insulin-degludec and Diabetes-Mellitus--Type-1

Clinical differences between degludec U100 (Deg-100) and glargine U300 (Gla-300) in type 1 diabetes (T1D) were unknown.. To indirectly compare the safety, efficacy, and cost-effectiveness between Deg-100 and Gla-300 in T1D adults via systematic review.. Medline, the Cochrane Library, ClinicalTrials.gov, and Google Scholar were searched (October 2021). Randomized controlled trials comparing Deg-100 or Gla-300 vs. glargine U100 in T1D adults (follow-up ≥ 12 weeks) were selected and analyzed using a frequentist network meta-analysis. Cost-effectiveness analysis (CEA) was conducted over a 1-year time horizon from societal perspectives.. Nine trials were included. Efficacy analysis suggested that Deg-100 was non-inferior to Gla-300 in reducing HbA. Low-certainty indirect evidence suggested that Deg-100 appeared to have a favorable reduction in rates of severe hypoglycemia and more cost-effective compared with Gla-300 in T1D adults.

Topics: Adult; Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting

Currently, glycemic variability has more deleterious effects than sustained hyperglycemia and is closely associated with acute and chronic complications of diabetes. Reducing glycemic excursion is becoming another vital goal of glycemic control in clinical practice. This study aimed to determine whether insulin degludec (IDeg) or insulin glargine (IGla) was more beneficial for reducing glycemic fluctuations.. This research was constructed according to the PRISMA guidelines. We searched eight databases and ClinicalTrials.gov from their inception to 30 November 2021. All randomized controlled trials comparing the efficacy of glucose variability between IDeg and IGla in diabetic patients were included.. Fourteen trials with 8,683 participants were included. In patients with T1DM, IDeg was associated with a lower mean (MD: -16.25, 95% CI -29.02 to -3.07, P = 0.01) and standard deviation (P = 0.03) compared to IGla in fasting blood glucose (FBG); in people with T2DM, IDeg was related to a lower mean of FBG versus insulin glargine 100 U/ml (IGla100) (P <0.001) and had a more extended time in the range (TIR) than IGla100 (SMD: 0.15, 95% CI 0.02 to 0.27, P = 0.02) but not longer than insulin glargine 300 U/ml (IGla300). Moreover, IDeg had a lower coefficient of variation of FBG than IGla (P = 0.0254). For other indicators of glycemic variability, namely, standard deviation of blood glucose for 24 h, the mean of 24-h blood glucose, mean amplitude of glycemic excursion, the coefficient of variation for 24 h, the mean of daily differences, area under the glucose curve, and M-value, no significant differences were identified between IDeg and IGla, regardless of T1DM or T2DM.. Based on the current studies, there was comparable efficacy between IDeg and IGla from multiple aspects of glycemic variability, regardless of T1DM or T2DM. However, IDeg may be superior to IGla in reducing FBG variability in T1DM and T2DM. Nonetheless, due to the limitations of the original studies, it is still unclear whether IDeg is superior to both IGla100 and IGla300. In T2DM, IDeg had more extended TIR than IGla100 but not longer than IGla300. Additionally, more well-designed randomized controlled trials comparing IDeg with IGla300 for different indicators of glycemic variability are still warranted.. PROSPERO, CRD42021283203.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Randomized Controlled Trials as Topic

The goal of this study was to compare the efficacy and tolerability of insulin degludec with those of other long-acting insulin analogues (insulin glargine and insulin detemir) in patients with type 1 or 2 diabetes mellitus (T1D or T2D).. Those randomized controlled trials comparing insulin degludec with other long-acting insulin analogues in the treatment of patients with T1D or T2D published on or before August 21, 2022, were retrieved from PubMed, Web of Science, the Cochrane Library, and EMBASE. The efficacy end points were the changes from baseline in hemoglobin A. Data from a total of 20 trials (19,048 patients) were included. The differences in the reductions in glycosylated hemoglobin between insulin degludec and other long-acting basal insulin analogues (insulin glargine and insulin detemir) used for the treatment of patients with T1D or T2D were not significant. However, the reduction in FPG was greater with insulin degludec (-0.370 mmol/L; 95% CI, -0.473 to -0.267 mmol/L; P ≤ 0.001). Throughout the treatment periods of all of the available trials, the estimated rate ratios of overall and nocturnal hypoglycemia were significantly decreased with insulin degludec compared with insulin glargine or insulin detemir in patients with T1D or T2D; the differences in the risks for severe hypoglycemia were not significant.. Compared with other long-acting insulin analogues (insulin glargine and insulin detemir), insulin degludec was associated with a significantly decreased FPG, with lower prevalences of overall and nocturnal hypoglycemia.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting

People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown.. To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus.. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020.. We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM.. Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument.. We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks. Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin. Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence. Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-cert. Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.

Topics: Adolescent; Adult; Bias; Child; Child, Preschool; Confidence Intervals; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Myocardial Infarction; Quality of Life; Randomized Controlled Trials as Topic; Stroke; Young Adult

We aimed to assess the comparative efficacy and safety of second-generation basal insulins (glargine U300 and degludec U100) vs. neutral protamine Hagedorn (NPH) and first-generation basal insulins (glargine U100 and detemir) in type 1 diabetes (T1D) adults.PubMed, the Cochrane Library, ClinicalTrials.gov, and Google Scholar (until January 2021) were systematically searched. Randomized controlled trials (RCTs) with ≥ 12 weeks of follow-up comparing efficacy (HbA

Topics: Adult; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Network Meta-Analysis; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Gain

The aim of this study is to provide an overview of several emerging anti-diabetic molecules.. Diabetes is a complex metabolic disorder involving the dysregulation of glucose homeostasis at various levels. Insulin, which is produced by β-pancreatic cells, is a chief regulator of glucose metabolism, regulating its consumption within cells, which leads to energy generation or storage as glycogen. Abnormally low insulin secretion from β-cells, insulin insensitivity, and insulin tolerance lead to higher plasma glucose levels, resulting in metabolic complications. The last century has witnessed extraordinary efforts by the scientific community to develop anti-diabetic drugs, and these efforts have resulted in the discovery of exogenous insulin and various classes of oral anti-diabetic drugs.. Despite these exhaustive anti-diabetic pharmaceutical and therapeutic efforts, long-term glycemic control, hypoglycemic crisis, safety issues, large-scale economic burden and side effects remain the core problems.. The last decade has witnessed the development of various new classes of anti-diabetic drugs with different pharmacokinetic and pharmacodynamic profiles. Details of their FDA approvals and advantages/disadvantages are summarized in this review.. The salient features of insulin degludec, sodium-glucose co-transporter 2 inhibitors, glucokinase activators, fibroblast growth factor 21 receptor agonists, and GLP-1 agonists are discussed.. In the future, these new anti-diabetic drugs may have broad clinical applicability. Additional multicenter clinical studies on these new drugs should be conducted.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enzyme Activators; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Receptors, Fibroblast Growth Factor

To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes).. We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta-analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily.. The absolute changes in HbA. In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat-to-target, which minimize differences in HbA

Topics: Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Network Meta-Analysis; Practice Guidelines as Topic

Insulin degludec is a new ultra-long-action basal insulin. Using treat-to-target protocols, controlled trials have shown comparable HbA

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Observational Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Good glycaemic control during pregnancy is key to reduce maternal and foetal complications. Insulin degludec, an ultralong acting analogue with a "peakless" and stable pharmacokinetic profile, has the potential advantage of reducing hypoglycaemia and glucose variability compared to other basal insulins. Therefore, degludec could be a reasonable therapeutic option for pregnant women with type 1 diabetes (T1D). However, degludec is not licensed for use during pregnancy owing to the lack of safety data.. We herein report details on pregnancy and foetal outcomes in three women with uncontrolled T1D treated with insulin degludec during the first trimester or the whole pregnancy. In addition, we report an updated review of similar cases reported in literature. Overall, no congenital neonatal malformation was observed in the six cases described. Three babies required neonatal intensive care unit admission for respiratory distress, apnoeas, bilirubin increase or hypoglycaemia. However, the observed neonatal complications were deemed unlikely to be related to degludec treatment.. In summary, while awaiting for the results of an ongoing randomized controlled trial, data on six cases of degludec exposure during pregnancy reassuringly suggest no embryo-foetal toxicity. More information is needed before degludec can be safely recommended during pregnancy.

Topics: Adult; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infant, Newborn; Insulin, Long-Acting; Male; Pregnancy; Pregnancy in Diabetics; Pregnancy Outcome; Young Adult

Second-generation basal insulin analogues (e.g. insulin degludec, insulin glargine 300 U/mL), were designed to further extend the duration of insulin action and reduce within-day and day-to-day variability, and consequently hypoglycaemia risk, versus earlier long-acting basal insulins. This review examines the pharmacokinetic/pharmacodynamic characteristics of insulin degludec (100, 200 U/mL) and insulin glargine (100, 300 U/mL), and their influence on clinical outcomes.. Available pharmacokinetic/pharmacodynamic publications comparing insulin degludec and insulin glargine were reviewed.. Both insulin degludec and insulin glargine 300 U/mL have more prolonged and stable pharmacokinetic/pharmacodynamic profiles than the earlier basal insulin analogue, insulin glargine 100 U/mL. Insulin glargine 300 U/mL (0.4 U/kg, morning) showed a more stable pharmacodynamic profile (20% lower within-day variability [P = 0.047]) and more even 24-h distribution (over each 6-h quartile) than insulin degludec 100 U/mL, whereas the supratherapeutic 0.6 U/kg dose demonstrated a similar, albeit non-significant, trend. In contrast, a second clamp study indicated lower day-to-day variability in the 24-h glucose-lowering effect (variance ratio 3.70, P < 0.0001), and more even dosing over each 6-h quartile, with insulin degludec 200 U/mL versus insulin glargine 300 U/mL (0.4 U/kg, evening). Methodological differences and differences in bioequivalence that may explain these discrepancies are discussed.. Compared with earlier insulin analogues, second-generation basal insulins have improved pharmacokinetic/pharmacodynamic profiles that translate into clinical benefits, primarily reduced nocturnal-hypoglycaemia risk. Additional head-to-head comparisons of insulin degludec and insulin glargine 300 U/mL at bioequivalent doses, utilising continuous glucose monitoring and/or real-world evidence, are required to elucidate the differences in their pharmacological and clinical profiles.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Prognosis

To review evidence comparing benefits and harms of long-acting insulins in patients with type 1 and 2 diabetes.. MEDLINE and two Cochrane databases were searched during February 2018. Two authors selected studies meeting inclusion criteria and assessed their quality. Comparative studies of adult or paediatric patients with diabetes treated with insulin degludec, detemir or glargine were included. Meta-analysis was used to combine results of similar studies, and the I. Of 2534 citations reviewed, 70 studies met the inclusion criteria. No statistically significant differences in HbA1c were seen between any two insulins or formulations. Hypoglycaemia was less probable with degludec than with glargine, including nocturnal hypoglycaemia in type 1 (rate ratio 0.68, 95% CI 0.56-0.81) and type 2 diabetes (rate ratio 0.73, 95% CI 0.65-0.82), and severe hypoglycaemia in type 2 diabetes (relative risk 0.72, 95% CI 0.54-0.96). Patients with type 2 diabetes had higher rates of withdrawal because of adverse events when treated with detemir compared with glargine (relative risk 2.1, 95% CI 1.4-3.3). Adults taking detemir gained about 1 kg less body weight than those taking degludec (type 1) or glargine (type 2).. No differences in glycaemic control were seen between insulin degludec, detemir and glargine. Hypoglycaemia was less probable with degludec than glargine, and patients taking detemir gained less body weight than those given degludec or glargine. In type 2 diabetes, withdrawals as a result of adverse events were more probable with detemir than glargine.

Topics: Blood Glucose; Comparative Effectiveness Research; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Treatment Outcome; Weight Gain

Since the introduction of insulin as a life-saving agent for patients with type 1 diabetes, insulin preparations have evolved to approximate physiologic insulin delivery profiles to meet prandial and basal insulin needs. While prandial insulins are designed to have quick time-action profiles that minimize postprandial glucose excursions, basal insulins are designed to have a protracted time-action profile to facilitate basal glucose control over 24 h. Given that all insulins have the same mechanism of action at the target tissue level, the differences in time-action profiles are achieved through different mechanisms of protraction, resulting in different behaviors in the subcutaneous space and different rates of absorption into the circulation. Herein, we evaluate the differences in basal insulin preparations based on their differential mechanisms of protraction, and the resulting clinical action profiles. Multiple randomized control trials and real-world evidence studies have demonstrated that the newer second-generation basal insulin analogs, insulin glargine 300 units/mL and insulin degludec 100 or 200 units/mL, provide stable glycemic control with once-daily dosing and are associated with a reduced risk of hypoglycemia compared with previous-generation basal insulin analogs insulin glargine 100 units/mL and insulin detemir. These advantages can lead to decreased healthcare resource utilization and cost. With this collective knowledge, healthcare providers and payers can make educated and well-informed decisions when determining which treatment regimen best meets the needs of each individual patient.Funding: Sanofi US, Inc.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Postprandial Period

Co-formulation of basal and bolus insulin components provides a simpler regimen for patients with type 2 diabetes than separate basal-bolus treatment. However, conventional premixed insulin products include a suboptimal protaminated basal component that requires resuspension prior to injection. Insulin degludec/insulin aspart (IDegAsp) is the first soluble co-formulation of a basal insulin with an ultra-long duration of action (IDeg) and a rapid-acting bolus insulin (IAsp) in a single injection.. In this review, the authors summarize findings from pre-clinical studies and the clinical trial program and provide guidance for the initiating and switching of IDegAsp in different patient populations. Pharmacodynamic analyses have revealed a rapid onset of action and distinct peak (IAsp), followed by a separate, flat and stable basal effect (IDeg component). Phase 3 studies have demonstrated the efficacy and safety of IDegAsp, with greater glycemic improvements than basal-only therapy in international and Japanese type 2 diabetes populations. IDegAsp also results in reduced insulin dose requirements and lower rates of hypoglycemia than premixed insulin.. IDegAsp provides a simple and effective insulin regimen in appropriately selected Japanese patients, with the flexibility to suit individual needs. The benefits of IDegAsp over conventional insulin regimens might help tackle clinical inertia with insulin intensification.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Half-Life; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin, Long-Acting

To determine the safety and efficacy of insulin degludec versus glargine in patients with type 1 (T1D) and type 2 (T2D) diabetes mellitus.. Databases were searched until July 5, 2017. We included randomized controlled trials comparing degludec with glargine in diabetic patients, each with a minimum of 16 weeks of follow-up.. Eighteen trials with 16,791 patients were included. Degludec was associated with a statistically significant reduction in risk for all confirmed hypoglycemia at the maintenance treatment period [estimated rate ratio (ERR) 0.81; 95% confidence interval (CI) 0.72‒0.92; P = 0.001], nocturnal confirmed hypoglycemia at the entire (ERR 0.71; 95% CI 0.63‒0.80; P < 0.001) and maintenance treatment period (ERR 0.65; 95% CI 0.59‒0.71; P < 0.001), all irrespective of the pooled diabetic populations and follow-up durations. The differences in the rate of hypoglycemia were more pronounced in nocturnal period and maintenance period and in T2D than T1D patients. Degludec reduced the incidence of severe hypoglycemia in T2D [ERR 0.65; (0.52; 0.89); P = 0.005] but not T1D patients. HbA1c concentration was slightly higher in degludec over glargine but was not clinically relevant [estimated treatment difference (ETD) 0.03; 95% CI - 0.00 to 0.06%; P = 0.06]. Fasting plasma glucose level was lower in degludec-treated patients (ETD - 0.28 mmol/L; 95% CI - 0.44 to - 0.11 mmol/L; P = 0.001). Several subgroup analyses showed largely consistent findings. The rates of adverse events including total mortality and cardiovascular events were not significantly different between two treatment strategies.. Insulin degludec appears to have better safety in reducing hypoglycemic events with similar efficacy compared with insulin glargine.

Topics: Databases, Factual; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Randomized Controlled Trials as Topic; Treatment Outcome

Diabetes, particularly type 2 diabetes (T2D), has become an epidemic in the United States, with a significant portion of patients unable to meet recommended glycemic targets. All individuals with type 1 diabetes (T1D) and a significant majority of those with T2D will ultimately require insulin therapy. However, there are several barriers to its use. The introduction of the new, ultra-long-acting basal insulins degludec and glargine U-300, and the single-injection combinations of insulin degludec/liraglutide and insulin glargine U-100/lixisenatide, offer options that may overcome several of those barriers, including the high risk of hypoglycemia, glycemic variability, and relatively short duration of action. This article spotlights the outcomes of the phase 3 clinical trials for these newer formulations, as well as more recent meta-analyses and real-world studies. It also highlights the implications for managed care plans as they move to add these insulins to their formularies.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Managed Care Programs; Randomized Controlled Trials as Topic; Treatment Outcome

Insulin degludec has been the product of a sophisticated and systematic biochemical engineering program which began with the release of insulin detemir. The goal was to produce a long-lasting basal insulin with low individual variability. Certainly, this goal has been achieved. Degludec has a duration of action approaching twice that of glargine. Another advantage of degludec is in its lack of unpredictable copolymerization of added aspart. In several studies, degludec has shown lower rates of nocturnal hypoglycemia than glargine. Degludec can be administered flexibly with a very flat insulin concentration curve at any time of day. Initial US Food and Drug Administration concerns about a possible increase in cardiac events in degludec-treated patients have been allayed by the results of a study targeting individuals with high cardiac risk. Degludec is now marketed in the US competing with glargine. Despite the long duration of action of degludec, attempted administration three times weekly resulted in less effective lowering of glycated hemoglobin and an increased incidence of hypoglycemia compared to daily glargine. Conversely the coformulation of degludec and liraglutide has proven very successful in reducing glycated hemoglobin levels with less hypoglycemia and less weight gain than with degludec alone and with less gastrointestinal symptoms than with liraglutide alone. A large study comparing glargine insulin and degludec in patients with increased cardiac risk is now ongoing. This study may or may not prove superiority of one or the other insulin, but, with the coming of biosimilar glargine insulin, cost factors may be dominant in determining which basal insulin is to be used. Nonetheless, the coformulation with liraglutide will likely insure the future of degludec insulin in the treatment of type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin, Long-Acting; United States

Despite the therapeutic advances in the treatment of diabetes, metabolic control instability due to glycemic variability (GV) is frequently observed in patients with diabetes on intensive insulin therapy and is associated with hyperglycemic peaks and hypoglycemic episodes. Hyperglycemia associated with GV has been implicated in the development of chronic complications due to its pro-oxidative consequences. On the other hand, hypoglycemia can be associated with increased cardiovascular risk secondarily to adrenergic activation. The ultra-long-acting insulin analogue, insulin degludec (IDeg), presents a flat and stable glucose-lowering effect both in Type 1 and Type 2 diabetes patients. In pharmacodynamic studies, IDeg has been associated with a lower variability in its insulin action than other alternatives for basal insulin, which might have clinical advantages for the stability of the glycemic control. The main objective of this review is to present pharmacological and clinical data regarding the efficacy and safety of IDeg for the treatment of diabetes focusing on its effects on GV and on hypoglycemia frequency.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Risk Factors

The goal of insulin therapy in people affected by type 1 diabetes mellitus consists in achieving an optimal metabolic control and so HbA1c levels below 7.5%, according to the conclusions of relevant scientific studies. In any case it seems that this target is far from being achieved, mostly in the pediatric population. However, many important pharmacological, technological and cultural milestones have been placed both in therapy and management of insulin-dependent diabetes even if the gap between growing knowledge in these fields and its application in daily clinical practice appears still too wide. A fundamental component of these advancements concerns the design of new insulin basal analogues; molecules used to realize a basal-bolus model of therapy with MDI scheme. Degludec insulin has been recently approved for the pediatric utilization (aged 1 to 17 years). A registration trial for pediatric population (aged 6 to 17 years) is in progress for glargine U-300 insulin. These two insulin types have different biochemical and pharmacological properties and they represent two different ways to achieve the ideal basal analogue. Insulin degludec and insulin glargine U-300 are the newest basal analogues and each of them has proper pharmacokinetic and pharmacodynamic characteristics. Their characteristics represent an effort to create the ideal solution. The aim of this review is to summarize the pharmacokinetic and pharmacodynamic properties of these new insulins, to list the most significant scientific findings regarding their pharmacology as well as clinical uses, with particular reference to the pediatric population in order to declare them to clinical experience and to report data on an initial experience with these analogues, especially with degludec insulin. Once again, evolution goes through the specialized training of the staff involved in the care of the diabetic patient and the constant education of the latter.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Health Services Needs and Demand; Humans; Hypoglycemic Agents; Infant; Insulin Glargine; Insulin, Long-Acting

Despite improvements in anti-hyperglycemic therapies, there are many unmet clinical needs that hinder successful glycemic control in people being treated with current basal insulin analogs.. This paper reviews the unmet needs associated with current basal insulin therapy and describes the most recent basal insulins for the treatment of diabetes.. PubMed was searched for articles on basal insulin analogs published between 2000 and April 2016.. Although long-acting insulin analogs, such as insulin glargine 100 units/mL and insulin detemir, have come towards approximating physiologic basal insulin levels, limitations such as hypoglycemia and intra- and inter-individual variability are associated with their use resulting in glycemic fluctuations. Some basal insulins lack 24 hour coverage, requiring some patients to split their dose, increasing the number of injections required to maintain glycemic control. Fear of hypoglycemia and the need for additional injections often leads to poor compliance and suboptimal glycemic control. Long-acting insulin analogs, such as insulin glargine 300 units/mL and insulin degludec, have improved upon the shortcomings of the current basal insulin analogs. Improved pharmacodynamic/pharmacokinetic profiles afford lower intra-patient variability and an extended duration of action, providing full and stable 24 hour basal insulin coverage with once daily dosing, and comparable efficacy to insulin glargine with lower rates of hypoglycemia.. The improved pharmacodynamic/pharmacokinetic profiles of new long-acting insulin formulations provide greater glycemic control with once daily dosing. With the growing number of therapeutic choices available, physicians have more scope to individualize patient options for basal insulin therapy.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male

A prospective meta-analysis of phase 3 trials showed lower rates of nocturnal hypoglycaemia with insulin degludec vs. insulin glargine. We investigated the consistency of the results across different definitions of hypoglycaemia.. This post-hoc, patient-level meta-analysis included six randomized, controlled, 26- or 52-week phase 3a trials in insulin-naïve participants with Type 2 diabetes mellitus (Type 2 diabetesinsulin naïve ), participants with Type 2 diabetes mellitus using basal-bolus therapy (Type 2 diabetesBB ) and those with Type 1 diabetes mellitus. We used three definitions of hypoglycaemia and different timescales for the nocturnal period. Rates were analysed for the entire core trial period, the 'maintenance period' only, and the extension trial set population. Analyses utilized a negative binomial regression model.. In Type 2 diabetesinsulin naïve participants, risk of nocturnal hypoglycaemia was significantly lower with insulin degludec vs. insulin glargine for all hypoglycaemia definitions and trial periods. Risk was also lower for the timescale 21.59-05.59, but not 00.01-07.59. For Type 2 diabetesBB , nocturnal hypoglycaemia rates were lower with insulin degludec vs. insulin glargine across all definitions, timescales and trial periods, with one exception. For individuals with Type 1 diabetes mellitus, nocturnal hypoglycaemia risk was significantly lower with insulin degludec during the maintenance period for the original definition (plasma glucose < 3.1 mmol/l, timescale 00.01-05.59) and in the extension trial set population for all hypoglycaemia definitions except for the nocturnal timescale 00.01-07.59.. Compared with insulin glargine, insulin degludec is associated with lower rates of nocturnal hypoglycaemia in people with Type 2 diabetes mellitus, and similar or lower rates in Type 1 diabetes mellitus, across different definitions.

