Impact of kidney function on the safety and efficacy of insulin degludec versus insulin glargine U300 in people with type 2 diabetes: A post hoc analysis of the CONCLUDE trial.
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SUBMITTER: Pieber TR
PROVIDER: S-EPMC9298323 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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).
| S-EPMC7054369 | biostudies-literature
Project description:INTRODUCTION:This study aimed to evaluate the short-term cost-effectiveness of insulin degludec 200 units/mL (degludec) versus insulin glargine 300 units/mL (glargine U300) from a Dutch societal perspective. METHODS:A previously published model estimated costs [2018 euros (EUR)] and effectiveness [quality-adjusted life years (QALYs)] with degludec compared with glargine U300 over a 1-year time horizon. The model captured hypoglycaemia rates and insulin dosing. Clinical outcomes were informed by CONCLUDE (NCT03078478), a head-to-head randomised controlled trial in insulin-experienced patients with type 2 diabetes. RESULTS:Treatment with degludec was associated with mean annual cost savings (EUR 24.71 per patient) relative to glargine U300, driven by a lower basal insulin dose and lower severe hypoglycaemia rate with degludec compared with glargine U300. Lower rates of non-severe nocturnal and severe hypoglycaemia resulted in improved effectiveness (+?0.0045 QALYs) with degludec relative to glargine U300. In sensitivity analyses, changes to the vast majority of model parameters did not materially affect model outcomes. CONCLUSIONS:This short-term analysis, informed by the latest clinical trial evidence, demonstrated that degludec was a cost-effective treatment option relative to glargine U300. As such, our modelling analysis suggests that degludec would represent an efficient use of Dutch public healthcare resources in this patient population.
| S-EPMC7467476 | biostudies-literature
Project description:Objective: To review clinical efficacy and safety of insulin glargine 300 units/mL (Gla-300), a novel high-concentration basal insulin. Data Sources: A MEDLINE search was performed to identify relevant articles published 1960 through February 2015 using the search term glargine 300. Published abstracts from conference proceedings of the American Diabetes Association 74th Scientific Sessions were identified. Study Selection and Data Extraction: Human studies that evaluated pharmacokinetics, efficacy, or safety of Gla-300 were included. Data Synthesis: Six trials investigated efficacy and safety of Gla-300; 3 of 6 trials were available in abstract form only. The EDITION group of trials compared Gla-300 to insulin glargine 100 units/mL (Gla-100) in several populations. These included subjects with type 1 diabetes continuing mealtime insulin and subjects with type 2 diabetes on basal and mealtime insulin, basal insulin and oral antidiabetic drugs (OADs), and with no prior insulin use. Three studies were multinational including 2 studies exclusive to Japanese participants. Each clinical trial was an open-label, multicenter, randomized study with 6 to 12 months of follow-up. Gla-300 demonstrated similar reductions in HbA1c compared to Gla-100. Basal insulin requirements increased by 11% to 17% with Gla-300 without excessive weight gain. Rates of overall hypoglycemia were similar with Gla-300 compared to Gla-100; however, 16% to 38% less nocturnal hypoglycemia was observed in type 2 clinical trials. Conclusions: Gla-300 in combination with mealtime insulin or OADs has shown comparable glycemic control with higher insulin dose requirements versus Gla-100, and may induce less hypoglycemia in patients with type 2 diabetes.
| S-EPMC5990197 | biostudies-other
Project description:BackgroundThere is an ongoing discussion about possible differences between insulin degludec (IDeg-100) and glargine U300 (IGlar-300). There is little data and head-to-head comparison of IDeg-100 and IGlar-300 regarding their simultaneous impact on glycemic variability and oxidative stress in patients with type 2 diabetes mellitus (T2DM).ObjectiveIn our randomized, open-label, crossover study, we compared the impact of IDeg-100 and IGlar-300 on glycemic variability and oxidative stress in insulin-naive patients with T2DM.MethodsWe recruited a total of 25 adult patients with T2DM (7 females) whose diabetes was uncontrolled (HbA1c ≥7.5%) on two or more oral glucose-lowering drugs; a total of 22 completed the study. Mean age was 57.3 (SD 6.99) years and duration of diabetes was 9.94 (SD 5.01) years. After the washout period, they were randomized alternately to first receive either IDeg-100 or IGlar-300 along with metformin. Each insulin was administered for 12 weeks and then switched. At the beginning and end of each phase, biochemical and oxidative stress parameters were analyzed. On 3 consecutive days prior to each control point, patients performed a 7-point self-monitoring of blood glucose profile. Oxidative stress was assessed by measuring thiol groups and hydroperoxides (determination of reactive oxygen metabolites test) in serum.ResultsIGlar-300 reduced mean glucose by 0.02-0.13 mmol/L, and IDeg-100 reduced glucose by 0.10-0.16 mmol/L, with no significant difference. The reduction of the coefficient of glucose variation also did not show a statistically significant difference. IGlar-300 increased thiols by 0.08 µmol/L and IDeg-100 increased thiols by 0.15 µmol/L, with no significant difference (P=.07) between them. IGlar-300 reduced hydroperoxides by 0.040 CARR U and IDeg-100 increased hydroperoxides by 0.034 CARR U, but the difference was not significant (P=.12).ConclusionsThe results of our study do not show a significant difference regarding glycemic variability between patients receiving either insulin IDeg-100 or IGlar-300, although IGlar-300 showed greater dispersion of data. No significant difference in oxidative stress was observed. In a larger study, doses of insulins should be higher to achieve significant impact on glycemic parameters and consequently on glycemic variability and oxidative stress.Trial registrationClinicalTrials.gov, NCT04692415; https://clinicaltrials.gov/ct2/show/NCT04692415.
