Continuous Glucose Monitoring-Derived Glucometrics in Adults with Type 1 Diabetes When Switching Basal Insulins.

Context: Limited evidence is available on the real-world effect of insulin degludec (IDeg) in type 1 diabetes (T1D), using continuous glucose monitoring (CGM)-derived metrics. Objective: To assess the real-world effect of switching to IDeg from other long-acting insulins on time in ranges (TIRs) measured by CGM, metabolic control, and insulin dose for people with T1D. Design: This retrospective multicenter study encompassed five time points during a 12-month pre-switch of IDeg and a 12-month follow-up period. For each visit, clinical and CGM data were collected to evaluate temporal trends in glycemic outcomes. Participants: Of 753 persons with T1D who were assessed for eligibility, 486 persons were included, mostly men (61.5%), 47.4 (16.9) years old and diabetes duration of 23.8 (14.2) years at IDeg-initiation. Main Outcome Measure: Primary outcome was the evolution of percent TIR (70-180 mg/dL or 3.9-10.0 mmol/L, TIR) before versus after switch to IDeg. Results: TIR over 24 h increased at 12 months versus baseline (56.7% vs. 52.3%, P < 0.001), mostly during daytime. Time <54 mg/dL (<3.0 mmol/L) over 24 h decreased at 12 months versus baseline (2.02% vs. 2.86%, P < 0.001), mostly during nighttime. Glycated hemoglobin (7.9% vs. 8.1%, P < 0.001) and coefficient of variation (40.0% vs. 41.5%, P < 0.001) improved at 12 months versus baseline. Mean daily basal, bolus and total insulin doses decreased at 12 months (P < 0.001 for all vs. baseline). Conclusions: This retrospective real-world study reports that switching basal insulin significantly improved time spent in glucometric ranges and glycemic variability in the studied population of people with T1D. Clinical Trial Registration number: NCT05434559.

Effectiveness of insulin degludec/liraglutide versus insulin degludec/insulin aspart in Japanese patients with type 2 diabetes.

Aims: To evaluate and compare the effectiveness of once-daily insulin degludec/liraglutide (IDegLira) to that of once-daily insulin degludec/insulin aspart (IDegAsp) after switching from basal insulin therapy at 6 months by assessing changes in hemoglobin A1c (HbA1c), body weight, and insulin doses in patients with type 2 diabetes (T2D). Materials and methods: A total of 91 patients with T2D with HbA1c levels exceeding 7.0% were included in this study. Adjusted least square mean changes in HbA1c, body weight, and total insulin doses were compared between the IDegLira group and IDegAsp group. Subgroup analyses were performed, stratified by median values of HbA1c (< 8.5 and ≥ 8.5%), obesity (body mass index < 25 and ≥ 25 kg/m2), and basal insulin doses (< 14 and ≥ 14 units) at baseline to assess treatment interaction by subgroup. Results: The IDegLira group showed a greater reduction in HbA1c levels than the IDegAsp group (- 0.17 vs - 0.79%, p = 0.003) with comparable body weight changes. The analyses of adjusted mean changes of total insulin doses showed that the IDegAsp group had a larger increase than the IDegLira group (3.64 vs 1.30 unis, p = 0.016). The effect of IDegLira on HbA1c levels was superior to that of IDegAsp in patients with high HbA1c. There were no inter-group differences in the rate of hypoglycemic episodes. Conclusions: Once-daily IDegLira had greater effects on HbA1c and a lesser increase in insulin doses than IDegAsp when patients are switched from basal insulin therapy. Moreover, the effect on HbA1c was enhanced in patients with high HbA1c levels at baseline.

The Short-Term Cost-Effectiveness of a Fixed-Ratio Combination of Insulin Degludec and Aspart: A Cost of Control Analysis in Australia and India.

