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Similar glycaemic control and risk of hypoglycaemia with patient- versus physician-managed titration of insulin glargine 300 U/mL across subgroups of patients with T2DM: a post hoc analysis of ITAS.

ABSTRACT:

Aims

The Italian Titration Approach Study (ITAS) demonstrated comparable HbA_1c reductions and similarly low hypoglycaemia risk at 6 months in poorly controlled, insulin-naïve adults with T2DM who initiated self- or physician-titrated insulin glargine 300 U/mL (Gla-300) in the absence of sulphonylurea/glinide. The association of patient characteristics with glycaemic and hypoglycaemic outcomes was assessed.

Methods

This post hoc analysis investigated whether baseline patient characteristics and previous antihyperglycaemic drugs were associated with HbA_1c change and hypoglycaemia risk in patient- versus physician-managed Gla-300 titration.

Results

HbA_1c change, incidence of hypoglycaemia (any type) and nocturnal rates were comparable between patient- and physician-managed arms in all subgroups. Hypoglycaemia rates across subgroups (0.03 to 3.52 events per patient-year) were generally as low as observed in the full ITAS population. Small increases in rates of 00:00-pre-breakfast and anytime hypoglycaemia were observed in the ≤ 10-year diabetes duration subgroup in the patient- versus physician-managed arm (heterogeneity of effect; p < 0.05).

Conclusions

Comparably fair glycaemic control and similarly low hypoglycaemia risk were achieved in almost all patient subgroups with patient- versus physician-led Gla-300 titration. These results reinforce efficacy and safety of Gla-300 self-titration across a range of phenotypes of insulin-naïve people with T2DM.

Clinical trial registration

EudraCT 2015-001167-39.

SUBMITTER: Giaccari A

PROVIDER: S-EPMC8110495 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimTo further investigate glycaemic control and hypoglycaemia in BRIGHT, focusing on the titration period.Materials and methodsBRIGHT was a multicentre, open-label, randomized, active-controlled, two-arm, parallel-group, 24-week study in insulin-naïve patients with uncontrolled type 2 diabetes initiated on glargine 300 U/mL (Gla-300) (N = 466) or degludec (IDeg-100) (N = 463). Predefined efficacy and safety outcomes were investigated during the initial 12-week titration period. In addition, patients' characteristics and clinical outcomes were assessed descriptively, stratified by confirmed (≤3.9 mmol/L) hypoglycaemia incidence during the initial titration period.ResultsAt week 12, HbA1c was comparable between Gla-300 (7.32%) and IDeg-100 (7.23%), with similar least squares (LS) mean reductions from baseline (-1.37% and - 1.39%, respectively; LS mean difference of 0.02; 95% confidence interval: -0.08 to 0.12). Patients who experienced hypoglycaemia during the initial titration period had numerically greater HbA1c reductions by week 12 than patients who did not (-1.46% vs. -1.28%), and higher incidence of anytime (24 hours; 73.3% vs. 35.7%) and nocturnal (00:00-06:00 hours; 30.0% vs. 11.9%) hypoglycaemia between weeks 13-24.ConclusionsThe use of Gla-300 resulted in similar glycaemic control as IDeg-100 during the initial 12-week titration period of the BRIGHT study, when less anytime (24 hours) hypoglycaemia with Gla-300 versus IDeg-100 has been reported. Experiencing hypoglycaemia shortly after initiating Gla-300 or IDeg-100 may be associated with hypoglycaemia incidence in the longer term, potentially impacting glycaemic management.

| S-EPMC7064957 | biostudies-literature

Glycaemic control and hypoglycaemia risk with insulin glargine 300 U/mL and insulin degludec 100 U/mL in older participants in the BRIGHT trial.

