Dr Kamal and colleagues published in Expert Opinion on Drug Safety Citation[1] a review on the side effects of insulin analogues, making a comparison with standard insulins. We would like to comment about some topics on which this interesting paper focuses. Short-acting analogues (lyspro, aspart) appear to be at an advantage regarding regular insulin because of their convenience, allowing more flexible insulinisation regimes. Nevertheless, they do not seem to be substantially more efficacious than standard insulin. In Siebenhofer´s meta-analysis Citation[2] cited by Kamal, a weighted mean difference of 0.1% in haemoglobin A1c levels was found in type 1 patients in favour of rapid-acting analogues, which would represent a number-needed-to-treat above 600 to prevent the development of a case of retinopathy Citation[3]. Even when available comparative information is more limited in respect to the long-acting analogues (glargine, detemir), it is also possible to anticipate minor differences (in terms of A1c reduction) regarding neutral protamine hagedorn insulin. In this context, safety is of major interest. And regarding safety, some issues are on debate (it is not our intention to be exhaustive on all the conflictive points). With hypoglycaemia being the chief adverse event for insulins, methodological aspects related to its evaluation are crucial. In a majority of trials, hypoglycaemic episodes are counted from the information provided by patients, after self-measurements, collected in ‘diaries’. This is a potential source of bias, considering that it would be possible to induce a differential perception of hypoglycaemia when changes in pharmacodynamic profile of an insulin preparation arise. Nocturnal hypoglycaemic episodes are frequently under-registered. It is still very difficult to obtain continuous glycaemic records in clinical trials for periods longer than 3 days. Another conflictive point resides in the definition of ‘hypoglycaemic event’; even today, it is possible to find heterogeneity among protocols in this field (cutoff, characteristics etc.). Interactions of analogues with insulin-sensitisers are also pending on deeper study, specifically regarding the incidence of heart failure. Combination therapy (insulin plus glitazone) increases the risk of developing oedema and heart failure when compared with glitazone monotherapy, and the available information on combination with analogues is still limited. Finally, regarding the use of analogues in pregnancy, two clinical situations should be considered: 1) gestational (GDM) and 2) pregestational diabetes mellitus (PGDM). GDM could be an indication for analogues, especially for short-acting Citation[4]; with reference to PGDM, there is a consensus that rapid-acting analogues do not interfere with embriogenesis (regarding glargine the available information does not allow a final recommendation). Referring to proliferative retinopathy, larger studies are needed to attain more definitive conclusions.
Conflict of interest
Claudio D González is Medical Director of Novo Nordisk Argentina.
Bibliography
- KAMAL AD, DIXON AN, BAIN SC: Safety and side effects of the insulin analgues. Expert Opin. Drug Saf. (2006) 5(1):131-143.
- SIEBENHOFER A, PLANK J, PIEBER TR: Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst. Rev. (2004):CD003287.
- SCHOOFF M, EHLERS K: Short-acting insulin analogues vs. human insulin for diabetes. Am. Fam. Physician (2005) 72(5):805-807.
- GONZALEZ C, SANTORO S, SALZBERG S et al.: Insulin analogue therapy in pregnancies complicated by diabetes mellitus. Expert Opin. Pharmacother. (2005) 6(5):735-742.