Abstract
Hypoglycaemia is a common side‐effect of diabetes therapies, particularly insulin, and imposes a substantial burden on individuals and healthcare systems. Consequently, regulatory approval of newer basal insulin (BI) therapies has relied on demonstration of a balance between achievement of good glycaemic control and less hypoglycaemia. Randomized controlled trials (RCTs) are the gold standard for assessing efficacy and safety, including hypoglycaemia risk, of BIs and are invaluable for obtaining regulatory approval. However, their highly selected patient populations and their conditions lead to results that may not be representative of real‐life situations. Real‐world evidence (RWE) studies are more representative of clinical practice, but they also have limitations. As such, data both from RCTs and RWE studies provide a fuller picture of the hypoglycaemia risk with BI therapies. However, substantial differences exist in the way hypoglycaemia is reported across these studies, which confounds comparisons of hypoglycaemia frequency among different BIs. This problem is ongoing and persists in recent trials of second‐generation BI analogues. Although they provide a lower risk of hypoglycaemia when compared with earlier BIs, they do not eliminate it. This review describes differences in the way hypoglycaemia is reported across RCTs and RWE studies of second‐generation BI analogues and examines potential reasons for these differences. For studies of BIs, there is a need to standardize aspects of design, analysis and methods of reporting to better enable interpretation of the efficacy and safety of such insulins among studies; such aspects include length of follow‐up, glycaemic targets, hypoglycaemia definitions and time intervals for determining nocturnal events.
Highlights
Hypoglycaemia remains a common side-effect of diabetes treatment with insulin and is associated with a range of morbidities, including falls and accidents, and adverse cardiovascular events.[1]
To demonstrate the diversity in reporting of hypoglycaemia across Randomized controlled trials (RCTs), the present review focuses on two treat-to-target trial programmes of second-generation basal insulin (BI) analogues, namely, the BEGIN trials, which compared insulin degludec (IDeg) with insulin glargine 100 U/mL (Gla-100),[18,19,20,21,22,23,24,25,26] and the EDITION trials, in which insulin glargine 300 U/mL (Gla-300) and Gla-100 were compared
A meta-analysis of the BEGIN trials demonstrated that, while the risk of hypoglycaemia during the titration period was similar for IDeg and Gla-100, a risk reduction was observed with IDeg vs Gla-100 during the maintenance period in individuals with type 2 diabetes (T2DM)
Summary
Hypoglycaemia remains a common side-effect of diabetes treatment with insulin and is associated with a range of morbidities, including falls and accidents, and adverse cardiovascular events.[1]. The disparities in definitions, methods of assessment and reporting of hypoglycaemia across RCTs and RWE studies, combined with the differences in trial designs, analyses and populations, present significant challenges when comparing different insulin molecules and formulations. These issues can obfuscate the true differences in the safety of glucose-lowering therapies and may explain the observed inconsistencies across various regulatory and advisory guidelines. The BEGIN and EDITION trials attempted to account for differing hypoglycaemia risk factors by grouping trial populations according to the nature of previous antihyperglycaemic therapy (eg, BEGIN basal-bolus type 2,18 BEGIN Low Volume[20] and the EDITION 1, 2 and 3 trials),[27,28,29] or by racial background (eg, the BEGIN Asia trial[21] and the EDITION JP1 and JP2 trials).[30,31] while this demonstrates the efficacy of BIs within specific populations, it complicates interpretation
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