Aims: To assess the cost-effectiveness of stepped care (education program plus continuous glucose monitoring (CGM) as needed), compared to immediate CGM use. Methods: Analyses were conducted from a societal perspective over a 12-month horizon. Data were used from the Ecspect-Hypo randomized clinical trial, including 52 individuals with type 1 diabetes (T1D) and impaired hypoglycemia-awareness or a history of recent severe hypoglycemic events (SHEs) (mean age 53 years; 56% female). Outcomes included self-reported SHEs, quality-adjusted life years (QALYs) based on the EuroQol questionnaire, and costs were assessed using Tic-P questionnaires. Incremental cost-effectiveness ratios (ICERs) were calculated and cost-effectiveness acceptability curves were estimated. Results: After 12 months, stepped care resulted in more SHEs (mean difference 0.33, 95%CI 0.056;0.60), less QALYs (mean difference-0.12, 95%CI-0.23;-0.0045), and lower societal costs (mean difference & euro;-252, 95%CI-921;656) compared to CGM. The ICER per prevented SHE was & euro;769, and per QALY gained & euro;5518. The probability that stepped care was cost-effective compared to CGM use was 0.73 at a willingness to pay (WTP) of & euro;0/ SHE prevented and per individual with restored hypoglycemia-awareness, and 0.14 at & euro;20,000/QALY gained. Conclusions: Over 12 months, at a WTP threshold of & euro;20,000/QALY, stepped care was not cost-effective compared to immediate CGM use in hypoglycemia-prone individuals with T1D.

AIMS:Individuals with Type 1 diabetes are at a higher risk of dementia compared to individuals without diabetes. Younger age at Type 1 diabetes onset has been linked to an increased risk of cardiovascular disease and higher mortality. This study aimed to determine whether younger age at Type 1 diabetes onset was also associated with all-cause dementia. MATERIALS AND METHODS:This nationwide prospective cohort study used data from individuals with Type 1 diabetes from the Swedish National Diabetes Register. All-cause dementia, including Alzheimer's disease, vascular dementia and non-Alzheimer's-non-vascular dementia, was prospectively ascertained as ICD-10 codes. Age at onset was stratified into < 10 years, 10-17 years and 18-30 years. The 18-30 years group was used as the reference group for all analyses. Cox regression modelling with age as the time-axis, from age at diabetes onset, was deployed to investigate dementia risk. RESULTS:Of 43 440 included individuals (mean age 33.0 (SD 14.0) years; 44% female), Type 1 diabetes developed before age 10 in 11 776 individuals (27%), between age 10 and 17 in 15 846 (36%) and between 18 and 30 (reference group) in 15 818 (36%). During a median 29.3 [17.6-43.7] years follow-up, 530 (1.2%) developed all-cause dementia. Compared to the reference group, all-cause dementia risk was increased in individuals aged < 10 years at onset (HR 1.37 [95% CI 1.08-1.73]), but not in individuals aged 10-17 years at onset (HR 1.04 [95% CI 0.85-1.26]) (fully adjusted model). CONCLUSIONS:Type 1 diabetes onset before age 10 is associated with an increased risk of all-cause dementia compared to onset between ages 18 and 30.

