We welcome González and Di Girolamo’s interesting comments Citation[1] on our review ‘Safety and side effects of the insulin analogues’ Citation[2] published in Expert Opinion on Drug Safety. We would like to take this opportunity to make the following responses.
Regarding the lack of improvement of HbA1c seen when comparing analogue insulins with conventional products, Siebenhofer et al. Citation[3] commented on the poor methodology of the studies included in their meta-analysis. Of the 42 studies originally selected for the analysis of change in HbA1c, 20 had to be excluded and in the remainder the mean treatment period was 3.6 months. Because HbA1c is an indicator of mean diabetic control over 3 months, and considering the time needed to titrate insulin doses, this would include studies too short for HbA1c to be affected. Consistent with this, subgroup analyses showed a more pronounced effect on HbA1c in favour of analogues for patients using CSII and in studies with an intervention period > 3 months. There is also the issue that studies performed for regulatory purposes are often inadequate when it comes to demonstrating superiority in normal clinical practice.
Concerning quality of life, improvement has only been observed in open-label studies of patients with Type 1 diabetes mellitus. No differences were seen in a double-blinded study of patients with Type 1 diabetes or in the studies of patients with Type 2 diabetes mellitus. Patients find injecting analogue insulins immediately with their meals convenient compared with the 30-minute wait after a regular insulin injection; in double-blind studies where both insulins are injected at the same time, this benefit is clearly lost.
The analogue insulins, with their faster onset of action, are expected to have an advantage over regular insulin in regulating postprandial glucose excursion, an independent risk factor for cardiovascular disease Citation[4]. In keeping with this, Anderson et al. showed a 2.0 mmol/l reduction in postprandial glycaemic peak with lispro compared with regular insulin Citation[5].
We agree with González and Di Girolamo that the definition of hypoglycaemia varies from study to study, ranging from 2.0 to 3.9 mmol/l, and heavily relies on patient self-reporting. There are, however, well-designed studies that have reported a superiority of analogue insulins over regular and NPH insulin in terms of nocturnal hypoglycaemia Citation[6]. The data on use of analogue insulins with the newer glitazones are very limited, although there are theoretical advantages to this combination in patients with severe insulin resistance. This combination is currently not licensed for use in the UK.
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