OBJECTIVES: The real-world ARISE study demonstrated initiation of fixed-ratio combination insulin degludec and aspart (IDegAsp) led to improvements in people achieving key glycemic control targets compared with prior therapies in Australia and India. This study evaluated the short-term cost-effectiveness of IDegAsp in these countries, in terms of the cost per patient achieving these targets. METHODS: A model was developed to evaluate the cost of control (treatment costs divided by the proportion of patients achieving each target) of IDegAsp versus prior therapies received in ARISE for 2 endpoints: glycated hemoglobin (HbA1c) <7.0%, and HbA1c less than a predefined individual treatment target. Costs, expressed from a healthcare payer perspective, were captured in 2022 Australian dollars (AUD) and 2022 Indian rupees (INR). RESULTS: The number of patients needed to treat to bring one to endpoints of HbA1c <7.0% and less than an individualized target with IDegAsp was 51% and 87% lower, respectively, than with prior therapies in Australia, and 52% and 66% lower, respectively, versus prior therapies in India. Cost of control was AUD 2449 higher and AUD 64 863 lower with IDegAsp versus prior therapies for endpoints of HbA1c <7.0% and less than an individualized target, respectively, in Australia and INR 211 142 and INR 537 490 lower with IDegAsp compared with prior therapies in India. CONCLUSIONS: IDegAsp was estimated to be cost-effective versus prior therapies when considering an individualized HbA1c target in Australia, and when considering an individualized HbA1c target and HbA1c <7.0% in India.

Efficacy and Safety of IDegAsp in a Real-World Korean Population with Type 2 Diabetes Mellitus.

Background: This study investigated the real-world efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in Korean adults with type 2 diabetes mellitus (T2DM), whose insulin treatment was switched to IDegAsp. Methods: This was a multicenter, retrospective, observational study comprising two 26-week treatment periods, before and after switching to IDegAsp, respectively. Korean adults with uncontrolled T2DM treated with basal or premix insulin (±oral antidiabetic drugs) were enrolled. The primary objective was to compare the degree of glycosylated hemoglobin (HbA1c) change in each 26-week observation period. The analyses included changes in HbA1c, fasting plasma glucose (FPG), body weight, proportion of participants achieving HbA1c <7.0%, hypoglycemic events, and total daily insulin dose (ClinicalTrials.gov, number NCT04656106). Results: In total, 196 adults (mean age, 65.95 years; mean T2DM duration, 18.99 years) were analyzed. The change in both HbA1c and FPG were significantly different between the pre-switching and the post-switching period (0.28% vs. -0.51%, P<0.001; 5.21 mg/dL vs. -23.10 mg/dL, P=0.005), respectively. After switching, the rate of achieving HbA1c <7.0% was significantly improved (5.10% at baseline vs. 11.22% with IDegAsp, P=0.012). No significant differences (before vs. after switching) were observed in body weight change, and total daily insulin dose. The rates of overall and severe hypoglycemia were similar in the two periods. Conclusion: In real-world clinical practice in Korea, the change of insulin regimen to IDegAsp was associated with an improvement in glycemic control without increase of hypoglycemia, supporting the use of IDegAsp for patients with T2DM uncontrolled with basal or premix insulin.

The effect of insulin analogs in people with type 1 diabetes at increased risk of severe hypoglycemia.

Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins.

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.

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.

Retrospective Study of IDegLira, a New Fixed-Ratio Combination, in Japanese Patients With Type 2 Diabetes Mellitus: Analysis of Background Factors Affecting Effectiveness After 6 Months of Treatment.

