Current and Future Strategies in Insulin Development and Treatment.

BACKGROUND: Recent advances in insulin research open new avenues for treatment, both, for type 1 and type 2 diabetes. In developed countries, standardized "ultra-rapid-acting insulins" are now also used in addition to rapid-acting insulins. First- and second-generation basal analogs are available. Third-generation basal analogs, which only need to be applied once a week, are in the pipeline. SUMMARY: Second-generation "ultra-rapid-acting insulins" insulins with faster onset and offset of action may be particularly useful for multiple daily injections and automated insulin delivery systems. An improved time-action profile of bolus insulin would be able to cover the rapid increase in glucose after meals with a rapid fall thereafter to avoid postprandial hypoglycemia. The third-generation basal insulins allowing once-weekly dosing made major steps toward becoming a clinical reality. However, issues with insulin affordability and availability remain problematic even in more affluent countries. Biosimilar insulins products can provide people with additional safe, high-quality, and potentially cost-effective options for treating diabetes. Particularly in low-middle income countries insulin therapy is facing issues not only of access but also storage, lack of diabetes education, and stigma. KEY MESSAGE: With the new bolus insulins, the physiological insulin secretion pattern can be mimicked better and better and hypoglycemia can be avoided. With the ever longer pharmacokinetic action profiles of the basal analogs, the injection frequency is reduced, which leads to better adherence and quality of life, but these insulins are not available for everyone who needs it worldwide.

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 programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (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 nonspecialized 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 emphasizes significant unmet needs for further research on early-stage type 1 diabetes to increase the rigor of future recommendations and inform clinical care.

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.

Towards the standardisation of adult person-reported outcome domains in diabetes research: A Consensus Statement development panel.

Diabetes is unique among chronic diseases because clinical outcomes are intimately tied to how the person living with diabetes reacts to and implements treatment recommendations. It is further characterised by widespread social stigma, judgement and paternalism. This physical, social and psychological burden collectively influences self-management behaviours. It is widely recognised that the individual's perspective about the impact of trying to manage the disease and the burden that self-management confers must be addressed to achieve optimal health outcomes. Standardised, rigorous assessment of mental and behavioural health status, in interaction with physical health outcomes is crucial to aid understanding of person-reported outcomes (PROs). Whilst tempting to conceptualise PROs as an issue of perceived quality of life (QoL), in fact health-related QoL is multi-dimensional and covers indicators of physical or functional health status, psychological and social well-being. This complexity is illuminated by the large number of person reported outcome measures (PROMs) that have been developed across multiple psychosocial domains. Often measures are used inappropriately or because they have been used in the scientific literature rather than based on methodological or outcome assessment rigour. Given the broad nature of psychosocial functioning/mental health, it is important to broadly define PROs that are evaluated in the context of therapeutic interventions, real-life and observational studies. This report summarises the central themes and lessons derived in the assessment and use of PROMs amongst adults with diabetes. Effective assessment of PROMs routinely in clinical research is crucial to understanding the true impact of any intervention. Selecting appropriate measures, relevant to the specific factors of PROs important in the research study will provide valuable data alongside physical health data.

Association Between Treatment Adherence and Continuous Glucose Monitoring Outcomes in People With Diabetes Using Smart Insulin Pens in a Real-World Setting.

OBJECTIVE: To evaluate the association of insulin injection adherence, smart insulin pen engagement, and glycemic control using real-world data from 16 countries from adults self-administering basal insulin degludec and bolus insulin with a smart insulin pen (NovoPen 6 or NovoPen Echo Plus) alongside continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS: Data were aggregated over 14-day periods. Treatment adherence was defined according to the number of missed basal and missed bolus insulin doses and smart pen engagement according to the number of days with data uploads. RESULTS: Data from 3,945 adults, including 25,157 14-day periods with ≥70% CGM coverage, were analyzed. On average, 0.2 basal and 6.0 bolus insulin doses were missed over 14 days. The estimated probability of missing at least one basal insulin dose over a 14-day period was 17.6% (95% CI 16.5, 18.7). Missing one basal or bolus insulin dose per 14 days was associated with a significant decrease in percentage of time with glucose levels in range (TIR) (3.9-10.0 mmol/L), of -2.8% (95% CI -3.7, -1.8) and -1.7% (-1.8, -1.6), respectively; therefore, missing two basal or four bolus doses would decrease TIR by >5%. Smart pen engagement was associated positively with glycemic outcomes. CONCLUSIONS: This combined analysis of real-world smart pen and CGM data showed that missing two basal or four bolus insulin doses over a 14-day period would be associated with a clinically relevant decrease in TIR. Smart insulin pens provide valuable insights into treatment injection behaviors.

