Multiple Insulin Injection Therapy Research Articles

Advanced decision support system for individuals with diabetes on multiple daily injections therapy using reinforcement learning and nearest-neighbors: In-silico and clinical results

Many individuals with diabetes on multiple daily insulin injections therapy use carbohydrate ratios (CRs) and correction factors (CFs) to determine mealtime and correction insulin boluses. The CRs and CFs vary over time due to physiological changes in individuals' response to insulin. Errors in insulin dosing can lead to life-threatening abnormal glucose levels, increasing the risk of retinopathy, neuropathy, and nephropathy. Here, we present a novel learning algorithm that uses Q-learning to track optimal CRs and uses nearest-neighbors based Q-learning to track optimal CFs. The learning algorithm was compared with the run-to-run algorithm A and the run-to-run algorithm B, both proposed in the literature, over an 8-week period using a validated simulator with a realistic scenario created with suboptimal CRs and CFs values, carbohydrate counting errors, and random meals sizes at random ingestion times. From Week 1 to Week 8, the learning algorithm increased the percentage of time spent in target glucose range (4.0 to 10.0 mmol/L) from 51 % to 64 % compared to 61 % and 58 % with the run-to-run algorithm A and the run-to-run algorithm B, respectively. The learning algorithm decreased the percentage of time spent below 4.0 mmol/L from 9 % to 1.9 % compared to 3.4 % and 2.3 % with the run-to-run algorithm A and the run-to-run algorithm B, respectively. The algorithm was also assessed by comparing its recommendations with (i) the endocrinologist's recommendations on two type 1 diabetes individuals over a 16-week period and (ii) real-world individuals' therapy settings changes of 23 individuals (19 type 2 and 4 type 1) over an 8-week period using the commercial Bigfoot Unity Diabetes Management System. The full agreements (i) were 89 % and 76 % for CRs and CFs for the type 1 diabetes individuals and (ii) was 62 % for mealtime doses for the individuals on the commercial Bigfoot system. Therefore, the proposed algorithm has the potential to improve glucose control in individuals with type 1 and type 2 diabetes.

58-OR: Glycemic Impact of Meal-Dosing Behavior in Users of the InPen Smart Insulin Pen (SIP) Paired with Continuous Glucose Monitoring (CGM)

Background: Data from connected insulin pen therapies are revealing both gaps and opportunities to significantly improve care for people on multiple daily insulin injections therapy. This real-world (RW) data analysis reports on the impact of meal-dosing behavior (missed and late) on glycemia in adult and pediatric InPen users with type 1 (T1D) or type 2 diabetes (T2D). Method: The RW data from 5,153 deidentified individuals who used the InPen SIP and CGM for at least 30 days between January 2020 and December 2021, and who had dosing and CGM data between 30 and 59 days since first bolus date, were analyzed using a meal detection algorithm. Users with <14 days of bolus data or inadequate CGM data (<14 days of 70% or more SG data/day) were excluded. Results: The impact of dosing behavior (≤2 versus >3 doses/day) and missed dose frequency (<20% versus ≥20%) on glycemia was analyzed (Table). A dosing frequency of >3 (including correction-only doses) and a missed dose frequency of <20% were associated with improved glycemic metrics. Overall, the frequency of on-time dosing was significantly correlated with user TIR (r=0.59, p<0.001). Conclusion: Real-world InPen with CGM use data provide insights into the impact of meal-dosing behavior on glycemic outcomes, which may inform counseling strategies for care teams and open the door to precision insulin injection management. Disclosure J.Macleod: Employee; Medtronic. M.Smith: Employee; Medtronic. G.Im: Employee; Medtronic. T.L.Cordero: Employee; Medtronic. R.A.Vigersky: Employee; Medtronic.

Comparative assessment of modern parameters of glycemic control in children with type 1 diabetes after switching to fast-acting insulin aspart using Flash Glucose Monitoring in real clinical practice

