Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes.

BACKGROUND: SAR342434 (SAR-Lis) is a biosimilar (follow-on) of insulin lispro (Humalog®; Ly-Lis). Two randomized, controlled, open-label, parallel-group, phase 3 studies were conducted to compare the efficacy and safety of SAR-Lis and Ly-Lis, both in combination with insulin glargine (Lantus®). SORELLA 1 was a 12-month study in 507 people with type 1 diabetes mellitus (T1DM); SORELLA 2 was a 6-month study in 505 people with type 2 diabetes mellitus (T2DM). In this study, the impact of anti-insulin antibodies (AIA) to SAR-Lis and Ly-Lis on safety and glycemic control is reported. METHODS: AIA were measured regularly throughout both studies at a centralized laboratory blinded to treatment groups using a drug-specific AIA assay. The AIA status (positive or negative), AIA titers, and cross-reactivity to human insulin, insulin glargine, and insulin glargine metabolite M1 were analyzed. The potential effect of AIA on safety, particularly as related to hypersensitivity reactions, hypoglycemia, and treatment-emergent adverse events, as well as on glycemic control (HbA1c, insulin dose), was evaluated. RESULTS: AIA positive status at baseline was similar for the two insulins, but higher in T1DM than in T2DM. In both studies, the percentage of people newly developing AIA in the two treatment groups, or having a ≥4-fold increase in AIA titers, did not differ. No relationship was observed between maximum individual AIA titers and change in HbA1c or insulin dose, hypoglycemia, or hypersensitivity reactions or between efficacy/safety measures and subgroups by presence or absence of treatment-emergent AIA. Hypersensitivity events and events adjudicated as allergic reactions were few and did not differ between the two groups. CONCLUSION: Insulin lispro SAR342434 and the originator insulin lispro had a similar immunogenicity profile in people with T1DM or T2DM.

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).

AIMS: Insulin 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). METHODS: EDITION 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. RESULTS: Among 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. CONCLUSIONS: In T1DM, Gla-300 provides glucose control comparable to that of Gla-100, and can be given at any time of day.

Comparison of Insulin Glargine 300 Units/mL and 100 Units/mL in Adults With Type 1 Diabetes: Continuous Glucose Monitoring Profiles and Variability Using Morning or Evening Injections.

OBJECTIVE: The objective of this study was to compare glucose control in participants with type 1 diabetes receiving insulin glargine 300 units/mL (Gla-300) or glargine 100 units/mL (Gla-100) in the morning or evening, in combination with mealtime insulin. RESEARCH DESIGN AND METHODS: In this 16-week, exploratory, open-label, parallel-group, two-period crossover study (clinicaltrials.gov identifier NCT01658579), 59 adults with type 1 diabetes were randomized (1:1:1:1) to once-daily Gla-300 or Gla-100 given in the morning or evening (with crossover in the injection schedule). The primary efficacy end point was the mean percentage of time in the target glucose range (80-140 mg/dL), as measured using continuous glucose monitoring (CGM), during the last 2 weeks of each 8-week period. Additional end points included other CGM glycemic control parameters, hypoglycemia (per self-monitored plasma glucose [SMPG]), and adverse events. RESULTS: The percentage of time within the target glucose range was comparable between the Gla-300 and Gla-100 groups. There was significantly less increase in CGM-based glucose during the last 4 h of the 24-h injection interval for Gla-300 compared with Gla-100 (least squares mean difference -14.7 mg/dL [95% CI -26.9 to -2.5]; P = 0.0192). Mean 24-h glucose curves for the Gla-300 group were smoother (lower glycemic excursions), irrespective of morning or evening injection. Four metrics of intrasubject interstitial glucose variability showed no difference between Gla-300 and Gla-100. Nocturnal confirmed (<54 mg/dL by SMPG) or severe hypoglycemia rate was lower for Gla-300 participants than for Gla-100 participants (4.0 vs. 9.0 events per participant-year; rate ratio 0.45 [95% CI 0.24-0.82]). CONCLUSIONS: Less increase in CGM-based glucose levels in the last 4 h of the 24-h injection interval, smoother average 24-h glucose profiles irrespective of injection time, and reduced nocturnal hypoglycemia were observed with Gla-300 versus Gla-100.

Efficacy and Safety of Flexible Versus Fixed Dosing Intervals of Insulin Glargine 300 U/mL in People with Type 2 Diabetes.

BACKGROUND: Insulin glargine 300 U/mL (Gla-300) has a more constant and prolonged action profile than insulin glargine 100 U/mL and in clinical studies is associated with similar glycemic control but less hypoglycemia. Whether its effects are altered by variability of injection time was examined in two 3-month substudies. MATERIALS AND METHODS: Eligible participants completing 6 months of optimized treatment with Gla-300 in EDITION 1 (n = 109) and EDITION 2 (n = 89), having a mean hemoglobin A1c (HbA1c) level of 7.3 % (SD 1.0 %), were randomized (1:1) to groups advised to increase variability of between-injection intervals to 24 ± up to 3 h or to maintain fixed 24-h intervals for 3 months. Changes of HbA1c level and other efficacy and safety measures were assessed. RESULTS: In the fixed-dosing group, 64% of participants reported all intervals within the 23-25-h range, compared with 15% of those advised flexible dosing. In the fixed- and flexible-dosing groups, 12% and 41%, respectively, of between-injection intervals were outside the 23-25-h range, and 2% and 16%, respectively, were outside the 21-27-h range. Least squares mean between-group difference in HbA1c change from baseline was 0.05 % (95% confidence interval [CI], -0.13 to 0.23); for fasting plasma glucose, 2.7 mg/dL (95% CI, -9.0 to 14.4); and for daily basal insulin dose, 0.00 U/kg (95% CI, -0.02 to 0.03). Frequencies of hypoglycemia and adverse events did not differ between groups. CONCLUSIONS: The efficacy and safety of Gla-300 demonstrated in EDITION 1 and EDITION 2 are maintained in substudies when the insulin was injected up to 3 h before or after the usual time of administration.