Project description:AimTo evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) versus insulin degludec 100 U/mL (IDeg-100) in predefined (</≥65 years) and post hoc (</≥70 years) age groups of people with type 2 diabetes (T2D) in the BRIGHT trial.Materials and methodsBRIGHT was the first head-to-head randomized trial comparing Gla-300 and Deg-100 in insulin-naïve adults with T2D. In this subanalysis, endpoints were studied by predefined (</≥65 years, N = 596/333) and post hoc (</≥70 years, N = 768/161) age groups.ResultsHeterogeneity of treatment effect was observed for HbA1c reductions across the </≥70 years subgroups, but not across the </≥ 65 years subgroups, with greater HbA1c reductions with Gla-300 versus IDeg-100 in those 70 years or older (least squares mean -0.34% [95% confidence interval: -0.589% to -0.100%]). There was no significant heterogeneity of treatment effect for incidence and rates of confirmed (≤3.9 mmol/L [≤70 mg/dL]) hypoglycaemia across any age subgroups over 24 weeks, but numerically lower incidence and rates were consistently observed for Gla-300 versus IDeg-100 in the 65 years or older and 70 years or older age groups in the initial 12 weeks.ConclusionsGla-300 may be a suitable treatment option in the growing population of older people with T2D. Further investigation is required to determine Gla-300 glycaemic benefits in high-risk populations without increasing the risk of hypoglycaemia.

| S-EPMC8252805 | biostudies-literature

Glycaemic control and hypoglycaemia during 12 months of randomized treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 1 diabetes (EDITION 4).

Project description:AimsInsulin glargine 300 U/mL (Gla-300) offers a flatter pharmacodynamic profile than insulin glargine 100 U/mL (Gla-100). We have compared these insulins over 1 year in people with type 1 diabetes (T1DM).MethodsEDITION 4 was a 6-month, multicentre, randomized, open-label phase 3 study. People with T1DM who completed the 6 months continued randomized Gla-300 or Gla-100 once daily, morning or evening, for a further 6 months.ResultsAmong 549 participants randomized, 444 completed the 12-month study period (Gla-300, 80%; Gla-100, 82%). Mean HbA1c decreased similarly from baseline to month 12 in the 2 treatment groups (difference, 0.02 [95% CI, -0.13 to 0.17]) %-units [0.2 (-1.5 to 1.9) mmol/mol]), to a mean of 7.86 %-units (62.4 mmol/mol) in both groups. For morning vs evening injection, there was no difference in HbA1c change over 12 months for Gla-100, but a significantly larger decrease in HbA1c was observed in the Gla-300 morning group than in the Gla-300 evening group (difference, -0.25 [-0.47 to -0.04] %-units [-2.7 (-5.2 to -0.4) mmol/mol]). Mean glucose from the 8-point SMPG profiles decreased from baseline, and was similar between the 2 treatment groups. Basal insulin dose was 20% higher with Gla-300 than with Gla-100, while hypoglycaemia event rates, analysed at night, over 24 hours, or according to different glycaemic thresholds, did not differ between treatment groups, regardless of injection time. Adverse event profiles did not differ between groups.ConclusionsIn T1DM, Gla-300 provides glucose control comparable to that of Gla-100, and can be given at any time of day.

| S-EPMC5763343 | biostudies-literature

Low Blood Glucose Index and Hypoglycaemia Risk: Insulin Glargine 300 U/mL Versus Insulin Glargine 100 U/mL in Type 2 Diabetes.

Project description:INTRODUCTION:We examined differences in hypoglycaemia risk between insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100) in individuals with type 2 diabetes (T2DM) using the low blood glucose index (LBGI). METHODS:Daily profiles of self-monitored plasma glucose (SMPG) from the EDITION 2, EDITION 3 and SENIOR treat-to-target trials of Gla-300 versus Gla-100 were used to compute the LBGI, which is an established metric of hypoglycaemia risk. The analysis also examined documented (blood glucose readings < 3.0 mmol/L [54 mg/dL]) symptomatic hypoglycaemia (DSH). RESULTS:Overall LBGI in EDITION 2 and SENIOR and night-time LBGI in all three trials were significantly (p < 0.05) lower with Gla-300 versus Gla-100. The largest differences between Gla-300 and Gla-100 were observed during the night. In all three trials, individual LBGI results correlated with the observed number of DSH episodes per participant (EDITION 2 [r = 0.35, p < 0.001]; EDITION 3 [r = 0.26, p < 0.001]; SENIOR [r = 0.30, p < 0.001]). Participants at moderate risk of experiencing hypoglycaemia (defined as LBGI > 1.1) reported 4- to 8-fold more frequent DSH events than those at minimal risk (LBGI ≤ 1.1) (p ≤ 0.009). CONCLUSIONS:The LBGI identified individuals with T2DM at risk for hypoglycaemia using SMPG data and correlated with the number of DSH events. Using the LBGI metric, a lower risk of hypoglycaemia with Gla-300 than Gla-100 was observed in all three trials. The finding that differences in LBGI are greater at night is consistent with previously published differences in the pharmacokinetic profiles of Gla-300 and Gla-100, which provides the physiological foundation for the presented results.

