Efficacy and safety of fixed-ratio combination insulin degludec/liraglutide in type 2 diabetes: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The efficacy and safety of fixed-ratio combination insulin degludec/liraglutide (IDegLira) for type 2 diabetes (T2DM) were extensively investigated by the global DUAL trials. However, the evidence on its efficacy and safety in T2DM has not been systematically reviewed. METHODS: Randomized controlled trials published in English that compared IDegLira with placebo or GLP-1 agonists or insulin in patients with T2DM were selected up to December 2022. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between "IDegLira versus Insulin," "IDegLira versus GLP-1RA," and "IDegLira versus Placebo". The risk of potential bias was assessed. RESULTS: In terms of glycaemic efficacy, IDegLira reduced levels of glycated haemoglobin (HbA1c; weighted mean differences (WMDs) 0.52%, 95% CI 0.33%-0.71%); fasting blood glucose (0.32 mg/dL, 0.14-0.50 mg/dL), and the nine-point self-measured plasma glucose (0.25 mmol/L, 0.25-0.36 mmol/L). Furthermore, IDegLira was generally better in the attainment of HbA1c < 7.0% or ≤6.5%, HbA1c < 7.0% or ≤6.5% without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes. In non-glycaemic efficacy aspects, IDegLira decreased systolic blood pressure but elevated heart rate. In terms of safety outcomes, IDegLira did not appear to be associated with a risk of hypoglycaemia (RR 1.23, 0.85-1.78) and nocturnal hypoglycaemia (0.89, 0.52-1.52) occurring when compared with other hypoglycaemic agents or placebo. CONCLUSIONS: IDegLira improves better glycaemic and non-glycaemic outcomes without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes in T2DM. Side effects of IDegLira are mild.

Cost-utility analysis and drug pricing of once-weekly insulin icodec versus once-daily insulin degludec for type 2 diabetes patients treated with basal insulin in China.

AIM: Insulin icodec is a first once-weekly administration basal insulin analogue for type 2 diabetes. This study aimed to investigate the price range of icodec for type 2 diabetes in the Chinese market, taking insulin degludec as reference. MATERIALS AND METHODS: Long-term health outcomes and costs for icodec and degludec were simulated using the United Kingdom Prospective Diabetes Study Outcomes Model (version 2.1) over 40 years from the Chinese healthcare provider's perspective. The efficacy and safety data were obtained from the ONWARDS 2 trial (Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): a phase 3a, randomised, open label, multicentre, treat-to-target trial). Cost-utility analysis and a binary search were used to investigate the price range of icodec. Sensitivity analyses were performed to verify the robustness of the base-case analysis results. RESULTS: After a 40-year simulation, the quality-adjusted life years (QALY) of icodec and degludec were 10.32 and 10.28 years, respectively. At the initial assumption of the same annual costs of icodec and degludec of $455.40, icodec was the dominant therapy compared with degludec, with higher QALYs and lower total cost. After the binary search, we observed that the annual cost range of icodec was $625.17-$855.25. This cost range was finally adjusted to be $597.66-$736.34 using one-way sensitivity analysis and confirmed using probabilistic sensitivity analysis and scenario analysis. The scenario analysis revealed that the annual cost range of icodec could be $506.70-$736.34 if the price of degludec decreased by 20% in the future. CONCLUSION: Insulin icodec appears to be more cost effective than degludec if the annual cost of icodec ranges from $597.66 to $736.34 for patients with type 2 diabetes in China.

The change in Fibrosis-4 index in Japanese patients with type 2 diabetes treated by a fixed-ratio combination therapy of insulin degludec and liraglutide: A retrospective observational study.