BACKGROUND: Postprandial hyperglycaemia contributes significantly to the lack of glycaemic control in patients with type 1 diabetes mellitus (DM1). At least a quarter of patients forget to inject insulin before meals once a week, and more than 40% of them inject bolus insulin immediately before meals, which does not correspond to the pharmacokinetic effects of ultrashort insulins and determines the need to use insulins with better imitations of physiological insulin secretion.AIM: To assess the effect of fast acting insulin aspart (FIAsp) on the current parameters of glycaemic control in children with DM1 after switching from insulin Asp (iAsp) using continuous glucose monitoring.MATERIALS AND METHODS: A multicenter observational 12-week prospective open-label uncontrolled comparative study was initiated. A group of insufficiently controlled patients were identified (n = 48) including a group on multiple insulin injections therapy (MII) (insulin degludec and IAsp) and a group on continuous subcutaneous insulin infusion (CSII) of iAsp. Three 14-day flash glucose monitoring (FMG) were performed: before transferring patients to FiAsp and after 2 and 12 weeks of the transfer. Key endpoints: HbA1c after 2 and 12 weeks on FiAsp relative to baseline, analysis of 5 FMG target glucose ranges, presented as an ambulatory glycemic profile. Additional indicators: dynamics of insulin daily dose, frequency of glucose self- monitoring, the number of severe hypoglycemia, adverse events that occurred during treatment.RESULTS: 2 weeks after the transfer from IAsp to FIAsp, TIR increased in the entire group of patients: from 53% [44.3; 66.5] to 57% [47.4; 71.0] (p-value = 0.010) and TAR decreased from 38% [24.8; 50.2] to 30.5% [22.0; 45, 0] (p-value = 0.0124). Maintaining and increase time spent in the target glucose ranges during a 12-week observation period, in parallel with a significant decrease in hypoglycemic episodes <3.9 mmol / L per week, on FIAsp therapy naturally leads to an improvement in diabetes control: a decrease in HbA1c from 8.15% up to 7.75% (p-value = 0.0224), more pronounced in the group of patients on CSII — from 7.9% to 7.5% (p-value = 0.028).CONCLUSION: Switching from IAsp to BDIAsp in routine clinical practice in the MII and CSII regimen in children and adolescents with type 1 diabetes allows achieving better glycemic control compared to the previous generation prandial insulin analog Iasp. The better diabetes control is associated with an increase or a trend towards an increase in TIR and a decrease or a trend towards a decrease in TAR and TBR, as well as a significant decrease in episodes of hypoglycemia.

Effect of the Chinese New Year Public Holiday on the Glycemic Control of T1DM With Intensive Insulin Therapy.

AimsThere is limited evidence that evaluates the glycemic control of type 1 diabetes mellitus (T1DM) during the Chinese New Year public holiday in China. The Chinese New Year public holiday represents various challenges to glycemic control, especially in T1DM patients, in China. We aimed to assess the effect of the Chinese New Year public holiday on several glucose metrics using flash glucose monitoring (FGM) in patients with T1DM.MethodsComplete FGM data for 1 week before, 1 week during and 1 week after the Chinese New Year public holiday were available for 71 T1DM patients treated with multiple daily insulin injection (MDI) therapy (n = 51) or continuous subcutaneous insulin infusion (CSII) treatment (n = 20). The mean age of the study participants was 13 (9, 30) years. Of note, 59.2% of the patients (n = 42) were adults, and 40.8% of the patients (n = 29) were minors. The interval between each two adjacent periods was one week. The indicators of mean glucose, glucose variability and time in different glycemic ranges were analyzed.ResultsThe Chinese New Year public holiday was associated with an increase in mean blood glucose (8.2 ± 1.9 vs. 8.9± 2.8; P < 0.001) and time above range (TAR) (26.1% ± 18.1% vs. 31.7% ± 23.9%; P < 0.001) but a decrease in time in range (TIR) (65.7% ± 16.8% vs. 59.9% ± 21.1%; P < 0.001) and coefficient of variation (CV) (38.2% ± 8.2% vs. 36.7% ± 7.7%; P =0.037). There was no statistically significant difference in time below range (TBR). The glycemic control deteriorated during the Chinese New Year public holiday in our study population regardless of age. Interestingly, in the CSII group, none of the metrics of glucose control significantly changed during the Chinese New Year public holiday.ConclusionsThese results suggested that less self-management may worsen glycemic control in the short term, indicating a need for more refined management algorithms during the Chinese New Year public holiday for T1DM patients.

Trajectory and predictors of HbA1c in children and adolescents with type 1 diabetes-A Danish nationwide cohort study.