| S-EPMC7261296 | biostudies-literature

Glycaemic control and hypoglycaemia benefits with insulin glargine 300 U/mL extend to people with type 2 diabetes and mild-to-moderate renal impairment.

Project description:AimTo investigate the impact of renal function on the safety and efficacy of insulin glargine 300?U/mL (Gla-300) and insulin glargine 100?U/mL (Gla-100).Materials and methodsA meta-analysis was performed using pooled 6-month data from the EDITION 1, 2 and 3 trials (N?=?2496). Eligible participants, aged ?18?years with a diagnosis of type 2 diabetes (T2DM), were randomized to receive once-daily evening injections of Gla-300 or Gla-100. Pooled results were assessed by two renal function subgroups: estimated glomerular filtration rate (eGFR) <60 and ?60?mL/min/1.73?m2 .ResultsThe decrease in glycated haemoglobin (HbA1c) after 6?months and the proportion of individuals with T2DM achieving HbA1c targets were similar in the Gla-300 and Gla-100 groups, for both renal function subgroups. There was a reduced risk of nocturnal (12:00-5:59 am) confirmed (?3.9?mmol/L [?70?mg/dL]) or severe hypoglycaemia with Gla-300 in both renal function subgroups (eGFR <60?mL/min/1.73?m2 : relative risk [RR] 0.76 [95% confidence interval {CI} 0.62-0.94] and eGFR ?60?mL/min/1.73?m2 : RR 0.75 [95% CI 0.67-0.85]). For confirmed (?70?mg/dL [?3.9?mmol/L]) or severe hypoglycaemia at any time of day (24?hours) the hypoglycaemia risk was lower with Gla-300 vs Gla-100 in both the lower (RR 0.94 [95% CI 0.86-1.03]) and higher (RR 0.90 [95% CI 0.85-0.95]) eGFR subgroups.ConclusionsGla-300 provided similar glycaemic control to Gla-100, while indicating a reduced overall risk of confirmed (?3.9 and <3.0?mmol/L [?70 and <54?mg/dL]) or severe hypoglycaemia, with no significant difference between renal function subgroups.

| S-EPMC6282564 | biostudies-literature

INSULIN GLARGINE 300 U/ML VS. 100 U/ML IN OLDER PEOPLE WITH T2DM: RESULTS FROM A RANDOMIZED TRIAL

Project description:Abstract SENIOR was a phase 3b, randomized, open-label, 2-arm, parallel-group, multicenter, 30-week trial. Randomization was stratified by screening HbA1c (<8.0 vs ?8.0 %), previous insulin use (Yes/No), and sulfonylurea or meglitinide use at screening (Yes/No). Insulin was titrated to the ADA-recommended glycemic target for healthy elderly individuals (fasting SMPG: 90–130?mg/dL [5.0–7.2 mmol/L]), a higher glycemic target than utilized previously in randomized controlled trials of insulin glargine 300?U/mL (Gla-300) versus 100?U/mL (Gla-100) in adults. The aim of the SENIOR trial was to compare the efficacy and safety of Gla-300 with Gla-100. In total, 1014 individuals (?65 years) with T2DM were included in the trial, of whom 241 were ?75 years old. The primary endpoint of non-inferiority of mean change in HbA1c for Gla-300 versus Gla-100 was achieved (least squares mean difference [95% CI]: 0.02, [?0.092 to 0.129] %). Similar percentages of participants in both groups reported confirmed (?70?mg/dL [?3.9 mmol/L]) or severe hypoglycemia. The annualized rates of documented symptomatic (?70?mg/dL [?3.9 mmol/L]) hypoglycemia were lower with Gla-300 versus Gla-100, both in the overall study population (1.85 vs 2.56 events/participant-year; rate ratio [RR] 0.74 [0.56 to 0.96]) and in the ?75 years subpopulation (1.12 vs 2.71 events/participant-year; RR 0.45 [0.25 to 0.83]). Frequency of adverse events, including cardiovascular events, falls and fractures was similar between treatments. These results indicate that Gla-300 was effective in older people with T2DM, with a good safety profile, resulting in comparable reductions in HbA1c and lower rates of documented symptomatic hypoglycemia versus Gla-100. Supported By: Sanofi (clinicaltrials.gov NCT02320721)

| S-EPMC6185084 | biostudies-literature

Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes.