Topics: Circadian Rhythm; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Practice Guidelines as Topic; Precision Medicine; Randomized Controlled Trials as Topic; Reproducibility of Results; Risk

Novel insulins have entered the market during recent years. The ultra-long acting insulins, insulin degludek and insulin glargine, the latter having a strength of 300 U/ml, exhibit a steady and predictable action curve. Studies have indicated that significantly fewer hypoglycemiae occur when using degludek in patients with either type 1 or type 2 diabetes, whereas similar evidence about glargine (300 U/mI) has been obtained in the treatment of type 2 diabetes. The long duration of action of both insulins brings long-needed flexibility to.their dosing.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin Glargine; Insulin, Long-Acting; Insulins

To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles.. Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised.. In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis.. IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Topics: Blood Glucose; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Substitution; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin, Long-Acting; Treatment Outcome

Since its discovery almost a century ago, insulin remains the mainstay of treatment of patients with type 1 diabetes mellitus. Although progress in the synthesis of new formulations has been remarkable, the physiological profile of insulin is still different from that observed with preparations available nowadays. In the last decade, the introduction into clinical practice of insulin analogues has allowed significantly improvement in glycemic control and has facilitated the spread of basal/bolus patterns, the most physiological ones until now. Despite the benefits of basal analogues, glycemia often varies considerably when used as a single daily injection and this is why new molecules have been further investigated. Improvement has been achieved especially in terms of duration and rate of hypoglycemia, the main limiting factor of intensive therapy. This article reviews the available data concerning the new basal insulin analogues, degludec, pegylated lispro and glargine U300, and new formulations currently under development.

Topics: Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting

Insulin degludec is a new-generation ultra-long-acting basal insulin which offers a significantly more predictable glucose-lowering effect than other long-acting insulin analogues. The aim of this study was to compare the effect of treatment with insulin degludec and long-acting insulin analogues glargine and detemir in type 1 diabetic (T1D) patients by means of a systematic review and meta-analysis.. The following electronic databases were searched up to January 2014: MEDLINE, EMBASE and The Cochrane Library. Additional references were obtained from the reviewed articles. There were included randomised controlled trials of at least 12-week duration with basal-bolus regimen therapies in T1D patients.. Current analysis included four studies involving 1,846 T1D patients. The combined data from all trials showed a statistically significant reduction in the basal insulin dose (MD -0.042, 95 % CI -0.067 to -0.018, p = 0.001) and the total daily insulin dose (MD -0.072, 95 % CI 0.016 to -0.027, p = 0.002) in the degludec group compared to other long-acting analogues. There was also a significant reduction of nocturnal hypoglycaemia in the degludec group compared to the controls (rate ratio 0.697, 95 % CI 0.617-0.786, p = 0.000). There were no differences between the groups in terms of glycated haemoglobin values, fasting plasma glucose (FPG) and adverse events.. Basal-bolus treatment with insulin degludec was superior to long-acting insulin analogues detemir and glargine in reducing the rate of nocturnal hypoglycaemia. In comparison with other long-acting analogues, treatment with insulin degludec was safe and patients obtained similar metabolic control expressed by HbA1c and FPG levels with the added benefit of a reduced basal and total insulin dose.

Topics: Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Insulin; Insulin, Long-Acting; Randomized Controlled Trials as Topic

The limitations of current basal insulin preparations include concerns related to their pharmacokinetic and pharmacodynamic properties, hypoglycaemia, weight gain, and perception of management complexity, including rigid dosing schedules. Insulin degludec (IDeg) is a novel basal insulin with improved pharmacokinetic and pharmacodynamic properties compared to insulin glargine (IGlar) including a long half-life of ∼25 h and a duration of action >42 h at steady state, providing a flat and stable blood glucose-lowering effect when injected once daily. Evidence from phase 3a clinical trials with a treat-to-target design in patients with type 1 and type 2 diabetes has shown that IDeg has similar efficacy to IGlar, with a 9% and 26% reduction in risk of overall and nocturnal hypoglycaemia, respectively (in the pooled population) during the entire treatment period, and a 16% and 32% reduction during the maintenance period, respectively. Given its pharmacodynamic properties, IDeg offers a broad dosing window, allowing for flexible dose administration, if required. Two different formulations of IDeg are available (100 units/mL [U100] and 200 units/mL), the latter providing the same IDeg dose as the U100 formulation in half the injection volume. The unique pharmacokinetic profile of IDeg facilitates glycaemic control while minimising the risk of nocturnal hypoglycaemia.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemia; Insulin; Insulin Glargine; Insulin, Long-Acting; Weight Gain

Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar).. Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose <3.1 mmol/L or severe episodes requiring assistance, and nocturnal hypoglycaemia occurred between 00:01 and 05:59. In all trials, the mean end-of-trial FPG was lower for IDeg than IGlar, reaching statistical significance in three trials. Similarly, IDeg was associated with a lower rate of nocturnal confirmed hypoglycaemia vs. IGlar, which was statistically significant in three trials, regardless of type of diabetes or background therapy.. This analysis shows that the lower rate of nocturnal confirmed hypoglycaemia seen with IDeg relative to IGlar is accompanied by a reduced mean FPG, in particular in patients with T2D.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Humans; Hypoglycemia; Insulin Glargine; Insulin, Long-Acting; Randomized Controlled Trials as Topic

Degludec is the most recent molecule of the ultra-long-acting basal insulin analogues approved for human use. It forms soluble multihexamers which after subcutaneous injection are converted into monomers, and are thus slowly and continuously absorbed into the bloodstream. This absorption mechanism confers degludec an ultra-long and stable action profile, with no concentration peaks. This paper discusses the most recent studies in patients with type 1 and 2 diabetes mellitus, which showed degludec to be non inferior in decreasing HbA1c, ensuring optimum glycemic control similar to that achieved with insulin glargine or detemir. Degludec also had an improved safety profile, as it was associated to a significantly lower rate of nocturnal hypoglycemia in both types of diabetes and to a potentially lower overall hypoglycemia rate in type 2 DM. Degludec also opens the possibility to use more flexible regimens.

Topics: Biomedical Research; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin, Long-Acting

The 21st century has seen the arrival of several insulin analogue products and the refinement of insulin regimens, with widespread advocacy of continuous titration algorithms and earlier initiation of supplementary insulin therapy (predominantly using basal insulins) in type 2 diabetes. Nevertheless, many insulin-treated diabetes patients remain in poor glycaemic control. This might reflect insufficient titration effort or lax adherence, but these issues could in some cases result from concerns about hypoglycaemia. Certainly there is scope for improving the pharmacokinetic/pharmacodynamic (PK/PD) profile of basal insulin, and three new products offer this prospect. Insulin degludec, now in clinical use, and PEGylated insulin lispro, in development, have greatly extended action profiles that result from two very different, but unique, mechanisms. With once-daily dosing, these insulins produce stable PK/PD profiles at steady state, associated with a low incidence of hypoglycaemia. The feasibility of varied daily dose timing has also been confirmed with insulin degludec. High strength formulations of insulin glargine and insulin degludec offer the prospect of a reduced injection number/volume in high dose users, and in the case of glargine, the PK/PD profile might also be favourably modified. This review considers critically the clinical evidence and expectations we should have for these new basal insulins.

Topics: Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Polyethylene Glycols

Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. To date, a large number of studies have been conducted to investigate the pharmacokinetic and pharmacodynamic properties of IDeg. Standardised methods for collection and analysis of blood samples (for pharmacokinetic endpoints) and euglycaemic clamp procedures (for pharmacodynamic endpoints) were applied across studies to enable cross-study evaluation of important pharmacokinetic and pharmacodynamic parameters. Data show that IDeg has a half-life of >25 h [compared with ~12 h for insulin glargine (IGlar)] and reaches steady state within 3 days of administration in all patient populations investigated. The pharmacokinetic profile of IDeg demonstrates an even distribution of exposure across one dosing interval. The pharmacodynamic profile of IDeg is flat and stable, demonstrated by an even distribution of glucose-lowering effect across all four 6-h intervals in a 24-h period (one dosing day). These properties were consistently demonstrated across different type 1 and type 2 diabetes mellitus patient populations, including those from different ethnic origins (both males and females with type 2 diabetes), the elderly, and patients with hepatic or renal impairment. IDeg has an ultra-long duration of action exceeding 42 h and demonstrates four times lower day-to-day within-subject variability in glucose-lowering effect than IGlar. This review discusses the pharmacokinetic and pharmacodynamic data accumulated thus far, and the relevance of these results from a clinical perspective.

Topics: Chemistry, Pharmaceutical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin, Long-Acting

Basal insulin analog therapy is the most common method of introducing insulin replacement therapy for the majority of patients with type 2 diabetes mellitus. Long-acting insulin analogs provide relatively peakless and more physiologic insulin replacement therapy than neutral protaminated Hagedorn insulin. Recently 2 new basal insulin analogs have been developed with superior pharmacokinetic and pharmacodynamics properties; insulin degludec and a pegylated insulin lispro. These agents are generally well tolerated and have been evaluated in both type 1 and type 2 diabetes. In this article we review the results of clinical trials assessing the efficacy, safety and tolerability of these newer longer-acting insulin analogs. In general rates of hypoglycaemia in these trials were low, glucose control was comparable to currently available basal insulin analogs, and rates of nocturnal hypoglycaemia were significantly and substantially lower. While further study will be required, advances in basal insulin replacement may offer important advantages over existing options for starting insulin strategies.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Lispro; Insulin, Long-Acting; Weight Loss

To evaluate health-related quality of life (health utility) scores in patients with diabetes receiving insulin degludec (IDeg) or insulin glargine (IGlar).. Patient-level data from six, randomized, controlled, open-label, multicentre, confirmatory, treat-to-target trials of 26- or 52 weeks' duration were pooled in this analysis. The Short Form 36 (SF-36) version-2 health questionnaire was completed by patients at baseline and end-of-trial. SF-36 scores for 4001 individual patients were then mapped onto the EuroQol-5D health utility scale, which has a range from -0.59 (a state worse than death) to 1.00 (perfect health).. IDeg treatment exhibited a significant improvement in health status of 0.005 (CI: 0.0006; 0.009) points compared with IGlar (p < 0.024). Gender, region, trial and age also had a significant influence on estimated utility scores as did baseline utility scores, p < 0.05. Prior to the removal of interaction variables a difference of 0.008 points was observed, p < 0.045. Previous insulin treatment did not have an impact on the final outcome.. This study shows that IDeg is associated with a modest, but statistically significant, improvement in health utility compared with IGlar in patients with diabetes.

Topics: Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Multicenter Studies as Topic; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Socioeconomic Factors; Surveys and Questionnaires; Treatment Outcome

Insulin treatment in type 1 and type 2 diabetes (T1D and T2D) is highly efficacious, but in practice, non-adherence and ineffective dose titration limit its effectiveness. Barriers to more effective insulin treatment are numerous, including hypoglycaemia, fear of hypoglycaemia and concern about weight gain. The regular treatment timing needed with conventional basal insulins [neutral protamine Hagedorn (NPH) insulin and the first-generation analogues glargine and detemir] may also make adherence to these treatments problematic for many patients. Indeed, surveys indicate that the rigidity of this schedule induces some patients with T1D and T2D to omit insulin doses. Degludec is a novel, ultra-long-acting basal insulin analogue that is as effective as insulin glargine, but significantly reduces patients' risk of nocturnal hypoglycaemia. Because of its peakless, extended and highly predictable glucose-lowering effect, once-daily dosing on a flexible schedule may be feasible with degludec. Studies testing this possibility suggest that degludec tolerates day-to-day variation in dose timing while maintaining full efficacy and low risk of nocturnal hypoglycaemia. Degludec would appear to be an appropriate choice for patients being considered for a basal analogue, and it may be particularly well suited to patients with unpredictable social or work schedules, those who travel frequently and those who find rigid scheduling of their insulin injections a burden or barrier to regular treatment.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Patient Selection

Insulin degludec (Tresiba(®)) is an ultra-long-acting insulin analogue that is also available as a coformulation with rapid-acting insulin aspart (insulin degludec/insulin aspart) [Ryzodeg(®)]. Insulin degludec has a flat, stable glucose-lowering profile with a duration of action of >42 h, and less within-patient day-to-day variability in glucose-lowering effect than the long-acting insulin analogue insulin glargine. In clinical trials, insulin degludec achieved similar glycaemic control to that seen with insulin glargine in patients with type 1 or 2 diabetes, but with a lower risk of nocturnal hypoglycaemia. In addition, trials examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes show the potential for adjusting the injection time, without compromising glycaemic control or safety. A 200 U/mL formulation of insulin degludec is also available for use in patients who require large volumes of basal insulin. Insulin degludec/insulin aspart was noninferior to the long-acting insulin analogue insulin detemir in patients with type 1 diabetes and has the potential to reduce the number of daily injections. Trial results also indicate that insulin degludec/insulin aspart may be an appropriate option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs. Subcutaneous insulin degludec was generally well tolerated in patients with type 1 or 2 diabetes. In conclusion, insulin degludec and insulin degludec/insulin aspart represent a useful advance in the treatment of type 1 or 2 diabetes.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Management; Drug Combinations; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin Antagonists; Insulin Aspart; Insulin, Long-Acting

During the past 10 years, several new basal insulin analogs have been developed. There has been for 3 years controversy on the potential increased risk for cancer with insulin glargine, which ceased with the publication of the ORIGIN trial in 2012. In insulin-treated persons with type 2 diabetes, it is usual to recommend that plasma insulin concentrations remain within a 50-200 pmol/L range in order to avoid overinsulinization, a potential causative factor for increased mitogenicity. Such concentrations are achieved when daily doses of insulin glargine or NPH insulin approximate 0.4 units/kg. However, the total plasma insulin concentrations are much greater in persons treated with insulin detemir and especially insulin degludec. These insulins derive their protracted action from the insertion of a long chain fatty acid moiety to the insulin molecule thereby increasing albumin binding. As a consequence, in persons with type 2 diabetes, stable total plasma concentrations as high as either 1600 or 6000 pmol/L are observed for insulin detemir or degludec, respectively. At present, the free to bound ratio of plasma insulin concentrations remains unknown for these two compounds. A first requirement is to understand how these insulins are eliminated or degraded and secondly to quantify the respective contributions of the free and bound fractions. Therefore, prior to early phase 2 or 3 randomized clinical trials, a better comprehension of the metabolism of all the new insulins would be invaluable.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting

Elderly patients with diabetes are more vulnerable to the occurrence and effects of hypoglycaemia; therefore, treatments with low risk of hypoglycaemia are preferred in this population. This study aimed to compare hypoglycaemia rates between insulin degludec (IDeg) and insulin glargine (IGlar) in elderly patients.. Hypoglycaemia data from patients ≥65 years of age with type 1 (T1DM) or type 2 (T2DM) diabetes from seven randomised, treat-to-target phase IIIa trials were used to compare IDeg and IGlar in a pre-planned meta-analysis. Overall, 917/4345 (21 %) randomised patients in the seven trials were elderly (634 IDeg, 283 IGlar). Overall confirmed hypoglycaemia was defined as <3.1 mmol/L or severe hypoglycaemia (symptoms requiring external assistance). Nocturnal hypoglycaemia included confirmed episodes from 0001 to 0559 hours (inclusive). Treatment comparisons of hypoglycaemia in T1DM patients were not performed due to low numbers of elderly patients with T1DM randomised (43 IDeg, 18 IGlar); statistical comparisons were also not made for severe hypoglycaemia due to the low number of events.. In elderly patients with T2DM, the rate of overall confirmed hypoglycaemia was significantly lower with IDeg than IGlar [estimated rate ratio (ERR) 0.76 (0.61; 0.95)95 % CI]; nocturnal confirmed hypoglycaemia was also significantly lower with IDeg [ERR 0.64 (0.43; 0.95)95 % CI]. Confirmed hypoglycaemia occurred in the majority of T1DM patients, whereas severe episodes occurred infrequently and at similar rates in both treatment groups in T1DM and T2DM.. Results of this pre-planned meta-analysis in elderly patients with diabetes demonstrate a significant reduction in hypoglycaemic events with IDeg relative to IGlar.

Topics: Aged; Aged, 80 and over; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Randomized Controlled Trials as Topic

After subcutaneous injection, IDeg self-associates to form multihexamer chains that slowly dissociate into monomers. This results in a duration of action of more than 42 hours as well as a smooth level action profile with low intra-individual variability. Pharmacokinetic studies foun IDeg to have a half-life of approximately 25 hours which is considerably longer than that from other current insulin formulations. Based on these properties, IDeg demonstrated low risk for nocturnal hypoglycaemic events in the clinical study program. Concurrently, phase 3 studies have provided evidence for a non-inferior glucose lowering effect when compared to other currently available basal insulin formulations. Moreover, the long duration of action suggests a flexible handling which could be better adapted to patients' needs in daily routine. This article gives an overview of the mechanism of action of IDeg and the latest results from phase 2 and phase 3 studies.

Topics: Biological Availability; Blood Glucose; Clinical Trials, Phase III as Topic; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Half-Life; Humans; Injections, Subcutaneous; Insulin, Long-Acting

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Weight Gain

Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM).. Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analysed.. Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.83[0.70;0.98](95%) (CI) , RR:0.64[0.48;0.86](95%) (CI) and RR:0.14[0.03;0.70](95%) (CI) . In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [RR:0.83[0.74;0.94](95%) (CI) and RR:0.68[0.57;0.82](95%) (CI) ). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.75[0.60;0.94](95%) (CI) ). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations.. The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes.

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

All the basal insulin products currently available have suboptimal pharmacokinetic (PK) properties, with none reliably providing a reproducible and peakless pharmacodynamic (PD) effect that endures over 24 h from once-daily dosing. Insulin degludec is a novel acylated basal insulin with a unique mechanism of protracted absorption involving the formation of a depot of soluble multihexamer chains after subcutaneous injection. PK/PD studies show that insulin degludec has a very long duration of action, with a half-life exceeding 25 h. Once-daily dosing produces a steady-state profile characterized by a near-constant effect, which varies little from injection to injection in a given patient. Clinically, insulin degludec has been shown consistently to carry a lower risk of nocturnal hypoglycaemia than once-daily insulin glargine, in both basal+bolus and basal-only insulin regimens. The constancy of the steady-state profile of insulin degludec also means that day-to-day irregularities at the time of injection have relatively little PD influence, thereby offering the possibility of greater treatment flexibility for patients.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Half-Life; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin, Long-Acting; Male; Randomized Controlled Trials as Topic; Treatment Outcome

To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and potential role in therapy of insulin degludec.. Articles were identified using the MEDLINE database (January 1996-December 2012). Abstracts and posters were identified from respective congressional websites and published supplements of the American Diabetes Association, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists (January 2008-December 2012). Clinicaltrials.gov was used to identify any ongoing clinical trials or completed trials whose results had not been presented or published.. All available studies were reviewed for inclusion; pharmacokinetic studies were limited to those reporting human data.. Insulin degludec is a novel, ultra-long-acting basal insulin analogue that has a similar safety and efficacy profile when compared with insulin glargine in patients with type 1 or type 2 diabetes. Clinical trials have indicated that there is less hypoglycemia, particularly nocturnal hypoglycemia, associated with this agent.. If insulin degludec is approved, it may offer an alternative basal insulin for patients needing more flexible dosing, having a history of nocturnal hypoglycemia, or those with severe insulin resistance needing a higher concentration of basal insulin.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Combinations; Drugs, Investigational; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin Resistance; Insulin, Long-Acting; United States; Weight Gain

Limitations of conventional human basal insulins like NPH have led to the development of more stable and peak less analogs. However, the first generation of basal analogs like glargine and detemir has certain shortcomings which do not allow them to be termed ideal basal insulins. Degludec, a novel basal insulin analog has the potential to overcome these limitations. This paper reviews the potential advantages of degludec over existing basal insulins and analogs. It discusses the basic and clinical studies performed on degludec so far, and highlights the possible role this molecule can play in the management of diabetes mellitus. In this paper, the recent patents on basal insulin have been reviewed so as to provide an insight into the advances in this field. In this article, we present a review of Degludec, as well as related patents.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Legislation, Drug; Patents as Topic; Treatment Outcome

Structure-based protein design has enabled the engineering of insulin analogs with improved pharmacokinetic and pharmacodynamic properties. Exploiting classical structures of zinc insulin hexamers, the first insulin analog products focused on destabilization of subunit interfaces to obtain rapid-acting (prandial) formulations. Complementary efforts sought to stabilize the insulin hexamer or promote higher-order self-assembly within the subcutaneous depot toward the goal of enhanced basal glycemic control with reduced risk of hypoglycemia. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus; Sanofi-Aventis, Paris, France) or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir; Novo-Nordisk, Basværd, Denmark). In the past year second-generation basal insulin analogs have entered clinical trials in an effort to obtain ideal flat 24-hour pharmacodynamic profiles. The strategies employ non-standard protein modifications. One candidate (insulin degludec; Novo-Nordisk a/s) undergoes extensive subcutaneous supramolecular assembly coupled to a large-scale allosteric reorganization of the insulin hexamer (the TR transition). Another candidate (LY2605541; Eli Lilly and Co., Indianapolis, IN, USA) utilizes coupling to polyethylene glycol to delay absorption and clearance. On the other end of the spectrum, advances in delivery technologies (such as microneedles and micropatches) and excipients (such as the citrate/zinc-ion chelator combination employed by Biodel, Inc., Danbury, CT, USA) suggest strategies to accelerate PK/PD toward ultra-rapid-acting insulin formulations. Next-generation insulin analogs may also address the feasibility of hepatoselective signaling. Although not in clinical trials, early-stage technologies provide a long-range vision of "smart insulins" and glucose-responsive polymers for regulated hormone release.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Drug Design; Female; Humans; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Insulin, Short-Acting; Male; Polyethylene Glycols; Polymers; Protein Engineering