Poor glycemic control in type 1 diabetes increases the risk of chronic complications and it is essential to identify life periods and predictors associated with deteriorating HbA1c . The aim was to describe specific HbA1c trajectories in Danish children and adolescents with type 1 diabetes and study associations with clinical and sociodemographic factors. 5889 children with type 1 diabetes were included from the nationwide Danish Registry of Childhood and Adolescent Diabetes with annual visits during 1996-2019. Trajectories of HbA1c were modeled with linear mixed-effects models (using age as time scale, included as cubic spline) and with an individual-specific random intercept and slope. The following cofactors were included stepwise into the model: sex, age at diagnosis, calendar year, parental education, immigrant status, health care region, blood glucose monitoring (BGM) frequency, treatment modalities: continuous subcutaneous insulin infusion (pump) versus multiple daily insulin injection therapy (pen) and continuous glucose monitoring. HbA1c overall increased during age while there was a significant decreasing secular trend. Older age at diagnosis was associated with a steeper trajectory, and non-Danish origin and shorter parental education were each associated with higher levels of HbA1c across age. A lower BGM frequency was associated with a markedly poorer HbA1c trajectory, while no significant differences were shown for different treatment modalities. Glycemic outcome worsened with age during childhood and adolescence, which is of clinical concern. Important predictors for a poorer glycemic trajectory were later age at diabetes diagnosis, shorter parental education, non-Danish origin and, in particular low BGM frequency.

A Position Statement of the Utilization and Support Status of Continuous Glucose Monitoring in Korea

The accuracy and convenience of continuous glucose monitoring (CGM), which efficiently evaluates glycemic variability and hypoglycemia, are improving. There are two types of CGM: professional CGM and personal CGM. Personal CGM is subdivided into real-time CGM (rt-CGM) and intermittently scanned CGM (isCGM). CGM is being emphasized in both domestic and foreign diabetes management guidelines. Regardless of age or type of diabetes, CGM is useful for diabetic patients undergoing multiple insulin injection therapy or using an insulin pump. rt-CGM is recommended for all adults with type 1 diabetes (T1D), and can also be used in type 2 diabetes (T2D) treatments using multiple insulin injections. In some cases, short-term or intermittent use of CGM may be helpful for patients with T2D who use insulin therapy other than multiple insulin injections and/or oral hypoglycemic agents. CGM can help to achieve A1C targets in diabetes patients during pregnancy. CGM is a safe and cost-effective alternative to self-monitoring blood glucose in T1D and some T2D patients. CGM used in diabetes management works optimally with proper education, training, and follow up. To achieve the activation of CGM and its associated benefits, it is necessary to secure sufficient repetitive training and time for data analysis, management, and education. Various supports such as compensation, insurance coverage expansion, and reimbursement are required to increase the effectiveness of CGM while considering the scale of benefit recipients, policy priorities, and financial requirements.

Dulaglutide as an Effective Replacement for Prandial Insulin in Kidney Transplant Recipients with Type 2 Diabetes Mellitus: A Retrospective Review.

Dulaglutide, a weekly injectable glucagon-like peptide-1 receptor agonist, has demonstrated effectiveness when combined with basal insulin. We examined whether the efficacy of dulaglutide is comparable to that of prandial insulin in kidney transplant (KT) recipients with type 2 diabetes mellitus (T2DM) undergoing multiple daily insulin injection (MDI) therapy. Thirty-seven patients, who switched from MDI therapy to basal insulin and dulaglutide, were retrospectively analyzed. Changes in glycosylated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels, body weight, and basal insulin dose were evaluated over 6 months. Dulaglutide was comparable to three injections of prandial insulin in terms of glycemic control (HbA1c 7.1% vs. 7.0%; 95% confidence interval [CI], –0.53 to 0.28; P=0.53). The basal insulin and dulaglutide combination resulted in a reduction in FPG levels by 9.7 mg/dL (95% CI, 2.09 to 41.54; P=0.03), in body weight by 4.9 kg (95% CI, 2.87 to 6.98; P<0.001), and in basal insulin dose by 9.52 IU (95% CI, 5.80 to 3.23; P<0.001). Once-weekly dulaglutide may be an effective alternative for thrice-daily prandial insulin in KT recipients with T2DM currently receiving MDI therapy.

Real-World Efficacy of the Hybrid Closed-Loop System.

