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Insulin Analogues and Cancer - A Possible Link That Needs Further Investigation

This is the title of a patient information sheet issued by the European Association for the Study of Diabetes [EASD] on June 26th, 2009.

As regular visitors to our website are already aware, there have been concerns for some time that the long-term safety of insulin analogues is unknown and insulin analogues have a greater potential for cell multiplication, with a possible increased risk of cancer due to their greater similarity to insulin-like growth factor 1 [IGF-1] . The EASD has investigated these concerns for Lantus [glargine] and published several studies looking at groups of people who are using insulin to treat their diabetes – people with Type 1 and Type 2 diabetes. Levemir [detemir] was introduced more recently and Professor Gale, Editor of Diabetolgia the journal in which the studies have been published, states: “We have yet to examine this in the same way as Lantus.”

The EASD recognise the limitations of these studies but the authors state in their press release: “We believe that people are entitled to know that the use of Lantus insulin might be associated with greater risk, but this must also be balanced against the possibility that we might be causing unnecessary alarm by raising these concerns.”

As a result, the EASD has issued a press release and also issued an information sheet for patients.

Insulin analogues display IGF-1-like mitogenic and anti-apoptotic activities in cultured cancer cells.

IDDT reminds everyone that it is very important not to stop taking your insulin. If you have concerns about the analogue insulins or wish to consider changing your insulin, then there are alternatives so you do have a choice and you should discuss this with your doctor.

As a patient-centred, independent charity the Trust has a responsibility to provide people with diabetes with information. The global insulin manufacturers are withdrawing some of the most widely used GM 'human' insulins and recommending treatment with insulin analogues. After very careful consideration, this Supplement has been produced to help inform people with diabetes about the risks and benefits of following this recommendation.

Insulin analogues are new biotechnology products and as such, are likely to have different patterns of toxicity with unknown consequences. The long-term effects and safety of insulin analogues have not been established.

The clinical benefits of insulin analogues have been extensively studied and have proved to be negligible in terms of glycaemic control but the biological effects have not been systematically studied despite their carcinogenic potential being recognised by the scientific community.

People with diabetes are no exception to the principle that they should have an informed choice of treatment including risks and benefits but the majority of them are not aware of the carcinogenic potential of insulin analogues or that their long-term safety has yet to be established.

Some patients may consider even a minimal carcinogenic risk with insulin analogues is unacceptable when there is little or no benefit in day to day blood glucose control.

"The carcinogenic potential of insulins is recognised by the scientific community."

Gupta K, et al
Am J Med Sci. 2002; 323(3)

"Recent publications concerning the assessment of carcinogenic potential of specific human insulin analogues are scarce"

Stammberger I, et al
Int J Toxico. 2002;21(3)

"People are being prescribed too many drugs, before the full consequences of adverse side effects are known."

"Tighter controls on the promotion of new drugs should be introduced until more is known of their potential side effects."

"Post-marketing surveillance in the UK is inadequate. This has several causes: lack of investigation of a drug's benefits and harms in real life situations and institutional indifference to the experience and reports of medicines users."

House of Commons
Health Committee Report, April 5^th 2005
The Influence of the Pharmaceutical Industry

Insulin analogues are artificial derivatives of the natural hormone insulin and are designed to have different absorption profiles compared to GM 'human' insulins.

Short-acting insulin analogues [eg Humalog and NovoRapid] are absorbed more quickly and are of shorter duration than GM 'human' insulin and long-acting analogues [Lantus, Levemir] are designed to have a longer action with a more consistent release during the day.

National Institute of Clinical Excellence [NICE] Guidance on the use of long-acting insulin analogues - insulin glargine [Lantus] December 2002

1. Insulin glargine [Lantus] is recommended as a treatment option for people with Type 1 diabetes

2. Insulin glargine is not recommended for routine use for people with Type 2 diabetes who require insulin therapy. It should be considered only for those people with Type 2 diabetes who require insulin therapy and who fall into the following categories:

· Those who require assistance from a carer or healthcare professional to administer their insulin.

· Those whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemic episodes.

· Those who would otherwise need twice daily basal insulin injections in combination with oral anti-diabetic drugs.

NICE estimates that 137,000 people in the UK would be eligible for insulin glargine treatment. The extra cost of glargine per annum for Type 1 diabetes is £101 compared to NPH [long-acting human insulin] and £162 for Type 2 diabetes compared to NPH. If all the potentially eligible people were changed to glargine, then this would cost the NHS around £16million per annum. These costs are based on vial costs and so would be increased with use of the more expensive cartridges.

