Long-term research is lacking -- potential harm remains unclear -- valid studies are urgently needed for growing and developing children and adolescents
Due to a lack of suitable studies, it remains unclear whether children and adolescents with type 1 diabetes benefit more or less from long-term treatment with rapid-acting insulin analogues than with short-acting human insulin. Certainly, there is no proof of additional benefit from the available results from clinical trials of maximum one year duration. This applies both in the comparison with human insulin and in the comparison between analogues only. This is the conclusion of the final report of the Institute for Quality and Efficiency in Health Care (IQWiG) published in November 2009.
The Institute believes that studies of longer duration are urgently needed because insulin performs a variety of functions particularly during stages of human growth and development and it is not clear what effect insulin analogues have.
Important data on children and adolescents were not available for the first assessment
The current investigation is a follow-up project to a benefit assessment of rapid-acting insulin analogues in type 1 diabetes, commissioned by the Federal Joint Committee (G-BA) and completed in March 2007. In that assessment, IQWiG could only draw conclusions for adults concerning the advantages and disadvantages of the drug class, as data on children and adolescents were missing from completed but as yet unpublished studies. One of the sponsors of these trials, Novo Nordisk, had refused to provide relevant information. Only after public pressure did Novo Nordisk change its position and agree to supply the data requested.
As an assessment under these altered conditions was likely to produce new findings, the G-BA awarded a follow-up commission to investigate the benefit and harm of insulin analogues solely in these younger patients. Its aim was firstly to compare rapid-acting insulin analogues with short-acting human insulin in children and adolescents with type 1 diabetes, and secondly to weigh up the effects of different rapid-acting analogues. IQWiG assessed all 3 analogue drugs approved in Germany: insulin aspart (tradename: Novorapid), insulin lispro (tradename: Humalog, Liprolog) and insulin glulisine (tradename: Apidra).
Longest study only lasted 1 year
IQWiG could only identify a total of 4 suitable studies that conducted comparisons among human insulin and insulin analogues in children and adolescents with type 1 diabetes. All 4 studies investigated the use of analogue insulin in intensified injection therapy. No relevant study was found on pump therapy, which is in common use. In the studies, the young patients were investigated for 24 to 26 weeks, in one case for 12 months. There are currently no studies with a duration of longer than 1 year.
Additional benefit could not be derived from studies
IQWiG found no proof of additional benefit of analogues in these studies. This applied to the comparison with human insulin as well as to comparisons between analogues only. The majority of data available concerned long-term glucose control in the form of the HbA1c value and the frequency of hypoglycaemia. If the results of these 2 aspects are analysed, no advantage is shown for any of the analogue insulins in any of the studies.
Insufficient research into potential harm
As suitable studies of several years' duration are lacking, scarcely any conclusions can be drawn concerning the potential harm of rapid-acting insulin analogues. However, in some of the studies, a serious metabolic crisis (ketoacidotic coma), leading to a coma, occurred more frequently in patients who injected insulin analogues. Nevertheless, the differences were not statistically significant, i.e. it could just have been a random observation. Due to the short observation period and the paucity of results, it cannot be confirmed whether the use of short-acting insulin analogues increases the risk of ketoacidosis.
Instruments used to measure quality of life and treatment satisfaction are not suitable
In addition, the studies do not permit any conclusions on quality of life or treatment satisfaction. Both of these outcomes were measured in only one study. Ultimately, however, the results could not be interpreted because the measuring instruments used were evidently not suitable for children. This is totally incomprehensible as instruments suitable for children and adolescents have been available for a long time.
IQWiG calls for more studies
Although at least 2 out of the current 3 analogue drugs have been prescribed for over 10 years to children and adolescents, there are scarcely any studies that are relevant to actual practice. IQWiG and its external experts are of the opinion that this situation must be put right urgently: "For children and adolescents in particular, this lack of studies is untenable", says IQWiG's director, Prof. Dr. med. Sawicki. According to Sawicki, "Childhood and adolescence is usually the time when type 1 diabetes occurs and these patients have to inject insulin for the rest of their life." This is why it is particularly necessary to investigate the effects of long-term treatment. Moreover, these young patients go through different stages of development, where it is possible that insulin analogues might have a completely different effect from human insulin on certain bodily functions. "Today we are aware of over 100 different insulin effects, but this list is far from complete. They must be very carefully tested in studies if they are administered during childhood and adolescence", claims the Institute's director.
Yet again, the final report reveals how important it is for the publication of study results to be made legally compulsory. Although some of the studies used in this assessment were already completed 5 years ago, they have still not been published and are therefore not generally accessible.
IQWiG published the preliminary results in the form of the preliminary report in July 2009 and interested parties were invited to submit comments. When the comments stage ended, the preliminary report was revised and sent as a final report to the contracting agency, the Federal Joint Committee, in September 2009. Documentation of the written comments and minutes of the oral debate are published in a separate document simultaneously with the final report. The report was produced in collaboration with external experts.