AIM: The efficacy of titratable fixed-ratio combination therapy by a combination preparation of insulin degludec and liraglutide (IDegLira) in Japanese patients with type 2 diabetes, focusing particularly on the change in Fibrosis-4 index (FIB-4), a noninvasive method for the evaluation of liver fibrosis, was investigated. METHODS: As the full analysis set, 113 patients were treated with IDegLira. The patients were categorized into two groups according to the absence (GLP-1RA-naïve group, n = 72) or presence (GLP-1RA-treated group, n = 41) of glucagon-like peptide-1 receptor agonist (GLP-1RA) use before starting IDegLira. The clinical parameters were retrospectively determined over 6 months. RESULTS: The glycated hemoglobin value was significantly reduced in both groups. The bodyweight significantly decreased from 67.4 ± 11.0 kg at baseline to 66.4 ± 11.6 kg at 6 months in the GLP-1RA-naïve group, although it slightly increased in the GLP-1RA-treated group. FIB-4 significantly decreased from 1.60 ± 0.84 at baseline to 1.49 ± 0.74 at 6 months in the GLP-1RA-naïve group. Although FIB-4 significantly increased in the GLP-1RA-treated group, it remained within the low-risk level for liver fibrosis. CONCLUSION: Fixed-ratio combination therapy using IDegLira for the treatment of type 2 diabetes is useful for glycemic control and weight management. In particular, IDegLira may be more effective for lowering FIB-4 than adding unused oral antidiabetic agents or increasing the dose of insulin in GLP-1RA-naïve patients.

Initiating or switching to insulin degludec/insulin aspart in a real-world population of adults with type 2 diabetes in Australia: results from a prospective, non-interventional study.

BACKGROUND: Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec and insulin aspart for the treatment of people with diabetes and suboptimal glycaemic control. Few real-world studies of IDegAsp treatment have been conducted. Here, we report results from the Australian cohort of the global ARISE study of real-world IDegAsp use. AIMS: To investigate glycaemic control and other clinical outcomes in people with type 2 diabetes (T2D) treated with IDegAsp in a real-world setting in Australia. METHODS: A total of 183 adults with T2D initiating or switching to IDegAsp in the Australian cohort of the open-label, non-interventional ARISE study were followed for 26-36 weeks from August 2019 to December 2020. RESULTS: IDegAsp was associated with significant reductions from baseline to end of study (EOS) in mean glycated haemoglobin (estimated change -0.8% (95% confidence interval (CI): -1.05 to -0.56; P < 0.0001)), fasting plasma glucose (-1.6 mmol/L (95% CI: -2.49 to -0.63; P = 0.0017)) and body weight (-2.6 kg (95% CI: -3.68 to -1.55; P < 0.0001)). In insulin-experienced patients, the mean total daily insulin dose did not change significantly (estimated change from baseline to EOS 3.8 (95% CI: -3.70 to 11.21; P = 0.3202)). The proportion of patients experiencing hypoglycaemia numerically decreased during the study (non-severe: 14.2-10.9%; nocturnal non-severe: 4.9-2.2%; and severe: 2.2-0%). CONCLUSIONS: Initiating or switching to IDegAsp in a real-world population of people with T2D in Australia was associated with significant improvements in glycaemic control and body weight, and numerically lower levels of hypoglycaemia compared with baseline.

Glycaemic control, risk of hypoglycaemia and all-cause mortality in new users of second-generation basal insulin with type 2 diabetes and chronic kidney disease: a nationwide register-based cohort study.

AIMS/HYPOTHESIS: The aim of this study was to compare the performance of the second-generation basal insulins, insulin degludec 100 U/ml (Deg-100) and insulin glargine 300 U/ml (Gla-300), in terms of change in HbA1c, hospitalisation for hypoglycaemia and all-cause mortality among individuals with type 2 diabetes and concurrent chronic kidney disease. METHODS: This register-based cohort study, based on the entire Danish diabetes population, included 6519 new users of Deg-100 and Gla-300 with type 2 diabetes and moderate to end-stage chronic kidney disease. HbA1c trajectories, from initiation of either Deg-100 (2013) or Gla-300 (2015) to end of follow-up (2020), were modelled with mixed-effect models while rates of hospitalisation for hypoglycaemia and all-cause mortality were modelled in separate models using Poisson likelihood. RESULTS: Of the 6519 (44% women) individuals included in the study, 3747 were exposed to Deg-100 and 2772 to Gla-300. Both mean (SD) type 2 diabetes duration (14.4 [6.6] years vs 15.2 [6.7] years) and median (IQR) chronic kidney disease duration (2.3 [1.3, 3.9] years vs 2.8 [1.6, 4.6] years) were significantly shorter in the Gla-300 group. The median (IQR) follow-up time was similar between groups: 1.0 (0.5-1.6) year for Gla-300 and 1.0 (0.3-1.5) year for Deg-100. In both groups mean HbA1c levels were reduced by 13-14 mmol/mol (1.2-1.3%) from initiation to end of follow-up, with the largest reduction (of 8-9 mmol/mol [0.7-0.8%]) occurring during the first year. There was no significant difference in HbA1c reduction between Deg-100 and Gla-300. Both the rate of hospitalisation for hypoglycaemia (rate ratio 1.02 [95% CI 0.70, 1.49], Deg-100 vs Gla-300) and the rate of all-cause mortality (rate ratio 0.98 [95% CI 0.84, 1.15], Deg-100 vs Gla-300) were similar between the groups. CONCLUSIONS/INTERPRETATION: We found no difference in HbA1c reduction, hospitalisation for hypoglycaemia or all-cause mortality between Gla-300 and Deg-100 in a real-world population of new users with type 2 diabetes and moderate to end-stage chronic kidney disease. Therefore, we conclude that these two treatment options are equally effective and safe in this vulnerable population.

