Patient Perspectives on the Benefits and Challenges of Diabetes and Digital Technology.

Diabetes technology continues to evolve, advancing with our understanding of human biology and improving our ability to treat people with diabetes. Diabetes devices are broadly classified into the following categories: glucose sensors, insulin delivery devices, and digital health care technology (i.e., software and mobile applications). When supported by education and individually tailored, technology can play a key role in optimizing outcomes. Digital devices assist in diabetes management by tracking meals, exercise, sleep, and glycemic measurements in real time, all of which can guide physicians and other clinicians in their decision-making. Here, as people with diabetes and patient advocates, as well as diabetes specialists, primary care providers, and diabetes care and education specialists, we present our perspectives on the advances, benefits, and challenges of diabetes technology in primary care practices.

CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes.

The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10-12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year's focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23-24, 2023 ( http://www.cvot.org ).

Continuous glucose monitoring-based time-in-range using insulin glargine 300 units/ml versus insulin degludec 100 units/ml in type 1 diabetes: The head-to-head randomized controlled InRange trial.

AIM: To use continuous glucose monitoring (CGM)-based time-in-range (TIR) as a primary efficacy endpoint to compare the second-generation basal insulin (BI) analogues insulin glargine 300 U/ml (Gla-300) and insulin degludec 100 U/ml (IDeg-100) in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: InRange was a 12-week, multicentre, randomized, active-controlled, parallel-group, open-label study comparing glucose TIR and variability between Gla-300 and IDeg-100 using blinded 20-day CGM profiles. The inclusion criteria consisted of adults with T1D treated with multiple daily injections, using BI once daily and rapid-acting insulin analogues for at least 1 year, with an HbA1c of 7% or higher and of 10% or less at screening. RESULTS: Overall, 343 participants were randomized: 172 received Gla-300 and 171 IDeg-100. Non-inferiority (10% relative margin) of Gla-300 versus IDeg-100 was shown for the primary endpoint (percentage TIR ≥ 70 to ≤ 180 mg/dl): least squares (LS) mean (95% confidence interval) 52.74% (51.06%, 54.42%) for Gla-300 and 55.09% (53.34%, 56.84%) for IDeg-100; LS mean difference (non-inferiority): 3.16% (0.88%, 5.44%) (non-inferiority P = .0067). Non-inferiority was shown on glucose total coefficient of variation (main secondary endpoint): LS mean 39.91% (39.20%, 40.61%) and 41.22% (40.49%, 41.95%), respectively; LS mean difference (non-inferiority) -5.44% (-6.50%, -4.38%) (non-inferiority P < .0001). Superiority of Gla-300 over IDeg-100 was not shown on TIR. Occurrences of self-measured and CGM-derived hypoglycaemia were comparable between treatment groups. Safety profiles were consistent with known profiles, with no unexpected findings. CONCLUSIONS: Using clinically relevant CGM metrics, InRange shows that Gla-300 is non-inferior to IDeg-100 in people with T1D, with comparable hypoglycaemia and safety profiles.

Insights into optimal basal insulin titration in type 2 diabetes: Results of a quantitative survey.

AIMS: Basal insulin (BI) treatment initiation and dose titration in type 2 diabetes (T2DM) are often delayed. Such "clinical inertia" results in poor glycaemic control and high risk of long-term complications. This survey aimed to determine healthcare professional (HCP) and patient attitudes to BI initiation and titration. METHODS: An online survey (July-August 2015) including HCPs and patients with T2DM in the USA, France and Germany. Patients were ≥18 years old and had been on BI for 6 to 36 months, or discontinued BI within the previous 12 months. RESULTS: Participants comprised 386 HCPs and 318 people with T2DM. While >75% of HCPs reported discussing titration at the initiation visit, only 16% to 28% of patients remembered such discussions, many (32%-42%) were unaware of the need to titrate BI, and only 28% to 39% recalled mention of the time needed to reach glycaemic goals. Most HCPs and patients agreed that more effective support tools to assist BI initiation/titration are needed; patients indicated that provision of such tools would increase confidence in self-titration. HCPs identified fear of hypoglycaemia, failure to titrate in the absence of symptoms, and low patient motivation as important titration barriers. In contrast, patients identified weight gain, the perception that titration meant worsening disease, frustration over the time to reach HbA1c goals and fear of hypoglycaemia as major factors. CONCLUSION: A disconnect exists between HCP- and patient-perceived barriers to effective BI titration. To optimize titration, strategies should be targeted to improve HCP-patient communication, and provide support and educational tools.

CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes.

Previous cross-sectional analyses demonstrated that CD8(+) and CD4(+) T-cell reactivity to islet-specific antigens was more prevalent in T1D subjects than in healthy donors (HD). Here, we examined T1D-associated epitope-specific CD4(+) T-cell cytokine production and autoreactive CD8(+) T-cell frequency on a monthly basis for one year in 10 HD, 33 subjects with T1D, and 15 subjects with T2D. Autoreactive CD4(+) T-cells from both T1D and T2D subjects produced more IFN-γ when stimulated than cells from HD. In contrast, higher frequencies of islet antigen-specific CD8(+) T-cells were detected only in T1D. These observations support the hypothesis that general beta-cell stress drives autoreactive CD4(+) T-cell activity while islet over-expression of MHC class I commonly seen in T1D mediates amplification of CD8(+) T-cells and more rapid beta-cell loss. In conclusion, CD4(+) T-cell autoreactivity appears to be present in both T1D and T2D while autoreactive CD8(+) T-cells are unique to T1D. Thus, autoreactive CD8(+) cells may serve as a more T1D-specific biomarker.

InRange: Comparison of the Second-Generation Basal Insulin Analogues Glargine 300 U/mL and Degludec 100 U/mL in Persons with Type 1 Diabetes Using Continuous Glucose Monitoring-Study Design.

INTRODUCTION: Suboptimal glycaemic control among people with type 1 diabetes (T1D) is known to lead to long-term micro- and macrovascular complications and, unfortunately, it is still prevalent even in the most affluent societies. Although glycated haemoglobin monitoring is considered to be the gold standard for assessing glycaemic control, such monitoring is unable to reliably measure acute glycaemic excursions. Continuous glucose monitoring (CGM) has been shown to improve glucose control and reduce the incidence of hypoglycaemia, and also allow a more complete assessment of overall glycaemic control and hyper- and hypoglycaemic excursions. The use of CGM has led to time-in-range, which is the time that a patient is within the glycaemic range of 70 to 180 mg/dL, to be adopted as a treatment target. To date, only limited data comparing the second-generation insulins glargine 300 U/mL (Gla-300) and degludec 100 U/mL (IDeg-100) in people with T1D are available, and there is no CGM literature on comparisons of the use of CGM results to assess primary, secondary and tertiary endpoints. The aim of the InRange study was to address this unmet need. METHODS: InRange is a multicentre, randomised, active-controlled, parallel-group, 12-week, open-label, phase 4, comparative study. Adults with T1D will be randomised to receive once-daily Gla-300 or IDeg-100 by subcutaneous injection in the morning. Following an 8-week titration period, CGM data will be collected over 20 consecutive days. PLANNED OUTCOMES: The primary objective is to demonstrate that Gla-300 is noninferior to IDeg-100 in terms of glycaemic control [time-in-range ≥ 70 to ≤ 180 mg/dL (≥ 3.9 to ≤ 10 mmol/L)] and variability, as assessed using CGM, in adults with T1D. The results are expected to help confirm the utility of CGM in clinical practice in this population and provide insight into its application as an outcome measure in clinical practice. TRIAL REGISTRATION: NCT04075513.

Correction to: InRange: Comparison of the Second-Generation Basal Insulin Analogues Glargine 300 U/mL and Degludec 100 U/mL in Persons with Type 1 Diabetes Using Continuous Glucose Monitoring-Study Design.

In the original publication, the timing of baseline CGM assessment was incorrectly stated in the text in two instances; it is correct in Fig. 1.