Project description:AimsTo conduct a patient-level meta-analysis of the EDITION 1, 2 and 3 studies, which compared the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) in people with type 2 diabetes (T2DM) on basal and mealtime insulin, basal insulin and oral antihyperglycaemic drugs, or no prior insulin, respectively.MethodsThe EDITION studies were multicentre, randomized, open-label, parallel-group, phase IIIa studies, with similar designs and endpoints. A patient-level meta-analysis of the studies enabled these endpoints to be examined over 6 months in a large population with T2DM (Gla-300, n = 1247; Gla-100, n = 1249).ResultsNo significant study-by-treatment interactions across studies were found, enabling them to be pooled. The mean change in glycated haemoglobin was comparable for Gla-300 and Gla-100 [each -1.02 (standard error 0.03)%; least squares (LS) mean difference 0.00 (95% confidence interval (CI) -0.08 to 0.07)%]. Annualized rates of confirmed (≤3.9 mmol/l) or severe hypoglycaemia were lower with Gla-300 than with Gla-100 during the night (31% difference in rate ratio over 6 months) and at any time (24 h, 14% difference). Consistent reductions were observed in percentage of participants with ≥1 hypoglycaemic event. Severe hypoglycaemia at any time (24 h) was rare (Gla-300: 2.3%; Gla-100: 2.6%). Weight gain was low (<1 kg) in both groups, with less gain with Gla-300 [LS mean difference -0.28 kg (95% CI -0.55 to -0.01); p = 0.039]. Both treatments were well tolerated, with similar rates of adverse events.ConclusionGla-300 provides comparable glycaemic control to Gla-100 in a large population with a broad clinical spectrum of T2DM, with consistently less hypoglycaemia at any time of day and less nocturnal hypoglycaemia.

| S-EPMC4676914 | biostudies-literature

Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the EDITION clinical studies in people with type 2 diabetes.

Project description:AimsTo investigate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) vs insulin glargine 100 U/mL (Gla-100) over 12 months in a patient-level meta-analysis, using data from the EDITION studies in people with type 2 diabetes (T2DM).MethodsEDITION 1, 2 and 3 were multicentre, randomized, open-label, 2-arm, parallel-group, treat-to-target phase IIIa studies. Similar study designs and endpoints enabled a meta-analysis to be conducted.ResultsReductions in glycated haemoglobin (HbA1c) were better sustained over 12 months with Gla-300 than with Gla-100 (least squares [LS] mean difference in change from baseline: -0.10 % [95% confidence interval {CI} -0.18 to -0.02] or -1.09 mmol/mol [95% CI -2.01 to -0.20]; P = .0174). Risk of confirmed (≤3.9 mmol/L) or severe hypoglycaemia was 15% lower with Gla-300 vs Gla-100 at night (relative risk 0.85 [95% CI 0.77-0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90-0.98]). Rates of hypoglycaemia were 18% lower with Gla-300 vs Gla-100 at night (rate ratio 0.82 [95% CI 0.67-0.99]), but comparable at any time of day. HbA1c <7.0 % without nocturnal hypoglycaemia was achieved by 24% more participants with Gla-300 than with Gla-100 (relative risk 1.24 [95% CI 1.03-1.50]). Severe hypoglycaemia was rare; in both treatment groups the incidence of events at any time of day was ≤3.6%, while rates were ≤0.08 events per participant-year.ConclusionsIn a broad population of people with T2DM over 12 months, use of Gla-300 provided more sustained glycaemic control and significantly lower hypoglycaemia risk at night and at any time of day compared with Gla-100.

| S-EPMC5836995 | biostudies-literature

Glycaemic goal attainment and hypoglycaemia outcomes in type 2 diabetes patients initiating insulin glargine 300 units/mL or 100 units/mL: Real-world results from the DELIVER Naive cohort study.