New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4).

OBJECTIVE: Insulin therapy in type 1 diabetes still provides suboptimal outcomes. Insulin glargine 300 units/mL (Gla-300), with a flatter pharmacodynamic profile compared with insulin glargine 100 units/mL (Gla-100), is an approach to this problem. RESEARCH DESIGN AND METHODS: People with type 1 diabetes, using a mealtime and basal insulin regimen, were randomized open-label to Gla-300 or Gla-100 and to morning or evening injection, continuing the mealtime analog, and followed for 6 months. RESULTS: Participants (n = 549) were a mean age of 47 years and had a mean duration of diabetes of 21 years and BMI of 27.6 kg/m(2). The change in HbA1c (primary end point; baseline 8.1%) was equivalent in the two treatment groups (difference, 0.04% [95% CI -0.10 to 0.19]) (0.4 mmol/mol [-1.1 to 2.1]), and Gla-300 was thus noninferior. Similar results with wider 95% CIs were found for morning and evening injection times and for prebreakfast self-measured plasma glucose (SMPG) overall. Results were also similar for Gla-300 when morning and evening injection time was compared, including overlapping 8-point SMPG profiles. Hypoglycemia did not differ, except for the first 8 weeks of the study, when nocturnal confirmed or severe hypoglycemia was lower with Gla-300 (rate ratio 0.69 [95% CI 0.53-0.91]). Hypoglycemia with Gla-300 did not differ by time of injection. The basal insulin dose was somewhat higher at 6 months for Gla-300. The adverse event profile did not differ and was independent of the Gla-300 time of injection. Weight gain was lower with Gla-300. CONCLUSIONS: In long-duration type 1 diabetes, Gla-300 provides similar glucose control to Gla-100, with a lower risk of hypoglycemia after transfer from other insulins, independent of time of injection, and less weight gain.

New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2).

OBJECTIVE: To compare the efficacy and safety of new insulin glargine 300 units/mL (Gla-300) with glargine 100 units/mL (Gla-100) in people with type 2 diabetes using basal insulin (≥42 units/day) plus oral antihyperglycemic drugs (OADs). RESEARCH DESIGN AND METHODS: EDITION 2 was a multicenter, open-label, two-arm study. Adults receiving basal insulin plus OADs were randomized to Gla-300 or Gla-100 once daily for 6 months. The primary end point was change in HbA1c. The main secondary end point was percentage of participants with one or more nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemic events from week 9 to month 6. RESULTS: Randomized participants (n = 811) had a mean (SD) HbA1c of 8.24% (0.82) and BMI of 34.8 kg/m(2) (6.4). Glycemic control improved similarly with both basal insulins; least squares mean (SD) reduction from baseline was -0.57% (0.09) for Gla-300 and -0.56% (0.09) for Gla-100 (mean difference -0.01% [95% CI -0.14 to 0.12]), with 10% higher dose of Gla-300. Less nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemia was observed with Gla-300 from week 9 to month 6 (relative risk 0.77 [95% CI 0.61-0.99]; P = 0.038) and during the first 8 weeks. Fewer nocturnal and any time (24 h) hypoglycemic events were reported during the entire 6-month period. Weight gain was lower with Gla-300 than with Gla-100 (P = 0.015). No between-treatment differences in safety parameters were identified. CONCLUSIONS: Gla-300 was as effective as Gla-100 and associated with a lower risk of hypoglycemia during the night and at any time of the day.

New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1).

OBJECTIVE: To compare the efficacy and safety of new insulin glargine 300 units/mL (Gla-300) with glargine 100 units/mL (Gla-100) in people with type 2 diabetes on basal insulin (≥42 units/day) plus mealtime insulin. RESEARCH DESIGN AND METHODS: EDITION 1 (NCT01499082) was a 6-month, multinational, open-label, parallel-group study. Adults with glycated hemoglobin A1c (HbA1c) 7.0-10.0% (53-86 mmol/mol) were randomized to Gla-300 or Gla-100 once daily with dose titration seeking fasting plasma glucose 4.4-5.6 mmol/L. Primary end point was HbA1c change from baseline; main secondary end point was percentage of participants with one or more confirmed (≤3.9 mmol/L) or severe nocturnal hypoglycemia from week 9 to month 6. RESULTS: Participants (n = 807) had mean age 60 years, diabetes duration 16 years, BMI 36.6 kg/m(2), and HbA1c 8.15% (65.6 mmol/mol). HbA1c reduction was equivalent between regimens; least squares mean difference -0.00% (95% CI -0.11 to 0.11) (-0.00 mmol/mol [-1.2 to 1.2]). Fewer participants reported one or more confirmed (≤3.9 mmol/L) or severe nocturnal hypoglycemic events between week 9 and month 6 with Gla-300 (36 vs. 46% with Gla-100; relative risk 0.79 [95% CI 0.67-0.93]; P < 0.005); nocturnal hypoglycemia incidence and event rates were also lower with Gla-300 in the first 8 weeks of treatment. No between-treatment differences in tolerability or safety were identified. CONCLUSIONS: Gla-300 controls HbA1c as well as Gla-100 for people with type 2 diabetes treated with basal and mealtime insulin but with consistently less risk of nocturnal hypoglycemia.