You may delay, but time will not. Beta cells lost are never found again: a case for timely initiation of basal insulin in type 2 diabetes.

Since its first use just over a century ago, insulin treatment has evolved dramatically, such that the molecules are physiologic in nature, and treatment can now closely resemble the natural hormone response over 24 hours. Newer, longer-acting basal insulin analogs have provided insulin therapies with improved characteristics and, therefore, ease of use, and can readily be incorporated as part of routine treatment for type 2 diabetes (T2D), but evidence suggests that insulin remains underused in people with T2D. We review the barriers to initiation of basal insulin and the education needed to address these barriers, and we provide practical pointers, supported by evidence, for primary care physicians and advanced practice providers to facilitate timely initiation of basal insulin in the people with T2D who will benefit from such treatment.

Type 2 diabetes is a complex disease. It causes increased amounts of sugar in the blood, which can cause damage to the body. Medications are given to people with type 2 diabetes to keep their blood sugar at normal levels. Unfortunately, type 2 diabetes worsens over time, so regular adjustments to medications are needed to keep blood sugar levels controlled.Basal insulin, which is a type of insulin that works over the entire day, is a key treatment for type 2 diabetes. It works best if it is started as soon as other medications (tablets or non-insulin injections) are not working to control blood sugar levels. Unfortunately, delays in starting basal insulin are common. Some healthcare professionals and people with type 2 diabetes believe insulin is difficult to use. False information on insulin is common; for example, some people with diabetes believe that their symptoms are caused by insulin treatment rather than high blood sugar.This review summarizes key information to encourage effective conversations between healthcare professionals and people with type 2 diabetes about starting basal insulin. Proactive, positive, early discussion of the benefits of basal insulin can help to: 1) address concerns, 2) set appropriate, individual treatment targets, and 3) provide practical information and training to help with injecting insulin. This will give people living with type 2 diabetes the knowledge and confidence to take an active part in managing their diabetes and overcome any barriers to using basal insulin.

Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial.

Importance: Once-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes. Objective: To evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes. Design, Setting, and Participants: Randomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol). Interventions: Participants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294). Main Outcomes and Measures: The primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes. Results: Among 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], -0.2 [95% CI, -0.3 to -0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, -6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, -0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01). Conclusions and Relevance: Among people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups. Trial Registration: ClinicalTrials.gov Identifier: NCT04795531.

Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin.

BACKGROUND: Insulin icodec is an investigational once-weekly basal insulin analogue for diabetes management. METHODS: We conducted a 78-week randomized, open-label, treat-to-target phase 3a trial (including a 52-week main phase and a 26-week extension phase, plus a 5-week follow-up period) involving adults with type 2 diabetes (glycated hemoglobin level, 7 to 11%) who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive once-weekly insulin icodec or once-daily insulin glargine U100. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; the confirmatory secondary end point was the percentage of time spent in the glycemic range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) in weeks 48 to 52. Hypoglycemic episodes (from baseline to weeks 52 and 83) were recorded. RESULTS: Each group included 492 participants. Baseline characteristics were similar in the two groups. The mean reduction in the glycated hemoglobin level at 52 weeks was greater with icodec than with glargine U100 (from 8.50% to 6.93% with icodec [mean change, -1.55 percentage points] and from 8.44% to 7.12% with glargine U100 [mean change, -1.35 percentage points]); the estimated between-group difference (-0.19 percentage points; 95% confidence interval [CI], -0.36 to -0.03) confirmed the noninferiority (P<0.001) and superiority (P = 0.02) of icodec. The percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec than with glargine U100 (71.9% vs. 66.9%; estimated between-group difference, 4.27 percentage points [95% CI, 1.92 to 6.62]; P<0.001), which confirmed superiority. Rates of combined clinically significant or severe hypoglycemia were 0.30 events per person-year of exposure with icodec and 0.16 events per person-year of exposure with glargine U100 at week 52 (estimated rate ratio, 1.64; 95% CI, 0.98 to 2.75) and 0.30 and 0.16 events per person-year of exposure, respectively, at week 83 (estimated rate ratio, 1.63; 95% CI, 1.02 to 2.61). No new safety signals were identified, and incidences of adverse events were similar in the two groups. CONCLUSIONS: Glycemic control was significantly better with once-weekly insulin icodec than with once-daily insulin glargine U100. (Funded by Novo Nordisk; ONWARDS 1 ClinicalTrials.gov number, NCT04460885.).

Basal weekly insulins: the way of the future!