Project description:AimsTo compare HbA1c and hypoglycaemia in insulin-naïve patients with type 2 diabetes (T2D) who initiated insulin glargine 300 units/mL (Gla-300) or 100 units/mL (Gla-100).Materials and methodsThis retrospective cohort study examined electronic medical records of insulin-naïve adults with T2D who initiated Gla-300 or Gla-100 during March 2015 through to December 2016 with active records for ≥12 months before and ≥6 months after initiation, and ≥1 valid HbA1c value during 6-month baseline and 90-180-day follow-up. Outcomes included HbA1c and hypoglycaemia. Cohorts were propensity score-matched (1:2) on baseline demographic and clinical characteristics. Sensitivity analyses were conducted using broader inclusion criteria.ResultsThe matched cohorts included 1004 Gla-300 and 2008 Gla-100 initiators (mean age 60.4 years; 53.2% male). During 6-month follow-up, Gla-300 versus Gla-100 initiators had a greater mean HbA1c decrease (-1.52 ± 2.08% vs. -1.30 ± 2.12%; P = 0.003) and more patients achieved HbA1c <7% (25.0% vs. 21.5%; P = 0.029) and <8% (55.0% vs. 49.2%; P = 0.002); and HbA1c <7% (21.9% vs. 17.4%; P = 0.003) and <8% (49.1% vs. 41.8%; P < 0.001) without hypoglycaemia. Gla-300 initiators were similarly or less likely to have any or inpatient/emergency department-associated hypoglycaemia during 3- and 6-month follow-up (e.g. any hypoglycaemia to 6 months: 9.7% vs. 12.5%; adjusted odds ratio 0.61; P = 0.057).ConclusionsAmong insulin-naïve adults with T2D, Gla-300 was associated with significantly better HbA1c reductions (latest value during 90-180-day follow-up) and similar or improved hypoglycaemia outcomes (3- and 6-month follow-up) than Gla-100.

| S-EPMC6618106 | biostudies-literature

The effect of concomitant DPPIVi use on glycaemic control and hypoglycaemia with insulin glargine 300 U/mL (Gla-300) versus insulin glargine 100 U/mL (Gla-100) in people with type 2 diabetes: A patient-level meta-analysis of EDITION 2 and 3.

Project description:To evaluate the effect of concomitant dipeptidyl peptidase IV inhibitor (DPPIVi) use on efficacy and safety of insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in people with type 2 diabetes on oral antihyperglycaemic drugs.A post hoc patient-level meta-analysis was performed using data from EDITION 2 (basal insulin [N = 811]) and EDITION 3 (insulin-naïve [N = 878]), multicentre, randomised, open-label, parallel-group, phase 3a trials of similar design. Endpoints analysed included HbA1c, hypoglycaemia and adverse events, investigated in subgroups of participants with and without concomitant DPPIVi use.Of 1689 participants randomised, 107 (13%, Gla-300) and 133 (16%, Gla-100) received DPPIVi therapy. The least squares mean change in HbA1c (baseline to month 6) was comparable between treatment groups, irrespective of DPPIVi use (no evidence of heterogeneity of treatment effect across subgroups, p = 0.753), although group sizes were unbalanced. The cumulative mean number of confirmed (?3.9 mmol/L [?70 mg/dL]) or severe hypoglycaemic events, and the risk and annualised rate of such events, were consistently lower for Gla-300 than Gla-100 during the night (between 00:00 and 05:59 h) or at any time of day (24 h period), irrespective of DPPIVi use. Severe hypoglycaemia occurred in 8/838 and 10/844 participants in the Gla-300 and Gla-100 groups, respectively, and was not affected by DPPIVi use. The adverse event profile was similar between treatment groups and DPPIVi subgroups.Glycaemic control with Gla-300 was comparable to Gla-100, with less hypoglycaemia during the night and at any time of day (24 h), irrespective of concomitant DPPIVi use.ClinicalTrials.gov NCT01499095; NCT01676220.

| S-EPMC5784896 | biostudies-literature

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