Hybrid closed-loop (HCL) insulin pump therapy (Medtronic 670G) is an emerging technology that is growing in use worldwide. Initial clinical trials demonstrated the effectiveness of HCL in reducing hypoglycemia and improving glucose control; however, these subjects were intensely monitored and supervised. There has been concern regarding the ability of patients to remain in auto mode. We aimed to assess HCL when used in a typical outpatient endocrine clinic. We initially analyzed data from 80 individuals with type 1 diabetes managed in an endocrine clinic by a single certified diabetes educator (CDE). We then included our other providers and had 230 subjects by the end of the study. Patients were either transitioned from traditional insulin pump or multiple daily insulin injection therapy (MDI) to HCL. Patients initiated to HCL pump therapy from July 2017 through February 2020 were studied. Endpoints of change in time in hypoglycemic/hyperglycemic range and time in target range were analyzed. The primary outcome was a change in percent time in the target range during manual mode compared with auto mode. There was an 18.2% increase in average time in target range when comparing manual mode to auto mode (59.3% vs 70.1%, P < .0001). Average time in hyperglycemic range was significantly reduced by 26.7% (39.0% vs 28.6%, P < .0001) but without increasing average time in hypoglycemic range (1.7% vs 1.3%, P = 0.95). HCL was effective in reducing hyperglycemia and increasing time in the target range but did not increase hypoglycemia. These data suggest HCL will improve the metrics of glucose control.

Real-world study on the effectiveness and safety of basal insulin IDegLira in type 2 diabetic patients previously treated with multi-injective insulin therapy.

Achieving glycemic target is paramount to control diabetes mellitus (DM) and reduce micro-vascular and macro-vascular complications. Despite the mostly recent-developed drugs, most patients still show an above desired glycated hemoglobin (HbA1c) level due to DM complex pathophysiology, therapeutic and dietary compliance and clinical inertia in introducing or intensifying insulin therapy. To support the promising results of clinical trials on the effectiveness and safety of the degludec/liraglutide combination (IDegLira) in type 2 DM patients with C-peptide values >1 ng/ml who were previously treated with basal-bolus multiple daily-dose insulin injections. This observational, prospective and non-randomized trial enrolled type 2 DM patients referred to our outpatient clinic between January 2019 and December 2019, who were shifted from multiple daily-dose insulin injection therapy to degludec/liraglutide combination as per the physician's decision. The main assessment was HbA1c variation at 6 months from baseline. Secondary assessments included variation in fasting glycemia, routine anthropometric assessments, blood chemistry, blood pressure and patients' quality of life (measured by the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), from baseline to 6 months. HbA1c (8.4 vs. 7.4%; p<0.0001) and body weight (94.1 vs. 93 kg; p<0.0001) were significantly lower after 6 months for patients on the degludec/liraglutide combination. A similar trend was observed in fasting glycemia levels (159 vs. 125 mg/dl; p<0.0001). An improved glycemic control was achieved with degludec/liraglutide despite a reduction in total daily insulin units (42 U at 6 months vs. 22 U at baseline; p<0.0001). In addition, higher scores in the DTSQ were registered after 6 months on degludec/liraglutide (mean score: 27 vs. 20; p<0.0001). The combination therapy also proved more convenient than basal-bolus therapy in terms of costs, with an average per-patient cost difference of €-0.41±0.59/die (p<0.0001). These real-world findings show that degludec/liraglutide seems to be more effective than basal-bolus insulin in achieving glycemic control, allowing cost sustainability and improving patient satisfaction.

1094-P: Short-Acting Exenatide and Markers of Cardiovascular Disease in Type 1 Diabetes: A Randomized, Double-Blinded, Placebo-Controlled Trial

In type 2 diabetes, some glucagon-like peptide 1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events. Whether GLP-1RAs have any effect on cardiovascular disease risk in patients with type 1 diabetes remains to be elucidated. We tested the effect of adding the short-acting GLP-1RA exenatide to insulin treatment on markers of cardiovascular risk in type 1 diabetes. In a randomized, double-blinded, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on multiple daily insulin injection therapy with body mass index &amp;gt;22.0 kg/m2 and HbA1c 7.5-10.0% (59-88 mmol/mol) were randomized (1:1) to preprandial subcutaneous injection of 10 µg exenatide (Byetta®) or placebo three times daily over 26 weeks as add-on treatment to existing insulin therapy. Reported data were secondary endpoints and analyzed in a baseline-adjusted linear mixed model in the intention-to-treat population. Exenatide changed total fat mass by -2.6 kg (95% CI -3.6;-1.6, P&amp;lt;0.0001) and lean body mass by -1.1 kg (95% CI -1.9;-0.4, P=0.01) compared to placebo as assessed by dual-energy X-ray absorptiometry. Central and peripheral fat mass reductions were similar. Exenatide did not change levels of interleukin 2 or 6; tumor necrosis factor alpha; C-reactive protein; N-terminal prohormone of brain natriuretic peptide; or 8-oxo-7,8-dihydroguanosine (RNA oxidation marker) and 8-oxo-7,8-dihydro-2’-deoxyguanosine (DNA oxidation marker). Exenatide added to insulin therapy in type 1 diabetes for 26 weeks resulted in body weight loss primarily from fat mass reduction but had no effect on circulating biomarkers of cardiovascular disease risk. Disclosure N.J. Johansen: Research Support; Self; AstraZeneca. T.F. Dejgaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. C. Schlüntz: None. E. Larsen: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H.E. Poulsen: Research Support; Self; Boehringer Ingelheim International GmbH. J.P. Gøtze: None. H. Møller: None. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp &amp; Dohme Corp., Sanofi. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Norgine B.V., Novo Nordisk A/S. Funding AstraZeneca

