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

Abstract

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.

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

“…A reduction in peripheral insulin action may enable lipolysis of adipocyte triglyceride, thus increasing free fatty acid flux to the liver where re‐esterification to triglycerides and secretion of very low‐density lipoproteins occurs. Of note, patients with type 2 diabetes naïve to insulin therapy had only minimal changes in triglyceride levels with BIL treatment; in contrast, insulin naïve patients who initiated GL therapy had a small but significant reduction in triglycerides, consistent with what has been demonstrated for exogenous insulin (and for GL in particular) . These observations support the notion that conventional basal insulin withdrawal, when BIL is introduced as a new basal insulin, may change the metabolic flux.…”

Similar HbA1c reduction and hypoglycaemia with variable‐ vs fixed‐time dosing of basal insulin peglispro in type 1 diabetes: IMAGINE 7 study

“…These data are consistent with what would be expected of the long half‐life observed for BIL in PK studies . Furthermore, in other studies, glycaemic variability was lower with BIL than with comparator insulins (insulin glargine and NPH) . Reduction of glycaemic variability may not only allow more effective titration of basal insulin and improved glycaemic efficacy compared to insulin glargine or NPH but may also reduce nocturnal hypoglycaemia and perhaps reduce the risk or delay the onset of long‐term health concerns .…”

“…Furthermore, in other studies, glycaemic variability was lower with BIL than with comparator insulins (insulin glargine and NPH) . Reduction of glycaemic variability may not only allow more effective titration of basal insulin and improved glycaemic efficacy compared to insulin glargine or NPH but may also reduce nocturnal hypoglycaemia and perhaps reduce the risk or delay the onset of long‐term health concerns . Of note, the study cohort was comprised of T1D patients with a mean duration of diabetes of 20 years in whom more than half achieved an HbA1c of less than 7% after 12 weeks of therapy (lead‐in period) and for most patients this was maintained for the next 24 weeks.…”

“…BIL is a novel insulin with a half‐life greater than 24 hours as determined by pharmacokinetic/pharmacodynamics (PK/PD) studies . Moreover, Phase 2 and 3 clinical trials have demonstrated that there is less glycaemic variability during treatment with BIL, compared to treatment with glargine or isophane insulin (NPH) …”

Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease

“…However, in two randomized studies, liraglutide treatment did not reduce liver fat in patients with T2DM . Only a few studies have investigated the effect of basal insulin on liver fat in NAFLD, and these studies have had controversial results …”