The basal-bolus concept of delivering insulin to diabetic patients makes physiological sense, as it mimics normal insulin release in people without diabetes. In line with this concept, a major effort put forth by insulin manufacturers has been to develop the ideal exogenous basal insulin product. The perfect basal insulin product would be injected into subcutaneous tissue without causing irritation, release insulin continuously at a constant rate for at least 24 hours, be stable, not contribute to weight gain, have a low risk of allergic reactions and, very importantly, minimize the risk of hypoglycaemia. While the perfect insulin has not yet been discovered, advancements are still being made. Insulin degludec is an ultra-long-acting basal insulin analogue that possesses a flat, stable glucose-lowering effect in patients with type 1 or type 2 diabetes mellitus. Insulin degludec achieves these pharmacokinetic properties by forming soluble multihexamers upon subcutaneous injection, resulting in the formation of a depot in the subcutaneous tissue that is slowly released and absorbed into circulation. Insulin degludec has been associated with slightly less weight gain and fewer nocturnal hypoglycaemic episodes when compared with insulin glargine in some, but not all, clinical studies. This article briefly reviews current evidence for the use of insulin degludec in patients with type 1 or type 2 diabetes mellitus and discusses the potential impact of this new basal insulin on clinical practice.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Patient Care; Randomized Controlled Trials as Topic; Treatment Outcome

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).. 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.. 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.. 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.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine

To compare efficacy and safety of degludec 100 IU/mL (Deg-100) and glargine 300 IU/mL (Gla-300) in adults with type 1 diabetes.. Open-label, single-center, randomized, parallel-group, 24-week trial in adults with type 1 diabetes, on basal-bolus insulin therapy, HbA1c ≤ 10%, using self-monitoring blood glucose. Participants were randomized 1:1 to a basal-bolus insulin regimen with Deg-100 (N = 129) or Gla-300 (N = 131). Primary efficacy endpoint: mean change in HbA1c from baseline to week-24. Main safety outcome: incidence rate of hypoglycemia during the study. Quality of life (DQOL) and satisfaction with diabetes treatment (DTSQ) were assessed.. At week 24, after adjusting for baseline HbA1c, the decrease in HbA1c did not differ between groups: Deg-100 (-0.07 ± 0.7%) and Gla-300 (-0.16 ± 0.77%) (P = 0.320). There were no significant differences between groups in HbA1c, nocturnal hypoglycemia, severe hypoglycemia, DQOL, or DTSQ scores. The incidence rates of hypoglycemia < 3.9 mmol/L (Deg-100: 115.24 events/person-year vs Gla-300: 99.01 events/person-year, p < 0.001); and < 3.0 mmol/L (Deg-100: 41.17 events/person-year vs Gla-300: 34.29 events/person-year, p < 0.001) were different between groups.. Deg-100 and Gla-300 have similar metabolic efficacy, incidence ratio of nocturnal and severe hypoglycemia, DQOL and DTSQ scores. Differences in the incidence rate of hypoglycemia < 3.9 mmol/L and < 3.0 mmol/L should be confirmed.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Quality of Life

To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia.. The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia.. There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of -4.3% (95% confidence interval [CI] -8.1 to -0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]).. Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine

It is generally recommended to reduce basal insulin doses after exercise to reduce the risk of post-exercise nocturnal hypoglycaemia. Based on its long t. The ADREM study (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) was a randomised controlled, crossover study in which we compared 40% dose reduction (D40), or postponement and 20% dose reduction (D20-P), with no dose adjustment (CON) in adults with type 1 diabetes at elevated risk of hypoglycaemia, who performed a 45 min aerobic exercise test in the afternoon. All participants wore blinded continuous glucose monitors for 6 days, measuring the incidence of (nocturnal) hypoglycaemia and subsequent glucose profiles.. Post-exercise adjustment of degludec does not mitigate the risk of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. Although reducing degludec reduced next-day time below range, this did not translate into fewer hypoglycaemic events, while postponing degludec should be avoided because of increased time above range. Altogether, these data do not support degludec dose adjustment after a single exercise bout.. EudraCT number 2019-004222-22 FUNDING: The study was funded by an unrestricted grant from Novo Nordisk, Denmark.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Exercise; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Male; Middle Aged

Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed safety and efficacy of BIF versus degludec in 265 patients with type 1 diabetes (T1D) using multiple daily injections.. During this randomized, parallel, open-label study, patients with T1D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to a fasting glucose level of 80-100 mg/dL. The primary end point was HbA1c change from baseline to week 26 (noninferiority margin, 0.4%). Secondary end points included percent time in range (TIR) (70-180 mg/dL), continuous glucose monitoring (CGM) fasting glucose (FG) level, and rate of hypoglycemia.. After 26 weeks, patients receiving BIF had noninferior HbA1c change from baseline versus those receiving degludec, with a statistically significant treatment difference of 0.17% (90% CI 0.01, 0.32; P = 0.07) favoring the comparator. Percent TIR was similar for patients in the BIF (56.1%) and degludec (58.9%; P = 0.112) groups at week 26. FG values were significantly higher for patients receiving BIF (158.8 mg/dL) versus degludec (143.2 mg/dL; P = 0.003). Rates of CGM-derived hypoglycemia were not statistically significantly different for BIF and degludec over 24 h for level 1 (P = 0.960) or level 2 (P = 0.517) hypoglycemia during the treatment period. Occurrence of serious adverse events was similar between the BIF and degludec groups.. Once-weekly BIF demonstrated noninferior glycemic control to once-daily degludec (treatment difference: 0.17% favoring degludec) and no difference in hypoglycemia or other safety findings in patients with T1D.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine

To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D).. Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat.. Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100.. Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Prospective Studies

For people with type 1 diabetes, there are limited evidence-based resources to support self-management when traveling across multiple time zones. Here, we compared glycemic control on insulin degludec versus glargine U100 as the basal insulin for adults using multiple daily injections (MDI) while traveling across multiple time zones.. This randomized crossover pilot study compared insulin degludec versus glargine U100 for adults with type 1 diabetes using MDI insulin during long-haul travel to and from Hawaii to New York. Insulin degludec was administered daily at the same time regardless of time zone, and glargine was administered per travel algorithm. Primary end point was the percentage of time in range (TIR) between 70 and 140 mg/dL during the initial 24 h after each direction of travel. Secondary end points included standard continuous glucose monitoring metrics, jet lag, fatigue, and sleep.. The study enrolled 25 participants (56% women, mean ± SD age of 35 ± 14.5 years, HbA1c of 7.4 ± 1.2% [57 ± 13.1 mmol/mol], and diabetes duration of 20.6 ± 15 years). There was no significant difference in glycemic outcomes between the two arms of the study, including TIR, hypoglycemia, or hyperglycemia. Neither group achieved >70% TIR 70-180 mg/dL during travel. Jet lag was greater on glargine U100 in eastward travel but not westward. Fatigue was greater after westward travel on glargine. Sleep was not significantly different between basal insulins.. In adults with type 1 diabetes using MDI of insulin and traveling across multiple time zones, glycemic outcomes were similar comparing insulin degludec and glargine U100.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Pilot Projects; Young Adult

We compared the efficacy of the second-generation basal insulin degludec (IDeg) to that of insulin aspart via pump using continuous glucose monitoring in patients with well-controlled type 1 diabetes.. In this 40-week, single-center, randomized, crossover-controlled trial, adults with well-controlled type 1 diabetes (hemoglobin A1C of <7.5% [<58 mmol/mol]) (N = 52) who were using an insulin pump and continuous glucose monitoring were randomized to 1 of 2 treatments for a 20-week period: a single daily injection of IDeg with bolus aspart via pump or a continuous subcutaneous insulin infusion (CSII) with aspart, followed by crossover to the other treatment. The primary endpoint was time in range (70-180 mg/dL) during the final 2 weeks of each treatment period.. Fifty-two patients were randomized and completed both treatment periods. The time in range for IDeg and CSII was 71.5% and 70.9%, respectively (P = .553). The time in level 1 hypoglycemia for the 24-hour period with IDeg and CSII was 2.19% and 1.75%, respectively (P = .065). The time in level 2 hypoglycemia for the 24-hour period with IDeg and CSII was 0.355% and 0.271%, respectively (P = .212), and the nocturnal period was 0.330% and 0.381%, respectively (P = .639). The mean standard deviation of blood glucose levels for the 24-hour period for IDeg and CSII was 52.4 mg/dL and 51.0 mg/dL, respectively (P = .294). The final hemoglobin A1C level for each treatment was 7.04% (53 mmol/mol) with IDeg, and 6.95% (52 mmol/mol) with CSII (P = .288). Adverse events were similar between treatments.. We observed similar glycemic control between IDeg and insulin aspart via CSII for basal insulin coverage in patients with well-controlled type 1 diabetes.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Cross-Over Studies; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin, Long-Acting

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).. 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% V̇O. 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.. DRKS00013509.

Topics: Adult; Biomarkers; Blood Glucose; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Drug Administration Schedule; Exercise; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin, Long-Acting; Male; Middle Aged; Prevalence; Risk Factors; Treatment Outcome; Young Adult

To prove equivalence of individual, clinically titrated basal insulin doses of glargine 300 units ⋅ mL. Subjects with T1D (. At the end of 3 months, Gla-300 and Deg-100 reduced slightly and, similarly, A1C versus baseline. Clamp average plasma glucose (0-24 h) was euglycemic with both insulins. The area under curve of glucose infused (AUC-GIR. In T1D, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 compared with Deg-100 are higher and associated with quite similar even 24-h distribution of PD and antilipolytic effects.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Single-Blind Method

To evaluate two methods of transition from an insulin pump to multiple daily injections (MDI) using long-acting insulin degludec (IDeg).. After a 1-week run-in period, adults with type 1 diabetes for longer than 1 year and HbA1c 48-69 mmol/mol (6.5%-8.5%), who had been using an insulin pump at least for 6 months, were randomly transitioned to either standard of care (discontinued insulin pump and started IDeg in 1:1 dose) or overlap (IDeg 1:1 at pump basal dose, but pump continued for the first 48 hours with a gradual basal reduction; 50% from 0-24 hours, 75% from 24-48 hours and then pump discontinued). Participants used blinded Dexcom G6 and the IDeg dose was not changed during the trial. Primary (% time above 180 mg/dL) and secondary (% time in 70-180 mg/dL and below 70 mg/dL) outcomes were compared between the two groups during 7 days of randomization.. Age, gender, diabetes duration and basal/bolus insulin doses were similar between patients randomized to standard of care (n = 17) or overlap (n = 13) transition. Compared with overlap transition, the standard of care group spent 4.8% more time in hyperglycaemia (least square mean 4.8% [95% CI -3.3%, 12.9%]) and 5.3% less time in range (-5.3% [-12.6%, -2.0%]), without a significant difference in hypoglycaemia (0.5% [-2.3%,3.4%]). No treatment-related adverse events were noted in either group.. The overlap transition method may result in a significant improvement in time-in-range without increasing hypoglycaemia during the first week of transition from an insulin pump to MDI using IDeg in adults with type 1 diabetes.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Insulin, Long-Acting

People with type 1 diabetes who use continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) often remove their pump before extended periods of exercise, but this approach might result in reduced glycaemic control and increased risk of hyperglycaemia and ketogenesis. We aimed to assess the efficacy and safety of a hybrid approach, in which basal insulin delivery was divided between CSII and a daily injection of insulin degludec.. In this single-centre, open-label, proof-of-concept, randomised crossover trial done at the LMC Diabetes & Endocrinology research centre, we recruited physically active and aerobically fit participants aged 18 years or older with type 1 diabetes who were using CSII. Participants were randomly assigned (1:1) by use of a computer-generated sequence to one of two sequences of either usual CSII, involving the continuation of the participant's usual CSII regimen, followed by crossover to hybrid CSII, in which the delivery of the participant's usual daily basal insulin dose was split (50% delivered by CSII and 50% delivered by a once-daily morning injection of 100 U/mL insulin degludec), or the opposite sequence (ie, hybrid CSII followed by crossover to usual CSII). Treatment was not masked to the investigators or participants. For each intervention, participants completed a moderate-intensity and a high-intensity in-clinic exercise session in the first week, followed by four high-intensity and two moderate-intensity home-based exercise sessions in the subsequent 3 weeks. Insulin pumps were suspended or disconnected 60 min before exercise and reconnected immediately after exercise during both treatment regimens. The coprimary outcomes were: (1) time spent in the target control range of 4·0-10·0 mmol/L blood glucose after high-intensity exercise, and (2) time spent in target control range of 4·0-10·0 mmol/L blood glucose after moderate-intensity exercise, measured by continuous glucose monitoring in the 6-h period from the start of the high-intensity and moderate-intensity in-clinic exercise sessions. Outcomes were assessed in a modified intention-to-treat population that included all participants who started both intervention phases and completed all of the in-clinic exercise visits. This trial is registered with ClinicalTrials.gov, NCT03838783, and is complete.. Between May 15, 2018, and March 5, 2019, we assessed 43 patients for eligibility, of whom 31 were randomly assigned to receive the usual CSII regimen (n=14) or hybrid CSII regimen (n=17) in the first phase (before crossover). The analysis population consisted of 24 participants who completed both study phases. Compared with the usual CSII regimen, participants on the hybrid CSII regimen had a significantly longer time in blood glucose range of 4-10 mmol/L during the 6-h period from the start of both moderate-intensity (mean difference 86 min [95% CI 61-147], p=0·005; percentage time in range 64% [SD 35] vs 40% [35]) and high-intensity in-clinic exercise session (60 min [11-109], p=0·01; 66% [32] vs 50% [27]). Participants on the hybrid CSII regimen also showed a higher time in blood glucose range of 4-10 mmol/L during home-based exercise sessions (mean difference 23 min [95% CI -1 to 46], p=0·055), with significantly lower time spent in hyperglycaemia than participants on the usual CSII regimen (mean difference 25 min [2-48], p=0·04). These exploratory outcomes also showed no significant difference in the amount of time spent in hypoglycaemia, nor the number of hypoglycaemic events, between the two interventions. There were three study-related adverse events reported with the usual CSII regimen (two hypotension events and one nausea event) and four with the hybrid CSII regimen (two hypotension events and two nausea events).. A hybrid regimen of injected insulin degludec and CSII (with pump removal during exercise) appears to be safe and effective in adults with type 1 diabetes who exercise regularly. This approach could offer improved glycaemic control immediately after exercise and should be further assessed in a larger-scale randomised trial.. Novo Nordisk.

Topics: Adult; Cross-Over Studies; Diabetes Mellitus, Type 1; Exercise; Female; Follow-Up Studies; High-Intensity Interval Training; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Insulin, Long-Acting; Male; Middle Aged; Proof of Concept Study; Young Adult

To compare the effects of insulin degludec (IDeg) and insulin glargine U300 (IGlarU300) on glycaemic stability in subjects with type 1 diabetes.. In this multicentre, crossover trial, 46 individuals with type 1 diabetes and essentially undetectable circulating C-peptide were randomly assigned to either the IDeg-first/IGlarU300-second group or the IGlarU300-first/IDeg-second group, and were treated with the respective basal insulins for 4-week periods. Data were collected in the last week of each treatment period. The primary aim was to examine the potential non-inferiority of IDeg relative to IGlarU300 with regard to day-to-day variability, as evaluated by the standard deviation (SD) of fasting blood glucose (FBG) levels. Intra-day glycaemic variability and other variables were also determined by continuous glucose monitoring (CGM).. The SD of FBG for IDeg was non-inferior to that for IGlarU300. The mean of FBG, coefficient of variation of FBG, and various glycaemic variability indexes determined by CGM did not differ between the two insulins. Whereas the administered doses of the insulins also did not differ, the mean glycaemic value was lower for IDeg than IGlarU300; the time above the target range (>180 mg/dL [10.0 mmol/L]) and the time below the target range (<70 mg/dL [3.9 mmol/L]) were shorter and longer, respectively, for IDeg than IGlarU300.. Our data suggest that IDeg and IGlarU300 have comparable glucose-stabilizing effects in individuals with type 1 diabetes. However, the glucose-lowering effect of IDeg may be greater than that of IGlarU300 when titrated with a unit-based protocol.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Cross-Over Studies; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting

With healthcare systems under increasing financial pressure from costs associated with diabetes care, it is important to assess which treatments provide clinical benefits and represent best value. This study evaluated the annual costs of insulin degludec (degludec) versus insulin detemir (IDet) in children and adolescents with type 1 diabetes (T1D) in the UK.. Using data from a randomized, treat-to-target, non-inferiority trial-BEGIN YOUNG 1-annual costs with degludec versus IDet in children and adolescents aged 1-17 years with T1D were estimated, as costs of these insulins and hyperglycemia with ketosis events. Analyses by age group (1-5, 6-11 and 12-17 years) and scenario (no ketosis benefit, no dose benefit, hyperglycemia with ketones >0.6 and >3.0 mmol/L and the additional costs of twice-daily IDet in 64% of patients) were also performed.. The mean annual cost per patient was estimated as £235.16 for degludec vs £382.91 for IDet, resulting in an annual saving of £147.75 per patient. These substantial cost savings were driven by relative reductions in the frequency of hyperglycemia with ketosis and basal insulin dose with degludec versus IDet. Annual savings in favor of degludec were observed across each age group (£122.63, £140.59 and £172.50 for 1-5, 6-11 and 12-17 years age groups, respectively). Five scenario analyses further demonstrated the robustness of the results, which included no ketosis or dose benefits in favor of degludec.. Degludec provides appreciable annual cost savings compared with IDet in children and adolescents with T1D in a UK setting. While a cost-effectiveness analysis could incorporate the health impact of treatment complications better than the present cost analysis, the strong generalizability of the data from this study suggests that degludec can help healthcare providers to maximize health outcomes despite increasingly stringent budgets.

Topics: Adolescent; Biomarkers; Blood Glucose; Child; Child, Preschool; Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infant; Insulin Detemir; Insulin, Long-Acting; Male; Prognosis; United Kingdom

Degludec is a long-acting insulin with a longer duration of action and a greater day-to-day reproducibility of absorption in comparison with previous long-acting insulin formulations. The aim is the definition of the change in insulin needs in patients switching from detemir/glargine to degludec in real-life conditions.. In this retrospective cohort observational study, all outpatients with either type 1 or type 2 diabetes, starting therapy with degludec insulin-after a prior treatment with either detemir or glargine insulin for at least 6 months-were included.. The analysis was performed on 266 patients, 172 and 96 with type 1 and type 2 diabetes, respectively. The equations describing the relationship between baseline and follow-up doses of basal insulin (6 months) were Y = 3.39 + 0.78X and Y = 0.44 + 0.69X, in patients receiving detemir/glargine either once or twice daily, respectively (Y = degludec dose at 6 months and X = basal insulin dose at switch). The corresponding equations for prandial insulin doses were y = 1.83 + 0.83*x and y = 2.85 + 0.80*x for those on pre-switch once or twice-daily basal insulin, respectively. In type 2 diabetes, the switch was associated with a reduction of basal insulin doses only in those with a prior twice-daily treatment with basal insulin. The reduction of prandial insulin reached statistical significance only in patients previously treated with basal insulin once daily.. The present results provide a suggestion for a simple method for the adjustment of basal and prandial insulin doses in type 1 diabetic patients, switching from glargine or detemir to degludec.

Topics: Adult; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Prognosis; Retrospective Studies

To compare the time spent in specified glycaemic ranges in people with type 1 diabetes (T1D) during 5 consecutive days of moderate-intensity exercise while on either 100% or 75% of their usual insulin degludec (IDeg) dose.. Time spent in euglycaemia over 5 days was greater for the 75% IDeg dose versus the 100% IDeg dose (4008 ± 938 minutes vs. 3566 ± 856 minutes; P = 0.04). Numbers of hypoglycaemic events (P = 0.91) and time spent in hypoglycaemia (P = 0.07) or hyperglycaemia (P = 0.38) was similar for both dosing schemes.. A 25% reduction in usual IDeg dose around regular exercise led to more time spent in euglycaemia, with small effects on time spent in hypo- and hyperglycaemia.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Exercise; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Time Factors; Young Adult

The stable, ultra-long duration of action of insulin degludec (degludec) minimizes fluctuations in glucose-lowering activity over the daily (24-h) dosing period, and comparative studies with other basal insulins suggest that these properties translate into a lower risk of hypoglycemia at equivalent levels of glycemic control. Results from the real-world European multicenter, retrospective chart review study of 2550 patients with type 1 and type 2 diabetes (T1D and T2D) in routine clinical care EU-TREAT (NCT02662114) showed that patients benefited from improved glycemic control and significantly reduced rates of hypoglycemia following a switch to degludec.. In this post hoc analysis, EU-TREAT patients were stratified into good (≤ 7.5% HbA1c), intermediate (> 7.5 to ≤ 8.5% HbA1c), and poor (> 8.5% HbA1c) glycemic control at baseline to investigate the possibility of differential benefits, either improved control or reduced risk of hypoglycemia, whichever the need. Changes in HbA1c, overall hypoglycemia, and total insulin dose from baseline to 6 and 12 months follow-up were assessed for each group.. For both T1D and T2D patients, those in good initial control experienced significant reductions in rates of hypoglycemia and total insulin dose following the switch, without compromising control. Those in poor initial control achieved significant improvements in HbA1c with no change in rates of hypoglycemia or total insulin dose.. This analysis expands the findings of EU-TREAT by showing differential changes in the clinical endpoints depending on particular need. It introduces the possibility that the differential benefits of degludec could address two of the renowned clinical challenges faced when treating diabetes: improving glycemic control for optimal management of T1D and titrating insulin dose in T2D, both without fear of increased hypoglycemia.. ClinicalTrials.gov, NCT02662114.. Novo Nordisk A/S.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Quality-Adjusted Life Years; Risk Reduction Behavior; Time Factors

Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial.. A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms.. In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Glucose; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Prognosis; Prospective Studies; Severity of Illness Index; Young Adult

To compare steady state pharmacodynamic and pharmacokinetic profiles of insulin glargine 300U/mL (Gla-300) with insulin degludec 100U/mL (Deg-100) in people with type 1 diabetes.. This single-centre, randomized, double-blind crossover euglycaemic clamp study included two parallel cohorts with fixed once-daily morning dose regimens. For both insulins participants received 0.4 (n=24) or 0.6U/kg/day (n=24), before breakfast, for 8 days prior to the clamp. The main endpoint was within-day variability (fluctuation) of the smoothed glucose infusion rate (GIR) over 24 hours (GIR-smFL. Gla-300 provides less fluctuating steady state pharmacodynamic profiles (i.e. lower within-day variability) and more evenly distributed pharmacokinetic profiles, compared with Deg-100 in a once-daily morning dosing regimen of 0.4U/kg/day.