Continuous subcutaneous insulin infusion reduces the risk of postoperative infection.

Perioperative hyperglycemia was associated with postoperative infection, and proper management of perioperative glucose has become critical in improving the prognosis of patients. A total of 1015 diabetic patients who underwent surgery and received insulin treatment for their hyperglycemia in our hospital were retrospectively reviewed. According to propensity matching, we obtained 253 pairs of patients from the group which received continuous subcutaneous insulin infusion (CSII) therapy (CSII group) and the group which received insulin injection therapy (non-CSII group). Perioperative glucose levels and corresponding outcomes were compared between the two groups. Compared with the non-CSII group, the CSII group had lower fasting and mean glucose levels, lower incidence of fever (operation day: 18.6% vs 10.2%; P = .014; first postoperative day: 55.1% vs 34.7%; P < .001), a positive rate of postoperative secretion culture (6.3% vs 1.2%; P = .004), and a shorter time of antibiotics use (total antibiotics use: P = .002; postoperative antibiotics use: P < .001) and hospital stays (P < .001). However, there was no difference in the total medical expenditure between the two groups (P = .499). Further analysis showed that CSII therapy was superior to multiple daily insulin injection (MDI) therapy in its effect on infection and other postoperative outcomes when 64 pairs of patients from the CSII group and MDI group were compared. CSII therapy provides better perioperative glucose control and a lower risk of postoperative infection without increasing the total medical expenditure.

1060-P: Effect of Dulaglutide and Long-Acting Insulin Combination Therapy in Patients with Type 2 Diabetes

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1-RA) are assumed to decrease the number of injections and improve blood glucose control in patients with type 2 diabetes (T2D). We aimed to evaluate the effects of switching from multiple daily insulin injection therapy (MDI) to combination therapy involving a long-acting GLP-1-RA, dulaglutide, and long-acting insulin on glycemic control. Methods: We examined patients with T2D who admitted to our department and underwent blood glucose management with MDI, followed by flash glucose monitoring. The treatment was subsequently switched to dulaglutide + long-acting insulin combination therapy. We evaluated the blood glucose excursion after MDI and 1 and 24 weeks after dulaglutide + long-acting insulin combination therapy. Furthermore, we evaluated hemoglobin A1c (HbA1c) after 12 and 24 weeks of dulaglutide + long-acting insulin combination therapy. Results: We enrolled 20 patients (mean age: 68.6 ± 11.7 years; HbA1c value: 10.1% ± 2.8%; previous MDI: n = 4). Mean blood glucose levels after MDI and 1 and 24 weeks after dulaglutide + long-acting insulin combination therapy were 124.8 ± 35.6, 122.5 ± 30.4, and 119 ± 21.3 mg/dl, respectively. Blood glucose level was significantly lower 24 weeks after dulaglutide + long-acting insulin combination therapy than shortly after MDI (P = 0.0048). Furthermore, blood glucose excursion tended to decrease after switching to dulaglutide + long-acting insulin combination therapy. After 12 and 24 weeks of the switch, HbA1c value significantly decreased (−3.6% ± 0.78%, P = 0.0003 and −3.7% ± 0.78%, P = 0.0002, respectively). Conclusions: The switch from MDI to dulaglutide + long-acting insulin combination therapy resulted in better blood glucose control, with reductions in blood glucose excursion and the number of self-injections; moreover, the effects continued for 24 weeks. Disclosure K. Ito: None. S. Satoh: None. Y. Kondo: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.