Basal insulin treatment is indispensable for patients with type 1 diabetes and often required by many with type 2 diabetes. Incremental advances lengthening the duration of action of insulin analogs and reducing pharmacodynamic variability have resulted in truly once-daily, long-acting basal insulin analogs. In the quest for better basal insulins to facilitate improvements in glycemic control and long-term outcomes, the driving need is to remove barriers delaying timely initiation of basal insulin, to maximize treatment adherence and persistence and reduce treatment burden without increasing risk of hypoglycemia. We review the range of investigational once-weekly insulins and their molecular strategies and profiles. Currently, the two most advanced clinical development programs are: (1) basal insulin icodec, an insulin analog acylated with a C20 fatty diacid (icosanedioic acid) side chain (Novo Nordisk) and (2) basal insulin Fc, a fusion protein that combines a single-chain insulin variant with a human immunoglobulin G fragment crystallizable domain (Eli Lilly). Available phase 2 data for these two once-weekly agents show comparable glycemic control to existing once-daily insulin analogs, with no greater risk of hypoglycemia. While phase 3 data are awaited to confirm efficacy and safety, we provide future clinical perspectives on practical considerations for the potential use of once-weekly insulins.

A fully artificial pancreas versus a hybrid artificial pancreas for type 1 diabetes: a single-centre, open-label, randomised controlled, crossover, non-inferiority trial.

BACKGROUND: For people with type 1 diabetes, there is currently no automated insulin delivery system that does not require meal input. We aimed to assess the efficacy of a novel faster-acting insulin aspart (Fiasp) plus pramlintide fully closed-loop system that does not require meal input. METHODS: In this open-label, randomised controlled, crossover, non-inferiority trial we compared the Fiasp (Novo Nordisk, Bagsværd, Denmark) plus pramlintide closed-loop system with no meal input (fully artificial pancreas) and the Fiasp-alone closed-loop system with precise carbohydrate counting (hybrid artificial pancreas). Adults (≥18 years) who had a clinical diagnosis of type 1 diabetes for at least 12 months, had glycated haemoglobin 12% or lower, and had been on insulin pump therapy for at least 6 months were enrolled at McGill University Health Centre, Montreal, QC, Canada. The Fiasp plus pramlintide fully closed-loop system delivered pramlintide in a basal-bolus manner with a fixed ratio of 10 µg:U relative to insulin. A research staff member counted the carbohydrate content of meals to input in the hybrid closed-loop system. Participants completed the two full-day crossover interventions in a random order allocated by a computer-generated code implementing a blocked randomisation (block size of four). The primary outcome was the percentage of time spent within the glucose target range (3·9-10·0 mmol/L), with a 6% non-inferiority margin, assessed in all participants who completed both interventions. This trial is registered with ClinicalTrials.gov, NCT03800875. FINDINGS: Between Feb 8, 2019, and Sept 19, 2020, we enrolled 28 adults, of whom 24 completed both interventions and were included in analyses. The percentage of time spent in the target range was 74·3% (IQR 61·5-82·8) with the fully closed-loop system versus 78·1% (66·3-87·5) with the hybrid Fiasp-alone closed-loop system (paired difference 2·6%, 95% CI -2·4 to 12·2; non-inferiority p=0·28). Eight (33%) participants had at least one hypoglycaemia event (<3·3 mmol/L) with the fully closed-loop system compared with 14 (58%) participants with the hybrid closed-loop system (2200-2200 h). Non-mild nausea was reported by three (13%) participants and non-mild bloating by one (4%) participant with the fully closed-loop system compared with zero participants with the hybrid closed-loop system. INTERPRETATION: The Fiasp plus pramlintide fully closed-loop system was not non-inferior to the Fiasp-alone hybrid closed-loop system for the overall percentage of time in the glucose target range. However, participants still spent a high percentage of time within the target range with the fully-closed loop system. Outpatient studies comparing the fully closed-loop hybrid systems with patient-estimated, rather than precise, carbohydrate counting are warranted. FUNDING: Diabetes Canada.

Efficacy, Pharmacokinetics, Biodistribution and Excretion of a Novel Acylated Long-Acting Insulin Analogue INS061 in Rats.