Moving from Insulin Substitution to the Treatment of the Underlying Autoimmune Disease in Type 1 Diabetes.

Currently, a paradigm change occurs in type 1 diabetes from insulin substitution to the treatment of the underlying autoimmune disease. Teplizumab, a humanized monoclonal anti-CD3 antibody, is the first FDA-approved disease-modifying treatment of preclinical stage 2 diabetes. Research of drugs like golimumab, a monoclonal antibody specific for TNF alpha, baricitinib, a tyrosine kinase inhibitor, or frexalimab, a monoclonal antibody against the CD40 ligand, is still ongoing. Repurposing drugs that have been used in other indications like the calcium channel blocker verapamil, antithymocyte globulin (ATG), an antibody preparation used in solid organ transplantation, glucagon-like peptide-1 agonists utilized in type 2 diabetes and obesity, or the antiviral drugs pleconaril and ribavirin have shown positive effects in preserving beta-cell function. While new therapies to halt autoimmunity and restore beta cells in stages one to three are being developed, replacing beta-cell function via inducible pluripotent stem cells have shown glucose control and insulin independence in long-standing type 1 diabetes, albeit with concomitant immunosuppression. Multicenter multinational initiatives developing a clinical trial network like INNODIA or a research platform with the goal of stopping type 1 diabetes in its early stages like EDENT1FI will be instrumental to study these new strategies.

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults.

AIMS/HYPOTHESIS: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. METHODS: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.

Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in type 1 diabetes and type 2 diabetes: Lipid goal attainment in a large German-Austrian diabetes registry.

AIM: To assess the implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline recommendations for lipid-lowering therapies among more than 30 000 patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) in a German and Austrian registry from 2020 to 2022. MATERIALS AND METHODS: Registry data from 2020 and 2021 of 32 170 adult patients (8314 patients with T1D and 23 856 with T2D) were stratified according to the 2019 ESC/EAS risk categories, and guideline-based low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) goal attainment was analysed. RESULTS: In patients with T1D (median age 38.35 [20.51-57.13] years), overall statin use was 19.3%, ezetimibe use was 2.2% and the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or fibrates was less than 1%. In patients with T2D (median age 68.76 [58.86-78.39] years), 45.7% received statins, 3.4% received ezetimibe, and fibrates and PCSK9 inhibitors were used by 1% and 0.1%, respectively. Among patients with T1D, 6.16% reached their risk-based recommended LDL-C goal of less than 55 mg/dL (very high risk), 10.97% of less than 70 mg/dL (high risk), and 69.50% of less than 100 mg/dL (moderate risk), respectively. In patients with T2D, 11.81% reached their risk-based goal of LDL-C less than 55 mg/dL, 16.25% of less than 70 mg/dL, and 51.33% of less than 100 mg/dL. Non-HDL-C goals were reached more often, with 15.3%, 25.52% and 91.61% in patients with T1D and 18.56%, 17.96% and 82.30% in patients with T2D for very high, high and moderate risk, respectively. CONCLUSION: Approximately 2 years after publication of the guidelines, LDL-C and non-HDL-C goal attainment was rarely achieved in patients with T1D and T2D with a high or very high cardiovascular risk.

Alterations in Dietary Behavior, Appetite Regulation, and Health-Related Quality of Life in Youth with Obesity in Germany during the COVID-19 Pandemic.