Background: The aim of the study was to provide real-world data on the effectiveness and safety of a new fixed-ratio combination, insulin degludec/liraglutide (IDegLira) injection in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: The primary endpoint was the change in glycated hemoglobin (HbA1c) level 6 months after the introduction of IDegLira. We also examined the rate of achievement of target HbA1c 7% and the individualized HbA1c targets set for each patient. Baseline characteristics associated with the change in HbA1c were also assessed. Seventy-five patients with T2DM were included in the analysis. Results: After the initiation of IDegLira, HbA1c decreased significantly from baseline with a change of -1.81% (baseline 9.61% and at 6 months 7.80%; P < 0.001). At baseline, the achievement rate of 7% HbA1c was 2.67% (n = 2), which increased to 36.0% (n = 27) after 6 months of IDegLira introduction (P < 0.05). The attainment rate of individualized HbA1c targets, which were set considering each patient's characteristics, improved from 2.67% (n = 2) to 49.3% (n = 37) (P < 0.001). Regardless of sex, body mass index, estimated glomerular filtration rate, duration of diabetes, or history of glucagon-like peptide-1 receptor agonist use, IDegLira significantly reduced HbA1c, but a higher C-peptide index was associated with a greater reduction in HbA1c. Conclusion: In this study, initiation of IDegLira in a real-world clinical setting was beneficial in lowering HbA1c in Japanese T2DM patients with inadequate glycemic control with existing therapy.

A phase-I randomized euglycemic clamp study to demonstrate the pharmacokinetic and pharmacodynamic equivalence of an insulin degludec biosimilar (B01411) with the reference product in healthy Chinese volunteers.

BACKGROUND: B01411 is a biosimilar candidate manufactured by Jilin Huisheng Biopharmaceutical Co. Ltd for the reference insulin degludec (Tresiba) (IDeg). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of the two IDeg products and to assess the PK/PD similarity of B01411 compared with the reference IDeg product. RESEARCH DESIGN & METHODS: A single-center, single-dose, randomized, crossover, open-labeled, phase I, euglycemic clamp study in healthy Chinese subjects to examine the bioequivalence of B01411 (0.4 U/kg) compared with the reference IDeg product. Blood samples were collected at a predefined time for the analysis of blood glucose (BG), IDeg, and C-peptide concentrations. The glucose infusion rate (GIR) was adjusted to maintain the BG at approximately 0.28 mmol/L below baseline throughout the clamp. RESULTS: Thirty-two subjects (20 males and 12 females) were enrolled, 31 of whom received both treatments. The 90% confidence intervals for the ratio of the least-squares geometric means for AUCIDeg,0-24 h, AUCGIR,0-24 h, IDegmax, and GIRmax were all in the range of 0.80-1.25. Only one adverse event of puncture site bruising occurred once in a subject in the B01411 group. CONCLUSION: B01411 exhibited a pharmacokinetic and pharmacodynamic similarity to the reference product. Both IDeg products were well tolerated. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn/index.html#. Identifier is CTR20192122.

Functional insulin aspart/insulin degludec-based microneedles for promoting postprandial glycemic control.

Insulin aspart (IAsp) and insulin degludec (IDeg), as the third generation of insulin, have a faster onset time or a more durable action period, which may simulate the secretion of insulin under physiological conditions. Microneedles (MNs) are transdermal delivery devices that may allow diabetic patients to easily deploy transdermal insulin therapy while considerably reducing injection pain. In this study, we investigated the combination of dissolving MNs with IAsp or IDeg therapy as an alternative to daily multiple insulin injections, aiming to improve glycemic control and patient compliance. Mechanical properties of the MNs, structural stability of insulin encapsulated in the MNs, and transdermal application characteristics were studied to assess the practicality of insulin-loaded MNs for diabetes therapy. In vivo experiments conducted on diabetic rats demonstrated that the IAsp- and IDeg-loaded MNs have comparable blood glucose control abilities to that of subcutaneous injections. In addition, the therapeutic properties of insulin-loaded MNs under diverse dietary conditions and application strategies were further investigated to provide new information to support future clinical trials. Taken together, the proposed MNs have the potential to improve balances between glycemic control, hypoglycemia risk, and convenience, providing patients with simpler regimens. STATEMENT OF SIGNIFICANCE: 1. The fabricated functional insulin-loaded dissolving microneedles closely matched the glucose rise that occurs in response to meals, demonstrating promising alternatives for multiple daily insulin injections. 2. The hypoglycemic properties of insulin microneedles were investigated under diverse dietary conditions and application strategies, yielding new information to support future clinical trials. 3. Molecular dynamics simulations were utilized to study the interactions between the insulin and microneedle matrix materials, providing a strategy for theoretically understanding drug stability as well as the release mechanism of drug-loaded microneedles.

