Equipotency of insulin glargine and regular human insulin on glucose disposal in healthy subjects following intravenous infusion

Abstract. The absolute glucose disposal of insulin glargine (Lantus) was compared to that of regular human insulin in healthy subjects (n=20) using the euglycaemic clamp technique in a single-dose, double-blind, randomized, two-way crossover design. Subjects received 30-minute intravenous infusions of insulin glargine (0.1 IU/kg) or human insulin (0.1 IU/kg) and a 20% glucose solution infused at a variable rate to maintain euglycaemia at the subjects baseline glucose level. At equal baseline blood glucose levels (4.42 mmol/l [range, 4.00–5.16 mmol/l] and 4.42 mmol/l [range, 4.01–4.94 mmol/l], respectively), the area under the glucose infusion rate (GIR) time curves from 0–6 hours (AUC_(0–6h)) was within the bioequivalence range (insulin glargine, 663.92 mg/kg; human insulin, 734.85 mg/kg). Both the time to maximum GIR and the suppression of serum C-peptide were similar with insulin glargine and human insulin. The resulting maximum serum insulin concentrations (C_max) were 151.16 µIU/ml and 202.23 µIU/ml, and the time to C_max (T_max) was 30 minutes (the duration of the infusion). The observed differences in the C_max (the mean value for insulin glargine was about 25% lower than that of human insulin) could be explained by lower cross-reactivity of insulin glargine in the human insulin radioimmunoassay. The employed intravenous route, though definitely not the intended clinical use of insulin glargine, provided the clinical evidence in healthy subjects that on a molar basis insulin glargine is equipotent to regular human insulin regarding glucose disposal.     

Investigational new insulin glargine 300 U/ml has the same metabolism as insulin glargine 100 U/ml

Insulin glargine is processed in vivo into soluble 21^A‐Gly‐human insulin (M1), the principal moiety responsible for metabolic effects, and subsequently into M2. This sub‐study compared metabolism and metabolite pharmacokinetic (PK) profiles of investigational new insulin glargine U300 (Gla‐300) with insulin glargine 100 U/ml (Gla‐100, Lantus®, Sanofi‐Aventis Deutschland GmbH, Frankfurt am Main, Germany) in people with type 1 diabetes. Participants received 0.4 (n = 18) or 0.6 U/kg Gla‐300 (n = 12), and 0.4 U/kg Gla‐100 (n = 30) once daily in randomized order for 8 days prior to a 36‐h euglycaemic clamp. Metabolites were quantified using immunoaffinity enrichment and liquid chromatography tandem mass spectrometry (LC‐MS/MS). Glargine metabolism was the same regardless of Gla‐100 or Gla‐300 administration; M1 was confirmed as the principal active moiety circulating in blood. Steady state concentrations of M1 were achieved after 2 days for Gla‐100, and 4 days for Gla‐300. Steady state M1 values defined prolonged and even flatter PK profiles after Gla‐300 administration compared with M1 profiles after Gla‐100.     

Optimization of basal insulin delivery in Type 1 diabetes: a retrospective study on the use of continuous subcutaneous insulin infusion and insulin glargine.

AIMS: To compare the effects on glycaemic control after using continuous subcutaneous insulin infusion (CSII) or insulin glargine. METHODS: Data were obtained from 17 diabetes outpatient clinics in Sweden, employing the same diabetes data management system. Type 1 diabetic patients using multiple dose injections were included prior to starting on either CSII (n = 563) or glargine (n = 513). The median duration of therapy was 25 months for CSII and 6 months for glargine. The comparison between the treatment modalities was carried out by multiple regression analysis and logistic regression analysis in an attempt at reducing the influence of confounding factors. RESULTS: The mean HbA1c decrease was 0.59 +/- 1.19% for CSII and 0.20 +/- 1.07% for glargine (P < 0.001, when assessed by logistic regression). An additional 0.1% lower HbA1c would be expected if glargine had been optimized with basal insulin 40-60% of the daily dose. The more pronounced effect of CSII was achieved with a lower daily dosage of insulin. In a multiple regression analysis with a change of HbA1c as the dependent variable, the following variables were significant: choice of treatment (P < 0.001), HbA1c prior to treatment (P < 0.001) and BMI prior to treatment (P < 0.01). CONCLUSION: Both regimes improved metabolic control, but CSII resulted in significantly higher reduction in HbA1c than after insulin glargine treatment, particularly in those individuals who had higher levels of HbA1c at baseline.     