Topics: Adolescent; Adult; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Young Adult

Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death.. To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes.. Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period.. Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence.. The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted.. Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P = .002; risk difference, -6.8%; 95% CI, -10.8% to -2.7%).. Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes.. clinicaltrials.gov Identifier: NCT02034513.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Risk Factors

This study implemented a randomized crossover design to evaluate the efficacy and safety of switching from insulin glargine (IGlar) to insulin degludec (IDeg) in 18 children (11 males, 7 females; age 11.0 ± 0.5 years) with type 1 diabetes. All subjects had previously used IGlar once daily at bedtime. We compared fasting plasma glucose (FPG) and HbA1c levels, frequencies of overall and nocturnal (2200 h - 0659 h) hypoglycemia, and basal insulin dose at the baseline with those measured during a 24-week period during which IGlar or IDeg was administered in combination with pre-meal rapid acting insulin analogues. IDeg was initially given at the same dose as IGlar but was subsequently titrated to achieve FPG levels of 90-140 mg/dL. There were no significant changes in FPG and HbA1c levels from the baseline during the 24-week study period with IGlar or IDeg. The daily basal insulin dose did not significantly differ with IGlar or IDeg. Although the frequencies of overall hypoglycemia were similar, nocturnal hypoglycemia significantly decreased at 12 and 24 weeks from the baseline with IDeg use (2 ± 0.4 vs. 0 ± 0.3, 0 ± 0.5 episodes/month, both P <0.05), whereas no significant change in the frequency of nocturnal hypoglycemia was observed with IGlar. No severe hypoglycemia occurred during the study period with either basal insulin analogues. These results suggest that IDeg, injected once at bedtime, may provide similar glycemic control as IGlar while better reducing the risk of nocturnal hypoglycemia in children with type 1 diabetes.

Topics: Adolescent; Blood Glucose; Child; Cross-Over Studies; Diabetes Mellitus, Type 1; Drug Substitution; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin Glargine; Insulin, Long-Acting; Male; Treatment Outcome

To use continuous glucose monitoring (CGM) to compare glycemic variability in patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) versus insulin detemir (IDet).. Ten patients with T1D were randomly assigned to receive once-daily IDeg, followed by twice-daily IDet, or vice versa. Glucose variability was evaluated by CGM after >4 weeks of the first insulin and again after crossover to the second insulin.. The total daily insulin dose (U/kg/day) and the total daily basal insulin dose (U/kg/day) were significantly lower during treatment with IDeg than with IDet [median (interquartile range): 0.55 (0.54-0.73) vs. 0.64 (0.54-0.83); P = 0.028, 0.24 (0.19-0.36) vs. 0.30 (0.19-0.39); P = 0.027]. The 24-hour mean glucose levels were not significantly different. However, their standard deviation (SD) was significantly smaller during treatments with IDeg than those with IDet [59.5 (39.5-71.0) vs. 72.8 (61.8-92.8); P = 0.008]. Their mean fasting glucose levels and the mean postprandial peak levels after breakfast and after dinner were significantly lower with IDeg.. A CGM-based comparison demonstrated that once-daily IDeg showed fewer glycemic fluctuations than twice-daily IDet. IDeg appears to stabilize blood glucose levels better during both daytime and nighttime (particularly, before and after breakfast) with a lower insulin dosage.

Topics: Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin, Long-Acting; Male; Middle Aged; Pilot Projects; Postprandial Period

To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes.. In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period.. Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P  < .0001). The distribution of glucose-lowering effect was stable across 6-hour intervals (24%-26%) for IDeg, while IGlar-U300 had greater effects in the first (35%) and last (28%) intervals compared with 6 to 12 hours (20%) and 12 to 18 hours (17%). Within-day variability (relative fluctuation) was 37% lower with IDeg than with IGlar-U300 (estimated ratio IDeg/IGlar-U300: 0.63, 95% CI 0.54; 0.73; P  < .0001). The day-to-day variability in glucose-lowering effect with IDeg was approximately 4 times lower than IGlar-U300 (variance ratio IGlar-U300/IDeg: 3.70, 95% CI 2.42; 5.67; P  < .0001). The day-to-day variability in glucose-lowering effect assessed in 2-hour intervals was consistently low with IDeg over 24 hours, but steadily increased with IGlar-U300 to a maximum at 10 to 12 hours and 12 to 14 hours after dosing (variance ratios 12.4 and 11.4, respectively).. IDeg has lower day-to-day and within-day variability than IGlar-U300 and a more stable glucose-lowering effect, which might facilitate titration and enable tighter glycaemic control with a reduced risk of hypoglycaemia.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin Resistance; Insulin, Long-Acting; Male; Middle Aged; Reproducibility of Results

Various factors influence the pharmacokinetic and pharmacodynamic properties of insulin analogs. The aim of the present study was to determine time to steady state of insulin degludec (IDeg), a basal insulin analog with an ultralong duration of action, after once-daily subcutaneous administration in subjects of varying age, diabetes type, and ethnicity.. Time to steady state was analyzed in 195 subjects across five Phase I randomized single-center double-blind studies: three in subjects with type 1 diabetes (T1DM), including one in elderly subjects, and two in subjects with type 2 diabetes (T2DM), including one with African American and Hispanic/Latino subpopulations. Subjects received once-daily IDeg (100 U/mL, s.c.) at doses of 0.4-0.8 U/kg for 6-12 days. Time to clinical steady state was measured from first dose until the serum IDeg trough concentration exceeded 90% of the final plateau level. The IDeg concentrations were log-transformed and analyzed using a mixed-effects model with time from first dose and dose level (where applicable) as fixed effects, and subject as a random effect.. Steady state serum IDeg concentrations were reached after 2-3 days in all subjects. In trials with multiple dose levels, time to steady state was independent of dose level in T1DM (P = 0.51) and T2DM (P = 0.75).. Serum IDeg concentrations reached steady state within 2-3 days of once-daily subcutaneous administration in all subjects with T1DM or T2DM, including elderly and African American and Hispanic/Latino subjects. At steady state, serum IDeg concentrations were unchanged from day to day.

Topics: Adolescent; Adult; Aged; Area Under Curve; Black or African American; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Hispanic or Latino; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin, Long-Acting; Male; Middle Aged; Time Factors; Young Adult

The long-term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26-week core + 26-week extension, controlled, open-label, parallel-group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal-time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p < 0.05. IDeg improved glycated haemoglobin after 1 year of treatment, similarly to IDet, but IDeg also provided a significantly greater reduction in fasting plasma glucose compared with IDet: estimated difference (IDeg - IDet) -1.11 (95% CI -1.83; -0.40) mmol/l; p < 0.05. The present study confirmed the long-term safety and tolerability profile of IDeg in patients with T1DM. IDeg provided a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Drug Administration Schedule; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin Detemir; Insulin, Long-Acting; Male; Meals; Middle Aged; Time

We compared changes in blood glucose (BG) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) or insulin glargine (IGlar) in a randomized, open-label, two-period, crossover trial. After individual titration and a steady-state period, patients performed 30 min of moderate-intensity cycle ergometer exercise (65% peak rate of oxygen uptake). BG, counter-regulatory hormones and hypoglycaemic episodes were measured frequently during and for 24 h after exercise. BG changes during exercise were similar with IDeg and IGlar [estimated treatment difference (ETD) for maximum BG decrease: 0.14 mmol/l; 95% confidence interval (CI) -0.15, 0.42; p = 0.34], as was mean BG (ETD -0.16 mmol/l; 95% CI -0.36, 0.05; p = 0.13). No hypoglycaemic episodes occurred during exercise. Post-exercise mean BG, counter-regulatory hormone response and number of hypoglycaemic episodes in 24 h after starting exercise were similar with IDeg (18 events in 13 patients) and IGlar (23 events in 15 patients). This clinical trial showed that, in patients with T1D treated with a basal-bolus regimen, the risk of hypoglycaemia induced by moderate-intensity exercise was low with IDeg and similar to that with IGlar.

Topics: Adolescent; Adult; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Exercise Test; Female; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Motor Activity; Risk; Young Adult

To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes.

Topics: Adult; Aged; Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged

We evaluated the efficacy and safety of switching to insulin degludec (IDeg) from insulin glargine (IGlar) as basal-bolus therapy in young people with type 1 diabetes. The subjects were 36 patients, 21.3±1.0 years of age, with type 1 diabetes. IGlar had previously been injected once daily in 25 patients and twice daily in 11. They were then switched from IGlar to once-daily injection of IDeg. Both fasting plasma glucose (FPG) and HbA1c levels decreased significantly from 134±3.9 mg/dL and 7.9±0.2% at baseline to 116±2.2 mg/dL and 7.4±0.2% at 12 months after starting IDeg (P<0.0001 and P≤0.001, respectively). Overall and nocturnal hypoglycemia (PG<70 mg/dL) frequencies also decreased significantly from 4.9±0.7 and 2.0±0.3 times/month to 2.4±0.3 and 0.4±0.1 times/month at 12 months after starting IDeg (P≤0.005 and P<0.0005, respectively). The daily basal insulin dose was significantly reduced from 0.48±0.04 units/kg/day at baseline to 0.38±0.03 units/kg/day at the end of the study period (P<0.0001), which corresponded to 79.2% of the baseline value. Trends were similar in patients receiving the once-daily injection and those given twice-daily injections, but basal-insulin value reductions from baseline were more marked in patients receiving twice-daily injections of basal insulin (76.0% vs. 82.6% of the baseline value). These results suggest that switching from IGlar to an appropriate dose of IDeg may effectively control hyperglycemia while reducing the frequency of hypoglycemia episodes in young Japanese people with type 1 diabetes.

Topics: Adolescent; Adult; Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Substitution; Female; Glycated Hemoglobin; Humans; Insulin Glargine; Insulin, Long-Acting; Male; Treatment Outcome; Young Adult

Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). The present study investigated the pharmacodynamic properties of IDegAsp in Japanese patients with type 1 diabetes mellitus.. In this randomized, double-blind, two-period, cross-over trial, 21 Japanese patients with type 1 diabetes mellitus received single doses of 0.5 U/kg IDegAsp and biphasic insulin aspart 30 in a randomized sequence (13-21 days washout between treatments). The pharmacodynamic response was evaluated in a 26-h euglycemic glucose clamp (target 5.5 mmol/L). Single-dose IDegAsp glucose infusion rate (GIR) profiles were extrapolated to steady state using modeling.. The IDegAsp single-dose GIR profile showed a clear distinction between the effects of the bolus (IAsp) and basal (IDeg) components in IDegAsp. When simulated to steady state, the GIR profile of IDegAsp was shifted upwards compared with the single-dose profile, and showed a rapid onset of action and a distinct peak from the IAsp component followed by a separate and sustained basal action from the long-acting IDeg component. For biphasic insulin aspart 30, the initial shape of the GIR profile was similar to IDegAsp, but GIR continuously decreased from maximum and reached zero 18-20 h post-dosing. The characteristics of the GIR profile for IDegAsp were retained when simulated to steady state in a twice-daily dosing regimen.. In Japanese patients with type 1 diabetes mellitus, the pharmacodynamic profile of IDegAsp is characterized by distinct prandial and basal effects from the IAsp and IDeg components, consistent with what has been reported previously in Caucasian patients with type 1 diabetes mellitus.

Topics: Adult; Asian People; Biphasic Insulins; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Combinations; Female; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin, Long-Acting; Japan; Male; Middle Aged

Continuous exercise (CON) and high-intensity interval exercise (HIIE) can be safely performed with type 1 diabetes mellitus (T1DM). Additionally, continuous glucose monitoring (CGM) systems may serve as a tool to reduce the risk of exercise-induced hypoglycemia. It is unclear if CGM is accurate during CON and HIIE at different mean workloads. Seven T1DM patients performed CON and HIIE at 5% below (L) and above (M) the first lactate turn point (LTP₁), and 5% below the second lactate turn point (LTP₂) (H) on a cycle ergometer. Glucose was measured via CGM and in capillary blood (BG). Differences were found in comparison of CGM vs. BG in three out of the six tests (p < 0.05). In CON, bias and levels of agreement for L, M, and H were found at: 0.85 (-3.44, 5.15) mmol·L(-1), -0.45 (-3.95, 3.05) mmol·L(-1), -0.31 (-8.83, 8.20) mmol·L(-1) and at 1.17 (-2.06, 4.40) mmol·L(-1), 0.11 (-5.79, 6.01) mmol·L(-1), 1.48 (-2.60, 5.57) mmol·L(-1) in HIIE for the same intensities. Clinically-acceptable results (except for CON H) were found. CGM estimated BG to be clinically acceptable, except for CON H. Additionally, using CGM may increase avoidance of exercise-induced hypoglycemia, but usual BG control should be performed during intense exercise.

Topics: Adult; Bicycling; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diet, Diabetic; Dietary Carbohydrates; Drug Monitoring; Drug Therapy, Combination; Glycated Hemoglobin; High-Intensity Interval Training; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Insulin, Short-Acting; Lactic Acid; Male; Monitoring, Ambulatory; Reproducibility of Results; Young Adult

To compare glucose variability in patients with type 1 diabetes (T1D) treated with insulin glargine (IGla) versus insulin degludec (IDeg) using continuous glucose monitoring (CGM).. Thirteen patients with T1D were randomly assigned to receive IDeg once-daily followed by IGla twice-daily or vice versa. They were evaluated for glucose variability by CGM after >4weeks of treatment with either insulin, and then were crossed over to the other, and evaluated by CGM after >4weeks.. The total daily insulin dose (TDD) (U/kg/day) and the total daily basal insulin dose (U/kg/day) in the patients were significantly lower while taking IDeg than while taking IGla (mean [95% confidence interval] 0.72 [0.61-0.83] vs. 0.76 [0.64-0.88]; P=0.001, 0.29 [0.22-0.36] vs. 0.33 [0.26-0.40]; P=0.001), although no significant difference was noted in the patients while on IDeg versus while on IGla in 24-h mean glucose and SDs of 24-h glucose. Again, the range of postprandial glucose increase was not significantly different between the meals in the patients while taking IDeg (P=0.288) but significantly different in the patients while taking IGla (P=0.033).. The use of once-daily IDeg leads not only to similar glycemic control to that seen with twice-daily IGla even in those who received IGla prior to the study, but also to significant decreases in TDD and long-acting basal insulin dose.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Cross-Over Studies; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Pilot Projects; Prognosis

The study presents a comparison of the glucose-lowering effects, glycemic variability, and insulin doses during treatment with insulin degludec or insulin glargine.. In this open-label, single-center, 2-way crossover study, 13 Japanese diabetic outpatients in the insulin-dependent state on basal-bolus therapy were assigned to receive either insulin glargine followed by insulin degludec, or insulin degludec followed by insulin glargine. Basal insulin doses were fixed in principle, and patients self-adjusted their bolus insulin doses. Seventy-two-hour continuous glucose monitoring was performed 2 weeks after switching the basal insulin.. Mean blood glucose (mg/dL) was not significantly different between insulin degludec and insulin glargine over 48 hours (141.8 ± 35.2 vs 151.8 ± 43.3), at nighttime (125.6 ± 40.0 vs 124.7 ± 50.4), or at daytime (149.3 ± 37.1 vs 163.3 ± 44.5). The standard deviation (mg/dL) was also similar (for 48 hours: 48.9 ± 19.4 vs 50.3 ± 17.3; nighttime: 18.7 ± 14.3 vs 13.7 ± 6.7; daytime: 49.3 ± 20.0 vs 44.3 ± 17.7). Other indices of glycemic control, glycemic variability, and hypoglycemia were similar for both insulin analogs. Total daily insulin dose (TDD) and total daily bolus insulin dose (TDBD) were significantly lower with insulin degludec than with insulin glargine (TDD: 0.42 ± 0.20 vs 0.46 ± 0.22 U/kg/day, P = .028; TDBD: 0.27 ± 0.13 vs 0.30 ± 0.14 U/kg/day, P = .036).. Insulin degludec and insulin glargine provided effective and stable glycemic control. Insulin degludec required lower TDD and TDBD in this population of patients.

Topics: Asian People; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting

Insulin degludec (IDeg) once-daily was compared with insulin detemir (IDet) once- or twice-daily, with prandial insulin aspart in a treat-to-target, randomized controlled trial in children 1-17 yr with type 1 diabetes, for 26 wk (n = 350), followed by a 26-wk extension (n = 280). Participants were randomized to receive either IDeg once daily at the same time each day or IDet given once or twice daily according to local labeling. Aspart was titrated according to a sliding scale or in accordance with an insulin:carbohydrate ratio and a plasma glucose correction factor. Randomization was age-stratified: 85 subjects 1-5 yr. (IDeg: 43), 138 6-11 yr (IDeg: 70) and 127 12-17 yr (IDeg: 61) were included. Baseline characteristics were generally similar between groups overall and within each stratification. Non-inferiority of IDeg vs. IDet was confirmed for HbA1c at 26 wk; estimated treatment difference (ETD) 0.15% [-0.03; 0.32]95% CI . At 52 wk, HbA1c was 7.9% (IDeg) vs. 7.8% (IDet), NS; change in mean FPG was -1.29 mmol/L (IDeg) vs. +1.10 mmol/L (IDet) (ETD -1.62 mmol/L [-2.84; -0.41]95% CI , p = 0.0090) and mean basal insulin dose was 0.38 U/kg (IDeg) vs. 0.55 U/kg (IDet). The majority of IDet treated patients (64%) required twice-daily administration to achieve glycemic targets. Hypoglycemia rates did not differ significantly between IDeg and IDet, but confirmed and severe hypoglycemia rates were numerically higher with IDeg (57.7 vs. 54.1 patient-years of exposure (PYE) [NS] and 0.51 vs. 0.33, PYE [NS], respectively) although nocturnal hypoglycemia rates were numerically lower (6.0 vs. 7.6 PYE, NS). Rates of hyperglycemia with ketosis were significantly lower for IDeg vs. IDet [0.7 vs. 1.1 PYE, treatment ratio 0.41 (0.22; 0.78)95% CI , p = 0.0066]. Both treatments were well tolerated with comparable rates of adverse events. IDeg achieved equivalent long-term glycemic control, as measured by HbA1c with a significant FPG reduction at a 30% lower basal insulin dose when compared with IDet. Rates of hypoglycemia did not differ significantly between the two treatment groups; however, hyperglycemia with ketosis was significantly reduced in those treated with IDeg.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Infant; Insulin Aspart; Insulin Detemir; Insulin, Long-Acting

We compared the effects of insulin degludec (IDeg; Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin) and insulin glargine (IGlar; A21Gly,B31Arg,B32Arg human insulin) on the day-to-day variability of fasting plasma glucose (FPG) levels in individuals with type 1 diabetes treated with basal-bolus insulin injections.. The effects of basal-bolus insulin therapy for 4 weeks with either IDeg or IGlar as the basal insulin in adult C-peptide-negative outpatients with type 1 diabetes were investigated in an open-label, multicentre, randomised, crossover trial. Randomisation was conducted using a centralised allocation process. The primary endpoints were the SD and CV of FPG during the final week of each treatment period. Secondary endpoints included serum glycoalbumin level, daily dose of insulin, intraday glycaemic variability and frequency of severe hypoglycaemia.. Thirty-six randomised participants (17 in the IDeg/IGlar and 19 in the IGlar/IDeg groups) were recruited, and data for 32 participants who completed the trial were analysed. The mean (7.74 ± 1.76 vs 8.56 ± 2.06 mmol/l; p = 0.04) and SD (2.60 ± 0.97 vs 3.19 ± 1.36 mmol/l; p = 0.03) of FPG were lower during IDeg treatment than during IGlar treatment, whereas the CV did not differ between the two treatments. The dose of IDeg was smaller than that of IGlar (11.0 ± 5.2 vs 11.8 ± 5.6 U/day; p < 0.01), but other secondary endpoints did not differ between the treatments.. IDeg yielded a lower FPG level and smaller day-to-day variability of FPG at a lower daily dose compared with IGlar in participants with type 1 diabetes. IDeg serves as a good option for basal insulin in the treatment of type 1 diabetes.. University Hospital Medical Information Network 000009965.. This research recieved no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Secretion; Insulin, Long-Acting; Insulin, Regular, Human; Male; Middle Aged; Reproducibility of Results

A medical need remains for a once-daily insulin with 24-h basal coverage in all patients. We characterize the steady-state (SS) pharmacokinetic/pharmacodynamic properties of insulin degludec (IDeg) versus insulin glargine (IGlar).. In this controlled, single-center study, 66 type 1 diabetes patients were randomized to two 8-day periods of once-daily IDeg or IGlar at 0.4, 0.6 or 0.8 U/kg. At SS, subjects underwent a 42-h euglycemic glucose clamp (5.5 mmol/l; 100 mg/dl). Glucose infusion rate (GIR), distribution of GIR and half-life were assessed.. Mean 24-h GIR profiles were flatter and more stable for all doses of IDeg versus IGlar. The evenly distributed glucose-lowering effect of IDeg was confirmed by the AUCGIR across one dosing interval, as each of the four 6-h intervals across one dosing interval contributed ∼ 25% of the AUCGIR,τ,SS. IGlar was most effective during the first 12 - 18 h after dosing. At SS, the half-life was 25.4 (IDeg) versus 12.1 h (IGlar). No safety concerns were identified for IDeg or IGlar.. IDeg has a longer half-life (> 25 h) than IGlar. Exposure and glucose-lowering effects are more stable and evenly distributed across one dosing interval for IDeg versus IGlar (Clinical trials.gov identifier: NCT01114542).