PURPOSE: Long-acting insulin analogues are known to be a major player in the management of glucose levels in type I diabetic patients. However, highly frequent hypo- and hyperglycemic incidences of current long-acting insulins are the important factor to limit stable management of glucose level for clinical benefits. To further optimize the properties for steadily controlling glucose level, a novel long-acting insulin INS061 was designed and its efficacy, pharmacokinetics, biodistribution and excretion profiles were investigated in rats. METHODS: The glucose-lowering effects were evaluated in a streptozocin-induced diabetic rats compared to commercial insulins via subcutaneous administration. The pharmacokinetics, biodistribution, and excretion were examined by validated analytical methods including radioactivity assay and radioactivity assay after the precipitation with TCA and the separation by HPLC. RESULTS: INS061 exhibited favorable blood glucose lowering effects up to 24 h compared to Degludec. Pharmacokinetic study revealed that the concentration-time curves of INS061 between two administration routes were remarkably different. Following intravenous administration, INS061 was quickly distributed to various organs and tissues and slowly eliminated over time with urinary excretion being the major route for elimination, and the maximum plasma concentrations (Cmax) and systemic exposures (AUC) increased in a linear manner. CONCLUSION: The present structural modifications of human insulin possessed a long-acting profile and glucose-lowering function along with favorable in vivo properties in rats, which establish a foundation for further preclinical and clinical evaluation.

Choice of basal insulin therapy is associated with weight and height development in type 1 diabetes: A multicenter analysis from the German/Austrian DPV registry in 10 338 children and adolescents.

BACKGROUND: Available basal insulin regimes differ in pharmacokinetic profiles, which may be related to subsequent changes in anthropometry in patients with type 1 diabetes. This analysis elucidates the standardized height and body mass index development (height and BMI standard deviation score [height-SDS and BMI-SDS]) in pediatric type 1 diabetes patients depending on the choice of basal insulin. METHODS: Longitudinal data of 10 338 German/Austrian patients from the Diabetes Prospective Follow-up (DPV, Diabetes Patienten Verlaufsdokumentation) database were analyzed. Patients aged 5.0 to 16.9 years were treated exclusively with neutral protamine Hagedorn (NPH), insulin detemir (IDet), insulin glargine (IGla), or continuous subcutaneous insulin infusion (CSII) for at least 3 years. Population-based German reference data were used to calculate height-SDS and BMI-SDS. Multiple linear regression was conducted. RESULTS: BMI-SDS increased significantly in all regimes (NPH P = .0365; IDet P = .0003; IGla P < .0001; and CSII P < .0001). Direct comparison of the therapies revealed a favorable association only for NPH vs IGla. A rise in BMI-SDS was observed for all insulins in females, but only for IGla in males. BMI-SDS increment was not observed before 8 years of age. Initially and at the end of the observation period, mean height was above the 50th percentile of the reference population. Across the cohort, height-SDS declined during the observation period, except for CSII. Apart from the 5.0- to 7.9-year-old subgroup, long-acting insulin analogues were associated with a significant loss of height-SDS. CONCLUSIONS: Choice of basal insulin regimen might influence height development. CSII appeared to have a favorable effect on growth trajectories. All therapies were associated with an increase of BMI-SDS, most evident in females.

Comparative clinical outcomes of insulin degludec and insulin glargine 300 U/mL after switching from other basal insulins in real-world patients with type 1 and type 2 diabetes.

AIMS/INTRODUCTION: To evaluate and compare the efficacy of insulin degludec (IDeg) and insulin glargine 300 U/mL (Gla300) 6 months after switching from other basal insulins by assessing the changes in glycated hemoglobin (HbA1c), body mass index (BMI), and insulin doses in patients with type 1 and type 2 diabetes in a real-world clinical setting. MATERIALS AND METHODS: A total of 307 patients with type 1 diabetes and 294 patients with type 2 diabetes with HbA1c >7.0% were studied. Adjusted mean changes in HbA1c, BMI, and insulin doses were compared between IDeg (IDeg group) and Gla300 (Gla300 group) switchers. Multivariable logistic regression analyses were carried out to examine whether the IDeg or Gla300 group was associated with HbA1c or insulin dose reduction and BMI gain. RESULTS: HbA1c was significantly decreased in both the IDeg and Gla300 groups. Adjusted mean changes in HbA1c (approximately -0.3% and -0.5% in type 1 diabetes and type 2 diabetes patients, respectively) and BMI were similar between both groups. The mean change in insulin dose was slightly larger for dose reduction in the IDeg group than in the Gla300 group. Multivariable logistic regression models showed that the IDeg group was significantly associated with insulin dose reduction after adjusting for basal insulin type, insulin dose, and number of basal insulin injections at baseline and other confounding factors. CONCLUSIONS: The current study suggested that IDeg and Gla300 have similar effects in reducing HbA1c and gaining BMI after switching from other basal insulins in Japanese patients with type 1 diabetes and type 2 diabetes. IDeg selection was associated with insulin dose reduction.

The differences between insulin glargine U300 and insulin degludec U100 in impact on the glycaemic variability, arterial stiffness and the lipid profiles in insulin naïve patients suffering from type two diabetes mellitus - outcomes from cross-over open-label randomized trial.