Cost-effectiveness analysis of once-daily insulin glargine 300 U/mL versus insulin degludec 100 U/mL using the BRAVO diabetes model.

AIMS: A cost-effectiveness analysis was conducted to compare insulin glargine 300 U/mL (Gla-300) versus insulin degludec 100 U/mL (IDeg-100) in insulin-naïve adults with type 2 diabetes (T2D) sub-optimally controlled with oral anti-diabetic drugs (OADs). METHODS: The BRAVO diabetes model was used to assess costs and outcomes for once-daily Gla-300 versus once-daily IDeg-100 from a US healthcare sector perspective. Baseline clinical data were based on BRIGHT, a 24-week, non-inferiority, randomised control trial comparing Gla-300 and IDeg-100 in adults with T2D sub-optimally controlled with OADs (with or without glucagon-like peptide-1 receptor agonists). Treatment costs were based on doses observed in BRIGHT as well as net prices. Costs associated with complications were based on published literature. Lifetime costs (US$) and quality-adjusted life-years (QALYs) were predicted and used to calculate incremental cost-effectiveness ratio estimates; extensive scenario and sensitivity analyses were conducted. RESULTS: Overall lifetime medical costs were estimated to be $327,904 and $330,154 for people receiving Gla-300 and IDeg-100, respectively; insulin costs were $43,477 and $44,367, respectively. People receiving Gla-300 gained 8.024 QALYs and 18.55 life-years, while people receiving IDeg-100 gained 7.997 QALYs and 18.52 life-years. Because Gla-300 was associated with a cost-saving of $2250 and 0.027 additional QALYs, it was considered to be dominant compared with IDeg-100. Results of the scenario and sensitivity analyses confirmed the robustness of the base case results. CONCLUSION: Gla-300 was the dominant treatment option compared with IDeg-100 based on the willingness-to-pay threshold of $50,000/QALY. Results remained robust against a wide range of alternative assumptions on key parameters.

Comparative efficacy and safety of Gla-300 versus IDegAsp in insulin-naïve people with type 2 diabetes mellitus uncontrolled on oral anti-diabetics.

AIM: To compare the efficacy and safety of insulin glargine-300 once daily (Gla-300) with insulin degludec/aspart (IDegAsp) once daily in patients with type 2 diabetes (T2D) inadequately controlled on oral anti-diabetic drugs (OADs). MATERIALS AND METHODS: A systematic literature review of randomized controlled trials was followed by an indirect treatment comparison of studies involving insulin naïve adults, inadequately controlled [glycated haemoglobin (HbA1c) ≥7.0%] on OADs, who received Gla-300 or IDegAsp once daily. Outcomes of interest were change in HbA1c, blood glucose, weight and insulin dose, as well as incidence and event rate of hypoglycaemia and other adverse events. RESULTS: Four trials with broadly similar baseline patient characteristics were included in the meta-analyses and indirect treatment comparison. At 24-28 weeks, the indirect comparison of Gla-300 to IDegAsp once daily estimated no statistically significant difference for change in HbA1c (%) from baseline [mean difference of 0.10% (95% CI: -0.20, 0.39; p = .52)]; a statistically significant mean difference of -1.31 kg (95% CI: -1.97, -0.65; p < .05) for change in body weight from baseline; statistically significant odds ratios of 0.62 (95% CI: 0.41, 0.93; p < .05) for incidence of any hypoglycaemia; and 0.47 (95% CI: 0.25, 0.87; p < .05) for incidence of anytime confirmed hypoglycaemia (plasma glucose <3.0-3.1 mmol/L). No significant differences were observed for insulin dose and adverse events. CONCLUSION: In insulin-naïve patients with T2D inadequately controlled on OADs, commencing Gla-300 shows a comparable HbA1c reduction, but with significantly less weight gain and a lower incidence of any and confirmed hypoglycaemia compared with commencing IDegAsp.