Topics: Adult; Area Under Curve; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glucose Clamp Technique; Half-Life; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Young Adult

Insulin degludec (Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin; IDeg) is a new basal insulin with an ultra-long flat action profile. The acute physiological responses to hypoglycaemia with IDeg and insulin glargine (A21Gly,B31Arg,B32Arg human insulin; IGlar) were compared.. Twenty-eight adult type 1 diabetic patients with normal hypoglycaemia awareness (age = 41 ± 12 years, HbA1c = 7.8 ± 0.6% [62.8 ± 7 mmol/mol]) were randomised to once-daily IDeg or IGlar for 5 days in a two-period crossover design. Participants and research staff were blinded to group assignment. Patients were assigned the lowest available randomisation number from a set of blinded randomisation codes provided by the trial sponsor. Hypoglycaemia was induced by administering three times the usual daily insulin dose at midnight on day 5. Plasma glucose (PG) was stabilised by glucose clamp (5.5 mmol/l) for 7-9 h post dosing. Next morning, PG was allowed to decrease stepwise from 5.5 to 3.5 mmol/l (maintained for 30 min) to 2.5 mmol/l (for 15 min). PG was then increased to 3.9 mmol/l (for 120 min), before being returned to baseline. Hypoglycaemic symptom score (HSS), hypoglycaemic awareness, cognitive function, counter-regulatory hormones and vital signs were assessed during each glucose plateau. The primary analysis was to compare IDeg vs IGlar with respect to HSS at nadir PG concentration (2.5 mmol/l).. The full analysis set for treatment comparisons comprised data from all 28 exposed patients. Rates of PG decline and PG at nadir were similar for IDeg and IGlar. No treatment differences in HSS (estimated difference: 0.17 [95% CI -1.71, 2.05]; p > 0.05), cognitive function or awareness were observed at any time. Growth hormone and cortisol responses during hypoglycaemia were greater with IDeg than IGlar (AUC treatment ratio [IDeg/IGlar]: 2.44 [1.30, 4.60], p < 0.01; and 1.23 [1.01, 1.50]; p < 0.05), and adrenaline (epinephrine) responses trended higher (1.40 [0.96, 2.04], p = 0.07). The rates of recovery from hypoglycaemia were similar.. IDeg and IGlar elicit comparable symptomatic and cognitive responses to induced hypoglycaemia. IDeg may elicit a moderately greater endocrine response, but times to PG recovery were similar for the two insulins.. ClinicalTrials.gov NCT01002768.. Novo Nordisk.

Topics: Adult; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Hypoglycemia; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged

Management of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia.. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults.. This trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18-35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUC(IDeg,τ,SS)) (τ = 0-24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (C(max,IDeg,SS)). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUC(GIR,τ,SS)), and the maximum GIR at steady state (GIR(max,IDeg,SS)).. Total exposure (AUC(IDeg,τ,SS)) and maximum concentration (C(max,IDeg,SS)) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUC(IDeg,τ,SS) and C(max,IDeg,SS) and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73-1.47) and 1.02 (95 % CI 0.74-1.39), respectively. Mean AUC(IDeg,0-12h,SS)/AUC(IDeg,τ,SS) was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUC(GIR,τ,SS) (the primary endpoint of this study) and GIR(max,IDeg,SS). Estimated mean age group ratios (elderly/younger adult) for AUC(GIR,τ,SS) and GIR(max,IDeg,SS) and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47-1.31) and 0.80 (95 % CI 0.54-1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects.. The exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes. Clinical trials.gov number: NCT00964418.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glucose Clamp Technique; Humans; Insulin, Long-Acting; Male; Safety; Young Adult

Insulin degludec (IDeg) is a basal insulin with an ultra-long pharmacokinetic profile in adults that at steady-state produces remarkably flat and stable insulin levels; however, no studies have yet reported on the pharmacokinetic properties of IDeg in subjects younger than 18 years of age. This was a single-centre, randomised, single-dose, double-blind, two-period crossover trial conducted in children (6-11 years), adolescents (12-17 years), and adults (18-65 years) with type 1 diabetes. Subjects received a single subcutaneous dose of 0.4 U/kg IDeg or insulin glargine (IGlar), respectively, on two separate dosing visits, with pharmacokinetic blood sampling up to 72-h postdose. A total of 37 subjects (12 children, 13 adolescents, and 12 adults) completed the trial. Total exposure of IDeg after a single dose (AUCIDeg ,0-∞, SD ) was higher in children compared to adults [estimated ratio children/adults 1.48 (95% confidence interval, CI: 0.98; 2.24)] and in adolescents compared to adults [estimated ratio adolescents/adults 1.33 (95% CI: 1.08; 1.64)]; however, the difference was only statistically significant for the latter comparison. No statistically significant difference in maximum concentration of IDeg (Cmax, IDeg , SD ) was observed. Estimated ratios for Cmax, IDeg , SD were (children/adults) 1.20 (95% CI: 0.90; 1.60) and (adolescents/adults) 1.23 (95% CI: 1.00; 1.51). Simulated mean steady state pharmacokinetic profiles supported a flat and stable IDeg exposure across a 24-h dosing interval. IDeg was detectable in serum for at least 72 h (end of blood sampling period) in all subjects following single dose. In conclusion, the ultra-long pharmacokinetic properties of IDeg observed in adults are preserved in children and adolescents with type 1 diabetes.

Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male

The efficacy and safety of insulin degludec (IDeg) was compared with insulin detemir (IDet), both administered once daily (OD) as basal treatment in participants with type 1 diabetes mellitus (T1DM). The primary outcome was non-inferiority of IDeg to IDet in glycated haemoglobin (HbA1c) reduction after 26 weeks.. This multinational, 26-week, controlled, open-label, parallel-group trial randomized adults with T1DM to IDeg or IDet as OD basal insulin treatment combined with mealtime bolus insulin aspart (IAsp). Participants with T1DM treated with any basal-bolus insulin regimen for ≥ 12 months prior to the trial, a mean HbA1c ≤ 10.0% (85.8 mmol/mol) and body mass index (BMI) ≤ 35.0 kg/m(2) at screening participated in the trial (IDeg: N = 302; IDet: N = 153).. After 26 weeks, HbA1c decreased 0.73% (8.0 mmol/mol) (IDeg) and 0.65% (7.1 mmol/mol) (IDet) [estimated treatment difference (ETD) IDeg-IDet: -0.09% (-0.23; 0.05)95% CI (-10.0 mmol/mol [-2.6; 0.6]95% CI ); confirming non-inferiority]. Mean fasting plasma glucose improved in both groups, and was lower with IDeg than IDet [ETD IDeg-IDet: -1.66 mmol/l (-2.37; -0.95)95% CI , p < 0.0001]. The rate of confirmed hypoglycaemia was similar with IDeg and IDet [45.83 vs. 45.69 episodes per patient-year of exposure (PYE); estimated rate ratio (RR) IDeg/IDet: 0.98 (0.80; 1.20)95% CI , p = 0.86]. The rate of nocturnal confirmed hypoglycaemia was lower with IDeg than IDet [4.14 vs. 5.93 episodes per PYE; RR IDeg/IDet: 0.66 (0.49; 0.88)95% CI , p = 0.0049]. Adverse event profiles were similar between groups.. IDeg administered OD in basal-bolus therapy effectively improved long-term glycaemic control in participants with T1DM with a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Topics: Adult; Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin, Long-Acting; Male; Meals; Time Factors; Treatment Outcome

The aim of this study was to analyze the changes in daily blood glucose fluctuation and insulin dose in patients with type 1 diabetes mellitus (T1DM) undergoing basal-bolus therapy following a switching of basal insulin used from insulin glargine or detemir to insulin degludec.. Seven patients with T1DM were enrolled. All patients treated with insulin glargine or detemir twice daily were switched to insulin degludec with 80-90 % of the prior insulin dose. During the study period, the basal insulin doses were adjusted by the attending physician. The patients underwent continuous glucose monitoring before, 3 days after, and 24 weeks after switching to insulin degludec. The daily insulin dose was analyzed before, 3 days after, and 24 weeks after switching. Glycated hemoglobin levels were measured before and 24 weeks after switching.. The blood glucose profile did not change significantly before and after switching. On the other hand, the total daily insulin dose and total daily basal insulin dose decreased significantly 24 weeks after switching.. In patients with T1DM undergoing insulin glargine or detemir treatment, it is possible to achieve similar glycemic control in the medium term with a once daily, lower dose of insulin degludec.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged

FlexTouch® (FT) is a new prefilled insulin pen with no push-button extension and a low injection force used to deliver several basal insulins, including insulin degludec across a wide dose range (1 - 80 units with FT 100 IU/ml [FT100] and 2 - 160 units with 200 IU/ml [FT200]). This study was carried out to evaluate whether the novel features of FT affect the preferences of the device among patients with diabetes and healthcare professionals compared with the widely used SoloSTAR® pen.. A multicenter, randomized, open-label, crossover study compared FT100 and FT200 with SoloSTAR. The study included patients with either type 1 (n = 22) or type 2 diabetes (n = 42), nurses (n = 32) and physicians (n = 32). Subjects were randomized to test each of the FT100, FT200 and SoloSTAR pens in a crossover set up. Subjects performed injections into a foam cushion at 4 - 6 different doses per device (2, 20, 40, 80, 120 and 160 IU).. Overall, a significantly higher proportion of subjects, including dexterity-impaired and pen-naive patients, preferred to use FT100 (93.0%; 119/128) and FT200 (91.4%; 117/128) compared with 2.3% (3/128) and 3.9% (5/128) who preferred SoloSTAR (p < 0.001), respectively.. FT100 and FT200 were preferred over SoloSTAR by nurses, physicians and patients with diabetes. This may be due to the novel design of FT, which improves ease of use, preference and confidence in delivering a complete, accurate dose of insulin, even at high doses.

Topics: Adult; Aged; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Delivery Systems; Female; Health Personnel; Humans; Hypoglycemic Agents; Injections; Insulin, Long-Acting; Male; Middle Aged; Nurses; Patient Preference; Physicians

Insulin degludec (IDeg) is a basal insulin with a stable, flat action profile and an even distribution of the blood glucose lowering effect over 24 hou rs. The terminal half-life of IDeg is about 25 hours, which reflects a mean prolongation by factor 2 compared to Insulin glargin (lGlar).This may enable for a more flexible daytime dosing versus up to now available basal insulins.. Two open, randomized, treat-to-target studies enrolled patients with type 1 diabetes (n =493) or type 2 diabetes (n = 687). Both phase 3 studies compared a daytime flexible dosing of IDeg (IDeg-flex) with IDeg at the evening meal (IDeg-evening) and IDler at a fixed daytime. In the IDeg-flex-group dosing intervals were predefined with variations between 8 and 40 hours.. In patients with type 1 diabetes IDeg-flex proved to be non-inferior with respect to reduction of HbA1C (-0.40%) versus IDeg-evening (-0.41%) and IGlar (-0.58%) after 26 weeks. In addition, nocturnal hypoglycemic events were reduced by 40% (p < 0.01) with IDeg-flex versus IGlar. In patients with type 2 diabetes reduction of HbA1C with ID)eg-flex (-1.28%) was non-inferior to IDeg-evening (-1.07%) and IGlar (-1.26%), respectively, whereas rates for hypoglycemia were comparable.. Patients with diabetes mellitus are enabled to dose a basal insulin flexibly when needed (minimum interval of 8 hours afterthe last injection is necessary). Impacts of this treatment option on quality of life and adherence and outcomes should be examined in observational trials.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Half-Life; Humans; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged

The goal of this study was to compare the long-term safety and efficacy of the basal insulin analogue, insulin degludec with insulin glargine (both with insulin aspart) in Type 1 diabetes, over a 2-year time period.. This open-label trial comprised a 1-year main trial and a 1-year extension. Patients were randomized to once-daily insulin degludec or insulin glargine and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l.. The rate of nocturnal confirmed hypoglycaemia was 25% lower with insulin degludec than with insulin glargine (P = 0.02). Rates of confirmed hypoglycaemia, severe hypoglycaemia and adverse events, and reductions in glycated haemoglobin and fasting plasma glucose were similar between groups. Despite achieving similar glycaemic control, insulin degludec-treated patients used 12% less basal and 9% less total daily insulin than did insulin glargine-treated patients (P < 0.01).. Long-term basal therapy using insulin degludec in Type 1 diabetes required lower doses and was associated with a 25% lower risk for nocturnal hypoglycaemia than insulin glargine.

Topics: Analysis of Variance; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Insulin, Long-Acting; Insulins; Male; Treatment Outcome

This study investigated the efficacy and safety of insulin degludec (IDeg) once daily (OD), varying injection timing day to day in subjects with type 1 diabetes.. This 26-week, open-label, treat-to-target, noninferiority trial compared IDeg forced flexible (Forced-Flex) OD (given in a fixed schedule with a minimum 8 and maximum 40 hours between doses) with IDeg or insulin glargine (IGlar) given at the same time daily OD. In the 26-week extension, all IDeg subjects were transferred to a free-flexible (Free-Flex) regimen, which allowed any-time-of-day dosing, and compared with subjects continued on IGlar.. After 26 treatment weeks, mean glycosylated hemoglobin was reduced with IDeg Forced- Flex (-0.40%), IDeg (-0.41%), and IGlar (-0.58%). IDeg Forced-Flex noninferiority was achieved. Fasting plasma glucose reductions were similar with IDeg Forced-Flex and IGlar but greater with IDeg (-2.54 mmol/L) than IDeg Forced-Flex (-1.28 mmol/L) (P = .021). At week 52, IDeg Free-Flex subjects had similar glycosylated hemoglobin but greater fasting plasma glucose reductions than IGlar subjects (-1.07 mmol/L) (P = .005). Confirmed hypoglycemia rates (plasma glucose <3.1 mmol/L or severe hypoglycemia) were similar at weeks 26 and 52. Nocturnal confirmed hypoglycemia was lower with IDeg Forced-Flex vs IDeg (37%; P = .003) and IGlar (40%; P = .001) at week 26 and 25% lower with IDeg Free-Flex vs IGlar (P = .026) at week 52.. IDeg can be administered OD at any time of day, with injection timing varied without compromising glycemic control or safety vs same-time-daily IDeg or IGlar. This may improve basal insulin adherence by allowing injection-time adjustment according to individual needs.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Self Administration; Treatment Outcome

The efficacy and safety of insulin degludec (degludec), a new-generation ultra-long-acting basal insulin, was compared with insulin glargine (glargine) in people with Type 1 diabetes mellitus in a 16-week, open-label, randomized trial. Health status, an important aspect of effective diabetes management, was also assessed.. Degludec (n = 59) or glargine (n = 59) were injected once daily, with insulin aspart at mealtimes. Health status assessment utilized the validated Short Form 36 Health Survey, version 2, which has two summary component scores for mental and physical well-being, each comprising four domains.. At study end, HbA(1c) reductions were comparable between groups, but confirmed nocturnal hypoglycaemia was significantly less frequent with degludec [relative rate 0.42 (95% CI 0.25-0.69)], and overall hypoglycaemia numerically less frequent [relative rate 0.72 (95% CI 0.52-1.00)]. After 16 weeks, a significant improvement in Short Form 36 Health Survey mental component score of +3.01 (95% CI 0.32-5.70) was obtained for degludec against glargine, attributable to significant differences in the social functioning [+8.04 (95% CI 1.89-14.18)] and mental health domains [+2.46 (95% CI 0.10-4.82)]. For mental component score, Cohen's effect size was 0.42, indicating a small-to-medium clinically meaningful difference. The physical component score [+0.66 (95% CI -2.30 to 3.62)] and remaining domains were not significantly different between degludec and glargine.. In the context of comparable overall glycaemic control with glargine, degludec improved mental well-being as measured using the mental component score of the Short Form 36 Health Survey. The improvements in overall mental component score and the underlying social functioning and mental health domains with degludec compared with glargine may relate to the observed reduction in hypoglycaemic events.

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Glycated Hemoglobin; Health Surveys; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Quality of Life; Surveys and Questionnaires; Treatment Outcome; Young Adult

Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes.. In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin [HbA(1c)] ≤10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA(1c) after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228.. Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA(1c) had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference -0·01% points [95% CI -0·14 to 0·11]; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA(1c) of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1·07 [0·89 to 1·28]; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 [0·59 to 0·96]; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups.. Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy.. Novo Nordisk.

Topics: Adult; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Insulin, Long-Acting; Male

Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. We compared the pharmacodynamic (PD) variability of IDeg and insulin glargine (IGlar) under steady-state conditions.. Day-to-day variability in glucose-lowering effect was investigated in 54 subjects with type 1 diabetes who underwent a 24-h euglycaemic glucose clamp on the 6th, 9th and 12th day of treatment with 0.4 U/kg of IDeg or IGlar once daily. Within-subject variability was estimated using a linear mixed model on log-transformed PD endpoints derived from the glucose infusion rate (GIR) profiles during the clamps.. For IDeg the day-to-day variability in glucose-lowering effect was four-times lower than for IGlar for total metabolic effect (AUC(GIR,0-24h,SS), CV 20% vs. 82%) and for the last 22 h [AUC(GIR,2-24h,SS) (not influenced by intravenous insulin during the clamp), CV 22% vs. 92%]. Furthermore, lower variability in the maximum effect was observed for IDeg vs. IGlar (GIR(max,SS), CV 18% vs. 60%). The lower within-subject variability of IDeg was consistent over time (CVs of 33% for AUC(GIR,0-2h,SS), 32% for AUC(GIR,10-12h,SS) and 33% for AUC(GIR,22-24h,SS)), whereas the variability of IGlar was higher and increased substantially 8 h post-dosing (CVs of 60% for AUC(GIR,0-2h,SS), 135% for AUC(GIR,10-12h,SS) and 115% for AUC(GIR,22-24h,SS)).. These results show that IDeg has a significantly more predictable glucose-lowering effect from day to day than IGlar.

Topics: Adolescent; Adult; Aged; Area Under Curve; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Young Adult

To evaluate efficacy and tolerability of a co-formulation of insulin degludec and insulin aspart (IDegAsp) with insulin aspart (IAsp) at other meals compared with basal-bolus therapy using insulin detemir (IDet) and IAsp.. Adults (n = 548) with type 1 diabetes (A1C 7.0-10.0%; BMI ≤35.0 kg/m(2)) were randomized 2:1 in a 26-week, multinational, parallel-group, treat-to-target trial to IDegAsp or IDet. IDegAsp was given with a meal, and IDet was given in the evening, with a second (breakfast) dose added if needed.. Non-inferiority for IDegAsp versus IDet was confirmed; A1C improved by 0.75% with IDegAsp and 0.70% with IDet to 7.6% in both groups (estimated treatment difference IDegAsp - IDet: -0.05% [95% CI -0.18 to 0.08]). There was no statistically significant difference between IDegAsp and IDet in the rates of severe hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively) or overall confirmed (plasma glucose <3.1 mmol/L) hypoglycemia (39.17 and 44.34 episodes/patient-year, respectively). Nocturnal confirmed hypoglycemia rate was 37% lower with IDegAsp than IDet (3.71 vs. 5.72 episodes/patient-year, P < 0.05). Weight gain was 2.3 and 1.3 kg with IDegAsp and IDet, respectively (P < 0.05). Total insulin dose was 13% lower in the IDegAsp group (P < 0.0001). No treatment differences were detected in Health-Related Quality of Life, laboratory measurements, physical examination, vital signs, electrocardiograms, fundoscopy, or adverse events.. IDegAsp in basal-bolus therapy with IAsp at additional mealtimes improves overall glycemic control and was non-inferior to IDet, with a reduced risk of nocturnal hypoglycemia and fewer injections in comparison with IDet + IAsp basal-bolus therapy.

Topics: Diabetes Mellitus, Type 1; Drug Administration Schedule; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin, Long-Acting; Meals

Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes.. In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m(2)) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52-1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65-1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25-0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44-1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments.. In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.

Topics: Adult; Aged; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Treatment Outcome; Young Adult

There is conflicting evidence on the effect of exercise on systemic insulin concentrations in adults with type 1 diabetes.. This prospective single-arm study examined the effect of exercise on systemic insulin degludec (IDeg) concentrations. The study involved 15 male adults with type 1 diabetes (age 30.7 ± 8.0 years, HbA1c 6.9 ± 0.7%) on stable IDeg regimen. Blood samples were collected every 15 minutes at rest, during 60 minutes of cycling (66% VO. Compared to baseline, systemic IDeg increased during exercise over time (. A single bout of aerobic exercise increases systemic IDeg exposure in adults on a stable basal IDeg regimen. This finding may have important implications for future hypoglycemia mitigation strategies around physical exercise in IDeg-treated patients.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Exercise; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Male; Prospective Studies; Young Adult

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Pregnancy; Pregnancy Outcome

Topics: Denmark; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Health Literacy; Humans; Hypoglycemic Agents; Pregnancy; Pregnancy Outcome; Prospective Studies

Optimizing glycemic control without risking hypoglycemia is crucial in toddlers and preschoolers with type 1 diabetes (T1D) to avoid cognitive impairment later in life. Hence, this study aims to compare glycemic parameters among toddlers and preschoolers with T1D in relation to different basal insulins. Sixty toddlers and preschoolers with T1D with mean age of 3.53 ± 1.17 years (range, 2-6) and mean diabetes duration of 9.37 ± 1.85 months were randomly assigned into three equal groups; group A received insulin degludec, group B received insulin glargine, and group C were on NPH. At baseline, the three groups were matched regarding clinical and laboratory parameters (p > 0.05). They were followed up at 3 and 6 months for insulin daily dose (IDD), hypoglycemia and severe-hypoglycemia frequency, and glycated hemoglobin (HbA1c). At the study endpoint, continuous glucose monitoring (CGM) was assessed in a random sample of 10 patients from each group. The mean time in range (TIR) of the studied cohort was 55.07 ± 24.05%, and their mean coefficient of variation (CV) was 42.82 ± 11.69%. The TIR was significantly higher in the degludec group (69.36 ± 18.54) and the glargine group (55.43 ± 26.51) than the NPH group (32.56 ± 9.11), p < 0.001. Meanwhile, the CV was significantly lower in the degludec group (35.12 ± 6.47) than the gargine (44.1 ± 13.13) and the NPH (53.8 ± 7.54) groups, p < 0.001. The insulin degludec and glargine groups had significantly lower HbA1c (p = 0.002), hypoglycemia (p = 0.006), severe hypoglycemia (p = 0.029), and IDD (p = 0.015) than the NPH group.. Insulin degludec and glargine resulted in better HbA1c and TIR with reduced hypoglycemia and IDD than NPH among toddlers and preschoolers with T1D. Moreover, CV was lowest in the insulin degludec group.. • Insulin therapy is the mainstay of T1D management. • Optimal insulin therapy for young children with T1D should provide effective glycemic.. • Insulin degludec and insulin glargine have better efficacy than NPH insulin among toddlers and preschoolers with T1D in the term of significantly lower coefficient of variation, HbA1c and IDD and significantly higher time in range. • Insulin degludec and insulin glargine have better safety in the term of less hypoglycemia and severe hypoglycemia episodes than NPH insulin among toddlers and preschoolers with T1D.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Child, Preschool; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Isophane

Kazda CM, Bue-Valleskey JM, Chien J, et al.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin, Long-Acting

A 58-year-old Japanese man was brought to the emergency room due to disturbance of consciousness. He regained consciousness on the day of admission and started taking hospital meals, but he needed intravenous glucose administration for eight days. The total amount of glucose administration was 4,464 g. It took over three weeks for exogenous insulin to be almost undetectable. While degludec binds to albumin and exerts glucose-lowering effects for a long time, the above-mentioned period of three weeks was consistent with the half-life of albumin. Hypoglycemia induced by massive dose of insulin degludec is persistent and prominent.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged

To evaluate pregnancy outcomes in a real-world setting of pregnant women with type 1 diabetes using the ultra-long-acting insulin analog degludec compared to other long-acting insulin analogs throughout pregnancy.. This was a secondary analysis of a prospective cohort study. The prospective cohort included consecutive, singleton pregnant women with type 1 diabetes receiving long-acting insulin analogs both before and during pregnancy: 67 women using degludec compared to 95 women using other long-acting insulin analogs in a routine care setting.. Women using degludec had similar clinical characteristics as women using other long-acting insulin analogs including HbA1c at 9 gestational weeks [6.5 (6.2-6.9) % (48 (44-52) mmol/mol) versus 6.5 (6.0-7.0) % (47 (42-53) mmol/mol), p = 0.52] and at 35 gestational weeks [6.0 (5.6-6.5) % (42 (38-47) mmol/mol) versus 6.1 (5.6-6.5) % (43 (38-48) mmol/mol), p = 0.68]. Pregnancy outcomes were similar regarding preeclampsia [10% (7/67) versus 8% (8/95), p = 0.66] and preterm delivery before 37 gestational weeks [16% (11/67) versus 23% (22/95), p = 0.29]. There were no perinatal deaths, and neonatal outcomes as large for gestational age infants [37% (25/67) versus 39% (37/95), p = 0.83], small for gestational age infants [4% (3/67) versus 5% (5/95), p = 1.0] and neonatal hypoglycemia [32% (21/65) versus 41% (34/83), p = 0.28] were similar between women using degludec and other long-acting insulin analogs.. The use of degludec during pregnancy resulted in similar pregnancy outcomes as use of other long-acting insulin analogs in women with type 1 diabetes in a real-world setting. This suggests that degludec initiated before pregnancy can be continued throughout gestation.