A post-hoc pooled analysis to evaluate the risk of hypoglycaemia with insulin glargine 300 U/mL (Gla-300) versus 100 U/mL (Gla-100) over wider nocturnal windows in individuals with type 2 diabetes on a basal-only insulin regimen

The EDITION trials in type 2 diabetes demonstrated comparable glycaemic control with less nocturnal and anytime (24-hour) hypoglycaemia for insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100). However, the predefined nocturnal window (0:00–5:59 AM ) may not be the most relevant for clinical practice. This post-hoc analysis compared expansions of the predefined nocturnal interval during basal insulin treatment without prandial insulin. Patient-level, 6-month data, pooled from the EDITION 2 and 3 trials and the EDITION JP 2 trial (N = 1922, basal insulin only) were analysed. Accompanying hypoglycaemia during treatment with Gla-300 was compared to that during treatment with Gla-100, using predefined (0:00–5:59 AM ) and expanded (10:00 PM –5:59 AM , 0:00–7:59 AM , 10:00 PM to pre-breakfast SMPG) windows. Confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic events were reported most frequently between 6:00 AM and 8:00 AM . Windows expanded beyond 6:00 AM included more events than other windows. The percentage of participants with at least one event was lower with Gla-300 than Gla-100 in all windows examined. Expanding the nocturnal interval allows better assessment of the risk of hypoglycaemia associated with basal insulin. The risk of nocturnal hypoglycaemia was consistently lower with Gla-300 versus Gla-100 using all four windows.     

甘精胰岛素300 U/ml与100 U/ml治疗中国2型糖尿病患者疗效和安全性的比较

目的比较甘精胰岛素300 U/ml(Gla-300)与100 U/ml(Gla-100)治疗非胰岛素类降糖药血糖控制不佳中国T2DM患者的疗效和安全性。方法本研究为EDITION AP(NCT02855684)中国亚组分析,在这项开放标签、随机对照的临床试验中,非Ins类降糖药物血糖控制不佳的474例中国T2DM患者按2:1比例随机予Gla-300(n=315)或Gla-100(n=159)治疗,观察两组26周时的疗效和安全性指标。结果两组自基线至治疗26周时HbA1c降幅的最小二乘均值差为0.05%,达到非劣效性评估终点。26周治疗期间,Gla-300组发生至少1次重度和/或证实夜间低血糖患者比例低于Gla-100组(31.5%vs 42.0%,P=0.03)。两组其余疗效和安全性指标差异无统计学意义。结论Gla-300治疗26周降低HbA1c效果与Gla-100相似,发生夜间低血糖风险更低。     

Glycaemic control and hypoglycaemia in people with type 2 diabetes switching from twice‐daily basal insulin to once‐daily insulin glargine 300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup analysis)

In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla‐300) and glargine 100 U/mL (Gla‐100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice‐daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice‐daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla‐300 or Gla‐100 (least squares mean difference ?0.01%; 95% confidence interval [CI] ?0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI ?0.25 to 0.57, in EDITION 2). Participants previously receiving twice‐daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla‐300 vs Gla‐100 at night (00:00–05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla‐300 provided similar glycaemic control with less hypoglycaemia compared with Gla‐100 in people with T2DM switching from twice‐daily to once‐daily basal insulin.     

Titration and optimization trial for the initiation of insulin glargine 100 U/mL in patients with inadequately controlled type 2 diabetes on oral antidiabetic drugs

For patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control, addition of basal insulin is recommended, but titration and optimization of basal insulin therapy in primary care is not well understood. We conducted an observational trial in 2470 patients with T2DM who initiated insulin glargine 100 U/L (Gla-100) on top of oral antidiabetic drugs. Physicians were free to choose either a “Davies,” “Fritsche” or “individual” titration algorithm. We found that fasting blood glucose (FBG) and glycated haemoglobin (HbA1c) levels were effectively reduced by Gla-100; 65.9% of patients achieved the primary endpoint (FBG ≤6.1 mmol/L (110 mg/dL) or an individual HbA1c target). There were no significant differences in efficacy and safety between the algorithms used. The mean FBG decreased by 3.2 mmol/L (59 mg/dL) over 12 months, while the mean HbA1c decreased by 15.3 mmol/mol (1.4%)%. From a starting dose of 11.7 U/d, the Gla-100 dosage was 22.8 U/d at 12 months, with similar values in each group. Rates of hypoglycaemia were low and did not differ by titration algorithm. We conclude that Gla-100 was effective at reducing FBG and HbA1c, independent of the titration algorithm, but observed that algorithms were inconsistently applied in clinical practice.     

Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine

The safety and efficacy of LY2963016 insulin glargine (LY IGlar) and Lantus^® insulin glargine (IGlar), products with identical primary amino acid sequences, were assessed in subgroups of patients with type 1 (T1D, n = 452) or type 2 diabetes (T2D, n = 299) reporting prestudy IGlar treatment in 52‐week open‐label (ELEMENT‐1) and 24‐week double‐blind (ELEMENT‐2) studies. At randomization, patients transitioned from their prestudy IGlar to equivalent doses of LY IGlar or IGlar. Primary efficacy (change in glycated haemoglobin from baseline to 24 weeks), other efficacy and select safety outcomes of LY IGlar were compared with those of IGlar. Continuous data were analysed using analysis of covariance, categorical data by Fisher's exact test, and treatment comparisons for hypoglycaemia by Wilcoxon test. No statistically significant treatment differences were identified for efficacy and safety outcomes except for weight change (T1D), overall incidence of detectable insulin antibodies (T2D), and serious adverse events (T2D). These differences were neither consistently observed across both studies nor observed in the total study populations, and their magnitude suggests they were not clinically meaningful. LY IGlar and IGlar show similar efficacy and safety profiles in patients reporting prestudy IGlar treatment.     

An observational study comparing continuous subcutaneous insulin infusion (CSII) and insulin glargine in children with type 1 diabetes

OBJECTIVE: The advantages of continuous subcutaneous insulin infusion (CSII) or insulin glargine have been demonstrated both in adult and paediatric diabetic patients; however, as no data comparing these two approaches during childhood are available, we have examined the efficacy of these two intensive approaches. RESEARCH DESIGN AND METHODS: We retrospectively evaluated data from 36 diabetic children, who had changed their previous insulin regimen [with isophane insulin (NPH) at bedtime] because of HbA1c levels >8.0%. Twenty patients underwent CSII, while the other 16 (significantly younger for age) started insulin glargine at bedtime. RESULTS: At 6 and 12 months, CSII-treated patients showed a significant reduction in HbA1c values from 8.5 +/- 1.8 to 7.4 +/- 1.1% and to 7.6 +/- 1.2%, respectively. The insulin requirement significantly decreased from 0.93 +/- 0.2 IU/kg to 0.73 +/- 0.2 IU/kg of body weight and to 0.74 +/- 0.15 IU/kg of body weight, respectively, while no significant differences were observed for BMI SDS, fructosamine and severe hypoglycaemic events. The patients treated with glargine showed a small decline in HbA1c values from 8.9 +/- 1.7 to 8.3 +/- 0.9% (not significant) in the first 6 months of treatment and to 8.2 +/- 0.9% after 12 months. CONCLUSION: The basal insulin supplementation can be supplied effectively in children with type 1 diabetes by either CSII or insulin glargine. As previously reported for adults, it is confirmed that CSII is the best current intensive approach aimed to the improvement of glycaemic control.     

A morning dose of insulin glargine prevents nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion with insulin lispro

AIM: The aim of this crossover trial was to evaluate the potential of partial substitution of basal insulin with glargine, administered once daily in the morning, to protect against nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion (CSII). METHODS: Seven patients with type 1 diabetes received 4 weeks of treatment with insulin lispro, administered by CSII, and 4 weeks of treatment with CSII and a partial basal replacement dose of insulin glargine administered in the morning. On day 28 of each treatment phase, patients were admitted to the research unit where dinner was served and their usual dinner insulin bolus dose given, after which CSII was discontinued at 7 pm. Plasma (p) beta-hydroxybutyrate and p glucose were measured every hour for 12 h thereafter. RESULTS: Plasma beta-hydroxybutyrate at 7 pm was 0.16+/-0.05 and 0.13+/-0.07 mmol/l with and without glargine, respectively, and increased to 0.17+/-0.10 and 0.60+/-0.3 mmol/l within 6 h (P=0.02). Plasma glucose increased without glargine, from 8.6+/-2.9 to 21.1+/-3.0 mmol/l (P=0.003), but did not rise significantly following glargine (13.6+/-4.7 vs. 12.6+/-5.6 mmol/l; P=0.65). CONCLUSIONS: Partial replacement with a morning dose of insulin glargine protects against the development of ketosis for as much as 12 h after postprandial interruption of CSII. This treatment strategy could, therefore, be useful for patients who are prone to ketosis but, for other reasons, are deemed suitable for CSII.     

