Cochrane review of short-acting insulin analogues versus regular human insulin in patients with diabetes mellitus

Cochrane review of short-acting insulin analogues versus regular human insulin in patients with diabetes mellitus

May 2004

It is the right of patients to have an informed choice of treatment and it is important that they have the best information possible to exercise this right. People with diabetes should be told of their insulin choices including information about risks and benefits and any adverse effects. Insulin analogues are the latest form of GM synthetic insulin and this review compares short-acting analogues [Humalog and NovoRapid] with regular ‘human’ insulin. It is important to note that insulin analogues have not been compared to natural animal insulins because no such trials have been carried out as far as we are aware.
In order to have an informed choice of treatment, it is necessary to look at evidence from high quality systematic reviews. The following Cochrane Review comparing insulin analogues and regular ‘human’ insulin provides just such high quality evidence.

This is an abstract of a regularly updated, systematic review prepared and maintained by the Cochrane Collaboration.

Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus
Siebenhofer A, Plank J, Berghold A, Narath M, Gfrerer R, Pieber T.

Background: In short acting insulin analogues the dissociation of hexamers is facilitated, achieving peak plasma concentrations about twice as high and within approximately half the time compared to regular human insulin. According to these properties this profile resembles the shape of non-diabetic patients more than that of regular human insulins. Despite this theoretical superiority of short acting insulin analogues over regular human insulin, the risk-benefit ratio of short acting insulin analogues in the treatment of diabetic patients is still unclear.

Objectives: To assess the effect of treatment with short acting insulin analogues versus regular human insulin. SEARCH STRATEGY: A highly sensitive search for randomised controlled trials combined with key terms for identifying studies on short acting insulin analogues versus regular human insulin was performed using the Cochrane Library (issue 1, 2003), MEDLINE and EMBASE. Date of last search was December 2003.

Selection criteria: We included randomised controlled trials with diabetic patients of all ages that compared short acting insulin analogues to regular human insulin. Intervention duration had to be at least 4 weeks. DATA COLLECTION AND ANALYSIS: Trial selection as well as evaluation of study quality was done by two independent reviewers. The quality of reporting of each trial was assessed according to a modification of the quality criteria as specified by Schulz and Jadad.

Main Results: Altogether 7933 participants took part in 42 randomised controlled studies. Most studies were of poor methodological quality. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was estimated to be -0.1% (95% CI: -0.2% to -0.1%) in favour of insulin analogue, whereas in patients with type 2 diabetes the WMD was estimated to be 0.0% (95% CI: -0.1% to 0.1%). In subgroup analyses of different types of interventions in type 1 diabetic patients, the WMD in HbA1c was -0.2% (95% CI: -0.3% to -0.1%) in favour of insulin analogue in studies using continuous subcutaneous insulin injections (CSII) whereas for conventional intensified insulin therapy (IIT) studies the WMD in HbA1c was -0.1% (95% CI: -0.2% to -0.0%). The WMD of the overall mean hypoglycaemic episodes per patient per month was -0.2 (95% CI: -1.2 to 0.9) and -0.2 (95%CI: -0.5 to 0.1) for analogues in comparison to regular insulin in patients with type 1 diabetes and type 2 diabetes, respectively. For studies in type 1 diabetic patients the incidence of severe hypoglycaemia ranged from 0 to 247.3 (median 20.3) episodes per 100 person-years for insulin analogues and from 0 to 544 (median 37.2) for regular insulin, in type 2 the incidence ranged from 0 to 30.3 (median 0.6) episodes per 100 person-years for insulin analogues and from 0 to 50.4 (median 2.8) for regular insulin. No study was designed to investigate possible long term effects (e.g. mortality, diabetic complications), in particular in patients with diabetes related complications.

Reviewers’ Conclusions: Our analysis suggests only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin. Until long term efficacy and safety data are available we suggest a cautious response to the vigorous promotion of insulin analogues. Due to fears of potentially carcinogenic and proliferative effects, most studies to date have excluded patients with advanced diabetic complications. For safety purposes, we need a long-term follow-up of large numbers of patients who use short acting insulin analogues. Furthermore, we need well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child.