Importance:Metformin and glyburide monotherapy are used as alternatives to insulin in managing gestational diabetes. Whether a sequential strategy of these oral agents results in noninferior perinatal outcomes compared with insulin alone is unknown. Objective:To test whether a treatment strategy of oral glucose-lowering agents is noninferior to insulin for prevention of large-for-gestational-age infants. Design, Setting, and Participants:Randomized, open-label noninferiority trial conducted at 25 Dutch centers from June 2016 to November 2022 with follow-up completed in May 2023. The study enrolled 820 individuals with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation who had insufficient glycemic control after 2 weeks of dietary changes (defined as fasting glucose >95 mg/dL [>5.3 mmol/L], 1-hour postprandial glucose >140 mg/dL [>7.8 mmol/L], or 2-hour postprandial glucose >120 mg/dL [>6.7 mmol/L], measured by capillary glucose self-testing). Interventions:Participants were randomly assigned to receive metformin (initiated at a dose of 500 mg once daily and increased every 3 days to 1000 mg twice daily or highest level tolerated; n = 409) or insulin (prescribed according to local practice; n = 411). Glyburide was added to metformin, and then insulin substituted for glyburide, if needed, to achieve glucose targets. Main Outcomes and Measures:The primary outcome was the between-group difference in the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex). Secondary outcomes included maternal hypoglycemia, cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission. Results:Among 820 participants, the mean age was 33.2 (SD, 4.7) years). In participants randomized to oral agents, 79% (n = 320) maintained glycemic control without insulin. With oral agents, 23.9% of infants (n = 97) were large for gestational age vs 19.9% (n = 79) with insulin (absolute risk difference, 4.0%; 95% CI, -1.7% to 9.8%; P = .09 for noninferiority), with the confidence interval of the risk difference exceeding the absolute noninferiority margin of 8%. Maternal hypoglycemia was reported in 20.9% with oral glucose-lowering agents and 10.9% with insulin (absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). All other secondary outcomes did not differ between groups. Conclusions and Relevance:Treatment of gestational diabetes with metformin and additional glyburide, if needed, did not meet criteria for noninferiority compared with insulin with respect to the proportion of infants born large for gestational age. Trial Registration:Netherlands Trial Registry Identifier: NTR6134.

IMPORTANCE Metformin and glyburide monotherapy are used as alternatives to insulin in managing gestational diabetes. Whether a sequential strategy of these oral agents results in noninferior perinatal outcomes compared with insulin alone is unknown. OBJECTIVE To test whether a treatment strategy of oral glucose-lowering agents is noninferior to insulin for prevention of large-for-gestational-age infants. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label noninferiority trial conducted at 25 Dutch centers from June 2016 to November 2022 with follow-up completed in May 2023. The study enrolled 820 individuals with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation who had insufficient glycemic control after 2 weeks of dietary changes (defined as fasting glucose >95 mg/dL [>5.3 mmol/L], 1-hour postprandial glucose >140 mg/dL [>7.8 mmol/L], or 2-hour postprandial glucose >120 mg/dL [>6.7 mmol/L], measured by capillary glucose self-testing). INTERVENTIONS Participants were randomly assigned to receive metformin (initiated at a dose of 500 mg once daily and increased every 3 days to 1000 mg twice daily or highest level tolerated; n = 409) or insulin (prescribed according to local practice; n = 411). Glyburide was added to metformin, and then insulin substituted for glyburide, if needed, to achieve glucose targets. MAIN OUTCOMES AND MEASURES The primary outcome was the between-group difference in the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex). Secondary outcomes included maternal hypoglycemia, cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission. RESULTS Among 820 participants, the mean age was 33.2 (SD, 4.7) years). In participants randomized to oral agents, 79% (n = 320) maintained glycemic control without insulin. With oral agents, 23.9% of infants (n = 97) were large for gestational age vs 19.9% (n = 79) with insulin (absolute risk difference, 4.0%; 95% CI, -1.7% to 9.8%; P = .09 for noninferiority), with the confidence interval of the risk difference exceeding the absolute noninferiority margin of 8%. Maternal hypoglycemia was reported in 20.9% with oral glucose-lowering agents and 10.9% with insulin (absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). All other secondary outcomes did not differ between groups. CONCLUSIONS AND RELEVANCE Treatment of gestational diabetes with metformin and additional glyburide, if needed, did not meet criteria for noninferiority compared with insulin with respect to the proportion of infants born large for gestational age.