Optimizing The Daily Units Of Insulin; Insulin Degludec Aspart Versus Premixed Insulin Aspart In The Standard Of Care Regimen For Type 2 Diabetics.

BACKGROUND: This study aimed to evaluate the impact of Insulin Degludec Aspart on daily insulin dose in comparison with premixed insulin aspart. METHODS: It was a Quasi-Experimental study conducted in the Department of Pharmacology, Army Medical College, National University of Medical Sciences, Rawalpindi and the Department of Medicine, Pak Emirates Military Hospital, Rawalpindi. One hundred and twenty participants with documented type 2 diabetes, taking premixed insulin aspart therapy were enrolled in the study. Sixty participants were substituted with insulin degludec aspart from premixed insulin aspart. Daily units of insulin were recorded for 12 weeks and compared for both groups. SPSS version 26 was used for analysing the study results. RESULTS: Participants of the insulin degludec aspart group showed a significant reduction in the daily insulin dose compared to the premixed insulin aspart group. Fifty-two units per day were administered in the participants of the premixed insulin aspart patients while insulin degludec aspart participants received 40 units of median daily insulin dose (p-value<0.001). CONCLUSIONS: Insulin degludec aspart proved superior to premixed insulin aspart in a reduction in the daily dose of insulin with insulin degludec aspart.

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.

Practical guide in using insulin degludec/insulin aspart: A multidisciplinary approach in Malaysia.

Insulin degludec/insulin aspart (IDegAsp) co-formulation provides both basal and mealtime glycaemic control in a single injection. The glucose level-lowering efficacy of IDegAsp is reported to be superior or non-inferior to that of the currently available insulin therapies with a lower rate of overall hypoglycaemia and nocturnal hypoglycaemia. An expert panel from Malaysia aims to provide insights into the utilisation of IDegAsp across a broad range of patients with type 2 diabetes mellitus (i.e. treatment-naive or insulin-naive patients or patients receiving treatment intensification from basal-only regimens, premixed insulin and basal-bolus insulin therapy). IDegAsp can be initiated as once-daily dosing for the main meal with the largest carbohydrate content with weekly dose adjustments based on patient response. A lower starting dose is recommended for patients with cardiac or renal comorbidities. Dose intensification with IDegAsp may warrant splitting into twice-daily dosing. IDegAsp twice-daily dosing does not need to be split at a 50:50 ratio but should be adjusted to match the carbohydrate content of meals. The treatment of patients choosing to fast during Ramadan should be switched to IDegAsp early before Ramadan, as a longer duration of titration leads to better glycated haemoglobin level reductions. The pre-Ramadan breakfast/lunch insulin dose can be reduced by 30%-50% and taken during sahur, while the preRamadan dinner dose can be taken without any change during iftar. Education on the main meal concept is important, as carbohydrates are present in almost all meals. Patients should not have a misconception of consuming more carbohydrates while taking IDegAsp.

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.

Real-World Effects of Second-Generation Versus Earlier Intermediate/Basal Insulin Analogues on Rates of Hypoglycemia in Adults with Type 1 and 2 Diabetes (iNPHORM, US).

