hospital-based care, days absent from work, costs and mortality.

AIMS: To assess hospital-based care, work absence, associated costs, and mortality in patients with type 2 diabetes with and without established cardiovascular disease (eCVD) compared to matched controls. MATERIALS AND METHODS: In a population-based cohort study, we analysed individual-level data from national health, social insurance and socio-economic registers for people diagnosed with type 2 diabetes before age 70 years and controls (5:1) in Sweden. Regression analysis was used to attribute costs and days absent due to eCVD. Mortality was analysed using Cox proportional hazard regression, stratified by birth year and adjusted for sex and education. RESULTS: Thirty percent (n = 136 135 of 454 983) of people with type 2 diabetes had ≥1 person-year with eCVD (women 24%; men 34%). The mean annual costs of hospital-based care for diabetes complications were EUR 2629 (95% confidence interval [CI] 2601-2657) of which EUR 2337 (95% CI 2309-2365) were attributed to eCVD (89%). The most costly person-years (10th percentile) were observed in a broad subgroup, 42% of people with type 2 diabetes and eCVD. People with type 2 diabetes had on average 146 days absent (95% CI 145-147) per year, of which 68 days (47%; 95% CI 67-70) were attributed to eCVD. The mortality hazard ratio for type 2 diabetes with eCVD was 4.63 (95%CI 4.58-4.68) and without eCVD was 1.86 (95% CI 1.84-1.88) compared to controls without eCVD. CONCLUSION: The sizable burden of eCVD on both the individual with type 2 diabetes and society calls for efficient management in order to reduce the risks for those living with eCVD and to postpone its onset.

Model-based predictions on health benefits and budget impact of implementing empagliflozin in people with type 2 diabetes and established cardiovascular disease.

AIM: To perform a model-based analysis of the short- and long-term health benefits and costs of further increased implementation of empagliflozin for people with type 2 diabetes and established cardiovascular disease (eCVD) in Sweden. MATERIALS AND METHODS: The validated Institute for Health Economics Diabetes Cohort Model (IHE-DCM) was used to estimate health benefits and a 3-year budget impact, and lifetime costs per quality-adjusted life years (QALY) gained of increased implementation of adding empagliflozin to standard of care (SoC) for people with type 2 diabetes and eCVD in a Swedish setting. Scenarios with 100%/75%/50% implementation were explored. Analyses were based on 30 model cohorts with type 2 diabetes and eCVD (n = 131 412 at baseline) from national health data registers. Sensitivity analyses explored the robustness of results. RESULTS: Over 3 years, SoC with empagliflozin (100% implementation) versus SoC before empagliflozin resulted in 7700 total life years gained and reductions in cumulative incidence of cardiovascular deaths by 30% and heart failures by 28%. Annual costs increased by 15% from higher treatment costs and increased survival. Half of these benefits and costs are not yet reached with current implementation below 50%. SoC with empagliflozin yielded 0.37 QALYs per person, with an incremental cost-effectiveness ratio of 16 000 EUR per QALY versus SoC before empagliflozin. CONCLUSIONS: Model simulations using real-world data and trial treatment effects indicated that a broader implementation of empagliflozin, in line with current guidelines for treatment of people with type 2 diabetes and eCVD, would lead to further benefits even from a short-term perspective.

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings.

BACKGROUND: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. METHODS: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. RESULTS: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. CONCLUSION: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.