Effects of flash glucose-sensing technology-based continuous glucose monitoring on compliance of patients with type 2 diabetes mellitus: study protocol for a randomized controlled trial

Background and objectives: Multiple insulin injection therapy has been widely used in the intensive treatment of diabetes mellitus and enabled more patients to obtain good glycemic control. Intensive insulin treatment such as multiple insulin injection every day had been proven to have effects on the protection of islet and delay the onset of diabetic complications. However, during the insulin intensive therapy, severe hypoglycemia must be avoided by intensive glucose monitoring because it can increase the risks of stroke and cardiovascular disease. Conventional invasive intensive blood glucose monitoring is limited in clinical practice because it can cause patient pain and inconveniences. Patient's poor compliance in blood glucose monitoring would restrict the application of insulin intensive therapy in patients outside the hospital. The latest method of flash glucose-sensing technology-based continuous glucose monitoring (CGM) made insulin intensive therapy safer and less painful for a patient with diabetes mellitus. However, little is reported on the effects of flash glucose-sensing technology based CGM in patients receiving multiple daily injections of insulin. This study will provide evidence to validate whether flash glucose-sensing technology-based CGM can increase the behavioral self-monitoring and compliance with self-management of a Chinese patient with diabetes mellitus receiving multiple daily injections of insulin compared with conventional invasive blood glucose monitoring. Subjects and methods: This is a prospective, single-center, open-label, randomized controlled trial. Forty patients with type 2 diabetes mellitus who receive multiple daily injections of insulin at the Department of Endocrinology, Northern Jiangsu People's Hospital, Yangzhou University, China between August 2018 and December 2019 are included in this study. These patients are randomly divided to undergo conventional blood glucose monitoring (n = 20) or a flash glucose-sensing technology-based CGM group (n = 20). Patient recruitment began in August 2018 and will end in June 2019. Analysis of primary outcome measure will be completed in June 2019. The study will end in December 2019. Study protocol: 1.0. The protocol was approved by the Medical Ethics Committee of Northern Jiangsu People's Hospital (approval No. 2018045) and is performed in strict accordance with the Declaration of Helsinki formulated by the World Medical Association. All participants provide written informed consent. Outcome measures: The primary outcome measure is the compliance of glycemic monitoring. The secondary outcome measures include the time taken for reaching the goal of glycemic control, HbA1c, self-management scores, the number of hypoglycemia attacks, and Hamilton Anxiety Scale score. Discussion: This study will provide evidence to validate whether flash glucose-sensing technology can increase patient's compliance of intensive insulin treatments, control blood glucose, and improve quality of life. Trial registration: This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800017456) on July 31, 2018.

Status and trends in the use of insulin analogs, insulin delivery systems and their association with glycemic control: comparison of the two consecutive recent cohorts of Japanese children and adolescents with type 1 diabetes mellitus.

Background Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients. Methods The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal-bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0-5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.

Real-World Data from the MiniMed™ 670G System Commercial Launch—Patients Previously Using MDI Therapy

The Medtronic MiniMed™ 670G hybrid closed-loop system with SmartGuard™ technology was released for commercial use in the U.S. in March 2017. Data from patients previously managing their diabetes with multiple daily insulin injections (MDI) therapy who transitioned to the MiniMed™ 670G system are reported. MiniMed™ 670G system data from patients who voluntarily uploaded to CareLink™ Personal software, from 3/17/17 to 12/14/17 (n=158), were de-identified and analyzed if there were ≥7 days of sensor wear. Comparisons were made of glycemic metrics between 4,529 patient-days in the initial open-loop Manual Mode and 14,1patient-days after initiating closed-loop Auto Mode features. The Table shows glycemic metrics during Manual Mode and after Auto Mode start and that time spent in target range increased, while time spent in low and high glucose levels decreased. Real-world findings from patients previously using MDI who transitioned to the MiniMed™ 670G system demonstrated increased TIR and reduced time in hypoglycemia and hyperglycemia, consistent with pivotal trial1 results in patients previously using pump therapy +/- CGM. Prior MDI patients also showed greater TIR the more time spent in Auto Mode. Disclosure S. Gopalakrishnan: Employee; Self; Medtronic. P. Agrawal: None. M. Stone: None. C. Fogel: Employee; Self; Medtronic. S.W. Lee: Employee; Self; Medtronic.