BACKGROUND AND AIMS: Diabetes mellitus type two is one of the major cardiovascular risk factors. Treatment of diabetes can reduce this risk, but the treatment options differ a lot in their risk-reducing capabilities. We compared the impact of insulin degludec (IDeg-100) and insulin glargine U300 (IGlar-300) on cardiovascular risk parameters - glycaemic variability (GV), arterial stiffness and lipid parameters - in insulin naive patients with DMT2. METHODS: To 23 individuals who previously had uncontrolled DMT2 on two or more oral antidiabetic drugs, IGlar-300 and IDeg-100 were applied for 12 weeks and then switched in a cross over design manner. Prior and after of each insulin phase, we analysed biochemical parameters,7-point SMBG profile over three days and arterial stiffness which was assessed indirectly by measuring the augmentation index (AIx) on the principles of applanation tonometry. RESULTS: There were no significant differences between IGlar-300 and IDeg-100 regarding reduction of mean glucose values and coefficient of variation (CV). Both insulins insignificantly reduced AIx for standardised pulse of 75 beats/min and without differences between them. IGlar-300 and IDeg-100 reduced triglycerides and increased HDL with no significant difference between the two insulins. IGlar-300 increased the total cholesterol level and IDeg-100 decreased total cholesterol, but without statistically significant difference. IGlar-300 increased LDL level by 0.508 mmol/L and IDeg-100 decreased LDL by 0.217 mmol/L, with statistically significant difference (p = 0.0215). CONCLUSIONS: This study did not show significant difference between IGlar-300 and IDeg-100 regarding glycaemic parameters and augmentation index using the same dose of 0.2 IU/kg for both insulins, but it has revealed possible differences in impact on lipid profile. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04692415 . Retrospectively registered on December 31th 2020.

Insulin doses requirements in patients with type 1 diabetes using glargine U300 or degludec in routine clinical practice.

There are not many real-world studies evaluating daily insulin doses requirements (DIDR) in patients with type 1 diabetes (T1D) using second-generation basal insulin analogs, and such comparison is necessary. The aim of this study was to compare DIDR in individuals with T1D using glargine 300 UI/mL (IGlar-300) or degludec (IDeg) in real clinical practice. An observational, retrospective study was designed in 412 patients with T1D (males: 52%; median age 37.0±13.4 years, diabetes duration: 18.7±12.3 years) using IDeg and IGla-300 ≥6 months to compare DIDR between groups. Patients using IGla-300 (n=187) were more frequently males (59% vs 45.8%; p=0.004) and had lower glycosylated hemoglobin (HbA1c) (7.6±1.2 vs 8.1%±1.5%; p<0.001) than patients using IDeg (n=225). Total (0.77±0.36 unit/kg/day), basal (0.43±0.20 unit/kg/day) and prandial (0.33±0.23 unit/kg/day) DIDR were similar in IGla-300 and IDeg groups. Patients with HbA1c ≤7% (n=113) used significantly lower basal (p=0.045) and total (p=0.024) DIDR, but not prandial insulin (p=0.241), than patients with HbA1c between 7.1% and 8% and >8%. Patients using IGla-300 and IDeg used similar basal, prandial and total DIDR regardless of metabolic control subgroup. No difference in basal, prandial and total DIDR was observed between patients with T1D using IGla-300 or IDeg during at least 6 months in routine clinical practice.

Ongoing efforts to improve the management of patients with diabetes in Bangladesh and the implications.

BACKGROUND: Prevalence rates of patients with diabetes are growing across countries, and Bangladesh is no exception. Associated costs are also increasing, driven by costs associated with the complications of diabetes including hypoglycemia. Long-acting insulin analogues were developed to reduce hypoglycemia as well as improve patient comfort and adherence. However, they have been appreciably more expensive, reducing their affordability and use. Biosimilars offer a way forward. Consequently, there is a need to document current prescribing and dispensing rates for long-acting insulin analogues across Bangladesh, including current prices and differences, as a result of affordability and other issues. METHODS: Mixed method approach including surveying prescribing practices in hospitals coupled with dispensing practices and prices among community pharmacies and drug stores across Bangladesh. This method was adopted since public hospitals only dispense insulins such as soluble insulins free-of-charge until funds run out and all long-acting insulin analogues have to be purchased from community stores. RESULTS: There has been growing prescribing and dispensing of long-acting insulins in Bangladesh in recent years, now accounting for over 80% of all insulins dispensed in a minority of stores. This increase has been helped by growing prescribing and dispensing of biosimilar insulin glargine at lower costs than the originator, with this trend likely to continue with envisaged growth in the number of patients. Consequently, Bangladesh can serve as an exemplar to other low- and middle-income countries struggling to fund long-acting insulin analogues for their patients. CONCLUSIONS: It was encouraging to see continued growth in the prescribing and dispensing of long-acting insulin analogues in Bangladesh via the increasing availability of biosimilars. This is likely to continue benefitting all key stakeholder groups.