Correction to: InRange: Comparison of the Second-Generation Basal Insulin Analogues Glargine 300 U/mL and Degludec 100 U/mL in Persons with Type 1 Diabetes Using Continuous Glucose Monitoring-Study Design.

In the original publication, the timing of baseline CGM assessment was incorrectly stated.

Burden of Cardiovascular Disease in Adult Patients with Type 1 Diabetes in the US.

BACKGROUND AND OBJECTIVES: The burden imposed by cardiovascular disease (CVD) on patients with type 1 diabetes (T1D) in the US has not been thoroughly addressed. In a retrospective observational analysis of the Optum® Clinformatics™ Data Mart database, the prevalence of CVD and cardiovascular risk factors (CVRF) as well as health economic outcomes were evaluated in adults with T1D. METHODS: Patients with at least one T1D medical claim between January 1, 2016, and December 31, 2016, were divided into cohorts based on the presence of CVD and/or CVRF. Descriptive and multivariate analyses enabled comparisons of healthcare resource utilization and costs between the cohorts. RESULTS: The analysis included 12,687 patients: CVD, 2871; CVRF, 5371; and no CVD/CVRF, 4445. The period prevalence of CVD and CVRF in the combined baseline and follow-up periods was 27% and 44%, respectively. Fewer patients in the no-CVD/CVRF cohort had a claim of a diabetes-related inpatient admission compared with the CVD cohort (8% vs. 26%, respectively; P < 0.001, standardized mean difference [SMD] > 0.1). Likewise, fewer patients with no CVD/CVRF visited the emergency department vs. those with CVRF or CVD (diabetes-related: 4% vs. 7% and 18%, respectively; P < 0.001, SMD > 0.1). Higher overall costs were observed for the CVD and CVRF vs. the no-CVD/CVRF cohort ($30,241 and $16,220, respectively, vs. $11,761; P < 0.05 and SMD ≥ 0.1 for both). CONCLUSIONS: Cardiovascular comorbidities are common among US adults with T1D. Considering their significant economic burden, optimal management is of the utmost importance to improve patient outcomes and reduce healthcare costs.

Reference Guide for Integrating Continuous Glucose Monitoring Into Clinical Practice.

PURPOSE: Large randomized trials have demonstrated the efficacy of continuous glucose monitoring (CGM) in persons with type 1 diabetes and insulin-treated type 2 diabetes. The purpose of this article is to provide basic knowledge about CGM technology, discuss the use of CGM data in clinical practice, and direct clinicians to online resources that provide comprehensive information and tools relevant to patient selection, education/training, and reimbursement. CONCLUSIONS: Effective use of CGM requires all members of the health care team to become knowledgeable and skilled in integrating CGM into their practices and in teaching their patients how to safely incorporate CGM use into their daily diabetes self-management.

New therapeutic options for treating type-2 diabetes: a review of insulin analogs and premixed insulin analogs.

There is a growing consensus that blood glucose control, and postprandial control in particular, must become more aggressive if we are to stem the growing tide of diabetes-related complications and mortality. For most patients, this means that insulin therapy must begin earlier and that insulin must be titrated sufficiently to achieve tighter glycemic targets. The limitations of traditional treatment regimens, delivery devices and conventional insulin formulations, in conjunction with patient factors, have prevented the majority of people with type-2 diabetes from realizing the potential benefits of insulin therapy and achieving recommended glycemic targets. Fortunately, modern insulin analog formulations, new treatment regimens, and advanced delivery devices are now available. This review will discuss features of these new tools, and compare the benefits of using premixed insulin versus a basal-only approach to initiating insulin therapy. Once physicians become familiar with these tools and incorporate them into daily practice, they will be able to better tailor diabetes self-management programs to the needs of individual patients. The result will be that more patients should be able to reach recommended glycemic targets with greater convenience and safety than has previously been available.

A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes.