| S-EPMC9308081 | biostudies-literature
Project description:ObjectiveTo assess the efficacy and safety of iGlarLixi (titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide) in patients with type 2 diabetes (T2D) living in North America (NA; USA and Canada) compared with the rest of the world (RoW).Research design and methodsPost hoc analysis included patient-level data from 509 sites/centers across two phase III trials: LixiLan-O (NCT02058147; insulin-naive patients; NA, n=371; RoW, n=796) and LixiLan-L (NCT02058160; inadequately controlled patients on basal insulin; NA, n=196; RoW, n=535). Efficacy outcomes were: change from baseline to Week 30 in glycated hemoglobin (HbA1c), postprandial glucose (PPG), PPG excursions, fasting plasma glucose (FPG) and body weight; proportion of patients achieving HbA1c <42 mmol/mol (<7.0%); proportion of patients achieving composite endpoint: HbA1c <42 mmol/mol (<7.0%), no weight gain or symptomatic hypoglycemia (blood glucose ≤3.9 mmol/L (≤70 mg/dL)). Safety endpoints included incidence of documented symptomatic hypoglycemia and gastrointestinal (GI) adverse events.ResultsSignificantly larger reductions (p≤0.003) in HbA1c from baseline to Week 30 were achieved with iGlarLixi, compared with iGlar or lixisenatide, in NA and RoW patients in LixiLan-O (iGlarLixi vs iGlar: -0.31 and -0.29, respectively; iGlarLixi vs lixisenatide: -0.84 and -0.69, respectively) and in LixiLan-L (iGlarLixi vs iGlar: -0.5 and -0.51, respectively). Documented symptomatic hypoglycemia was similar between NA and RoW patients. iGlarLixi resulted in significant weight benefits versus iGlar (change from baseline -1.58 and -1.29 kg for NA and RoW patients, respectively; p<0.001). GI adverse events were similar for iGlarLixi and iGlar, but significantly higher for lixisenatide.ConclusionsiGlarLixi improved glycemic parameters versus iGlar or lixisenatide alone in both NA and RoW patients, with beneficial weight effects versus iGlar. iGlarLixi treatment responses, hypoglycemia risk and GI adverse events in NA patients were comparable with patients in the RoW.Trial registryClinicaltrials.gov NCT02058147 and NCT02058160.
| S-EPMC6501856 | biostudies-literature
Project description:Aims/introductionWe compared the efficacy and safety of insulin degludec/aspart (IDegAsp) twice-daily injections with insulin glargine 300 U/mL and insulin glulisine basal-bolus therapy (Gla300/Glu) using insulin glargine 300 U/mL (Gla300) and insulin glulisine (Glu).Materials and methodsA total of 20 patients with type 2 diabetes mellitus were treated with IDegAsp twice-daily injections; achievement of target preprandial glucose concentration of 100-130 mg/dL at breakfast and supper was determined using a wearable flash glucose monitoring system. Patients were later switched to Gla300/Glu basal-bolus therapy before breakfast and before supper. Data were collected on days 2-4 and days 12-14 for each treatment period. The study's primary efficacy end-point was the mean percentage of time with a target glucose range of 70-180 mg/dL, and safety end-points were the mean percentage of time with hypoglycemia having glucose levels <70 mg/dL, clinically important hypoglycemia with glucose levels <54 mg/dL and nocturnal (00.00-06.00) hypoglycemia.ResultsConsidering efficacy, the mean percentage of time for the target glucose range of IDegAsp was significantly lower than that of Gla300/Glu (73.1 [69.4-81.1] vs 84.2 [80.2-93.1], P = 0.001). Considering safety, the mean percentages of hypoglycemia (<70 mg/dL; 2.1 [0.0-9.4] vs 14.4 [4.4-22.3]), clinically important hypoglycemia (<54 mg/dL; 0.0 [0.0-0.2] vs 1.9 [0.0-5.6]) and nocturnal (00.00-06.00 hours) hypoglycemia (0.5 [0.0-5.9] vs 8.9 [3.1-11.8]) of Gla300/Glu were significantly lower than those of IDegAsp (P = 0.012, 0.036 and 0.007, respectively).ConclusionsWhen compared with the IDegAsp twice-daily injections, Gla300/Glu basal-bolus therapy might achieve more effective glycemic control without hypoglycemic risk.
| S-EPMC6825933 | biostudies-literature
Project description:BACKGROUND:Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec. METHODS:We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome. RESULTS:Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups. CONCLUSIONS:Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).