Intervention of the Flash Glucose Sensing Technology on Glycemic Control and Treatment Satisfaction in Patients with Type 2 Diabetes Treated Intensively by Insulin—A Randomized Controlled Trial

Objective: To determine the satisfaction from treatment and effectiveness of flash glucose monitoring system (FGM) in patients with type 2 diabetes. Design and Methods: 101 individuals with type 2 diabetes on multiple daily insulin injection (MDI) therapy for ≥1 year (mean duration 21.81±7.65 years) and HbA1c 7.4-10.2% (57-88 mmol/mol) were randomized to the intervention (n=53) or the standard care group (n=48). Those in the intervention group were instructed to use FGM and once a week 7-points BG assessment to confirm any a symptomatic hypoglycemia. The control group continued the routine BG measurement as before the study and add once a week 7-points BG measurement at constant day. For 12 weeks, both groups were instructed to adjust insulin dose in the frequent face-to-face and telephone visits. Satisfaction from treatment, quality of life, comfort using FGM, HbA1c and hypoglycemia events were evaluated. Results: The mean age was 66.75 ± 7.55; 64.35% were male. Total treatment satisfaction increased in the intervention group (p=0.053). At the 12 week of the study, subjects in the intervention group found treatment significantly more flexible (p=0.019), convenient (p=0.052), and would recommend it more to their counterparts (p=0.023). The mean HbA1c was 8.51 ± 0.81%. After 10 weeks, HbA1c changes were -0.82% in the intervention group and -0.29% in the control (p=0.0013). 67.9% subjects from the intervention study and 27.1% from the control group reduced HbA1c ≥0.5% HbA1c (p&amp;lt;0.001); and 39.6% subjects from the intervention and 16.7% from the control group reduced HbA1c≥1.0% (p=0.0076) without increasing frequency of hypoglycemia. Conclusion: FGM potentially produces a modification of behavior/life style and improves treatment satisfaction. It improves glycemic control in subjects with type 2 diabetes treated by MDI without increased frequency of hypoglycemia. Disclosure M. Yaron: None. E. Roitman: Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; GlucoMe. Stock/Shareholder; Self; GlucoMe. G. Aharon-Hananel: None. Z. Landau: None. T. Ganz: None. M. Karp: None. M. Ish-Shalom: None. J. Singer: None. J. Wainstein: None. I. Raz: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; DarioHealth. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Orgenesis Inc., Pfizer Inc., Sanofi R&amp;D, SmartZyme Biopharma. Consultant; Self; Bristol-Myers Squibb Company. Speaker's Bureau; Self; Bristol-Myers Squibb Company, Johnson &amp; Johnson Diabetes Institute, LLC., Merck Sharp &amp; Dohme Corp., Novartis Pharma K.K., Sanofi-Aventis. Consultant; Self; FuturRx Ltd, Insuline Medical,Camereyes Ltd, Exscopia, Medial EarlySign Ltd. Stock/Shareholder; Self; Glucome Ltd, InsuLine Medical Ltd.. Consultant; Self; Dermal Biomics Inc. Stock/Shareholder; Self; Orgenesis Inc.. Speaker's Bureau; Self; Teva Pharmaceutical Industries Ltd.. Advisory Panel; Self; Concenter BioPharma/Silkim Ltd, Camereyes Ltd. Stock/Shareholder; Self; CameraEyes Ltd. Advisory Panel; Self; Breath of Life PharmaLtd, Panaxia.

New-onset insulin-dependent diabetes due to nivolumab.

SummaryNivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab.Learning points:Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1).Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1.Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents.

Satisfaction of switching to combination therapy with lixisenatide and basal insulin in patients with type 2 diabetes receiving multiple daily insulin injection therapy: A randomized controlled trial.

Aims/IntroductionWe compared the satisfaction levels of patients with type 2 diabetes undergoing combination therapy with lixisenatide (LIX) and basal insulin with that of patients undergoing multiple daily insulin injection (MDI) therapy.Materials and MethodsThe study was a 12‐week open‐label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes receiving MDI for >3 months. Patients were randomly assigned to each treatment cohort: (i) a group that continued MDI (MDI group); and (ii) a group that switched from MDI to combination therapy with LIX and basal insulin (LIX group). The primary outcome was change in Diabetes Treatment Satisfaction Questionnaire scores from baseline to 12 weeks between these two groups. Key secondary outcomes were glycated hemoglobin and body weight changes.ResultsA total of 31 patients were initially enrolled in the study, and 26 of them completed the study. The change in Diabetes Treatment Satisfaction Questionnaire scores in the LIX group was significantly greater compared with that in the MDI group. Mean changes in glycated hemoglobin levels were −0.05 ± 0.37% in the MDI group and 0.04 ± 0.38% in the LIX group (P = 0.36). Mean changes in body weight were +0.6 ± 1.8 kg in the MDI group and −2.5 ± 1.8 kg in the LIX group (P < 0.01).ConclusionsSwitching from MDI to combination therapy with LIX and basal insulin improved satisfaction levels while maintaining glycemic control in Japanese patients with type 2 diabetes.