BACKGROUND: This study aimed to evaluate the impact of the COVID-19 pandemic on the nutritional patterns, eating behavior, dietary content, and health-related quality of life (HrQoL) of adolescents with preexisting obesity. METHODS: Anthropometric and metabolic parameters were measured, and validated questionnaires on eating habits, nutritional content, and HrQoL were administered to 264 adolescents with obesity during the COVID-19 pandemic (June 2020-June 2022) and 265 adolescents with obesity before the pandemic (from June 2017 to June 2019). RESULTS: Both study cohorts were comparable in age and sex distribution. Significant differences were found between the COVID-19 and pre-COVID-19 cohorts in HOMA-index (3.8 (interquartile range [IQR])): 3.3; 4.1) vs. 3.2 (IQR: 2.8; 3.5, p < 0.001), total cholesterol (208.8 mg/dL (IQR: 189.9; 214.5) vs. 198.5 mg/dL (IQR: 189.5; 207.4), p < 0.001), and GPT (93.4 (IQR 88.7; 96.5) vs. 72.8 U/L (IQR 68.9; 75.7), p < 0.001). The COVID-19 cohort reported significantly higher consumption of obesity-promoting food components, such as soft drinks, meat, sausages, fast food and delivery food, chocolate, and sweets. There was also a significant decrease in cognitive hunger control (p = 0.002) and an increase in distractibility potential (p = 0.001) while eating. HrQoL was significantly lower in the COVID-19 cohort (p = 0.001). CONCLUSIONS: This study reveals the adverse associations of exposure to the public health measures during the COVID-19 pandemic with nutrition, dietary content, and HrQoL in adolescents with preexisting obesity. These findings underscore the importance of tailored preventive and treatment strategies for addressing the specific challenges of disruptive events such as pandemics, especially in population-based context.

Intermittent Use of Continuous Glucose Monitoring: A New Paradigm in Treatment of Type 2 Diabetes.

OBJECTIVES: To suggest how continuous glucose monitoring (CGM) may be used intermittently in individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The use of CGM is largely in those with type 1 diabetes (T1D), in whom it makes sense to use CGM continuously as CGM provides a valuable tool to not only adjust their insulin doses but also to match it with their diet, physical activity, and other lifestyle modifications. In the case of T2D, however, especially for those not on insulin, the use of CGM may not be needed on a continuous basis. The use of CGM on an intermittent basis is rarely discussed in the literature. This article tries to provide clinical situations where CGM can be used intermittently. RESULTS: Intermittent use of CGM defined as the "use of CGM once in 2 or 3 months or a fixed frequency," and may be useful in several situations in those with T2D. We suggest the following indications for the intermittent use of CGM in T2D-newly diagnosed patients where treatment is being started, uncontrolled diabetes where treatment is being altered, starting intensive lifestyle modification, during infections, during preoperative control, in children and adolescents with T2D, as a motivational tool to improve behavioral modification, after metabolic surgery, and in patients on steroids, apart from other indications. CONCLUSION: Intermittent use of CGM in T2D can be useful in special situations and can also be cost saving particularly in resource-constrained regions of the world.

An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria.

BACKGROUND: The FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany. METHODS: German patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared. RESULTS: Overall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT's albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible. CONCLUSIONS: Certain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.

Prevalence of LDL-hypercholesterolemia and other cardiovascular risk factors in young people with type 1 diabetes.

BACKGROUND: Mortality and morbidity in people with Type 1 diabetes (T1D) is mainly caused by cardiovascular disease (CVD). Early treatment of cardiovascular risk factors (CVRFs) is of great importance. OBJECTIVE: To analyze the prevalence of LDL-hypercholesterolemia and other CVRFs in youth with T1D. METHODS: Clinical and laboratory parameters, and vascular thickness measurement were obtained in youth with T1D (age 6-18 years, T1D duration >1 year) attending a diabetes clinic. LDL-hypercholesterolemia, microalbuminuria and arterial hypertension were defined as CVRFs. RESULTS: A total of 333 youth (48% girls; age: 13.3 years [10.3-15.5], median [interquartile range]) participated in the study. The T1D duration was 5.9 years [3.5-9.4] with HbA1c of 7.4% [6.8-8.0]. Intima media thickness (N=223) was 538.0 µm [470.0-618.0]). LDL-hypercholesterolemia was present in 30 participants (9%; 18 girls; age: 14.3 years [11.2-15.7]). None of the participants had persistent microalbuminuria, although 59 (18.3%) had elevated albumin excretion in a random urine specimen. LDL-hypercholesterolemia was associated with increased blood pressure (p<0.05), insulin requirement (p<0.05), HbA1c (p<0.05), triglyceride (p<0.001) and total cholesterol (p<0.001), and a family history of premature CVD (p<0.001), but negatively correlated with HDL cholesterol levels (p<0.05). Sex, pubertal status, duration of diabetes, type of therapy, and physical activity did not differ between participants with and without LDL- hypercholesterolemia. Arterial hypertension was present in 11 participants (3.3%; 4 girls; age: 14.1 years [11.1-16.1]). CONCLUSION: LDL-hypercholesterolemia affected 9% of youth with T1D in this cohort and was associated with other CVRFs. A holistic therapeutic concept for these young people is essential.