Direct Assessment of Oligomerization of Chemically Modified Peptides and Proteins in Formulations using DLS and DOSY-NMR.

PURPOSE: Protein higher order structure (HOS) including the oligomer distribution can be critical for efficacy, safety and stability of drug products (DP). Oligomerization is particularly relevant to chemically modified protein therapeutics that have an extended pharmacokinetics profile. Therefore, the direct assessment of protein oligomerization in drug formulation is desired for quality assurance and control. METHODS: Here, two non-invasive methods, dynamic light scattering (DLS) and diffusion ordered spectroscopy (DOSY) NMR, were applied to measure translational diffusion coefficients (Ddls and Dnmr) of proteins in formulated drug products. The hydrodynamic molecular weights (MWhd), similar to hydrodynamic size, of protein therapeutics were derived based on a log(Ddls) vs log(MWhd) correlation model established using protein standards. RESULTS: An exponent value of -0.40 ± 0.01 was established for DLS measured log(D) vs. log(MWhd) using protein standards and a theoretical exponent value of -0.6 was used for unstructured polyethylene glycol (PEG) chains. The analysis of DLS derived MWhd of the primary species showed the fatty acid linked glucagon-like peptide 1 (GLP-1) was in different oligomer states, but the fatty acid linked insulin and PEG linked proteins were in monomer states. Nevertheless, equilibrium and exchange between oligomers in formulations were universal and clearly evidenced from DOSY-NMR for all drugs except peginterferon alfa-2a. CONCLUSION: The correlation models of log(D) vs. log(MWhd) could be a quick and efficient way to predict MWhd of protein, which directly informs on the state of protein folding and oligomerization in formulation.

Direct comparison two fixed-ratio combination glucagon-like peptide receptor agonist and basal insulin on glycemic and non glycemic parameters in type 2 diabetes.

BACKGROUND: Two types of fixed-ratio combinations of basal insulin and a glucagon-like peptide-1 receptor agonist (GLP-1RA) have been approved for use in type 2 diabetes. One is insulin degludec/liraglutide (iDergLira), and the other is insulin glargine/lixisenatide (iGlarLixi). Direct comparisons between these two combination is not available. METHODS: The retrospective study included 186 patients with type 2 diabetes mellitus (DM) with inadequate glycemic control on metformin and basal insulin (degludec, glargine 100, glargine 300) who were switched to fixed-ratio combination GLP-1 RA and basal insulin. Patients were divided into two groups based on the basal insulin before study: group I (n = 86) treated with degludec were switched to iDegLira and patients group II (n = 99), treated with glargine were switched to iGlarLixi. The aim of this study was to directly compare the effects between two fixed - ratio combination on glycemic parameters and non glycemic parameters. Follow up was 6 months. RESULTS: Mean HbA1c decreased similarly (- 1.2% vs.-1.1%). Higher percentage patients in iDegLira group had reached the HbA1c < 7% after 6 months (22% vs. 18.2%, p < 0.05). The mean change in fasting plasma glucose (FPG) was comparable for the two groups, while mean decrease postprandial plasma glucose (PPG) level were lower in iGlarLixi group (2 vs 1.8 mmol/l, p > 0.05). Change in body weight was significant in iDegLira group (1.8 kg vs. 0.7 kg, p < 0.001). At the end of the study patients showed decrease in total cholesterol (TC) and low-density lipoprotein (LDL) for 0.2 mmol/L in iDegLira, 0.1 mmol/l in iGlarLixi, triglycerides decreased 0.3 mmol/l in both groups, high-density lipoprotein(HDL) increased 0.1 mm/l in iGlarLixi. CONCLUSION: Our results showed that more patients with iDegLira had HbA1c less than 7% and these combination had better effect on weight loss. There was no difference observed in FPG and PPG, lipid profile and rate of hypoglycemia.

The efficacy of insulin degludec and insulin glargine over NPH insulin among toddlers and preschoolers with type 1 diabetes using glycemic variability and time in range.

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. CONCLUSION: 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. WHAT IS KNOWN: • Insulin therapy is the mainstay of T1D management. • Optimal insulin therapy for young children with T1D should provide effective glycemic. WHAT IS NEW: • 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.