Continuous Glucose Monitoring Use in Type 1 Diabetes: Longitudinal Analysis Demonstrates Meaningful Improvements in HbA1c and Reductions in Health Care Utilization.

Real-time continuous glucose monitoring (rtCGM) improves glycemic control in type 1 diabetes (T1D) patients treated with continuous subcutaneous insulin infusion (CSII). However, the benefits of rtCGM in T1D patients treated with multiple daily insulin injection (MDI) therapy has not been well studied. We explored the effects of rtCGM versus self-monitoring of blood glucose (SMBG) on clinical outcomes within a large T1D population treated with either CSII or MDI therapy. This retrospective, longitudinal analysis utilized datasets from T1D patients enrolled in a commercial health plan to assess changes in HbA1c in 187 naïve to rtCGM users and 6260 SMBG users. Propensity score modeling was used to assess inpatient admissions, emergency room (ER) visits in 1130 patients (565 rtCGM, 565 SMBG). Differences in HbA1c reduction (rtCGM+MDI vs rtCGM+CSII) were evaluated. Larger, clinically meaningful HbA1c reductions were seen among rtCGM versus SMBG users: -0.5% ( P = .004) versus -0.2% ( P < .0001); 0.3% diff in diff, P = .03. All-cause inpatient admissions were lower for rtCGM users: -42%, P = .013. Emergency room visits coded for diabetic ketoacidosis (DKA) were four times higher for SMBG patients than rtCGM patients: 17 versus 4, P = .0318. HbA1c reductions were most notable with rtCGM+MDI versus rtCGM+CSII treatment: -0.6% ( P = .01) versus -0.3% ( P = .16). Use of rtCGM in T1D patients facilitates greater HbA1c improvements and reduced health care system utilization compared with traditional SMBG use regardless of insulin administration method. Treatment with rtCGM in conjunction with MDI confers similar or greater glycemic benefits without the additional costs associated with CSII therapy.

Effects of advanced carbohydrate counting guided by an automated bolus calculator in Type 1 diabetes mellitus (StenoABC): a 12‐month, randomized clinical trial

To test whether concomitant use of an automated bolus calculator for people with Type 1 diabetes carrying out advanced carbohydrate counting would induce further improvements in metabolic control. We conducted a 12-month, randomized, parallel-group, open-label, single-centre, investigator-initiated clinical study. We enrolled advanced carbohydrate counting-naïve adults with Type 1 diabetes and HbA1c levels 64-100 mmol/mol (8.0-11.3%), who were receiving multiple daily insulin injection therapy. In a 1:1-ratio, participants were randomized to receive training in either advanced carbohydrate counting using mental calculations (MC group) or advanced carbohydrate counting using an automated bolus calculator (ABC group) during a 3.5-h group training course. For 12 months after training, participants attended a specialized diabetes centre quarterly. The primary outcome was change in HbA1c from baseline to 12 months. Between August 2012 and September 2013, 168 participants (96 men and 72 women) were recruited and randomly assigned to the MC group (n = 84) and the ABC group (n = 84). Drop-out rates were 23.8 and 21.4%, respectively (P = 0.712); 130 participants completed the study. The baseline HbA1c was 75 ± 9 mmol/mol (9.0 ± 0.8%) in the MC group and 74 ± 8 mmol/mol (8.9 ± 0.7%) in the ABC group. At 12 months, change in HbA1c was significant within both groups: MC group: -2 mmol/mol (95% CI -4 to -1) or -0.2% (95% CI -0.4 to -0.1; P = 0.017) and ABC group: -5 mmol/mol (95% CI -6 to -3) or -0.5% (95% CI -0.6 to -0.3; P < 0.0001), but HbA1c reductions were significantly greater in the ABC group (P = 0.033). No episodes of severe hypoglycaemia were reported. People with Type 1 diabetes initiating advanced carbohydrate counting obtained significantly greater HbA1c reductions when guided by an automated bolus calculator (NCT02084498).