Topics: Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infant, Newborn; Insulin Glargine; Insulin, Long-Acting; Pregnancy; Pregnancy Outcome; Prospective Studies

The effects of switching Canadians from other basal insulins to degludec (IDeg) in an outpatient setting are unknown. Our aim in this study was to evaluate the clinical effectiveness and safety of switching insulin-treated adults with either type 1 (T1DM) or type 2 (T2DM) diabetes mellitus to IDeg.. This was a retrospective observational cohort study of Albertans who were switched to IDeg between December 1, 2018, and December 1, 2019, and followed until March 1, 2020. We used administrative databases (provincial cohort) and electronic medical records (clinic cohort) to gather data and interrupted time series for the primary outcome analysis.. We analyzed a provincial cohort of 5,294 patients, 287 of whom were also included in the clinic cohort (T1DM, n=80; T2DM, n=207). After switching to IDeg, glycated hemoglobin (A1C) decreased by -0.3 (95% confidence interval [CI], -0.4% to -0.2%) and the reduction in A1C was maintained throughout the follow-up period. Rates of all-cause hospitalizations/emergency department visits per patient were not affected (hospitalizations pre-switch 0.07 [95% CI, 0.07 to 0.08], post-switch 0.08 [95% CI, 0.06 to 0.09], p=0.45; ED visits pre-switch 0.25 [95% CI, 0.23 to 0.27], post-switch 0.26 [95% CI, 0.23 to 0.29], p=0.27). In the clinic cohort, at switch, there was an average basal insulin dose reduction of 11.2% (T1DM), 12.3% (T2DM) and 16.3% (patients with insulin resistance).. Patients with inadequate glycemic control or who find their basal insulin dosing inconvenient may benefit from switching to Ideg, with the potential for small improvementa in A1C at lower basal insulin doses.

Topics: Adult; Blood Glucose; Canada; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Substitution; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Retrospective Studies

The patient was 82-year-old man with type 1 diabetes mellitus. He had been using insulin degludec (IDeg) and insulin glulisine (IGlu) for treatment. He was admitted to our hospital due to diabetic ketoacidosis. As he started eating after recovery, we restarted intensive insulin therapy for glycemic control. Although he had eaten almost whole meals, his fasting blood glucose was extremely low, and the existence of nocturnal hypoglycemia was apparent. We reduced the dose and changed the injection time (evening→morning) of IDeg. We also stopped the evening IGlu injection; however, his nocturnal hypoglycemia did not improve. We decided to switch IDeg to insulin glargine U300 and to attach an intermittently scanned continuous glucose monitor (isCGM). His nocturnal hypoglycemia improved three days later. Since he had chronic heart failure and premature ventricular contractions, we used a Holter electrocardiogram to investigate the difference in arrythmia during hypoglycemia and non-hypoglycemia. As a result, the number of premature ventricular contractions was apparently high during hypoglycemia. In the present case, which involved an elderly patient with type 1 diabetes mellitus, chronic heart failure and nocturnal hypoglycemia, switching IDeg to insulin glargine U300 improved nocturnal hypoglycemia. IDeg differs from insulin glargine U300 in that it has a fatty acid side chain, which leads IDeg to combine with serum albumin. We thought that the increased level of free fatty acid due to hypoglycemia was competing against albumin combined IDeg, which increased free IDeg, and as a result, encouraged hypoglycemia.

Topics: Aged; Aged, 80 and over; Chronic Disease; Diabetes Mellitus, Type 1; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Ventricular Premature Complexes

To evaluate the efficacy of degludec/aspart (IDegAsp) insulin co-formulation in children and adolescents with poorly controlled type 1 diabetes (T1DM).. Patients with poorly controlled T1DM on basal-bolus insulin regimes and having compliance problems related to insulin injections were switched to IDegAsp and were included. Data on hemoglobin A1c (HbA1c) levels, hypoglycemic episodes, frequency of diabetic ketoacidosis (DKA) and insulin doses were recorded at baseline and after one year of IDegAsp treatment.. Fifty patients (22 girls; 44%) were started on IDegAsp. The mean±standard deviation (range) age and duration of diabetes were 12.9±3.4 (4-18) and 5.2±3.1 (1.0-13.7) years, respectively. At the end of one year, 38 patients were still on IDegAsp, whereas 12 patients had opted to resume their original treatments. In those who continued on IDegAsp, HbA1c levels did not change, but the number of self-reported mild-moderate hypoglycemic episodes decreased significantly (p<0.05). In the year before switching to IDegAsp, 11 DKA attacks in 9 patients were observed, whereas this decreased to 4 DKA attacks in 4 patients after one year of IDegAsp therapy (p=0.06).. IDegAsp regimen may improve clinical management in poorly controlled basal-bolus insulin regimen T1DM patients who have frequent hypoglycemia and DKA attacks, as well as in those with poor compliance with multiple injections. Although a simplified basal-bolus IDegAsp regimen is an attractive option for patients with T1DM, some may not adapt to this treatment due to the fixed IAsp dose of IDegAsp.

Topics: Adolescent; Blood Glucose; Child; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin, Long-Acting; Male

This study investigated whether a 30-day co-treatment with 1 g/kg glutamine dipeptide (GdiP) and 1 U/kg regular (rapid acting) or 5 U/kg degludec (long acting) insulins modifies glucose homeostasis and liver metabolism of alloxan-induced type 1 diabetic (T1D) male Swiss mice undergoing insulin-induced hypoglycemia (IIH). Glycemic curves were measured in fasted mice after IIH with 1 U/kg regular insulin. One hour after IIH, the lipid profile and AST and ALT activities were assayed in the serum. Morphometric analysis was assessed in the liver sections stained with hematoxylin-eosin and glycolysis, glycogenolysis, gluconeogenesis and ureagenesis were evaluated in perfused livers. T1D mice receiving GdiP or the insulins had a smaller blood glucose drop at 60 minutes after IIH, which was not sustained during the subsequent period up to 300 minutes. The 30-day treatment of T1D mice with insulin degludec, but not with regular insulin, improved fasting glycemia, body weight gain and serum activity of AST and ALT. Treatments with insulin degludec, GdiP and insulin degludec + GdiP decreased the liver capacity in synthesizing glucose from alanine. GdiP, in combination with both insulins, was associated with increases in the serum triglycerides and, in addition, regular insulin and GdiP increased AST and ALT activities, which could be the consequence of hepatic glycogen overload. GdiP and the insulins improved the IIH, although to a small extent. Caution is recommended, however, with respect to the use of GdiP because of its increasing effects on serum triglycerides and AST plus ALT activities.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dipeptides; Glucose; Glutamine; Homeostasis; Hypoglycemia; Insulin; Insulin, Long-Acting; Insulins; Liver; Male; Mice; Triglycerides

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).. 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.. 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/m. 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.

Topics: Adult; Aged; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Hospitals, Special; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Outcome Assessment, Health Care; Patient Satisfaction; Prospective Studies; Quality of Life; Thailand

To determine whether the occurrence of nocturnal asymptomatic, serious, clinically important hypoglycemia (NSH) could be predicted based on glucose values on the previous day and the following morning of the day of onset.. This study examined patients with type 1 diabetes who underwent continuous glucose monitoring assessments and received insulin degludec. NSH was defined as glucose level <54 mg/dL detected between 24.00 and 06.00 hours. The participants were evaluated to determine the following: (i) glucose level at bedtime (24.00 hours) on the previous day (BG); (ii) fasting glucose level (FG); and (iii) the range of post-breakfast glucose elevation. The patients were divided into those with NSH and those without, and compared using t-tests. Optimal cut-off values for relevant parameters for predicting NSH were determined using receiver operating characteristic analysis.. The study included a total of 31 patients with type 1 diabetes (mean glycated hemoglobin value 7.8 ± 0.7%). NSH occurred in eight patients (26%). BG and FG were significantly lower in those with NSH than in those without (P = 0.044, P < 0.001). The range of post-breakfast glucose elevation was significantly greater in those with NSH than in those without. The cut-off glucose values for predicting NSH were as follows: BG = 90 mg/dL (sensitivity 0.83/specificity 0.75/area under the curve 0.79, P = 0.017) and FG = 69 mg/dL (0.83/0.75/0.86, P = 0.003).. The results showed that in patients with type 1 diabetes receiving insulin degludec, BG <90 mg/dL and FG <69 mg/dL had an approximately 80% probability of predicting the occurrence of NSH.

Topics: Adult; Asymptomatic Diseases; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Sensitivity and Specificity

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.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Retrospective Studies; Young Adult

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.. 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.. 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.. 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.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Substitution; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Insulins; Japan; Logistic Models; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Health Expenditures; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Markov Chains; Middle Aged; Models, Economic; Quality-Adjusted Life Years; Retrospective Studies

With appearance of new insulins on the market, new clinical challenges, much like unintended consequences, came into light in our daily practice. One of the most pressing issues has become an issue of switching patients to and from newer insulins in various clinical situations. A proper switch from 1 medication to another requires understanding of pharmacokinetics (PK) and pharmacodynamics (PD) of both drugs. Unfortunately, there is no research in this area and, as a result, there are no guidelines nor is there even a consensus. We present 5 clinical scenarios in which the patients were transitioned to or from insulin degludec. Because there are no data and no current consensus, we have polled 200 diabetes care providers soliciting their opinion as to how they would handle these clinical situations. Our poll of endocrinologists revealed multiple approaches as well as elements of confusion among providers. Even though all answers, summarized following each case, might be reasonable, and there might not be a single correct answer, we wish to express our opinion that is based on PK and PD of these insulins. Because there is more than 1 correct way of implementing these transitions, we urge our colleagues to institute a very close follow-up of these patients with frequent adjustments of insulin dose to avoid stacking with potential hypoglycemia.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin, Long-Acting; Male; Middle Aged; Prognosis; Young Adult

Absztrakt: Az 1-es típusú diabetes mortalitása, bár csökkenő tendenciát mutatva, jelentősen meghaladja a standard mortalitást. Ez egyúttal a diabetesszel megélt életévek rövidülésével jár együtt. Az esetismertetés tárgya egy 86 éves diabetestartammal a 91. életévét megélő nőbeteg, akit több mint 55 éven keresztül egyetlen orvos – a szerző – kezelt/gondozott. Az 1932-ben, ötéves korában fellépett diabetest először naponta háromszor adagolt gyors hatású inzulinnal, majd 1940-től kezdve naponta egyszer alkalmazott gyors hatású és cink-protamin inzulinnal, később sertés, majd humán kristályos cinkinzulinnal, majd az utolsó 16 évben gyors hatású NPH-inzulin keverékével kezelték. Ennek oka az volt, hogy a beteg rögeszmésen ragaszkodott a napi egyszeri inzulinadáshoz, és hogy esetében mindegyik inzulin hatástartama 24 órásnak bizonyult. Az évtizedeken át folyamatosan túladagolt egyszeri inzulinadás következménye a szinte naponta, főként az éjjeli órákban fellépő hypoglykaemia lett, következményes nagyfokú vércukor-ingadozásokkal. Az 1930-as évek közepétől a hatvanas évekig polarimetriás, majd száraz kémiás módszerrel vizeletcukor-önellenőrzést végzett a nyolcvanas évek elejéig, majd áttért a vércukor-önellenőrzésre. Az ötvenes években két sikertelen terhessége volt, 2010–11-ben egymás után jobb, majd bal oldali combnyaktörést szenvedett, majd mindkét szemén megműtötték a cataractáját. Az utolsó 25 évben HbA

Topics: Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 1; Fatal Outcome; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Myocardial Infarction; Treatment Outcome

The ReFLeCT study demonstrated that switching to insulin degludec from other basal insulins was associated with reductions in glycated hemoglobin and hypoglycemic events in type 1 (T1D) and type 2 diabetes (T2D), and reductions in insulin doses in T1D. The aim of the present analysis was to assess the short- and long-term cost-effectiveness of switching to insulin degludec in Sweden.. Short-term outcomes were evaluated over 1 year in a Microsoft Excel model, while long-term outcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model. Cohort characteristics and treatment effects were sourced from the ReFLeCT study. Costs (in 2018 Swedish krona [SEK]) encompassed direct medical expenditure and indirect costs from loss of workplace productivity. In the long-term analyses, patients were assumed to receive insulin degludec or continue prior insulin therapy (primarily insulin glargine U100) for 5 years, before all patients intensified to once-daily degludec and mealtime aspart.. Switching to insulin degludec was associated with improved quality-adjusted life expectancy of 0.04 and 0.02 quality-adjusted life years (QALYs) over 1 year, and 0.16 and 0.08 QALYs over patient lifetimes, in T1D and T2D. Combined costs in T1D and T2D were estimated to be SEK 1,249 lower and SEK 1,181 higher over the short-term, and SEK 157,258 and SEK 2,114 lower over the long-term. Benefits were due to lower insulin doses in T1D, reduced rates of hypoglycemia, and lower incidences of diabetes-related complications. Insulin degludec was associated with an incremental cost-effectiveness ratio of SEK 64,298 per QALY gained for T2D over 1 year and considered dominant for T1D and T2D in all other comparisons.. Insulin degludec was projected to be cost-effective or dominant versus other basal insulins for the treatment of T1D and T2D in Sweden.

Topics: Cost of Illness; Cost-Benefit Analysis; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glycated Hemoglobin; Health Expenditures; Health Services; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Models, Econometric; Quality-Adjusted Life Years; Sweden

Observational studies of insulin degludec (degludec) with hypoglycemia events prospectively recorded are lacking.. To evaluate the safety and effectiveness of degludec in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) switching from other basal insulins in routine care.. Results From Real-World Clinical Treatment With Tresiba® was a multinational, multicenter, prospective, observational, single-arm study comprising a 4-week baseline period (preswitch basal insulin) and 12-month follow-up (degludec).. Routine clinical practice.. Insulin-treated patients (≥18 years) with T1D (n = 556) or T2D (n = 611) with treatment plans to initiate degludec.. Switching to degludec from other basal insulins.. Change from baseline in number of overall hypoglycemic events recorded in patient diaries.. In T1D, the 12-month follow-up/baseline rate ratios (95% CI) of overall [0.80 (0.74 to 0.88)], nonsevere [0.83 (0.76 to 0.91)], severe [0.28 (0.14 to 0.56)], and nocturnal [0.61 (0.50 to 0.73)] hypoglycemia suggested significantly lower hypoglycemia rates with degludec (all Ps < 0.001). At 12 months, HbA1c, fasting plasma glucose (FPG), and basal insulin dosage decreased significantly. Body weight increased, and treatment satisfaction improved significantly. In T2D, the hypoglycemia rate ratios were overall [0.46 (0.38 to 0.56)], nonsevere [0.53 (0.44 to 0.64)], and nocturnal [0.35 (0.20 to 0.62)] (all Ps < 0.001; too few events for analysis of severe hypoglycemia). At 12 months, HbA1c and FPG decreased significantly. Body weight and insulin dosages remained unchanged, and treatment satisfaction was significantly improved.. In a routine clinical care setting, switching to degludec from other basal insulins was associated with significantly lower rates of hypoglycemia, improved glycemic control, and treatment satisfaction in patients with T1D or T2D.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Substitution; Europe; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin, Long-Acting; Insulins; Male; Middle Aged

Insulin degludec (IDeg) is the longest-acting basal insulin available. Whether IDeg compared to shorter-acting basal insulins like insulin glargine U100 (IGlarU100) reduces the rate of diabetic ketoacidosis (DKA) in adolescents with type 1 diabetes is unknown.. We hypothesized that adolescents with type 1 diabetes would have lower DKA rates and mean hemoglobin A1c (HbA1c) when using IDeg as compared to IGlarU100.. To avoid selection bias, we used self-control case series methodology. Adolescents with type 1 diabetes treated for DKA from January 2015 through December 2018 who switched basal insulin from IGlarU100 to IDeg were eligible for analysis. Thirty-five patients were included, each acting as their own control. Mean HbA1c and DKA rate for the 12 months prior to and after switching to IDeg were compared.. Mean HbA1c prior to and after switching to IDeg was unchanged (97 ± 20 vs. 97 ± 21 mmol/mol [11.0 ± 1.8 vs. 11.0 ± 1.9%]). Median DKA rate (admissions/year) while on IGlar-U100 was 1 with an interquartile range (IQR) of 1-2. After switching to IDeg, median DKA admission rate remained 1, however the IQR decreased to 0-1 (one-sided p value 0.0004). Median change in DKA rate was 1 fewer admission per year, with a maximum reduction of 3 admissions. Higher baseline rates of DKA increased the odds of a patient reducing his/her DKA rate by 1 admission per year or more.. Using IDeg for basal insulin in adolescent patients may decrease the rate of DKA relative to IGlarU100 despite no improvement in HbA1c and may be cost-effective.

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Retrospective Studies

To investigate the association between day-to-day fasting self-monitored blood glucose (SMBG) variability and risk of hypoglycaemia in type 1 (T1D) and type 2 diabetes (T2D), and to compare day-to-day fasting SMBG variability between treatments with insulin degludec (degludec) and insulin glargine 100 units/mL (glargine U100).. Data were retrieved from two double-blind, randomized, treat-to-target, two-period (32 weeks each) crossover trials of degludec vs glargine U100 in T1D (SWITCH 1, n = 501) and T2D (SWITCH 2, n = 720). Available fasting SMBGs were used to determine the standard deviation (SD) of day-to-day fasting SMBG variability for each patient and the treatment combination. The association between day-to-day fasting SMBG variability and overall symptomatic, nocturnal symptomatic and severe hypoglycaemia was analysed for the pooled population using linear regression, with fasting SMBG variability included as a three-level factor defined by population tertiles. Finally, day-to-day fasting SMBG variability was compared between treatments.. Linear regression showed that day-to-day fasting SMBG variability was significantly associated with overall symptomatic, nocturnal symptomatic and severe hypoglycaemia risk in T1D and T2D (P < 0.05). Day-to-day fasting SMBG variability was significantly associated (P < 0.01) with all categories of hypoglycaemia risk, with the exception of severe hypoglycaemia in T2D when analysed within tertiles. Degludec was associated with 4% lower day-to-day fasting SMBG variability than glargine U100 in T1D (P = 0.0082) and with 10% lower day-to-day fasting SMBG variability in T2D (P < 0.0001).. Higher day-to-day fasting SMBG variability is associated with an increased risk of overall symptomatic, nocturnal symptomatic and severe hypoglycaemia. Degludec has significantly lower day-to-day fasting SMBG variability vs glargine U100.

Topics: Adolescent; Adult; Blood Glucose; Blood Glucose Self-Monitoring; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Humans; Hypoglycemia; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Young Adult

Historically, data on the rate of hyperglycemia and ketosis have not been collected in clinical trials. However, it is clinically important to assess the rate of these events in children with type 1 diabetes (T1D). This question was addressed in two pediatric trials using insulin degludec (degludec).. To assess the rate of hyperglycemia and ketosis in two-phase 3b trials investigating degludec (Study 1) and degludec with insulin aspart (IDegAsp [Study 2]) vs insulin detemir (IDet).. Patients (aged 1-17 years inclusive) with T1D treated with insulin for ≥3 months.. Study 1: patients were randomized to degludec once daily (OD) or IDet OD/twice daily (BID) for 26 weeks, followed by a 26-week extension phase. Study 2: patients were randomized to IDegAsp OD or IDet OD/BID for 16 weeks. Bolus mealtime IAsp was included in both studies. In Study 1, hyperglycemia was recorded if plasma glucose (PG) was >11.1 mmol/L, with ketone measurement required with significant hyperglycemia (>14.0 mmol/L). In Study 2, hyperglycemia was recorded with PG >14.0 mmol/L where the subject looked/felt ill, with ketone measurement also required in these hyperglycemic patients. In this post hoc analysis, the hyperglycemia threshold was 14.0 mmol/L for uniformity.. Despite similar rates of hyperglycemia with degludec/IDegAsp compared with IDet, the rates of ketosis were lower with degludec/IDegAsp.. These trials, the first to systematically collect data on ketosis in pediatric patients with T1D, demonstrate the potential of degludec/IDegAsp to reduce rates of metabolic decompensation, compared with IDet.