Biosimilar insulins have been commercially available in the EU since 2014. Currently, six biosimilar insulins are approved in the EU and four in the US. However, commercial success has been limited, which may be in part due to concerns among physicians and people with diabetes that biosimilar insulins are substandard in efficacy, safety, and quality compared to reference products. Indeed, unlike generic drugs, which are identical chemical copies of their reference counterparts, in a biological manufacturing process, subtle differences can arise between products, even if the tertiary molecular structures are the same. Therefore, there is a clear regulatory pathway for the approval of biosimilars. For biosimilar insulins, preclinical (hormone receptor and cell) studies are needed to investigate potential differences in the response to biosimilar insulins and their reference medicinal products. In addition, there is a requirement for pivotal clinical pharmacology studies involving the euglycaemic glucose clamp technique to investigate comparative time-action profiles, whereas later-phase clinical safety, efficacy, and immunogenicity studies usually are no longer needed for the approval of biosimilar insulins. This narrative review provides an overview of pivotal phase 1 clamp and supportive larger phase 3 studies that supported the registration of biosimilar insulins in the EU and US, and discusses the need for interchangeability and immunogenicity studies. Overall, the current regulatory approach in the EU and in the USA ensures that there are no relevant differences between biosimilar insulins and their reference products. Therefore, people with diabetes and prescribers can use EU or US approved biosimilars without any concerns. PLAIN LANGUAGE SUMMARY: Six biosimilar insulins are approved by the EU regulator, the European Medicines Agency, and are currently available on the EU market. Three biosimilar insulins are approved by the US regulator, the Food and Drugs Agency, and are currently available on the US market. However, commercial success has been limited, which may be in part due to concerns among physicians and people with diabetes that biosimilar insulins are perhaps not quite the same as the original products with respect to efficacy, safety, and quality. Such concerns could be valid, because unlike generic drugs, which are identical chemical copies of their reference counterparts, biosimilar protein biosimilar and originator drugs cannot be chemically identical. In a biological manufacturing process, subtle difference can and will arise between products, even if the tertiary molecular structures, that is the amino acid sequence, the interactions between different parts of the protein and the three-dimensional folding, are the same. To assure that these unavoidable subtle differences do not result in differences in efficacy, safety and quality, there is a clear regulatory pathway for the approval of biosimilars. In addition to chemical studies, preclinical studies are needed to investigate potential differences in the response to biosimilar insulins and their reference medicinal products. These include e.g. studies investigating affinity to the insulin receptor, and how the insulins induce their effect in cell models. Next, pivotal clinical pharmacology studies involving the euglycaemic glucose clamp technique to investigate comparative time action profiles are required. Later phase clinical safety, efficacy and immunogenicity studies usually are no longer needed for the approval of biosimilar insulins. This narrative review provides an overview of pivotal phase 1 clamp and supportive larger phase 3 studies which supported registration of biosimilar insulins in the EU and US, and discusses the need for interchangeability and immunogenicity studies. Overall, the current regulatory approach in the EU and in the USA ensures that there are no relevant differences between biosimilar insulins and their reference products. Therefore, people with diabetes and prescribers can use EU or US approved biosimilars without any concerns.

Introduction: Glucagon-like peptide-1 receptor agonists reduce insulin requirements and improve glucose control when administered before cardiac surgery. An increase in endogenous insulin release is the most likely mechanism, but this has never been studied in the setting of cardiac surgery. We hypothesized that liraglutide increases pancreatic insulin secretion during cardiac surgery with cardiopulmonary bypass (CPB). Methods: We performed a planned prospective substudy of a multicenter randomized-controlled trial (GLOBE trial, NTR6323). Patients undergoing cardiac surgery with CPB were randomized to receive either two preoperative subcutaneous injections of liraglutide or a matching placebo. We measured hormone concentrations before and after surgery, including insulin, glucagon, C-peptide and free fatty acid (FFA), and calculated HOMA-B, HOMA-IR and insulin/glucagon ratios. We compared between-group and before and after surgery differences in outcomes. Results: Metabolic hormone concentrations were measured in 37 participants. HOMA-B revealed that liraglutide increased insulin secretion relative to glycemia (258 ± 179 vs 116 ± 180, difference (95% CI): 142 (24–261), P = 0.004). While insulin, C-peptide and glucagon levels did not differ significantly between groups, the insulin/glucagon ratios were significantly higher in the liraglutide group (preoperatively: 1.09 ± 0.45 vs 0.79 ± 0.35 difference (95% CI): −0.30 (−0.57 to −0.03), P = 0.039). Overall, postoperative insulin levels decreased >60% from preoperative insulin levels (55 ± 31 to 21 ± 9.8, difference (95% CI): −29 (−36 to −22), P < 0.001). Conclusion: Preoperative liraglutide administration increased beta-cell function, measured as HOMA-B, and higher insulin/glucagon ratios. These results could explain the lower glucose and FFA concentrations in the liraglutide-treated patients. Interestingly, in both groups, we observed a remarkable drop in insulin and other hormone levels over the course of surgery.