Hyperglycaemic hyperosmolar state in an obese prepubertal girl with type 2 diabetes: case report and critical approach to diagnosis and therapy.

INTRODUCTION: Isolated Hyperosmolar Hyperglycaemic Syndrome (HHS) is a life-threatening condition characterized by elevated serum glucose concentrations and hyperosmolality without significant ketosis. It is often described in obese adults with unknown Type 2 Diabetes (T2D), rarely in youth. In childhood the most common cause of metabolic glucose related derangement is Diabetic Ketoacidosis (DKA) in Type 1 Diabetes (T1D). Interestingly, both components can be combined with each other, thus the prevalent condition needs to be recognised implying a different therapeutic approach. CASE PRESENTATION: In this case, we report a prepubertal Caucasian obese girl admitted for two episodes of combined HHS/DKA in order to elucidate her clinical course taking into account the current pediatric recommendations based on adult guidelines for HHS. CONCLUSIONS: The treatment of HHS and even more of HHS/DKA in youth is still controversial as no specific guidelines for children are available especially during the prepubertal age. The description of our case might be helpful and offer relevant points for future consensus.

Use of insulin glargine during pregnancy: A review.

BACKGOUND AND AIMS: Hyperglycemia during pregnancy is increasing globally. Insulin therapy is considered the standard of care for its optimum management. Insulin glargine, in spite of widespread use in non-pregnant adults, lacks randomized controlled trial evidence as safe basal insulin during pregnancy. Aim of this review is to discuss major available evidences and recommendations on the use of insulin glargine during pregnancy. METHODS: Evidences related to use of insulin glargine during pregnancy, including animal studies, placental transfer studies, case reports as well as observational studies were retrieved using PUBMED & Google scholar. Recommendations regarding use of insulin glargine during pregnancy by international and Indian organizations were reviewed. RESULTS: Trans-placental transfer studies show that insulin glargine does not cross placenta when used at therapeutic concentrations. Although there are no randomized controlled trials on insulin glargine in pregnancy, it's use during pregnancy is not associated with any adverse maternal or neonatal outcomes as shown in many case reports and observational studies (both prospective and retrospective). It's use during pregnancy is hence considered safe by many organizations across the globe. CONCLUSIONS: Insulin glargine can be continued safely during pregnancy in women who are already taking it prior to pregnancy and have achieved good glycemic control with it. However we require preferably randomized controlled trials or large prospective observational studies to establish it as first line or preferred basal insulin for management of hyperglycemia during pregnancy.

Extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin adjustments in individuals with type 1 diabetes.

AIM: To detail the extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin dose adjustments in individuals with type 1 diabetes (T1D) using multiple daily injections of insulins aspart (IAsp) and degludec (IDeg). METHODS AND RESULTS: Sixteen individuals with T1D, completed a single-centred, randomised, four-period crossover trial consisting of 23-h inpatient phases. Participants administered either a regular (100%) or reduced (50%) dose (100%; 5.1 ± 2.4, 50%; 2.6 ± 1.2 IU, p < 0.001) of individualised IAsp 1 h before and after 45-min of evening exercise at 60 ± 6% V̇O2max. An unaltered dose of IDeg was administered in the morning. Metabolic, physiological and hormonal responses during exercise, recovery and nocturnal periods were characterised. The primary outcome was the number of trial day occurrences of hypoglycemia (venous blood glucose ≤ 3.9 mmol L -1). Inclusion of a 50% IAsp dose reduction strategy prior to evening exercise reduced the occurrence of in-exercise hypoglycemia (p = 0.023). Mimicking this reductive strategy in the post-exercise period decreased risk of nocturnal hypoglycemia (p = 0.045). Combining this strategy to reflect reductions either side of exercise resulted in higher glucose concentrations in the acute post-exercise (p = 0.034), nocturnal (p = 0.001), and overall (p < 0.001) periods. Depth of hypoglycemia (p = 0.302), as well as ketonic and counter-regulatory hormonal profiles were similar. CONCLUSIONS: These findings demonstrate the glycemic safety of peri-exercise bolus dose reduction strategies in minimising the prevalence of acute and nocturnal hypoglycemia following evening exercise in people with T1D on MDI. Use of newer background insulins with current bolus insulins demonstrates efficacy and advances current recommendations for safe performance of exercise. CLINICAL TRIALS REGISTER: DRKS00013509.