Basal Insulin Degludec and Glycemic Control Compared to Aspart Via Insulin Pump in Type 1 Diabetes (BIGLEAP): A Single-Center, Open-Label, Randomized, Crossover Trial.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: We observed similar glycemic control between IDeg and insulin aspart via CSII for basal insulin coverage in patients with well-controlled type 1 diabetes.

Comparative efficiency and safety of insulin degludec/aspart with insulin glargine in type 2 diabetes: a meta-analysis of randomized controlled trials.

Recent studies have found compared with insulin glargine (IGlar), insulin degludec/aspart (IDeg/Asp) may provide adequate glycemic control and prevent hypoglycemia events in type 2 diabetes mellitus (T2DM). Consequently, we performed a meta-analysis to appraise and compare the efficiency and safety of IDeg/Asp and IGlar in the treatment of T2DM. We sought the databases including PubMed, Embase, Scopus, Cochrane library to confirm related articles which inspected the effect of IDeg/Asp versus IGlar for the treatment of T2DM until May 2021. Finally, six randomized controlled trials (RCTs) of 1,346 patients were included. The results showed that IDeg/Asp significantly decreased the mean hemoglobin A1c (HbA1c) level but was prone to serious adverse events, and IGlar increased the nocturnal confirmed hypoglycemia events. Besides, there were no significant changes in other indicators, including mean fasting plasma glucose (FPG) level, nine-point self-measured plasma glucose (SMPG) level, and adverse events. What's more, we found that there was no significant difference in the occurrence of hypoglycemia overall, but our subgroup analysis of confirmed hypoglycemia revealed the population in this subgroup (duration of diabetes ≤11 years) might has its particularity effecting the hypoglycemia outcome. Concerning efficiency, IDeg/Asp may have advantages in controlling the mean HbA1c level. Regarding safety, IGlar might increase the risk of nocturnal confirmed hypoglycemia. Further evidence is needed to compare better the efficiency and safety of IDeg/Asp versus IGlar therapy.

Simultaneous quantitative determination of insulin aspart and insulin degludec in human plasma using simple shoot LC method.

Combining short-acting and long-acting insulin analogs was a real challenge that was overcome by NovoNordisk through the co-formulation of insulin aspart and insulin degludec in single-dosage form. The proposed study provides a simple, short, and reliable HPLC method with diode array detection that is developed and validated for the simultaneous determination of insulin aspart and insulin degludec in human plasma. The proposed method achieved good separation between the two analytes utilizing a C8 column at 35°C in a very short run time (6 min), with a simple, low-cost, and reliable extraction method through precipitation of plasma protein. Gradient elution was applied using a mobile phase consisting of 0.1 M sodium sulfate (pH 3.4) and acetonitrile. The method was validated according to EMA Guideline on Bioanalytical Validation. The proposed method had a linear range from 3.0 to 300 µg/mL for insulin aspart and from 3.5 to 300 µg/mL for insulin degludec. The intra- and inter-day precision of insulin aspart were 0.36-3.33% and 1.59-8.84%, respectively, and accuracy was between 10.06 and 3.09% The intra- and inter-day precision of insulin degludec were 0.29-1.93% and 0.89-5.14%, respectively, and accuracy was between -5.29 and 3.91%.

[Switching insulin degludec to insulin glulisine improved nocturnal hypoglycemia and ventricular arrythmia in an elderly type 1 diabetes patient with chronic heart failure: A case report].

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.

Oligomerization of Pharmaceutically Relevant Insulin Analogues for Varying Concentration and Salinity Revealed by Small-Angle X-ray Scattering.

Two different insulin analogues, insulin degludec and lithocholyl insulin, were studied by small-angle X-ray scattering with respect to their self-assembly and interactions in solution at different concentrations of insulin and salt, NaCl. Very different behavior was observed for the two. Insulin degludec, linked to a hexadecanedioic acid, consistently formed di-hexamers, without any further oligomeric growth upon screening of electrostatic repulsions, indicating a stable di-hexamer unit without further oligomerization, as expected in the presence of phenol. The other insulin analogue, linked to the sterol lithocholic acid, formed n-hexamers with n ranging from 1 to 15, increasing with NaCl concentration and insulin concentration, indicating attractive forces in competition with the electrostatic repulsion and solution entropy. At the highest concentration of insulin and NaCl, a liquid crystal phase was observed, which has not previously been identified, featuring a quadratic structure organized into layers, which might hold interesting properties for pharmaceutical applications.