AIMS:To explore the relationship between weight loss and insulin sensitivity in response to tirzepatide or semaglutide. MATERIALS AND METHODS:We conducted a post hoc exploratory analysis of a 28-week, double-blind, randomized trial in people with type 2 diabetes treated with metformin, randomized to tirzepatide 15 mg, semaglutide 1 mg or placebo. We evaluated the relationship between change in body weight and change in insulin sensitivity determined from hyperinsulinemic euglycemic clamp (M value), or from mixed-meal tolerance testing (Matsuda index). RESULTS:Tirzepatide was associated with a greater improvement than semaglutide in insulin sensitivity assessed using hyperinsulinemic euglycemic clamps (p < 0.001). With tirzepatide, improvements in insulin sensitivity were associated with percent change in weight (R = -0.656, p < 0.0001). With semaglutide, change in insulin sensitivity was less strongly correlated with percent change in weight (R = -0.268, p = 0.0820; p = 0.0242 vs. tirzepatide). In regression analyses, the slope of the relationship between change in M value and change in weight was statistically different between semaglutide and tirzepatide (p = 0.0461). These relationships were also assessed using the Matsuda index as the metric of insulin sensitivity, and using change in fat mass as the determinant of change in insulin sensitivity. CONCLUSIONS:Improvement in insulin sensitivity was proportional to weight and fat loss, with greater strength of association with tirzepatide. In regression analysis, tirzepatide was associated with greater improvement in insulin sensitivity per unit weight loss than semaglutide. The greater improvement in insulin sensitivity following treatment with tirzepatide was not simply attributable to greater weight or fat loss.

One hundred years after insulin became commercially available, new formulations are still being developed. A first once-weekly insulin has been introduced on various markets, and results of the registration studies of a second once-weekly insulin are becoming available. In this narrative review, we discuss the mechanisms of prolongation, early clinical research study results, and the registration studies of these insulins, with a critical appraisal.

OBJECTIVE:Life expectancy of individuals with type 1 diabetes has increased, extending exposure to age-related conditions including dementia. Although earlier studies have linked type 1 diabetes with higher dementia risk, the relationships with dementia subtypes and associated risk factors are incompletely understood. RESEARCH DESIGN AND METHODS:In this cohort study, 43,440 individuals with type 1 diabetes from the Swedish National Diabetes Register and 217,109 age-, sex-, and county-matched control individuals from the Swedish Total Population Register were included. Cox regression was used to study the relation between type 1 diabetes and risk of all-cause dementia and dementia subtypes (Alzheimer disease, vascular dementia, and non-Alzheimer-nonvascular dementia). We also examined the relationship between various risk factors and risk of all-cause dementia in type 1 diabetes. RESULTS:After a median follow-up time of 14.3 (7.9-20.0) years, dementia was recorded in 530 (1.2%) individuals with type 1 diabetes and 1,867 (0.9%) age-, sex-, and county-matched control individuals (mean baseline age 33.0 [14.0] years). Compared with control individuals, individuals with type 1 diabetes had a higher risk of all-cause dementia (hazard ratio [HR] 2.02 [95% CI 1.83-2.23], Alzheimer disease (HR 1.38 [95% CI 1.13-1.69]), vascular dementia (HR 3.73 [95% CI 3.07-4.52]) and non-Alzheimer-nonvascular dementia (HR 1.87 [95% CI 1.63-2.15]). Risk factors related to dementia risk in type 1 diabetes beyond age were lower education level, being single, higher systolic blood pressure, higher HbA1c, history of stroke or transient ischemic attack, history of cardiovascular disease, and longer diabetes duration. CONCLUSIONS:The risk of all-cause dementia and dementia subtypes is higher in individuals with type 1 diabetes compared with matched control individuals.