Titration of Long-Acting Insulin Using Continuous Glucose Monitoring and Smart Insulin Pens in Type 1 Diabetes: A Model-Based Carbohydrate-Free Approach.

Objective: Multiple daily injections (MDI) therapy is the most common treatment for type 1 diabetes (T1D), consisting of long-acting insulin to cover fasting conditions and rapid-acting insulin to cover meals. Titration of long-acting insulin is needed to achieve satisfactory glycemia but is challenging due to inter-and intra-individual metabolic variability. In this work, a novel titration algorithm for long-acting insulin leveraging continuous glucose monitoring (CGM) and smart insulin pens (SIP) data is proposed. Methods: The algorithm is based on a glucoregulatory model that describes insulin and meal effects on blood glucose fluctuations. The model is individualized on patient's data and used to extract the theoretical glucose curve in fasting conditions; the individualization step does not require any carbohydrate records. A cost function is employed to search for the optimal long-acting insulin dose to achieve the desired glycemic target in the fasting state. The algorithm was tested in two virtual studies performed within a validated T1D simulation platform, deploying different levels of metabolic variability (nominal and variance). The performance of the method was compared to that achieved with two published titration algorithms based on self-measured blood glucose (SMBG) records. The sensitivity of the algorithm to carbohydrate records was also analyzed. Results: The proposed method outperformed SMBG-based methods in terms of reduction of exposure to hypoglycemia, especially during the night period (0 am-6 am). In the variance scenario, during the night, an improvement in the time in the target glycemic range (70-180 mg/dL) from 69.0% to 86.4% and a decrease in the time in hypoglycemia (<70 mg/dL) from 10.7% to 2.6% was observed. Robustness analysis showed that the method performance is non-sensitive to carbohydrate records. Conclusion: The use of CGM and SIP in people with T1D using MDI therapy has the potential to inform smart insulin titration algorithms that improve glycemic control. Clinical studies in real-world settings are warranted to further test the proposed titration algorithm. Significance: This algorithm is a step towards a decision support system that improves glycemic control and potentially the quality of life, in a population of individuals with T1D who cannot benefit from the artificial pancreas system.

Effectiveness of Insulin Degludec in Thai Patients with Diabetes Mellitus: Real-World Evidence From a Specialized Diabetes Center.

BACKGROUND: Insulin degludec, an ultra-long-acting insulin analogue, has been available in Thailand since October 2016. Although clinical trial results revealed less hypoglycemia, data from real-world settings is limited especially in Asian patients. This study aimed to evaluate prospectively the real-world effectiveness, safety, quality of life (QOL) and patient satisfaction with insulin degludec among Thai patients with diabetes mellitus (DM). METHODS: From October 2016 to September 2017, all patients who had started insulin degludec for at least 3 months were observed and evaluated at baseline, 3, 6, and 12 months. QOL was assessed using WHOQOL-BREF-THAI and level of satisfaction was measured by 7-point Likert scale. Glycemic fluctuation from paired iPro2 continuous glucose monitoring (CGM) obtained 4-6 weeks apart were also evaluated from a subset of patients with T1DM who switched from insulin glargine to insulin degludec. RESULTS: A total of 55 patients (T2DM 76.4%, females 54.5%, mean age 57.1±16.1 years, duration of diabetes 16.7±8.8 years, BMI 27.3±5.5 kg/m2, baseline A1C 9.3±2.3%, median duration of treatment 8 months) were included in the study. In T1DM patients (n=13), the overall mean A1C reduction at 12 months was 0.5% with minimal weight gain of 0.9 kgs at 12 months. In T2DM patients (n=42), the overall mean A1C reduction at 12 months was 0.8% with minimal weight loss of 0.4 kgs at 12 months. The proportion of T1DM patients who could achieve optimal glycemic control increased slightly from 14.3 to 18.2% but the proportion of T2DM patients who could achieve optimal glycemic control increased from 30.8 to 53.8%. Patient satisfaction showed a sustained improvement throughout the duration of study. In four T1DM patients who had paired CGM data, insulin degludec provided greater reductions in glycemic variability endpoints with increased time-in-range when compared with previous insulin glargine. DISCUSSION: Our data suggested that the effectiveness of insulin degludec was consistent with the results seen in clinical trials with lower risk of patients-reported hypoglycemia, and a significant improvement in glycemic control. Patients also reported higher treatment satisfaction. More long-term and cost-effectiveness data are needed to establish the role of this ultra-long-acting insulin in real-world settings.

Fixed-Ratio Combinations of Basal Insulin and GLP-1RA in the Management of Type 2 Diabetes Mellitus: Highlights from the Literature.