Topics: Adolescent; Blood Glucose; Child; Child, Preschool; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Drug Combinations; Female; Humans; Hyperglycemia; Hypoglycemia; Infant; Insulin Aspart; Insulin Detemir; Insulin, Long-Acting; Male; Randomized Controlled Trials as Topic; Retrospective Studies

To investigate whether the benefits of switching to insulin degludec observed in the European retrospective chart review study EU-TREAT were dependent on the previous basal insulin used.. People with Type 1 or Type 2 diabetes were switched to insulin degludec from other basal insulins ≥6 months before data collection. Participants were stratified into three groups based on their previous basal insulin: insulin glargine 100 units/ml (Type 1: n=888; Type 2: n=259); insulin detemir (Type 1: n=726; Type 2: n=415); and neutral protamine Hagedorn (Type 1: n=53; Type 2: n=95). Their glycaemic control and hypoglycaemia incidence at 6 and 12 months post-switch vs pre-switch was then evaluated.. Switching to insulin degludec from other basal insulins can improve glycaemic control and/or reduce hypoglycaemia risk in people with diabetes (although there was a nonsignificant reduction in HbA

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Europe; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

To report glycemic control and pregnancy outcome in pregnant women with type 1 diabetes on insulin degludec.. Twenty-two women with type 1 diabetes on degludec from conception to delivery between 2014 and 2018 were compared with 51 pregnant women with type 1 diabetes on glargine.. Baseline characteristics were comparable, however HbA1c was higher at median 9 (range 5-19) weeks in women on degludec compared to women on glargine (6.9% (5.7-8.7); (52 (39-72) mmol/mol) versus 6.4% (5.1-10.1); (46 (32-87) mmol/mol), p = 0.04). HbA1c was similar in late pregnancy (6.3% (5.6-7.1); (45 (38-54) mmol/mol) versus 6.1% (5.2-9.0); (43 (33-75) mmol/mol), p = 0.28). The prevalence of severe hypoglycemia was 3 (14%) versus 6 (12%), p = 1.00 during pregnancy and 0 versus 1, p = 1.00 during hospital admittance after delivery. Most women on degludec used one daily injection in early (20 (91%) versus 25 (49%), p = 0.001) and late pregnancy (21 (96%) versus 19 (37%), p < 0.001). No significant differences in obstetrical and neonatal outcomes were found between the groups. Maternal hospital admittance after delivery was 2 (1-5) versus 3 (2-11) days (p = 0.004).. Glycemic control in late pregnancy, severe hypoglycemia during and immediately after pregnancy as well as pregnancy outcome were comparable in women on degludec or glargine. Degludec initiated preconceptionally may be continued in pregnancy.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Middle Aged; Pregnancy; Pregnancy in Diabetics; Pregnancy Outcome; Prevalence; Treatment Outcome; Young Adult

Drug rebates are almost universally negotiated privately between the manufacturer and the payer in the US. The aim of the present study was to illustrate the use of a "rebate table" to improve the transparency and utility of published budget impact analyses in the US by modeling ranges of hypothetical rebates for two comparators. Worked examples were conducted to illustrate the budgetary implications of using insulin degludec (IDeg) relative to insulin glargine (IGlar) U100 in patients with type 1 or 2 diabetes.. A short-term (1-year) budget impact model was developed to evaluate the costs of switching to IDeg from IGlar in patients with type 1 or 2 diabetes on basal-bolus and basal-only insulin, respectively. The analysis used insulin dose and hypoglycemia data from recent randomized trials, data on the prevalence of diabetes, and estimates of the proportion of patients using each insulin regimen. The model was configured to run multiple rebate scenarios to generate a rebate table in a hypothetical 1 million member commercial plan.. Relative to IGlar, IDeg resulted in reductions in non-severe and severe hypoglycemia incidence and costs both in patients with type 1 and patients with type 2 diabetes. Insulin acquisition costs were higher, and respective rebates of 7.3% and 10.6% were required for IDeg to break-even with IGlar at the full list price. Incremental per member per month IDeg costs without a rebate were USD 0.04 in type 1 diabetes and USD 0.80 in type 2 diabetes.. Using IDeg instead of IGlar at list price could result in a modest increase in costs when considering insulin and hypoglycemia costs alone, but modest incremental rebates with IDeg would result in cost neutrality relative to IGlar. In addition, IDeg would result in reduced incidence of severe and non-severe hypoglycemia.

Topics: Budgets; Cost Savings; Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Costs; Female; Humans; Insulin Glargine; Insulin, Long-Acting; Insurance, Pharmaceutical Services; Male; Models, Economic; United States

Insulin degludec (IDeg) has significantly lower day-to-day and within-day variability compared to insulin glargine (IGlar) 100U/mL (U100) and 300U/mL (U300). Here, we report post hoc assessments to confirm the robustness of these observations while accounting for potential experimental confounders.. Two euglycemic clamp studies in type 1 diabetes patients, comparing IDeg to IGlar-U100 (Study A, parallel design, 54 patients; Study B, crossover, 22 patients) and one study comparing IDeg to IGlar-U300 (Study C, crossover, 57 patients), all dosed at 0.4U/kg, were evaluated. Pharmacodynamic parameters were assessed at steady state from glucose infusion rate (GIR) profiles following three 24-hour euglycemic clamps in Studies A (162 clamps) and C (342 clamps), and one 42-hour clamp in Study B (44 clamps).. Pooled data (Studies A and B) showed that IDeg had an even distribution of glucose-lowering effect over the 24-hour dosing interval that was consistent with Study C. IGlar-U100 showed a constant decrease in glucose-lowering effect over 24 hours while IGlar-U300 had a lower effect in the middle of the dosing interval (6-18 hours). Relative within-day variability of IDeg was 40% and 37% lower than IGlar-U100 and -U300, respectively. Exclusion of profiles with low response in Study C (19/342 clamps) did not impact the difference in the distribution of glucose-lowering effect or within-day variability. Day-to-day variability was significantly lower with IDeg compared to IGlar-U100 and -U300 based on smoothed and unsmoothed GIR data.. Significantly lower relative within-day and day-to-day variability was confirmed irrespective of experimental considerations for IDeg compared to IGlar-U100 and IGlar-U300.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Retrospective Studies

To evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin-treated patients with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM) under conditions of routine clinical care.. This was a multicentre, retrospective, chart review study. In all patients, basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are presented as mean [95%CI].. T1DM (n = 1717): HbA1c decreased by -2.2 [-2.6; -2.0] mmol/mol (-0.20 [-0.24; -0.17]%) at 6 months vs baseline (P < .001). Rate ratio of overall (0.79 [0.69; 0.89]), non-severe nocturnal (0.54 [0.42; 0.69]) and severe (0.15 [0.09; 0.24]) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period (P < .001 for all). Total daily insulin dose decreased by -4.88 [-5.52; -4.24] U (-11%) at 6 months vs baseline (P < .001). T2DM (n = 833): HbA1c decreased by -5.6 [-6.3; -4.7] mmol/mol (-0.51 [-0.58; -0.43] %) at 6 months vs baseline (P < .001). Rate ratio of overall (0.39 [0.27; 0.58], P < .001), non-severe nocturnal (0.10 [0.06; 0.16], P < .001) and severe (0.075 [0.01; 0.43], P = .004) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period. Total daily insulin dose decreased by -2.48 [-4.24; -0.71] U (-3%) at 6 months vs baseline (P = .006). Clinical outcomes for T1DM and T2DM at 12 months were consistent with results at 6 months.. This study demonstrates that switching patients to IDeg from other basal insulins improves glycaemic control and significantly reduces the risk of hypoglycaemia in routine clinical practice.

Topics: Administration, Oral; Aged; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Insulins; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Topics: Adult; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male

The frequency of hypoglycemia in patients with T1DM is high and results in a poorer quality-of-life and low treatment satisfaction. The aim of this study is to demonstrate the effect of changing the basal insulin (glargine or detemir) to insulin degludec.. An observational analytical study was conducted on a cohort of 110 patients with T1DM. The patients were administered three questionnaires to assess treatment satisfaction (DTSQ-s), fear of hypoglycemia (HFS-II) and quality-of-life (EQ-5D), before the change and at 6 months. A statistical analysis was performed for repeated measures.. The change to insulin degludec in patients with T1DM improved their metabolic control, increased their satisfaction with the insulin therapy, and offered them improved quality-of-life.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Patient Preference; Quality of Life; Spain; Surveys and Questionnaires

Topics: Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting

Prior to the availability of degludec and regular human insulin inhalation powder in the type 1 diabetic patient glycemic control with subcutaneous insulin injections was difficult to obtain due to nocturnal, pre-prandial and often severe hypoglycemia as well as post-prandial hyperglycemia and hypoglycemia due to 'stacking' of insulin. A 62-year-old female with type 1 diabetes for 56 years who could not be controlled with continuous subcutaneous insulin aspart infusion obtained glycemic control without significant hypoglycemia or increased post-prandial glycemic excursions utilizing degludec insulin for basal needs and technosphere before meals and between meals if needed. The availability of degludec and technosphere insulin improved the management of brittle type 1 diabetes.

Topics: Administration, Inhalation; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Middle Aged; Treatment Outcome

Topics: Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Marketing

Ultra-long-acting insulin degludec (DEG) has a longer duration of action and less daily variability relative to other basal insulin (BI), and thus may benefit patients with type 1 diabetes mellitus (T1DM). We examined the impact of switching BI to DEG on glycemic control and insulin dose in T1DM.. T1DM patients (n = 22; six male; mean age: 64.5 ± 12.6 years) receiving basal-bolus insulin therapy were included. Initially, the BI dose was replaced with DEG in a 1:1 ratio; 80-100% of the total dose was replaced with DEG for multiple basal insulin injections. DEG was titrated according to study protocol. Changes in HbA1c, daily insulin dose, glycemic self-monitored blood glucose variations, and hypoglycemia frequency were evaluated for 24 weeks.. Once-daily DEG significantly decreased HbA1c levels when switched from once-daily BI (7.9 ± 0.8 vs. 7.5 ± 0.9%, p = 0.020) and maintained HbA1c when switched from twice-daily BI (8.5 ± 1.6 vs. 8.4 ± 1.2%, p = 0.457). The BI dose decreased by -7.8 ± 13.9% (p = 0.017) and -16.6 ± 16.9% (p = 0.050) when switched from once-daily BI and twice-daily BI, respectively. The total bolus insulin dose significantly decreased when switched from once-daily BI (21.7 ± 8.3 to 19.3 ± 8.8 U/day, p = 0.016) especially in the injection before breakfast and evening meal. Body weight and hypoglycemia frequency was not significantly different.. DEG improved glycemic control when switched from once-daily BI and maintained glycemic control when switched from twice-daily BI without increasing hypoglycemia.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Male; Middle Aged; Pilot Projects; Time Factors

The objective of this study was to assess the cost-effectiveness of insulin degludec versus insulin glargine, from the Spanish NHS in three groups of patients.. A short-term cost utility model was developed to estimate effectiveness results in terms of the total number of hypoglycaemic events and their disutility impact throughout the year on the initial level of quality of life for patients in each treatment.. Degludec was the dominant strategy for T2DM BOT and exhibited an incremental cost-effectiveness ratio of 52.70€/QALY and 11,240.88€/QALY for T1DM B/B and T2DM B/B, respectively. Lower costs are primarily driven by lower nocturnal and severe hypoglycaemic events, which were reduced versus IGlar. Improvements in clinical outcomes in all three patient groups are result of the reduced number of hypoglycaemic events showing 0.0211, 0.0328 and 0.0248 QALYs gained when compared to IGlar for T1DM B/B, T2DM BOT and T2DM B/B, respectively. Different scenario analyses showed that the ICERS were stable to plausible variations in the analysed parameters, except when the same number of SMBG for both treatments is used, with T2DM B/B showing an ICER over the accepted threshold.. This analysis demonstrates that degludec is a cost-effective option in the Spanish NHS, when used in patients currently treated with long-acting insulin.

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Costs; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Models, Economic; Quality of Life; Quality-Adjusted Life Years; Spain; Time Factors

To evaluate whether nocturnal asymptomatic hypoglycemia (NAH) can be predicted by fasting glucose levels or post-breakfast glucose fluctuations in patients with type 1 diabetes (T1D) receiving insulin degludec.. Patients with T1D receiving insulin degludec underwent at-home CGM assessments. Indices for glycemic variability before and after breakfast included fasting glucose levels and the range of post-breakfast glucose elevation. For comparison, the patients were classified into those with NAH and those without. The optimal cut-off values for the relevant parameters were determined to predict NAH using ROC analysis.. The study included a total of 31 patients (mean HbA1c values, 7.8 ± 0.7%), and 16 patients (52%) had NAH. Those with NAH had significantly lower fasting glucose levels than did those without (82 ± 48 mg/dL vs. 144 ± 69 mg/dL; P = 0.009). The change from pre- to post-breakfast glucose levels was significantly greater among those with NAH (postprandial 1-h, P = 0.028; postprandial 2-h, P = 0.028). The cut-off values for prediction of NAH were as follows: fasting glucose level <84 mg/dL (sensitivity 0.80/specificity 0.75/AUC 0.80; P = 0.004), 1-h postprandial elevation >69 mg/dL (0.75/0.67/0.73; P = 0.033), and 2-h postprandial elevation >99 mg/dL (0.69/0.67/0.71; P = 0.044).. The results suggest that fasting glucose level of < 84 mg/dL had approximately 80% probability of predicting the occurrence of NAH in T1D receiving insulin degludec. It was also shown that the occurrence of hypoglycemia led to greater post-breakfast glucose fluctuations and steeper post-breakfast glucose gradients.

Topics: Adult; Aged; Area Under Curve; Biomarkers; Blood Glucose; Breakfast; Diabetes Mellitus, Type 1; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Photoperiod; Pilot Projects; Postprandial Period; Prognosis

Insulin degludec is an insulin analog with an ultra-long duration of action that exhibits less intra-patient variability in its glucose-lowering activity, and reduces nocturnal, overall, and severe hypoglycemia relative to insulin glargine. The aim of the present study was to evaluate the cost-effectiveness of insulin degludec relative to insulin glargine in patients with: type 1 diabetes (T1D), type 2 diabetes receiving basal-only therapy (T2DBOT), and type 2 diabetes receiving basal-bolus therapy (T2DBB) in Denmark.. A short-term (1 year) cost-utility model was developed to model insulin use, non-severe and severe hypoglycemia, and self-monitoring of blood glucose in patients using insulin degludec and insulin glargine from the perspective of a Danish healthcare payer. Where possible, data were derived from Danish patients with diabetes and meta-analyses of clinical trials comparing insulin degludec with insulin glargine. Using these characteristics, the model estimated costs and quality-adjusted life years (QALYs) gained for the two insulin regimens in each of the three diabetes populations.. Insulin degludec dominated insulin glargine (i.e. reduced costs while improving quality-adjusted life expectancy) in patients with T1D and patients with type 2 diabetes using a basal-only insulin regimen. In the T2DBB cohort, insulin degludec was associated with an incremental cost-effectiveness ratio of DKK 221,063 per QALY gained, which would be considered cost-effective at a willingness-to-pay threshold of EUR 30,000 (∼DKK 224,000) per QALY gained. Sensitivity analysis showed that results were most affected by changes in hypoglycemia rate ratio assumptions, but were broadly insensitive to changes in individual input parameters.. Insulin degludec reduces incidence of hypoglycemia and improves quality-of-life in patients with diabetes. Over a 1-year time horizon, insulin degludec resulted in cost savings relative to insulin glargine in T1D and T2DBOT cohorts, while being cost-effective in T2DBB.

Topics: Cost-Benefit Analysis; Denmark; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting

To quantify the annual budget impact if all US commercially insured type 1 diabetes mellitus patients on basal-bolus therapy (T1DM. A short-term (1 year) budget impact model was developed to evaluate the costs of IDeg vs. IGlar in three treatment groups (T1DM. Among T1DM. The results of this analysis suggest that the reduced insulin utilization and fewer hypoglycemic episodes associated with IDeg may translate into reduced costs for payers. The model is limited by simplification of a complex disease state and assumptions surrounding disease state, treatment patterns, and costs. Therefore, results may not accurately reflect actual health plans or real-world practice patterns.

Topics: Budgets; Cost Savings; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Needles; United States

To assess resource utilization associated with severe hypoglycaemia across three insulin regimens in a large phase 3a clinical programme involving people with Type 1 diabetes treated with basal-bolus insulin, people with Type 2 diabetes treated with multiple daily injections and people with Type 2 diabetes treated with basal-oral therapy.. Data relating to severe hypoglycaemia events (defined as episodes requiring external assistance) from the insulin degludec and insulin degludec/insulin aspart programme (15 trials) were analysed using descriptive statistics. Comparators included insulin glargine, biphasic insulin aspart, insulin detemir and sitagliptin. Mealtime insulin aspart was used in some regimens. This analysis used the serious adverse events records, which documented the use of ambulance/emergency teams, a hospital/emergency room visit ≤ 24 h, or a hospital visit > 24 h.. In total, 536 severe hypoglycaemia events were analysed, of which 157 (29.3%) involved an ambulance/emergency team, 64 (11.9%) led to hospital/emergency room attendance of ≤ 24 h and 36 (6.7%) required hospital admission (> 24 h). Although there were fewer events in people with Type 2 diabetes compared with Type 1 diabetes, once a severe episode occurred, the tendency to utilize healthcare resources was higher in Type 2 diabetes vs. Type 1 diabetes. A higher proportion (47.6%) in the basal-oral therapy group required hospital treatment for > 24 h versus the Type 1 diabetes (5.0%) and Type 2 diabetes multiple daily injections (5.3%) groups.. This analysis suggests that severe hypoglycaemia events often result in emergency/ambulance calls and hospital treatment, incurring a substantial health economic burden, and were associated with all insulin regimens.

Topics: Administration, Oral; Adult; Clinical Trials, Phase III as Topic; Cohort Studies; Costs and Cost Analysis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Health Care Costs; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Middle Aged; Severity of Illness Index; Sitagliptin Phosphate

We examined insulin antibody formation in patients with type 1 (T1D) or type 2 diabetes (T2D) treated with once-daily insulin degludec (IDeg) or insulin glargine (IGlar) to evaluate the impact of antibody formation on efficacy and safety. Insulin antibodies were measured using subtraction radioimmunoassays in six phase IIIa clinical trials using IDeg (n = 2250) and IGlar (n = 1184). Spearman's correlation coefficient was used to evaluate associations between cross-reacting antibodies and change from baseline glycated haemoglobin (HbA1c) and insulin dose. IDeg- and IGlar-specific antibodies remained low [<1% bound/total radioactivity (B/T)] and with low levels of antibodies cross-reacting with human insulin in patients with T1D (<20% B/T) and T2D (<6% B/T). Spearman's correlation coefficients between insulin antibody levels and change in HbA1c or insulin dose were low in both treatment groups. No clinically meaningful differences in adverse event (AE) rates were observed in patients with >10% B/T or without an absolute increase in antibodies cross-reacting with human insulin. IDeg treatment resulted in few immunogenic responses in patients with T1D and T2D; antibody formation was not associated with change in HbA1c, insulin dose or rates of AEs.

Topics: Antibody Formation; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunity, Cellular; Insulin Antibodies; Insulin, Long-Acting; Randomized Controlled Trials as Topic

This is first observational prospective study of insulin degludec in routine clinical practice that we evaluated the effect on glycemic control and risk of hypoglycemia in basal-bolus insulin therapy. We found that insulin degludec can maintain glycemic control at a lower insulin dose and frequency of hypoglycemia in type 1 diabetes, while it can improve glycemic control at equally insulin dose in type 2 diabetes. These results mean that insulin degludec is of use in routine clinical practice.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Injections, Subcutaneous; Insulin, Long-Acting; Japan; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome

Topics: Adult; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Spain; Young Adult

The present study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg) in Japanese patients with type 1 diabetes.. This was a randomized, single-center, double-blind, two-period, crossover, multiple-dose trial. Patients were randomized into two treatment sequences, and received IDeg or insulin detemir for 6 days and a washout period (7-21 days) before switching treatment. Blood samples for pharmacokinetic measurements were obtained before each dose and up to 120 h after the last dose of each treatment period. Pharmacodynamic measurements were obtained using a 26-h euglycemic clamp procedure after the last dose of each treatment period.. A total of 22 patients were randomized (14 men, 8 women; mean glycosylated hemoglobin at baseline of 7.5% [based on Japanese Diabetes Society value]). At steady state, total glucose-lowering effect (area under the glucose infusion rate [GIR] curve during one dosing interval [τ, 0-24 h] at steady state [AUCGIR ,τ, SS]) was 1,446 mg/kg and total exposure (geometric mean) of IDeg (AUCID eg,τ, SS) was 81,270 pmol h/L. Both the glucose-lowering effect and the exposure of IDeg were evenly distributed over the dosing interval, with AUC for the first 12-h intervals being approximately 50% of the total (geometric mean; AUCGIR ,0-12h, SS/AUCGIR ,τ, SS = 48%; AUCID eg,0-12h, SS/AUCID eg,τ, SS = 53%).. IDeg has a flat, consistent and ultra-long glucose-lowering effect that is evenly distributed across a 24-h interval and an ultra-long duration of action in Japanese patients with type 1 diabetes. These data support once-daily dosing of IDeg in all patients. Overall, the pharmacodynamic and pharmacokinetic end-points and safety observations are consistent with those previously reported in Caucasian patients.

Topics: Asian People; Blood Glucose; Diabetes Mellitus, Type 1; Female; Hemoglobins; Humans; Insulin, Long-Acting; Japan; Male; Random Allocation; White People

The aim of the present prospective observational study was to assess long-term efficacy and safety of insulin degludec as a part of a basal-bolus therapy for Japanese patients with type 1 or type 2 diabetes in routine clinical practice.. In the present study, 93 type 1 diabetes patients and 135 type 2 diabetes patients treated with insulin glargine or detemir were switched from their basal insulin to insulin degludec. The primary end-points were the changes in glycated hemoglobin (HbA1c) from baseline at 3, 6 and 12 months. The secondary end-points were changes in body mass index, insulin dose, frequency of hypoglycemia and adverse events.. HbA1c levels from baseline were significantly reduced at 3, 6, and 12 months by 0.4, 0.4 and 0.3% in type 1 diabetes patients, respectively, and by 0.5, 0.5 and 0.3% in type 2 diabetes patients, respectively. Body mass index in type 1 diabetes patients increased significantly (P < 0.05), whereas that in type 2 diabetes patients did not change. Basal insulin dose decreased significantly at 3 months after switching (P < 0.05), and returned baseline dose at 12 months in type 1 diabetes and type 2 diabetes patients. The frequency of both total and nocturnal hypoglycemia decreased significantly in type 1 diabetes and type 2 diabetes patients (P < 0.05). The result of multiple regression analysis showed that baseline HbA1c was a significant independent variable of the percentage change in HbA1c with switching.. In both type 1 diabetes and type 2 diabetes patients, switching from insulin glargine or insulin detemir to insulin degludec led to improvement of glycemic control with a significant reduction of hypoglycemia.

