The Effect of Adjusting for Baseline Hypoglycemia when Analyzing Hypoglycemia Data: A Systematic Analysis of 15 Diabetes Clinical Trials

Aims: The primary objective was to demonstrate that basal insulin peglispro (BIL) was noninferior compared with insulin glargine (GL) for haemoglobin A1c (HbA1c) at 26 weeks with a non-inferiority margin of 0.4%. Results: At 26 weeks, mean HbA1c was 7.06% AE 0.04% and 7.43% AE 0.06% for patients assigned to BIL (N = 295) and GL (N = 160), respectively (difference -0.37% [95% CI: −0.50 to −0.23], P < .001); more patients on BIL achieved HbA1c <7% (44.9% vs 27.5%, P < .001). Compared with GL, patients using BIL lost weight, with lower fasting serum glucose and betweenday fasting blood glucose variability, and 36% less nocturnal hypoglycemia, 29% more total hypoglycemia and more severe hypoglycemia. Total and prandial insulin doses were lower with BIL; basal insulin doses were higher. Alanine aminotransferase increased with BIL, with more patients having elevations ≥3 × ULN. BIL treatment was associated with more frequent injection site reactions and an increase from baseline in serum triglycerides. Conclusions:In patients with type 1 diabetes, treatment with BIL compared to GL for 26 weeks was associated with lower HbA1c, less nocturnal hypoglycemia, lower glucose variability and weight loss. Increases in total and severe hypoglycemia, triglycerides, aminotransferases and injection site reactions were also noted. K E Y W O R D Sbasal insulin, glycaemic control, hypoglycaemia, randomised trial, type 1 diabetes

Section: Discussionmentioning

confidence: 99%

“…Achievement of HbA1c targets (last observation carried forward) was compared between treatments using logistic regression. Hypoglycemic events during a study interval were compared between treatments using a negative binomial regression by adjusting for pre‐randomization hypoglycemia rate …”

Section: Methodsmentioning

confidence: 99%

A randomized clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 1

Garg

Dreyer

Jinnouchi³

et al. 2016

“…HbA1c < 7.0%, and HbA1c < 7.0% with no nocturnal hypoglycaemia were compared between treatments using a logistic regression (for data at week 52 with last observation carried forward) as the primary analysis and a longitudinal logistic regression as a sensitivity analysis. The number of hypoglycaemic events during a specific period was compared between treatments using a negative binomial regression by adjusting for baseline sulphonylurea/meglitinide use and pre‐randomization (baseline) hypoglycaemia rate. In addition, a statistical joint modelling on HbA1c and basal insulin dose was conducted to evaluate the HbA1c reduction per 10 units of basal insulin (peglispro vs glargine) from baseline and week 52.…”

Section: Methodsmentioning

confidence: 99%

Basal insulin peglispro versus insulin glargine in insulin‐naïve type 2 diabetes: IMAGINE 2 randomized trial

Davies

Russell‐Jones

Selam

et al. 2016

AimsTo compare, in a double‐blind, randomized, multi‐national study, 52‐ or 78‐week treatment with basal insulin peglispro or insulin glargine, added to pre‐study oral antihyperglycaemic medications, in insulin‐naïve adults with type 2 diabetes.Material and methodsThe primary outcome was non‐inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients.ResultsPeglispro was non‐inferior to glargine in HbA1c reduction [least‐squares (LS) mean difference: −0.29%, 95% confidence interval (CI) −0.40, −0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio (OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro‐treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/L), and aspartate transaminase levels (27 vs 24 IU/L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro‐treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001).ConclusionsCompared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions.

“…The proportion of patients with the last non‐missing HbA1c value <7% was analysed using logistic regression. The hypoglycaemia rate was estimated and compared between treatments using negative binomial regression analysis, after adjustment for pre‐randomization (baseline) . Major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction or stroke) and MACE+ (MACE plus hospitalization for unstable angina) were analysed using a Cox proportional hazard model.…”

Section: Methodsmentioning

confidence: 99%

Randomized, double‐blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 3

Bergenstal¹,

Lunt

Franek

et al. 2016

AimsTo compare the efficacy and safety of basal insulin peglispro (BIL), which has a flat pharmacokinetic and pharmacodynamic profile and a long duration of action, with insulin glargine (GL) in patients with type 1 diabetes.Materials and methodsIn this phase III, 52‐week, blinded study, we randomized 1114 adults with type 1 diabetes in a 3 : 2 distribution to receive either BIL (n = 664) or GL (n = 450) at bedtime, with preprandial insulin lispro, using intensive insulin management. The primary objective was to compare glycated haemoglobin (HbA1c) in the groups at 52 weeks, with a non‐inferiority margin of 0.4%.ResultsAt 52 weeks, mean (standard error) HbA1c was 7.38 (0.03)% with BIL and 7.61 (0.04)% with GL {difference −0.22% [95% confidence interval (CI) −0.32, −0.12]; p < 0.001}. At 52 weeks more BIL‐treated patients reached HbA1c <7% (35% vs 26%; p < 0.001), the nocturnal hypoglycaemia rate was 47% lower (p < 0.001) and the total hypoglycaemia rate was 11% higher (p = 0.002) than in GL‐treated patients, and there was no difference in severe hypoglycaemia rate. Patients receiving BIL lost weight, while those receiving GL gained weight [difference −1.8 kg (95% CI −2.3, −1.3); p < 0.001]. Treatment with BIL compared with GL at 52 weeks was associated with greater increases from baseline in levels of serum triglyceride [difference 0.19 mmol/l (95% CI 0.11, 0.26); p < 0.001] and alanine aminotransferase (ALT) levels [difference 6.5 IU/l (95% CI 4.1, 8.9), p < 0.001], and more frequent injection site reactions.ConclusionsIn patients with type 1 diabetes, treatment with BIL compared with GL for 52 weeks resulted in a lower HbA1c, more patients with HbA1c levels <7%, and reduced nocturnal hypoglycaemia, but more total hypoglycaemia and injection site reactions and higher triglyceride and ALT levels.