DUAL II China: Superior HbA1c reductions and weight loss with insulin degludec/liraglutide (IDegLira) versus insulin degludec in a randomized trial of Chinese people with type 2 diabetes inadequately controlled on basal insulin.

AIM: To assess the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec (degludec) in Chinese people with type 2 diabetes (T2D) treated with basal insulin. MATERIALS AND METHODS: In DUAL II China, a randomized, double-blinded, multicentre, treat-to-target trial, Chinese adults with T2D and HbA1c of 7.5% or more on basal insulin and metformin, with or without other oral antidiabetic drugs (OADs), were randomized 2:1 to 26 weeks of treatment with either IDegLira (max. dose 50 U degludec/1.8 mg liraglutide) or degludec (max. 50 U/day), respectively, combined with metformin. At 26 weeks, superiority of IDegLira over degludec was assessed for change in HbA1c (primary endpoint), and body weight and number of severe or blood glucose (BG)-confirmed hypoglycaemic episodes (confirmatory secondary endpoints). RESULTS: Overall, 453 participants were randomized to IDegLira (n = 302) or degludec (n = 151). Superiority was confirmed for IDegLira over degludec in HbA1c change (-1.9% vs. -1.0%, respectively, estimated treatment difference [ETD] [95% confidence interval]: -0.92% [-1.09; -0.75], P < .0001), body weight change (-0.7 vs. +0.4 kg, respectively, ETD [95% CI]: -1.08 kg [-1.63; -0.52], P = .0002) and severe or BG-confirmed hypoglycaemia (estimated rate ratio [95% CI]: 0.53 [0.30; 0.94], P = .0297). The odds of achieving HbA1c less than 7.0% without hypoglycaemia and/or weight gain were greater with IDegLira than degludec (P < .0001 for all). Daily insulin dose at 26 weeks was lower for IDegLira (34.3 U) than degludec (37.4 U) (P = .0014). No unexpected safety signals were observed. CONCLUSIONS: IDegLira may be an efficacious and well-tolerated treatment intensification option for Chinese people with T2D uncontrolled on basal insulin and OADs.

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

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

Quality of life in patients with type 2 diabetes after switching to insulin degludec: results from a cross-sectional survey.

PURPOSE: Five quality of life (QoL) domains are particularly important to patients with type 2 diabetes (T2D) using basal insulin-sense of physical well-being, sense of safety regarding hypoglycemia, sense of diabetes as burdensome, feelings of freedom and flexibility, and sleep quality. METHODS: An online survey assessed these QoL domains in adult patients with T2D in the USA who had switched from a previous basal insulin to insulin degludec (IDeg): modified versions of the World Health Organization (Five) Well-Being Index (WHO-5), Hypoglycemia Attitudes and Behavior Scale (HABS; confidence and anxiety subscales only), and Diabetes Distress Scale (DDS; emotional burden and regimen-related distress subscales only); three items assessing feelings of freedom and flexibility; and one item assessing sleep quality (hours of restful sleep). Patients rated each item for their previous basal insulin and currently while using IDeg. Correlations between sleep quality and the other QoL scales were also assessed. RESULTS: In total, 152 patients completed the survey and were included in the study sample. Patients reported significantly improved scores while using IDeg on all WHO-5, DDS, HABS, feelings of freedom and flexibility item scores, and total raw/mean subscale scores (P < 0.0001). Patients also reported a significantly greater number of hours of restful sleep [mean (SD) 6.6 (2.0) vs. 5.5 (1.8); P < 0.0001]. Better sleep quality statistically significantly correlated with improved QoL in all other domains assessed. CONCLUSIONS: Treatment with IDeg after switching from a previous basal insulin was associated with statistically significant improvements in all QoL domains assessed.

Insulin degludec and glutamine dipeptide modify glucose homeostasis and liver metabolism in diabetic mice undergoing insulin-induced hypoglycemia.

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.

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial.

AIMS/HYPOTHESIS: A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin. METHODS: This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0-5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period. RESULTS: Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300. CONCLUSIONS/INTERPRETATION: There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300. TRIAL REGISTRATION: ClinicalTrials.gov NCT03078478 FUNDING: This trial was funded by Novo Nordisk (Bagsvaerd, Denmark).