| S-EPMC5731244 | biostudies-literature
Project description:ObjectiveThe role of U300 glargine insulin for the inpatient management of type 2 diabetes (T2D) has not been determined. We compared the safety and efficacy of glargine U300 versus glargine U100 in noncritically ill patients with T2D.Research design and methodsThis prospective, open-label, randomized clinical trial included 176 patients with poorly controlled T2D (admission blood glucose [BG] 228 ± 82 mg/dL and HbA1c 9.5 ± 2.2%), treated with oral agents or insulin before admission. Patients were treated with a basal-bolus regimen with glargine U300 (n = 92) or glargine U100 (n = 84) and glulisine before meals. We adjusted insulin daily to a target BG of 70-180 mg/dL. The primary end point was noninferiority in the mean difference in daily BG between groups. The major safety outcome was the occurrence of hypoglycemia.ResultsThere were no differences between glargine U300 and U100 in mean daily BG (186 ± 40 vs. 184 ± 46 mg/dL, P = 0.62), percentage of readings within target BG of 70-180 mg/dL (50 ± 27% vs. 55 ± 29%, P = 0.3), length of stay (median [IQR] 6.0 [4.0, 8.0] vs. 4.0 [3.0, 7.0] days, P = 0.06), hospital complications (6.5% vs. 11%, P = 0.42), or insulin total daily dose (0.43 ± 0.21 vs. 0.42 ± 0.20 units/kg/day, P = 0.74). There were no differences in the proportion of patients with BG <70 mg/dL (8.7% vs. 9.5%, P > 0.99), but glargine U300 resulted in significantly lower rates of clinically significant hypoglycemia (<54 mg/dL) compared with glargine U100 (0% vs. 6.0%, P = 0.023).ConclusionsHospital treatment with glargine U300 resulted in similar glycemic control compared with glargine U100 and may be associated with a lower incidence of clinically significant hypoglycemia.
| S-EPMC7411278 | biostudies-literature
Project description:IntroductionIn the EDITION clinical trial programme, patients with type 2 diabetes mellitus (T2DM) receiving insulin glargine (IGlar) U300 required 10-15% more insulin than those receiving IGlar U100. This study sought to determine whether this difference was apparent in real-world practice.MethodsIn this observational, retrospective cohort study, electronic medical records in the Big-Pac® database (Real Life Data) relating to adult insulin-naïve patients with T2DM who initiated IGlar U100 or U300 treatment in Spain in 2016-2017 and remained on treatment for 18 months were selected. IGlar U100- and U300-treated patients were matched 1:1 (propensity score matching). The primary analysis compared changes from baseline in mean daily IGlar dose (U and U/kg) at 6 (± 2), 12 (± 2) and 18 (± 2) months between cohorts (paired t tests). Changes in glycated haemoglobin (HbA1c) and weight were analysed descriptively.ResultsThe IGlar U100 and U300 cohorts included 556 matched pairs (46.9% female) with the following mean (standard deviation) values at baseline, respectively: age 63.6 (12.8) versus 63.7 (11.9) years; years since diagnosis 9.5 (1.4) versus 9.5 (1.3); HbA1c 8.8 (1.3) versus 8.7 (1.5) %; weight 84.6 (16.9) versus 84.7 (17.1) kg. Mean IGlar dose at baseline was 0.19 U/kg/day (both cohorts). Patients receiving IGlar U300 showed a greater increase from baseline in IGlar dose at 6, 12 and 18 months [mean dose (U/kg/day) 5.1%, 10.3% and 12.8% greater, respectively, in IGlar U300-treated patients]. Mean HbA1c was 8.1% in both cohorts at 18 months. Mean (SD) weight at 18 months with IGlar U100 and IGlar300 was 86.8 (17.0) kg and 85.0 (17.1) kg, respectively.ConclusionIn real-world practice, insulin dose was significantly higher in IGlar U300-treated than U100-treated patients at 6, 12 and 18 months, with similar reductions in HbA1c. At equal IGlar price/unit in Spain, the increased dose requirements of IGlar U300 would result in higher costs.
| S-EPMC8280027 | biostudies-literature
Project description:The relationship between baseline fasting C-peptide (FCP) and glucose control was examined in insulin-naïve people with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs commencing basal insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla-100) in the absence of sulfonylurea/glinides. Participants with FCP measurement from the EDITION 3 trial (n = 867) were stratified according to baseline FCP (≤0.40, >0.40-1.20, >1.20 nmol/L); 11.0%, 70.9% and 18.1% contributed to each group. Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 26 weeks. Glycaemic control (HbA1c, FPG) at 26 weeks was similar in each FCP group between insulins. However, end-of-study insulin dose was greater with higher FCP for both insulins. More people with lower baseline FCP experienced hypoglycaemia with both insulins, but with numerically lower incidence for Gla-300 versus Gla-100 across all FCP groups for all definitions (time periods and levels) of hypoglycaemia. This suggests that Gla-300 might be particularly advantageous for people who are at higher risk of hypoglycaemia.
| S-EPMC7496109 | biostudies-literature