insulin-degludec and Hyperglycemia

Insulin degludec/liraglutide (Xultophy(®)), a fixed-ratio combination of an ultra-long-acting insulin analogue and a glucagon-like protein-1 (GLP-1) receptor agonist, is available in the EU for the management of inadequately controlled type 2 diabetes. Once-daily subcutaneous insulin degludec/liraglutide as add-on therapy to oral antidiabetics was effective and generally well tolerated in adults with inadequately controlled type 2 diabetes in several well designed 26-week phase III trials. In insulin-naive patients, add-on insulin degludec/liraglutide provided significantly greater improvements in glycated haemoglobin (HbA1c) levels than add-on insulin degludec, liraglutide or placebo, or unchanged GLP-1 receptor agonists (i.e. liraglutide or exenatide). In the extension of one of these trials, the efficacy of add-on insulin degludec/liraglutide was maintained for a total of 52 weeks. In insulin-experienced patients, add-on insulin degludec/liraglutide was significantly more effective with regard to improvements in HbA1c levels than add-on insulin degludec (at equivalent doses) or ongoing insulin glargine therapy. Add-on insulin degludec/liraglutide was associated with a lower incidence of confirmed hypoglycaemia than add-on insulin degludec in insulin-naive patients or ongoing insulin glargine in insulin-experienced patients, and a lower initial rate of nausea than add-on liraglutide. Thus, once-daily subcutaneous insulin degludec/liraglutide is a useful add-on therapy option for adult patients with inadequately controlled type 2 diabetes.

Topics: Adult; Diabetes Mellitus, Type 2; Drug Combinations; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin, Long-Acting; Liraglutide

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

Topics: Anti-Obesity Agents; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Combinations; Drug Monitoring; Drug Resistance, Multiple; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Metformin; Obesity; Overweight; Weight Gain; Weight Loss

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

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

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

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

The time-course when changes in glycemic control and body weight were first manifest in patients with type 2 diabetes mellitus (T2DM) treated with a combination of insulin degludec and liraglutide (IDegLira) was assessed, comparing IDegLira to its individual components.. Data from weeks 0-12 from two studies were analyzed, one comparing IDegLira to each component (DUAL I), and one comparing IDegLira to insulin degludec titrated to a maximum 50 units (DUAL II). Efficacy endpoints included glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) reduction, proportion of patients achieving HbA1c [<7.0 % (<53.0 mmol/mol)] and FPG (≤7.2 mmol/L) targets, and proportion achieving HbA1c target without hypoglycemia and without hypoglycemia and weight gain.. Mean HbA1c was lower, and the proportion of patients reaching target HbA1c greater, with IDegLira versus comparators (both studies) at weeks 8 and 12. Proportions of patients reaching target HbA1c without hypoglycemia and without hypoglycemia and weight gain were higher for IDegLira versus insulin degludec, though not versus liraglutide. Mean FPG was lower with IDegLira, and the proportion achieving target FPG higher, versus components (both studies) from weeks 4-12. IDegLira was associated with mean weight reduction from weeks 4-12, although less than with liraglutide alone. Hypoglycemia occurred infrequently in weeks 0-12, with no difference in incidence between IDegLira and insulin degludec in either study.. IDegLira reduces plasma glucose to a greater extent than its components, measurable within the first 12 weeks of therapy, and without weight gain or an increased hypoglycemia risk versus insulin degludec.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Liraglutide; Male; Middle Aged; Weight Gain; Weight Loss

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

The variable pathogenesis and progressive nature of type 2 diabetes emphasise the need for new antidiabetic treatments. The long acting glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors have improved the treatment. Novel approaches include inhibitors of sodium glucose co-transporter 2, which increase renal glucose elimination, G-protein-coupled receptor agonists, which potentiate insulin and incretin hormone secretion. Proof of principle has been shown for glucagon receptor agonists, glucokinase activators and treatment with dual intestinal peptides, which all induce weight loss and improve glucose tolerance.

Topics: Benzofurans; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dopamine Agonists; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Peptides, Cyclic; Receptors, G-Protein-Coupled; Receptors, Glucagon; Sodium-Glucose Transporter 2 Inhibitors; Sulfones; Weight Loss