INTRODUCTION: Second-generation basal insulin analogues have been shown to reduce hypoglycemia in several trials and observational studies of select populations; however, it remains unclear whether these results persist in real-world settings. Using self-reported hypoglycemia events, we assessed whether second-generation basal insulin analogues reduce rates of hypoglycemia events (non-severe/severe; overall/daytime/nocturnal) compared to earlier intermediate/basal insulin analogues among people with insulin-treated type 1 or 2 diabetes. METHODS: We used prospectively collected data from the Investigating Novel Predictions of Hypoglycemia Occurrence Using Real-World Models (iNPHORM) panel survey. This US-wide, 1-year internet-based survey assessed hypoglycemia experiences and related sociodemographic and clinical characteristics of people with diabetes (February 2020-March 2021). We estimated population-average rate ratios for hypoglycemia comparing second-generation to earlier intermediate/basal insulin analogues using negative binomial regression, adjusting for confounders. Within-person variability of repeated observations was addressed with generalized estimating equations. RESULTS: Among iNPHORM participants with complete data, N = 413 used an intermediate/basal insulin analogue for ≥ 1 month during follow-up. After adjusting for baseline and time-updated confounders, average second-generation basal insulin analogue users experienced a 19% (95% CI 3-32%, p = 0.02) lower rate of overall non-severe hypoglycemia and 43% (95% CI 26-56%, p < 0.001) a lower rate of nocturnal non-severe hypoglycemia compared to earlier intermediate/basal insulin users. Overall severe hypoglycemia rates were similar among second-generation and earlier intermediate/basal insulin users (p = 0.35); however, the rate of severe nocturnal hypoglycemia was reduced by 44% (95% CI 10-65%, p = 0.02) among second-generation insulin users compared to earlier intermediate/basal insulin users. CONCLUSION: Our real-world results suggest second-generation basal insulin analogues reduce rates of hypoglycemia, especially nocturnal non-severe and severe events. Whenever possible and feasible, clinicians should prioritize prescribing these agents over first-generation basal or intermediate insulin in people with type 1 and 2 diabetes.

Initiating or Switching to Insulin Degludec/Insulin Aspart in Adults with Type 2 Diabetes in Malaysia: Results from a Prospective, Non-interventional Real-World Study.

Objectives: Insulin degludec (IDeg)/insulin aspart (IAsp; IDegAsp) is a co-formulation of 70% IDeg and 30% IAsp. According to several randomized controlled trials, IDegAsp is effective and safe for patients with type 2 diabetes mellitus (T2DM). A subgroup analysis of the ARISE study was conducted to explore the safety and efficacy of IDegAsp among Malaysian patients with T2DM in real-world settings. Methodology: ARISE, an open-label, multicenter, non-interventional, prospective study was conducted between August 2019 and December 2020. Adult Malaysian patients with T2DM who were enrolled from 14 sites received IDegAsp as per the local label for 26 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) levels from baseline to end of study (EOS). Results: Of the 182 patients included in the full analysis set, 159 (87.4%) completed the study. From baseline to EOS, HbA1c (estimated difference [ED]: -1.3% [95% CI: -1.61 to -0.90]) and fasting plasma glucose levels (ED: -1.8 mmol/L [95% CI: -2.49 to -1.13]) were significantly reduced (p<0.0001). The patient-reported reduced hypoglycemic episodes (overall and nocturnal) during treatment. Overall, 37 adverse events were observed in 23 (12.6%) patients. Conclusion: Switching or initiating IDegAsp treatment resulted in significant improvements in glycemic control and a reduction in hypoglycemic episodes.

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.

Time to Reach Glycaemic and Body Weight Loss Thresholds with Tirzepatide in Patients with Type 2 Diabetes: A Pre-planned Exploratory Analysis of SURPASS-2 and SURPASS-3.