Topics: Aged; Asian People; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Japan; Male; Middle Aged; Outpatients; Prospective Studies; Treatment Outcome

The effects of insulin on cardiomyocytes, such as positive inotropic action and glucose uptake are well described. However, in vitro studies comparing long-acting insulin analogues with regard to cardiomyocyte signalling and function have not been systematically conducted.. Insulin receptor (IR) binding was assessed using membrane embedded and solubilised IR preparations. Insulin signalling was analysed in adult rat ventricular myocytes (ARVM) and HL-1 cardiac cells. Inotropic effects were examined in ARVM and the contribution of Akt to this effect was assessed by specific inhibition with triciribine. Furthermore, beating-rate in Cor.4U(®) human cardiomyocytes, glucose uptake in HL-1 cells, and prevention from H2O2 induced caspase 3/7 activation in cardiac cells overexpressing the human insulin receptor (H9c2-E2) were analysed. One-way ANOVA was performed to determine significance between conditions.. Insulin degludec showed significant lower IR affinity in membrane embedded IR preparations. In HL-1 cardiomyocytes, stimulation with insulin degludec resulted in a lower Akt(Ser(473)) and Akt(Thr(308)) phosphorylation compared to insulin, insulin glargine and its active metabolite M1 after 5- and 10-min incubation. After 60-min treatment, phosphorylation of Akt was comparable for all insulin analogues. Stimulation of glucose uptake in HL-1 cells was increased by 40-60 %, with a similar result for all analogues. Incubation of electrically paced ARVM resulted for all insulins in a significantly increased sarcomere shortening, contractility- and relaxation-velocity. This positive inotropic effect of all insulins was Akt dependent. Additionally, in Cor.4U(®) cardiomyocytes a 10-20 % increased beating-rate was detected for all insulins, with slower onset of action in cells treated with insulin degludec. H9c2-E2 cells challenged with H2O2 showed a fivefold increase in caspase 3/7 activation, which could be abrogated by all insulins used.. In conclusion, we compared for the first time the signalling and functional impact of the long-acting insulin analogues insulin glargine and insulin degludec in cardiomyocyte cell models. We demonstrated similar efficacy under steady-state conditions relative to regular insulin in functional endpoint experiments. However, it remains to be shown how these results translate to the in vivo situation.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Mice; Myocytes, Cardiac; Rats; Receptor, Insulin; Signal Transduction

Insulin degludec improved glycemic control in a type 1 diabetes patient undergoing hemodialysis.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Middle Aged; Renal Dialysis; Treatment Outcome

Degludec is an ultralong-acting insulin analogue with a flat and reproducible pharmacodynamic profile. As some patients with type 1 diabetes (T1D) fail to achieve 24-h coverage with glargine or detemir despite twice-daily injections, we studied the effect of switching T1D patients from twice-daily glargine or detemir to degludec.. In this prospective observational study, T1D patients on twice-daily glargine or detemir were enrolled. At baseline and 12 weeks after switching to degludec, we recorded HbA1c, insulin dose, 30-day blood glucose self monitoring (SMBG) or 14-day continuous glucose monitoring (CGM), treatment satisfaction (DTSQ), fear of hypoglycemia (FHS). We included 29 patients (mean age 34 ± 11 years; diabetes duration 18 ± 10 years). After switching to degludec, HbA1c decreased from 7.9 ± 0.6% (63 ± 6 mmol/mol) to 7.7 ± 0.6% (61 ± 6 mmol/mol; p = 0.028). SMBG showed significant reductions in the percent and number of blood glucose values <70 mg/dl and in the low blood glucose index (LBGI) during nighttime. CGM showed a significant reduction of time spent in hypoglycemia, an increase in daytime spent in target 70-180 mg/dl, and a reduction in glucose variability. Total insulin dose declined by 17% (p < 0.001), with 24% reduction in basal and 10% reduction in prandial insulin. DTSQ and FHS significantly improved.. Switching from twice-daily glargine or detemir to once daily degludec improved HbA1c, glucose profile, hypoglycemia risk and treatment satisfaction, while insulin doses decreased. ClinicalTrials.govNCT02360254.

Topics: Adult; Biomarkers; Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Substitution; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Italy; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome; Young Adult

Insulin degludec (IDeg) is a long-acting basal human insulin analog produced using recombinant DNA technology. The insulin structure is modified at the B30 position to allow a di-hexamer conformation in the presence of phenol and zinc.

Topics: Adult; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin, Long-Acting; Male; Middle Aged; Treatment Outcome

Here, we discuss certain practical issues related to use of insulin degludec, a new long-acting basal insulin analogue. Degludec provides uniform ("peakless") action that extends over more than 24 hours and is highly consistent from dose to dose. Like the 2 previously available basal analogues (detemir and glargine), degludec is expected to simplify dose adjustment and enable patients to reach their glycemic targets with reduced risk of hypoglycemia. Phase 3 clinical trials involving type 1 and type 2 diabetes have demonstrated that degludec was noninferior to glargine in allowing patients to reach a target glycated hemoglobin (A1C) of 7%, and nocturnal hypoglycemia occurred significantly less frequently with degludec. In addition, when dosing intervals vary substantially from day to day, degludec continues to be effective and to maintain a low rate of nocturnal hypoglycemia. Degludec thus has the potential to reduce risk of nocturnal hypoglycemia, to enhance the flexibility of the dosing schedule and to improve patient and caregiver confidence in the stability of glycemic control. A dedicated injector, the FlexTouch prefilled pen, containing degludec 200 units/mL, will be recommended for most patients with type 2 diabetes. Degludec will also be available as 100 units/mL cartridges, to be used in the NovoPen 4 by patients requiring smaller basal insulin doses, including most patients with type 1 diabetes.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged

The aim of this study was to evaluate the cost-effectiveness of insulin degludec (IDeg) vs insulin glargine (IGlar) as part of a basal-bolus treatment regimen in adults with T1DM, using a short-term economic model.. Data from two phase III clinical studies were used to populate a simple and transparent short-term model. The costs and effects of treatment with IDeg vs IGlar were calculated over a 12-month period. The analysis was conducted from the perspective of the UK National Health Service. Sensitivity analyses were conducted to assess the degree of uncertainty surrounding the results. The main outcome measure, the incremental cost-effectiveness ratio (ICER), was the cost per quality-adjusted life-year (QALY).. IDeg is a cost-effective treatment option vs IGlar in patients with T1DM on a basal-bolus regimen. The base case ICER was estimated at £16,895/QALY, which is below commonly accepted thresholds for cost-effectiveness in the UK. Sensitivity analyses demonstrated that the ICER was stable to variations in the majority of input parameters. The parameters that exerted the most influence on the ICER were hypoglycemia event rates, daily insulin dose, and disutility associated with non-severe nocturnal hypoglycemic events. However, even under extreme assumptions in the majority of analyses the ICERs remained below the commonly accepted threshold of £20,000-£30,000 per QALY gained.. This short-term modeling approach accommodates the treat-to-target trial design required by regulatory bodies, and focuses on the impact of important aspects of insulin therapy such as hypoglycemia and dosing. For patients with T1DM who are treated with a basal-bolus insulin regimen, IDeg is a cost-effective treatment option compared with IGlar. IDeg may be particularly cost-effective for sub-groups of patients, such as those suffering from recurrent nocturnal hypoglycemia and those with impaired awareness of hypoglycemia.

Topics: Blood Glucose Self-Monitoring; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Models, Econometric; National Health Programs; Needles; Quality-Adjusted Life Years; United Kingdom

Clinical experience of patients is an additional source of information that can inform prescribing decisions for new therapies in practice. In diabetes, for example, patients with recurrent hypoglycemia may be excluded from trials conducted for regulatory purposes. Using insulin degludec (IDeg), a new basal insulin with an ultra-long duration of action as an example, an interim analysis is presented describing whether the decision to prescribe IDeg to patients experiencing treatment-limiting problems on their existing insulin regimes represented good clinical and economic value.. Records from the first 51 consecutive patients with diabetes (35 type 1 [T1D] and 16 type 2 [T2D]) switching to insulin degludec from either insulin glargine (IGlar) or insulin detemir (IDet), mostly due to problems with hypoglycemia (39/51, 76.5%), were reviewed at up to 37 weeks. Patients indicated frequency of hypoglycemia and completed a disease-specific questionnaire reporting six measures of confidence and treatment satisfaction. For the largest group of exposed patents, the T1D module of the IMS Core Diabetes Model (CDM) was used to evaluate the cost-effectiveness of the treatment decision.. HbA1c decreased by 0.5 ± 0.3% points and 0.7 ± 0.3% points for T1D and T2D, respectively. Hypoglycemic events decreased by >90%. Combined mean scores were ≥ 3.7 (1 = much worse, 3 = no change, 5 = much improved) for all six satisfaction and confidence items. In T1D, the treatment decision was highly cost-effective in the CDM lifetime analysis. Even when excluding benefits beyond hypoglycemia reduction, predicted cost per quality-adjusted life-year for IDeg vs IGlar/IDet was £10,754.. These data illustrate the complementary nature of clinical trial and practice data when evaluating the value of therapeutic innovations in diabetes care. There were reductions in patient-reported hypoglycemia, reduced HbA1c, and improved treatment satisfaction in relation to the decision to prescribe IDeg. Initial health economic evaluation suggested that the decision to prescribe IDeg in this phenotypic group of T1D patients represented good value for money.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Male; Middle Aged; Patient Satisfaction; Quality-Adjusted Life Years; Retrospective Studies

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Injections, Subcutaneous; Insulin Glargine; Insulin, Long-Acting

Topics: Adolescent; Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hyperglycemia; Hypoglycemia; Injections, Subcutaneous; Insulin, Long-Acting; Young Adult

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemia; Insulin, Long-Acting

Insulin degludec, a basal insulin with an ultra-long duration of action, became available in Sweden from July 2013. The diabetes team at Danderyd Hospital decided to perform a clinical follow-up of patients with type 1 diabetes switching to insulin degludec to evaluate its clinical performance, using a simple form and available measures, thereby indirectly assessing cost-effectiveness.. This was a prospective, open-label, single-arm, observational, clinical follow-up from August 2013 to February 2015 of consecutive patients who switched to insulin degludec according to predefined indications (i.e., currently administering basal insulin twice daily, unacceptable HbA1c, repeated hypoglycemic events and/or unstable glucose, difficulty with fixed-time administration) in conjunction with professional judgment and patient wishes. Information about HbA1c, insulin dose and frequency of hypoglycemia (self-reported by patient recall) was collected at baseline and repeated after 4-6 months.. In February 2015, data were available on 357 patients. Median time to follow-up was 20 weeks. Mean (SD) HbA1c decreased from 68.9 (15.7) to 65.8 (14.3) mmol/mol, p < 0.0001, and this improvement was achieved despite less insulin. Median reduction of the total insulin dose (basal + prandial) was 12% (interquartile range [IQR] -20% to -3%). The mean (SD) number of self-reported hypoglycemic events in the previous 4 weeks decreased from 8.2 (8.9) to 6.4 (7.6) events, p < 0.0001, and nocturnal hypoglycemic events were reduced from 1.6 (2.9) to 0.7 (2.0) events, p < 0.0001.. Due to improvement in glycemic control, reduction of hypoglycemic events and reduction of insulin dose, we concluded that insulin degludec was clinically useful and economically justifiable for our patients with type 1 diabetes. Not every patient may benefit to the same degree after switching to insulin degludec. Controlled studies are needed to confirm these benefits in a larger sample of real-world patients.

Topics: Adult; Aged; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin, Long-Acting; Male; Middle Aged; Outpatients; Prospective Studies

Topics: Adolescent; Adult; Blood Glucose; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Injections, Subcutaneous; Insulin, Long-Acting

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Approval; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Recombinant Proteins

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin, Long-Acting

Topics: Clinical Trials as Topic; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting

Insulin isophane (NPH) is the standard long-acting human insulin for patients with type 1 and type 2 diabetes. Long-acting human insulin analogues are also available: insulin glargine and insulin detemir. Uncertainties remain concerning their long-term adverse effects. Insulin degludec (Tresiba, Novo Nordisk) is another long-acting human insulin analogue, also approved in the EU for patients with type 1 and type 2 diabetes. It was authorised at a concentration of 100 units per ml, like other insulins, and also at a concentration of 200 units per ml. There are no comparative data on insulin degludec 200 units per ml in patients using high doses of insulin. Insulin degludec has mainly been evaluated in ten randomised, unblinded, "non-inferiority" trials lasting 26 to 52 weeks, nine versus insulin glargine and one versus insulin detemir. Insulin degludec was administered at a fixed time each evening, or in either the morning or evening on alternate days, at varying intervals of 8 to 40 hours between doses. Efficacy in terms of HbA1c control was similar to that of the other insulin analogues administered once a day. The frequency of severe hypoglycaemia was similar in the groups treated with insulin degludec and those treated with the other insulins (10% to 12% among patients with type 1 diabetes and less than 5% in patients with type 2 diabetes). Deaths and other serious adverse events were similarly frequent in the different groups. A meta-analysis of clinical trials, carried out by the US Food and Drug Administration, suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction, stroke and cardiovascular death. Other adverse effects observed in these trials were already known to occur with human insulin and its analogues, including weight gain, hypersensitivity reactions, reactions at the injection site, etc. The trials were too short in duration to assess long-term harms, particularly cancer. Clinical experience with insulin degludec in pregnant women is very limited. It is therefore best to avoid using this analogue during pregnancy. In France, the concentration of all other insulins injected with a syringe or prefilled pen is 100 units per ml. The new concentration of 200 units per ml contained in insulin degludec prefilled pens creates a risk of confusion and overdose. In practice, there is already a relatively wide range of options available for patients with type 1

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Patient Selection; Risk Assessment; Risk Factors; Treatment Outcome

Insulin degludec is a new-generation basal insulin with an ultra-long duration of action. The insulin degludec and insulin degludec/insulin aspart clinical trial programme was truly global, involving 40 different countries and encompassing a multitude of ethnic populations. It is the largest insulin development clinical trial programme on record--with more than 11,000 patients included worldwide. It includes two main components: BEGIN (insulin degludec studied across the spectrum of diabetes) and BOOST (insulin degludec in a fixed-dose combination with insulin aspart). In clinical trials (phase 2 and phase 3a), insulin degludec achieved similar glycaemic control to that seen with insulin glargine in patients with type 1 or 2 diabetes, but with a lower risk of nocturnal hypoglycaemia. In addition, trials examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes show the potential for adjusting the injection time, without compromising glycaemic control or safety. A 200 U/mL formulation of insulin degludec is also available for use in patients who require large volumes of basal insulin. Subcutaneous insulin degludec is generally well tolerated in patients with type 1 or 2 diabetes and represents a useful advance in the treatment of type 1 or 2 diabetes.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypoglycemic Agents; Insulin, Long-Acting

Hypoglycaemia is a key safety concern in diabetes management. It is potentially dangerous and the fear of hypoglycaemia may lead to sub-optimal dosing and inadequate glycaemic control. On the other hand, hypoglycaemia may generate adverse effects and disease complications, will compromise the quality of life and will substantially increase the economic burden of treatment budged. Today, treat to target clinical trial designs are mandate for clinical development of any newer anti-diabetic medication. While similar glycaemic targets are expected to be achieved by test and comparator, the newer molecules are definitely expected to show advantage over standard comparator in terms of reduction in frequency and severity of hypoglycaemia. An ultra-long acting basal analogue insulin degludec (IDeg), has been recently approved for the treatment of type 2 and type 1 diabetes mellitus (T2DM and T1DM). The pooled patient-level data for self-reported hypoglycaemia from seven phase 3a trials with IDeg has shown significantly lower episodes of nocturnal confirmed and numerical low overall confirmed hypoglycaemia with IDeg, compared to Insulin glargine (IGlar), which was more pronounced during maintenance phase of treatment in all populations. The most plausible explanation being that, the flat peakless profile of IDeg with least glycaemic variability leads to less hypoglycaemia and adds to the safety profile of this ultra-long acting insulin. The real life practice will further validate the findings of clinical trials.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Quality of Life

Insulin degludec (IDeg) is a basal insulin with a stable, flat action profile and an even distribution of the blood glucose lowering effect over 24 hou rs. The terminal half-life of IDeg is about 25 hours, which reflects a mean prolongation by factor 2 compared to Insulin glargin (lGlar).This may enable for a more flexible daytime dosing versus up to now available basal insulins.. Two open, randomized, treat-to-target studies enrolled patients with type 1 diabetes (n =493) or type 2 diabetes (n = 687). Both phase 3 studies compared a daytime flexible dosing of IDeg (IDeg-flex) with IDeg at the evening meal (IDeg-evening) and IDler at a fixed daytime. In the IDeg-flex-group dosing intervals were predefined with variations between 8 and 40 hours.. In patients with type 1 diabetes IDeg-flex proved to be non-inferior with respect to reduction of HbA1C (-0.40%) versus IDeg-evening (-0.41%) and IGlar (-0.58%) after 26 weeks. In addition, nocturnal hypoglycemic events were reduced by 40% (p < 0.01) with IDeg-flex versus IGlar. In patients with type 2 diabetes reduction of HbA1C with ID)eg-flex (-1.28%) was non-inferior to IDeg-evening (-1.07%) and IGlar (-1.26%), respectively, whereas rates for hypoglycemia were comparable.. Patients with diabetes mellitus are enabled to dose a basal insulin flexibly when needed (minimum interval of 8 hours after the last injection is necessary). Impacts of this treatment option on quality of life and adherence and outcomes should be examined in observational trials.

Topics: Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin, Long-Acting; Randomized Controlled Trials as Topic

Insulin degludec is a new basal insulin analogue with an ultra-long duration of action that provides a flat and stable action profile with a duration of action greater than 42 hours. Two clinical trials comparing insulin degludec and insulin glargine in basal-bolus therapy have recently been published. Both were 52-week, multicentre, randomised (3:1), treat-to-target trials in patients already using insulin. In both type 1 (n=629) and type 2 diabetes (n=1006), insulin degludec was non-inferior to insulin glargine with respect to reduction in HbA1c at 52 weeks. There were also no significant differences between treatment groups with respect to fasting plasma glucose. At similar levels of glycaemic control, however, insulin degludec was associated with lower rates of hypoglycaemia than insulin glargine. In type 1 diabetes, overall confirmed hypoglycaemia (plasma glucose concentration<3.1 mmol/L or severe episodes requiring assistance) was similar in the two treatment groups, but nocturnal confirmed hypoglycaemia (occurring from 00h01 to 05h59) was 25% lower with insulin degludec (P=0.021). In type 2 diabetes, overall confirmed hypoglycaemia was 18% lower (P=0.0359) and nocturnal confirmed hypoglycaemia was 25% lower (P=0.0399) with insulin degludec. Reductions in hypoglycaemia could reduce physicians' and patients' fears and encourage them to titrate insulin more aggressively, and to adhere more closely to treatment, with consequent better glycaemic control. The results of these trials suggest that insulin degludec has a place in the French clinical setting in basal-bolus therapy in type 1 and type 2 diabetes.

Topics: Clinical Trials, Phase III as Topic; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Randomized Controlled Trials as Topic

Insulin overdose can cause harm due to hypoglycaemia, effects on electrolytes and acute hepatic injury. The established long-acting insulin analogue preparations (detemir and glargine) can present specific management problems because, in overdose, their effects are extremely prolonged, often lasting 48-96 hours. The primary treatment is continuous intravenous 10% or 20% glucose infusion with frequent capillary blood glucose monitoring. Surgical excision of the insulin injection site has been used successfully, even days after the overdose occurred. Once the effects of overdose have receded, diabetes treatment must be restarted with care, especially in patients with type 1 diabetes. Monitoring serum insulin concentration has been successfully used to predict when the effects of the overdose will cease.

Topics: Adult; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Drug Overdose; Electrolytes; Glucose; Humans; Hypoglycemia; Infusions, Intravenous; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Male; Sweetening Agents

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Insulins; Male

To evaluate the annual cost-utility of insulin degludec compared with glargine in patients with: type 1 diabetes (T1D), type 2 diabetes receiving basal-only therapy (T2D-BOT), and type 2 diabetes receiving basal-bolus therapy (T2B-BB) in Sweden.. A cost-utility model was programmed in Microsoft Excel to evaluate clinical and economic outcomes. The clinical trials were designed as treat-to-target, with insulin doses adjusted in order to achieve similar glycemic control between treatments, thus long-term modeling is not meaningful. Basal and bolus insulin doses, incidence of hypoglycemic events, frequency of self-monitoring of blood glucose, and possibility for flexibility in timing of dose administration were specified for each insulin in three diabetes populations, based on data collected in Swedish patients with diabetes and a meta-analysis of clinical trials with degludec. Using these characteristics, the model estimated costs from a societal perspective and quality-adjusted life years (QALYs) in the two scenarios.. Use of degludec was associated with a QALY gain compared with glargine in T1D (0.31 vs 0.26 QALYs), T2D-BOT (0.76 vs 0.69 QALYs), and T2D-BB (0.56 vs 0.47 QALYs), driven by reduced incidence of hypoglycemia and possibility for flexibility around timing of dose administration. Therapy regimens containing degludec were associated with increased costs compared to glargine-based regimens, driven by the increased pharmacy cost of basal insulin, but partially offset by other cost savings. Based on estimates of cost and clinical outcomes, degludec was associated with incremental cost-effectiveness ratios of SEK 19,766 per QALY gained, SEK 10,082 per QALY gained, and SEK 36,074 per QALY gained in T1D, T2-BOT, and T2-BB, respectively.. The hypoglycemic event rates in the base case analysis were derived from a questionnaire-based study that relied on patient interpretation and recall of hypoglycemic symptoms. The relative rates of hypoglycemia with degludec compared to glargine were derived from a meta-analysis of phase III trials, which may not reflect the relative rates observed in real-world clinical practice. Both of these key limitations were explored in one-way sensitivity analyses.. Based on reduced incidence of hypoglycemia and possibility for flexibility around timing of dose administration, use of degludec is likely to be cost-effective compared to glargine from a societal perspective in T1D, T2-BOT, and T2-BB in Sweden over a 1-year time horizon.

Topics: Cost of Illness; Cost-Benefit Analysis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Models, Economic; Quality-Adjusted Life Years; Sweden

Topics: Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Insulin, Long-Acting; Male