Skin manifestations in rare types of diabetes and other endocrine conditions.

As the most visible and vulnerable organ of the human organism, the skin can provide an impression of its state of health. Rare forms of diabetes and endocrinopathies are often diagnosed late or primarily misinterpreted due to their rarity. Skin peculiarities associated with these rare diseases may be indicative of the underlying endocrinopathy or form of diabetes. At the same time, rare skin changes in diabetes or endocrinopathies can also be a major challenge for dermatologists, diabetologists and endocrinologists in optimal patient and therapy management. Active collaboration between these different specialist groups can therefore lead to increased patient safety, better therapeutic success and more targeted diagnostics.

Direct LDL-C estimation in preschoolers: Practicable first step for FH screening.

BACKGROUND: Individuals with FH develop cardiovascular disease due to lifelong cumulative exposure to elevated LDL-C. Effective screening for FH is not yet established. OBJECTIVE: To evaluate the practicability of a FH screening by measuring directly the LDL-C in preschoolers. METHODS: LDL-C measurement through capillary blood sampling during the compulsory routine check-ups by the pediatrician in children aged 2 to 6 years including information on family history as dyslipidemia and/or premature cardiovascular disease in first and second grade of pedigrees. RESULTS: 15,009 children (52.2% males, median age 3.9 years [IQR 3.0-5.1]) participated in the study. Positive family history for hyperlipidemia was stated in 40.9% cases, in 12.0% also in at least one 1st degree relative. In the total cohort, median LDL-C was 93 mg/dL [IQR 79-109 mg/dL]. Boys had significantly higher LDL-C levels than girls (p < 0.0001), whereas there was no difference regarding their age (p = 0.757). Children from families with a positive history for hypercholesterolemia/dyslipidemia had significantly higher LDL-C levels (p < 0.001) and were more frequently among those with LDL-C values above 135 mg/dL (3.5 mmol/L, 96th percentile; 53.2% vs. 40.3%, p < 0.001) and those with LDL-C levels above 160 mg/dL (4.1 mmol/L, 99th percentile; 45.3% vs. 40.7%, p < 0.001) than children without positive family history. CONCLUSIONS: Direct measurement of LDL-C levels in children at ages 2-6 years during the compulsory routine check-ups as well as at any voluntary visits to the pediatrician's office is practicable and delivers reliable information, which can be used for a FH screening strategy in the general population.

Ultra rapid lispro showed greater reduction in postprandial glucose versus Humalog in children, adolescents and adults with type 1 diabetes mellitus.

AIM: This study compared the pharmacokinetics, glucodynamics and tolerability following single subcutaneous doses of ultra rapid lispro (URLi) versus Humalog in children (6-11 years), adolescents (12-17 years) and adults (18-64 years) with type 1 diabetes mellitus (T1D). MATERIALS AND METHODS: The study was a randomized, two-period, subject- and investigator-blind, crossover design in participants with T1D. Participants received a 0.2 U/kg bolus dose immediately before a liquid mixed meal tolerance test. Insulin lispro and glucose concentrations were measured. RESULTS: The study included 13 children, 14 adolescents and 15 adults. Consistently across the age groups, onset of appearance was 4-5 min faster, the early 50% tmax was reduced by 7-13 min, and exposure in the first 15 min was increased by 3.5-6.5-fold following URLi compared with Humalog (all p < .01). Exposure after 3 h was decreased by 37-58% (p = .02) and the duration was reduced by 56 min (p = .006) in children and 36 min (p = .022) in adolescents with URLi compared with Humalog. The maximum and overall exposure were similar between treatments. Postprandial glucose at 1 h was reduced by 42 mg/dl in children (p = .008), 19 mg/dl (p = .195) in adolescents and 34 mg/dl (p = .018) in adults following URLi versus Humalog. The glucose excursion during a 5-h test meal period was reduced by 16% in children and 9% in adolescents compared with Humalog. URLi was well tolerated in all age groups. CONCLUSIONS: URLi showed an accelerated insulin lispro absorption and greater postprandial glucose reduction compared with Humalog in children, adolescents and adults with T1D.