OBJECTIVE: To assess safety, efficacy, and tolerability of pramlintide dose escalation with proactive mealtime insulin reduction, followed by insulin optimization, in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: This 29-week, double-blind, placebo-controlled study randomized 296 patients to pramlintide or placebo as an adjunct to insulin. During initiation, pramlintide was escalated from 15 to 60 microg/meal (15-microg increments) with recommended reductions (30-50%) in mealtime insulin. Insulin was subsequently adjusted to optimize glycemic control. End points included safety and change in HbA1c (A1C), postprandial glucose, insulin, weight, and tolerability. RESULTS: Baseline A1C was 8.1% for both groups and at week 29 had decreased comparably (pramlintide -0.5% [95% CI -0.61 to -0.33]; placebo -0.5% [-0.63 to -0.35]). Pramlintide treatment significantly reduced postprandial glucose excursions (incremental area under the curve [AUC](0-3h): pramlintide -175 +/- 40, placebo -64 +/- 38 mg x h(-1) x dl(-1); P < 0.0005) and weight (pramlintide -1.3 +/- 0.30, placebo +1.2 +/- 0.30 kg; P < 0.0001). At week 29, insulin dose decreased by 28 and 4% in pramlintide- and placebo-treated groups, respectively. Nausea, reported by 63 and 36% of patients in pramlintide and placebo groups (P < 0.01), respectively, was predominately mild to moderate in intensity. Severe hypoglycemia rates were low in both groups (pramlintide 0.57 +/- 0.09, placebo 0.30 +/- 0.06 event rate/patient-year; P < 0.05), with increased rates observed in patients remaining at 30 microg pramlintide. CONCLUSIONS: Pramlintide dose escalation with reduced mealtime insulin was effective during therapy initiation in patients with type 1 diabetes. While both groups experienced equivalent A1C reductions relative to placebo, pramlintide-treated patients experienced reductions in postprandial glucose excursions and weight, not achievable with insulin therapy alone.

Addressing Unmet Needs With Injectable Medications in Type 2 Diabetes Treatment: Glucagon-Like Peptide-1 Receptor Agonists.

Since 2005, four new GLP-1RAs (liraglutide, albiglutide, dulaglutide, and lixisenatide) and a once-weekly formulation of exenatide were approved for the treatment of persons with T2DM. Another GLP-1RA, semaglutide, is under review by the FDA, as is exenatide administered via an osmotic mini-pump.

Comparative Assessment of Lixisenatide, Exenatide, and Liraglutide Pen Devices: A Pilot User-Based Study.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively recent addition to the treatment options for type 2 diabetes mellitus (T2DM) and are administered using prefilled pen devices. METHOD: In this open-label task and interview-based pilot study, 3 GLP-1 receptor agonist pen devices-exenatide (Byetta®, Bristol-Myers Squibb/AstraZeneca), liraglutide (Victoza®, Novo Nordisk), and lixisenatide (Lyxumia®, Sanofi-Aventis)-were comparatively assessed in a randomized order in 30 participants with T2DM for ease of use, using a series of key performance measures (time taken to complete a series of tasks, number of user errors [successful performance], and user satisfaction rating). Linear and logistic regression analysis was conducted for the lixisenatide and liraglutide pens versus the exenatide pen. Participants' mean age was 60 years; 27% and 20% of the participants had visual impairments and reduced manual dexterity, respectively. RESULTS: Tasks were completed faster (P < .001) and with higher successful performance (P = .001) with the lixisenatide pen than with the exenatide pen, whereas the liraglutide pen was not statistically significant versus the exenatide pen on these parameters. Overall, user satisfaction was statistically higher for the lixisenatide and liraglutide pens versus the exenatide pen (P < .001 for both). CONCLUSIONS: Lixisenatide and liraglutide pens are associated with higher user satisfaction compared with the exenatide pen. In addition, the lixisenatide pen is faster and results in fewer errors than its comparator (exenatide). The lixisenatide pen may therefore be a suitable choice for patients with T2DM, including older and pen device-naïve patients, and those with visual impairments and reduced manual dexterity.

AUTONOMY: the first randomized trial comparing two patient-driven approaches to initiate and titrate prandial insulin lispro in type 2 diabetes.