Predictors of treatment response in type-2 diabetes patients initiating basal-supported oral therapy with insulin glargine 100 U/mL: A sub-analysis of the Titration and OPtimisation (TOP) registry

The aim of this study was to identify predictors of long-term response to the initiation of basal-supported oral therapy (BOT) with insulin glargine (IGlar-100). Patients from the observational TOP registry were grouped based on those who had achieved (responders) and those who had not achieved (non-responders) their HBA1c target and/or FBG ≤110 mg/dL 12 months after IGlar-100 initiation. Independent predictors of treatment response were identified by regression analysis. Data for 2444 patients were analysed (responders, n = 1610; non-responders, n = 834). Although the IGlar-100 dose increase over 12 months was larger for non-responders (+12.83 vs +9.46 U/d; P < 0.0001), the corresponding decrease in HbA1c was smaller (−0.88% vs −1.57%). Independent predictors of response included lower BMI (OR, 0.97; 95% CI, 0.95-1.00), lower FBG (OR, 0.98; 95% CI, 0.97-0.98) and HbA1c values at baseline (OR, 0.24; 95% CI, 0.18-0.31), a less ambitious HbA1c target (OR, 5.07; 95% CI, 3.37-7.63) and bedtime administration of IGlar-100 (OR, 1.55; 95% CI, 1.12-2.14). In conclusion, HbA1c was the clinically most significant baseline characteristic predictive of response to BOT. This may suggest an advantage of IGlar-100 initiation prior to excessive hyperglycaemia escalation.     

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

Aims

To 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).

Methods

EDITION 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.

Results

Reductions 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.

Conclusions

In 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.     

Italian Titration Approach Study (ITAS) with insulin glargine 300 U/mL in insulin-naïve type 2 diabetes: Design and population

Background and aims

Fostering patient's self-managing of basal insulin therapy could improve glucose control, by removing patient's and physician's barriers to basal insulin initiation, titration and glucose monitoring. The Italian Titration Approaches Study (ITAS) aims at demonstrating non-inferiority (<0.3% margin) in efficacy of glucose control (change in glycated hemoglobin [HbA1c] after 24 weeks) by the same titration algorithm of insulin glargine 300 U/mL (Gla-300), managed by the (nurse assisted) patient versus the physician, in insulin naïve patients with Type 2 Diabetes Mellitus (T2DM), uncontrolled with previous treatments.

Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy.

AIMS: To compare glycaemic control and risk of hypoglycaemia of twice-daily insulin detemir with once-daily insulin glargine in subjects with Type 1 diabetes. METHODS: In this 26-week, multicentre, open-label, parallel-group trial, 320 subjects with Type 1 diabetes received either insulin detemir twice daily or insulin glargine once daily. each in combination with premeal insulin aspart. RESULTS: After 26 weeks, HbA(1c) had decreased from 8.8 to 8.2% in the insulin detemir group and from 8.7 to 8.2% in the insulin glargine group. Home-measured fasting plasma glucose (PG) was lower with insulin glargine than with insulin detemir (7.0 vs. 7.7 mmol/l, P < 0.001). The overall shape of the home-measured nine-point PG profiles was comparable between treatments (P = 0.125). Overall, there was no significant difference in within-subject variation in PG (P = 0.437). Within-subject variation in predinner PG was lower with insulin detemir than with insulin glargine (P < 0.05). The overall risk of hypoglycaemia was similar with no differences in confirmed hypoglycaemia. However, the risk of severe and nocturnal hypoglycaemia was 72% and 32%, respectively, lower with insulin detemir than with insulin glargine (P < 0.05). Body weight gain was not significantly different comparing insulin detemir and insulin glargine (0.52 kg vs. 0.96 kg, P = 0.193). CONCLUSIONS: Treatment with twice-daily insulin detemir or once-daily insulin glargine, each in combination with insulin aspart, resulted in similar glycaemic control. The overall risk of hypoglycaemia was comparable, whereas the risks of both severe and nocturnal hypoglycaemia were significantly lower with insulin detemir.