New pieces of evidence suggest that combining basal insulin with glucagone-like peptide 1 receptor agonists (GLP-1RA) in patients with type 2 diabetes could promptly ameliorate glucose control and prevent both hypoglycemic events and unnecessary weight gain compared to more intensive insulin regimens. To review the efficacy/effectiveness and safety of fixed-ratio combinations of basal insulin and GLP- 1RA (FRCs). Authors searched PubMed/MEDLINE, ClinicalTrials.gov, Cochrane Library, and Google Scholar for freely available original articles, randomized clinical trials (RCTs), clinical reviews, and meta-analysis written in English until January 2020. FRCs provide significative reductions in HbA1c levels in both insulin-naïve (-1.4% to -2%) and insulin- experienced (-1.5% to -2%) type 2 diabetic patients with moderate glucose impairment. More patients achieved the recommended glycemic targets on FRCs compared to those on mono-therapy with basal insulin or GLP-1RAs. The intensification with FRCs results in better glycemic control compared to basal insulin at fasting as well as during the postprandial state. The frequency of hypoglycemia is similar or lower in patients treated with FRCs than in those on basal insulin alone at a similar dose. Weight trend can be variable, ranging from -2.7 to +2 Kg for iDegLira and -0.7 to -1.3 Kg for iGlar- Lixi. However, a lower weight gain is obtained with iDegLira compared to iDeg (-2.2 to -2.5 Kg), iGlar (-1.7 to -3.2 Kg), and basal-bolus (-3.6 Kg) as well as with iGlarLixi compared to iGlar (-1.4 Kg). FRCs should be considered to safely improve the metabolic control in type 2 diabetic patients with moderate glycemic impairment while on oral medications, basal oral regimen or GLP-1RAs. However, a few but significative pieces of evidence suggest that FRCs could be a safe and effective treatment instead of a low dose basal-bolus intensification for patients with mild or moderate glucose impairment in order to reduce the risk of hypoglycemia and unnecessary weight gain, and for simplifying treatment regimen as well.

IDegLira fixed-ratio combination in the real world: a retrospective observational single-center Italian experience.

OBJECTIVE: An improvement of type 2 diabetes treatment is represented by the recent availability of a fixed-ratio combination of slow insulin degludec and GLP-1 RA liraglutide (IDegLira), which shows encouraging clinical trial results. This work represents a real-world evidence study to evaluate if the obtained clinical results are also confirmed in the clinical practice, in an Italian type 2 diabetes patients' population. PATIENTS AND METHODS: This retrospective observational study was conducted in the Diabetology Service of the Umbria local sanitary agency (USL Umbria 1) in Perugia. The study investigated all diabetic patients >18 years, who underwent anti-diabetic treatment with basal insulin with or without the concomitant consumption of one or more oral anti-diabetic agent (BOT group) or GLP-1 RA or rapid-acting insulin bolus (BB group), with unsatisfactory glycemic control for either hypoglycemic episodes or weight gain. The observation period was February 2018 to April 2019. RESULTS: IDegLira results to be effective in reducing HbA1c and fasting plasma glucose, especially among GLP-1 RA and BOT subgroup. In BOT group, a statistical difference was noted from the first month of treatment, also for post-prandial glycemia. Obtained results were achieved at a moderate dose of IDegLira reported during the study, which also represents a significant reduction of the amount of basal insulin in BB patients. CONCLUSIONS: Obtained results suggest that in a real-world setting, the switch to IDegLira treatment is a valid option for patients with unsatisfactory glycemic control, or who experienced side effects such as weight gain and hypoglycemia of other insulin therapies.

Assessment of basal insulin adherence using 2 methodologies among Texas Medicaid enrollees with type 2 diabetes.