OBJECTIVE: To compare two self-titration algorithms for initiating and escalating prandial insulin lispro in patients with type 2 diabetes inadequately controlled on basal insulin. RESEARCH DESIGN AND METHODS: The trial was designed as two independent, multinational, parallel, open-label studies (A and B), identical in design, to provide substantial evidence of efficacy and safety in endocrine and generalist settings. Subjects were 18-85 years old (study A: N = 528; study B: N = 578), on basal insulin plus oral antidiabetic drugs for ≥3 months, and had an HbA1c 7.0% to ≤12.0% (>53.0 to ≤107.7 mmol/mol). Once optimized on insulin glargine, subjects were randomized to one of two self-titration algorithm groups adjusting lispro either every day (Q1D) or every 3 days (Q3D) for 24 weeks. The primary outcome was the change in HbA1c from baseline. The primary and secondary objectives were evaluated for the overall population and subjects ≥65 years old. RESULTS: Baseline HbA1c was similar (study A: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.453; study B: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.162). Both algorithms had significant and equivalent reductions in HbA1c from baseline (study A: Q3D -0.96% [-10.49 mmol/mol], Q1D -1.00% [-10.93 mmol/mol], Q3D-Q1D 0.04% [0.44 mmol/mol] [95% CI -0.15 to 0.22 (-1.64 to 2.40)]; study B: Q3D -0.92% [-10.06 mmol/mol], Q1D -0.98% [-10.71 mmol/mol], Q3D-Q1D 0.06% [0.66 mmol/mol] [95% CI -0.12 to 0.24 (-1.31 to 2.62)]). The incidence and rate of hypoglycemia were similar for Q3D and Q1D in both studies. In general, no clinically relevant differences were found between the two algorithms in subjects ≥65 years old in either study. CONCLUSIONS: Prandial insulin lispro can effectively and safely be initiated, by either of two self-titrated algorithms, in a variety of practice settings.

Impact of Biosimilar Insulins on Clinical Practice: Meeting Report.

The availability of biosimilar insulins can potentially lead to lower insulin costs and increased access for patients with diabetes, worldwide. However, clinicians and regulatory agencies have raised several concerns regarding the safety and efficacy of these new medications. The European regulatory agencies have established guidelines for market approval of biosimilar insulins; however, many issues remain unresolved. Moreover, although the FDA has developed preliminary pathways for biosimilar protein development and is prepared to review each application on a case-by-case basis, insulins do not fall under this pathway at this time. The development of effective postmarketing surveillance protocols, determination of product interchangeability, and product identification/labeling remain key concerns. Numerous issues surround the development and commercialization of biosimilar insulins; thus, it is important that all stakeholders fully understand the complexity of these issues and how they can potentially affect patient care. Bridging the educational gap among clinicians and regulatory agencies will be challenging but necessary for ensuring patient safety.

Temporal intra-individual variation of immunological biomarkers in type 1 diabetes patients: implications for future use in cross-sectional assessment.

Multiple immune parameters such as frequencies of autoreactive CD4(+), CD8(+) T-cells and CD4(+)CD25(+)Foxp3(+) T-cells have been explored as biomarkers in human T1D. However, intra-individual temporal variation of these parameters has not been assessed systematically over time. We determined the variation in each of these parameters in a cohort of T1D and healthy donors (HDs), at monthly intervals for one year. Despite low intra- and inter-assay co-efficient of variation (CV), mean CVs for each of the immune parameters were 119.1% for CD4(+) T-cell-derived IFN-γ, 50.44% for autoreactive CD8(+) T-cells, and 31.24% for CD4(+)CD25(+)Foxp3(+) T-cells. Further, both HDs and T1D donors had similar CVs. The variation neither correlated with BMI, age, disease duration or insulin usage, nor were there detectable cyclical patterns of variation. However, averaging results from multiple visits for an individual provided a better estimate of the CV between visits. Based on our data we predict that by averaging values from three visits a treatment effect on these parameters with a 50% effect size could be detected with the same power using 1.8-4-fold fewer patients within a trial compared to using values from a single visit. Thus, our present data contribute to a more robust, accurate endpoint design for future clinical trials in T1D and aid in the identification of truly efficacious therapies.