INTRODUCTION: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, provides clinically meaningful improvements in glycaemic control and body weight loss in people with type 2 diabetes. The early efficacy profile of tirzepatide after treatment initiation is of interest. In this exploratory pre-planned analysis, we evaluated the time to achieve glycaemic control and body weight loss thresholds with tirzepatide. METHODS: In two randomised studies, we compared time to achieve HbA1c (< 7.0% and ≤ 6.5%) and weight loss (≥ 5%, SURPASS-2 only) thresholds among people treated with tirzepatide (5, 10, and 15 mg), semaglutide 1 mg in SURPASS-2, and titrated insulin degludec in SURPASS-3. Longitudinal logistic regression models were used to explore the proportion of participants achieving HbA1c and body weight loss thresholds at 4, 12, and 24 weeks. The time to achieve these thresholds was analysed and compared between groups using the Cox proportional-hazards model. RESULTS: Overall, greater proportions of participants achieved the HbA1c and body weight loss thresholds at 4, 12, and 24 weeks with tirzepatide compared with semaglutide 1 mg and insulin degludec. The median time to achieve HbA1c < 7.0% (8.1 weeks with each tirzepatide dose, 12.0 weeks with semaglutide 1 mg, and 12.1 weeks with insulin degludec) and ≤ 6.5% (12.1, 15.7, and 24.1 weeks, respectively) was faster with tirzepatide than semaglutide 1 mg and insulin degludec. In SURPASS-2, the median time to first achieve a body weight loss of ≥ 5% was faster with tirzepatide 5 mg (16.0 weeks) and 10 and 15 mg (12.4 weeks) than with semaglutide 1 mg (24.0 weeks). CONCLUSION: Analyses of data from SURPASS-2 and -3 revealed that tirzepatide treatment enabled more people with type 2 diabetes to achieve glycaemic thresholds and these were achieved faster than with semaglutide 1 mg or insulin degludec. Tirzepatide-treated participants also achieved a body weight loss of ≥ 5% significantly faster with tirzepatide than with semaglutide 1 mg. TRIAL REGISTRATION NUMBERS: NCT03987919; NCT03882970.

Comparison of Efficacy and Safety of Commercially Available Fixed-Ratio Combinations of Insulin Degludec/Liraglutide and Insulin Glargine/Lixisenatide: A Network Meta-analysis.

OBJECTIVES: Our aim in this study was to compare the efficacy and safety of commercially available fixed-ratio combinations (FRCs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and basal insulins by a network meta-analysis of randomized controlled trials (RCTs) of people with type 2 diabetes. METHODS: We present a systematic review and network meta-analyses of RCTs of individuals with type 2 diabetes randomized to FRCs or to their components for ≥24 weeks. All reports were obtained from PubMed or ClinicalTrials.gov up to February 28, 2022. The primary outcome was glycated hemoglobin (A1C) level attained. Secondary outcomes included fasting plasma glucose, change in body weight, and incident hypoglycemia. Treatment effects were estimated as mean difference (MD) and standard error (SE), or as odds ratio (OR) with 95% confidence interval (CI) using the fixed combination of insulin glargine 100 IU/mL and lixisenatide (iGlarLixi) as reference. RESULTS: We included 29 RCTs from among the 1,404 articles identified. No direct comparisons between FRCs were found. After excluding some insulin-capped trials to reach model consistency, both FRCs were more efficacious regarding A1C than their components, but no difference between FRCs was found (MD, -0.10%; SE, 0.10%). The effect of the fixed combination of insulin degludec and liraglutide (IDegLira) (MD, -0.47 mmol/L; SE, 0.24 mmol/L) and basal insulins was similar to that of iGlarLixi (reference) on fasting glucose, whereas GLP-1RAs had lower efficacy than iGlarLixi. Weight gain was lower with GLP-1RAs and IDegLira (MD, -0.72 kg; SE, 0.32 kg) than with iGlarLixi (reference) and higher with basal insulins. Incident hypoglycemia (based on different definitions) was least frequent with GLP-1RAs, followed by IDegLira (OR, 0.78; 95% CI, 0.39 to 1.57), iGlarLixi (reference), and basal insulins. CONCLUSIONS: For A1C, both FRCs were more efficacious over their individual components, with similar efficacies of the 2 FRCs.

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.