BACKGROUND: Basal insulin is often recommended as the initial therapy for patients with type 2 diabetes who require insulin treatment. Adequate adherence is critical to diabetes management, yet suboptimal insulin adherence has been reported. Second-generation long-acting (SGLA) insulin has higher dosing flexibility and lower hypoglycemia risk and may improve adherence. However, little is known regarding adherence to SGLA insulin and how adherence to SGLA insulin compares with intermediate-acting neutral protamine Hagedorn (NPH) and first-generation long-acting (FGLA) insulin. Measurement of insulin adherence is challenging because of the inaccuracies of recorded days supply of insulin, and traditional medication possession ratio (MPR) may be negatively affected. Adjusted MPR (aMPR) has been developed in an effort to address this issue. OBJECTIVE: To examine the unadjusted and adjusted associations between basal insulin type and adherence to basal insulin using MPR and aMPR. METHODS: This retrospective database study used Texas Medicaid prescription claims from January 1, 2014, through June 30, 2017. The index date was the date of the first basal insulin prescription without the same prescription 6 months before (pre-index), and all patients were followed for 12 months (post-index). Patients aged 18-63 years with ≥ 1 pre-index prescription of an oral hypoglycemia agent (OHA) or a glucagon-like peptide-1 receptor agonist (GLP-1 RA), without any post-index prescription of premixed insulin or a basal insulin different from index insulin, and with continuous enrollment throughout the pre- and post-index periods, were included. The dependent variable was basal insulin adherence over 12 months, measured using MPR and aMPR. Unadjusted and adjusted adherence comparisons were conducted by basal (background) insulin type (NPH, FGLA, and SGLA). Covariates included age, gender, baseline use of basal insulins and comorbid medications, total number of medications, OHA adherence, post-index number of OHAs, and use of bolus insulins and GLP-1 RAs. Analysis of variance, chi-square tests, and multiple logistic regression analyses were performed. RESULTS: Of the 5,034 patients included, NPH, FGLA, and SGLA insulin users accounted for 3.7%, 89.8%, and 6.5%, respectively. The overall mean (SD) age was 50.9 (9.9) years, and 65.9% were female. In the unadjusted bivariate analyses, SGLA insulin users had significantly higher adherence, using either MPR (SGLA 0.68 [0.25] vs. FGLA 0.59 [0.27] vs. NPH 0.55 [0.27]; P < 0.0001) or aMPR (0.83 [0.23] vs. 0.78 [0.26] vs. 0.73 [0.28]; P = 0.0001). After controlling for covariates, insulin type was not significantly associated with the likelihood of being adherent (MPR or aMPR ≥ 0.8) using either measure. CONCLUSIONS: Adherence to SGLA insulin was not different from adherence to other basal insulins after controlling for patient characteristics. Yet, MPR and aMPR have limitations and warrant further confirmation of the study findings. Before new adherence measures for insulin therapy are developed, MPR and aMPR should be used with caution. DISCLOSURES: No specific funding was received for this manuscript. The authors report no potential conflicts of interest. Part of the data from this study was presented as posters at the American Pharmacists Association 2020 Annual Meeting & Exposition, March 20-23, 2020, in National Harbor, MD, and at the International Society for Pharmacoeconomics and Outcomes Research 2020 Conference, May 16-20, 2020, in Orlando, FL.

Once-Weekly Insulin for Type 2 Diabetes without Previous Insulin Treatment.

BACKGROUND: It is thought that a reduction in the frequency of basal insulin injections might facilitate treatment acceptance and adherence among patients with type 2 diabetes. Insulin icodec is a basal insulin analogue designed for once-weekly administration that is in development for the treatment of diabetes. METHODS: We conducted a 26-week, randomized, double-blind, double-dummy, phase 2 trial to investigate the efficacy and safety of once-weekly insulin icodec as compared with once-daily insulin glargine U100 in patients who had not previously received long-term insulin treatment and whose type 2 diabetes was inadequately controlled (glycated hemoglobin level, 7.0 to 9.5%) while taking metformin with or without a dipeptidyl peptidase 4 inhibitor. The primary end point was the change in glycated hemoglobin level from baseline to week 26. Safety end points, including episodes of hypoglycemia and insulin-related adverse events, were also evaluated. RESULTS: A total of 247 participants were randomly assigned (1:1) to receive icodec or glargine. Baseline characteristics were similar in the two groups; the mean baseline glycated hemoglobin level was 8.09% in the icodec group and 7.96% in the glargine group. The estimated mean change from baseline in the glycated hemoglobin level was -1.33 percentage points in the icodec group and -1.15 percentage points in the glargine group, to estimated means of 6.69% and 6.87%, respectively, at week 26; the estimated between-group difference in the change from baseline was -0.18 percentage points (95% CI, -0.38 to 0.02, P = 0.08). The observed rates of hypoglycemia with severity of level 2 (blood glucose level, <54 mg per deciliter) or level 3 (severe cognitive impairment) were low (icodec group, 0.53 events per patient-year; glargine group, 0.46 events per patient-year; estimated rate ratio, 1.09; 95% CI, 0.45 to 2.65). There was no between-group difference in insulin-related key adverse events, and rates of hypersensitivity and injection-site reactions were low. Most adverse events were mild, and no serious events were deemed to be related to the trial medications. CONCLUSIONS: Once-weekly treatment with insulin icodec had glucose-lowering efficacy and a safety profile similar to those of once-daily insulin glargine U100 in patients with type 2 diabetes. (Funded by Novo Nordisk; NN1436-4383 ClinicalTrials.gov number, NCT03751657.).