Background: Glucose is an essential molecule in energy metabolism. Dysregulated glucose metabolism, the defining feature of diabetes, requires active monitoring and treatment to prevent significant morbidity and mortality. Current technologies for intermittent and continuous glucose measurement are invasive. Noninvasive glucose measurement would eliminate this barrier toward making glucose monitoring more accessible, extending the benefits from people living with diabetes to prediabetes and the healthy. Methods: A novel spectroscopy-based system for measuring glucose noninvasively was used in an exploratory, prospective, single-center clinical study (NCT06272136) to develop and test a machine learning-based computational model for continuous glucose monitoring without per-subject calibration. The study design blinded the development investigators to the validation analyses. Results: Twenty subjects were enrolled. Fifteen were used for the development set, and five in the validation set. All study participants were adults with insulin-treated diabetes and median glycated hemoglobin (HbA(1c)) of 7.3% (interquartile range [IQR] = 6.7-7.7). The computational model resulted in a mean absolute relative difference (MARD) of 14.5% and 96.5% of the paired glucose data points in the A plus B zones of the Diabetes Technology Society (DTS) error grid. The correlation between the average model sensitivity by wavelength and the spectrum of glucose was 0.45 (P < .001). Conclusions: Our findings suggest that Raman spectroscopy coupled with advanced computational methods can enable continuous, noninvasive glucose measurement without per-subject invasive calibration.

Introduction and Objective: Currently available glucagon-like peptide-1 receptor agonists are dosed once-daily or once-weekly. Extending the dosing interval aims to increase convenience and adherence. We developed NEX-22A, a prolonged-release formulation of liraglutide based on atomic layer deposition (ALD) technology, for once-monthly subcutaneous (s.c.) injection. This open, single ascending dose, phase 1 study assessed the pharmacokinetics (PK), safety and tolerability of a single s.c. injection of NEX-22A. Methods: Three cohorts (N=9) received doses of NEX-22A at 1.5 mg, 4.5 mg and 10 mg, respectively. The PK and safety profiles were followed for 36 days. Results: At baseline, participants (3 female and 6 male) had a mean ± SD age of 59.7 ± 4.1 years, BMI 28.3 ± 3.8 kg/m2 and HbA1c 7.2 ± 0.4%. A dose-linear increase in peak concentrations and duration of PK exposure was observed (Fig. 1). Following administration of NEX-22A 10 mg, liraglutide plasma concentrations were detected for up to 30 days with a maximum concentration (Cmax ) of ~4.9 nmol/L, between 24-48 hours post-injection. Seven participants experienced mild injection site reactions (most common: erythema), which usually resolved within 1 week. No gastrointestinal adverse events were reported. Conclusion: NEX-22A, a novel once-monthly formulation of liraglutide using ALD technology, was well tolerated and showed exposure for up to 30 days after a single s.c. injection. J. DeVries: Research Support; Neodyne, Gan & Lee Pharmaceuticals. Consultant; Gan & Lee Pharmaceuticals. Research Support; Liom. Advisory Panel; Liom. Speaker's Bureau; Novo Nordisk A/S. T. Heise: Research Support; ADOCIA, Afon Technology, AstraZeneca, Altimmune Inc, Biocon, BIOTON, Civica Foundation, Eli Lilly and Company, Zealand Pharma A/S, Betagenon, Cass Pharmaceuticals, Novo Nordisk A/S, Corteria, Zealand Pharma A/S, Cytoki, Enyo Pharma, Gan & Lee Pharmaceuticals, Genova, Nanexa, Neodyne, SamChunDang Pharma. Co., Spiden, Sun Pharmaceutical Industries Ltd. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk A/S. Consultant; Gan & Lee Pharmaceuticals. G. Andersen: None. E. Westrin: Other Relationship; Nanexa AB. M. Nehlin: Consultant; Nanexa AB. M. Gårdmark: None. K.A. Bäck: Employee; Nanexa AB. O.R. Luhr: Consultant; Nanexa AB. Study funded by Nanexa