The full version of this Cochrane Review can be found at: www.cochrane.org

What does this review of short-acting insulin analogues and regular ‘human’ insulin mean for people with diabetes?
Cochrane reviews are designed to assess the evidence from randomised controlled trials to provide high quality evidence to help patients and doctors make informed choices about insulin treatment. So this review provides just this! Looking at the review in details tells us the following:

The trials:
Altogether 7933 participants took part in 42 randomised controlled studies. 25 studies were carried out in people with Type 1 diabetes, 5 in people with Type 2 diabetes, 5 with a combination people with Type 1 and Type 2 diabetes and one in women with gestational diabetes.

The evidence from the review says:

• There was only a minor benefit of short acting insulin analogues compared to ‘human’ insulin.
• Until long term efficacy and safety data are available we suggest a cautious response to the vigorous promotion of insulin analogues.
• Due to fears of potentially carcinogenic and proliferative effects, most studies to date have excluded patients with advanced diabetic complications.
• For safety purposes, we need a long-term follow-up of large numbers of patients who use short acting insulin analogues.
• Furthermore, we need well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child.
• 81% of the studies were sponsored by the analogues insulin manufacturers themselves and sponsors were not declared in the remaining 7 studies.

Other information from the review:

• Quality – most studies, 83%, were of poor methodological quality.
• Long-term effects – no study was designed to investigate possible long-term effects (e.g. mortality, diabetic complications), in particular in patients with diabetes related complications.
• The severity of diabetes – this was rarely reported in the studies and in the 17% of studies where pre-existing complications were described in detail eg retinopathy, neuropathy and nephropathy, the outcome on these complications when under drug treatment was only reported in one trial dealing with pregnancy.
• Hypoglycaemia – 17 studies had to be excluded, some because there was no information. Analysis did not confirm the often-claimed advantage of reduced hypoglycaemia after analogue treatment as there were no statistical differences in overall hypoglycaemia when analogues were compared with regular insulin.
• Nocturnal hypos – only 6 studies mentioned night hypos and overall nocturnal hypoglycaemic events were presented in only two studies. One showed a significantly reduced rate with analogue treatment from midnight to 6.00am whereas the other study showed no statistically difference from bedtime to breakfast time.
• Quality of life – 11 studies reported on quality of life and analogues showed a significant improvement compared to regular human insulin but this was largely due to convenience, flexibility and continuation of treatment. The reviewers suggest that this is probably due to the difference in injection timings with analogues injected immediately before a meal compared to 30 minutes before for regular human insulin.
• The mitogenic and carcinogenic potential of insulin analogues – in terms of these effects, the review says that only very limited information on the long-term safety is currently available.

Human insulin has a weak mitogenic effect. [Mitogenic effect mean cell multiplication with the potential for the development of tumours.] The molecular composition of insulin analogues and/or structure has been modified compared to human insulin and these structural modifications could increase the mitogenic potency possibly resulting in the development of tumours especially with long-term use of insulin analogues. This is thought to be due to the structural similarity to insulin-like-growth-factor-1 [IGF-1] and/or faulty signalling through the insulin receptor. The similarity to IGF-1 could also affect the progression of retinopathy.
The first example of this mitogenic effect was in the AspB10 insulin analogue, developed by Novo Nordisk. Trials were stopped because it was found to induce mammary tumours in rats. Therefore the European Agency for the Evaluation of Medicinal Products [EMEA] states that a thorough assessment of the carcinogenic potential is indicated for all new insulin analogues.

It is also worth looking at the EMEA approval documents for each analogue insulin on their website www.emea.europa.eu

IDDT is not being alarmist, although we may be accused of it!
All this information is already in the public domain and we cannot and should not avoid discussion of these potential effects of insulin analogues – they must form part of our informed choice when considering whether to use them. Indeed, at IDDT’s meeting with the Dept of Health [May 26th 2004] when analogues were discussed as an alternative choice to animal insulins, we pointed out that although analogues have not been compared to animal insulin, there is an 80year long-term safety history of animal insulin without obvious tumour development. This cannot be said for the insulin analogues – we simply don’t know and won’t know for many years to come and even then, this assumes that there is or will be continual monitoring of these effects in people using analogues.