Apoptosis - normal self-induced termination of a cell's life, to become replaced by a new one.
Carcinogenic - a substance that has cancer forming properties.
Carcinoma - a type of cancer.
Co-morbidity - the presence of several diseases/conditions.
Endpoints - a research term that defines what is being measured in the study to show the outcomes of a treatment.
Hexamers - the bonding together of insulin molecules forms a six-pack [hexamer] but only individual insulin molecules are biologically active so the body must first break the six-pack.
IGF-1 or insulin-like growth factor - a hormone which has a broad range of effects including promotion of cell survival, cell proliferation of cells, inhibition of apoptosis, stimulation of metabolism.
Insulin receptors - insulin receptors are the chemical structures on cells, where insulin binds to the cell and where insulin can get its messages inside the cell.
In-vitro testing - literally means 'in glass' and is a research term for observations made outside the body eg the action of drugs on bacteria, in-vitro fertilisation means the fertilisation of the egg outside the body
In-vivo testing - studying something in living creatures [human beings and animals]
Monomers - single insulin molecules
Mitogenicity - promotion of the division and proliferation of any cell, including malignant and non-malignant tumour cells.
Neoplasm - another word for a tumour that literally means 'new formation'
Sprague-Dawley rats - a type of rat used in research into the possible development of breast tumours because of its high spontaneous incidence rate of breast cancer ie the type of rat used is the one that is most likely to produce breast tumours if this risk is present.
Subcutaneous injection - injection into the tissue beneath the skin.
Thrombocytes - blood platelets involved in coagulation to stop bleeding
Toxicity - the poisonous effects of a substance.

Genetically engineered, genetically modified and GM are used interchangeably throughout this document. The same applies to the names of insulin and their brand names:

NPH - Neutral Protamine Hagedorn also referred to as isophane insulin and is the most commonly used long-acting insulin in the UK.

This Supplement contains our concerns in two versions. This first version uses layman's language and is less technical but it is based on the more technical version that follows which provides more detail and the supporting references.

Regulatory requirements for insulin analogues: weighing therapeutic benefits against potential carcinogenicity

Authors:
Prof. Dr. med. Ernst Chantelau

Mrs Jenny Hirst
Co-Chairman
Insulin Dependent Diabetes Trust
PO Box 294
Northampton
UK

In September 2004, the commonly used arthritis drug Vioxx was withdrawn from the market after it became publicly known that patients taking it were at twice the relative risk of heart attack and stroke as those taking a placebo or dummy pill. During the five years that it was on the market, it is likely that many people suffered heart attack, even death, and stroke. Questions have been raised about the effectiveness of the regulatory system and how long this information was known prior to drug's subsequent withdrawal.

Adverse events associated with the effects of the anti-depressant, paroxetine [Seroxat] highlighted in the BBC programme, Panorama, resulted in the Committee on Safety of Medicines [CSM] issuing a safety statement about the recommended dose. However, this statement was not based on new evidence but "on a review of the original dose finding studies carried out for the licensing of paroxetine". In other words, information the CSM had before the drug reached to market and once again lives were unnecessarily harmed or lost as a result of this system failure.

These situations necessarily raise questions about the effectiveness of drug regulatory authorities, their speed of response and their vigilance. They demonstrate the need for more effective research prior to a drug reaching the market and of equal importance, the need for improved post-marketing surveillance when new drugs are used on the wider population. Patients are rightly concerned about the safety of the drugs they take and the systems in place to ensure their short and long-term safety and effectiveness. These needs are especially important with the introduction of new biotechnology products, such as insulin analogues, which can have unpredictable adverse effects.

There is a now a wide range of drugs available and the pattern of drug toxicity is likely to change with the introduction of new biotechnology products.

An early example of this was genetically engineered tryptophan introduced in 1988 and withdrawn within months because it was associated with 37 deaths and 1500 people being permanently disabled. Genetic engineering was implicated because the toxin responsible has never been shown to be present in the non-genetically engineered tryptophan that was used for many years without these adverse effects.

Adverse reactions can occur immediately or within weeks, months or years after starting to take a drug. Reporting suspected adverse reactions [ADRs] is not a mandatory requirement for physicians and health professionals. So spontaneous reporting schemes of suspected ADRs, such as the Yellow Card Scheme in the UK, are the cornerstone of post-marketing surveillance and are still the only way of monitoring the safety of a drug throughout its life. The problem with spontaneous reporting is that less than 10% of all serious and only 2-4% of non-serious suspected ADRs are actually reported.

Thus with 90% of serious adverse drug reactions going unreported, it is unsurprising that patients are concerned about the safety of drugs and the systems in place for monitoring them.

In 1982, genetically engineered insulin, misleadingly named 'human' insulin, was the first drug genetically engineered drug to be marketed. In common with tryptophan, there was a failure to recognise that drugs produced by biotechnology could have different patterns of toxicity and it appears that when giving marketing approval, the regulatory authorities considered the method of manufacture to be unimportant. It is possible that assumptions about the safety of GM 'human' insulin could have been made because its predecessor, natural animal insulin, had an excellent and long history of safety.

During the 1980s in the UK over 80% of people with insulin-requiring diabetes were changed to genetically engineered 'human' insulin for no clinical reasons but on assumptions of its superiority, and not on evidence of its superiority, over natural animal insulin previously used. An estimated 10% of people reported, and continue to report, adverse effects when using GM insulin but patients' reports of adverse reaction reports were largely ignored and GM 'human' insulin became first line treatment for people with insulin requiring diabetes.

No long-term, large-scale studies to compare GM 'human' and animal insulin have ever been carried out and in 2002 a Cochrane Review showed that the vast majority of the studies that have been carried out are of methodologically poor quality. It also showed that many of the important issues for patients such rates of diabetes complications and mortality and quality of life issues were never investigated in high quality randomised clinical trials. So 'human' insulin was given marketing authorisation:

· without consideration of the method of manufacture and possible unexpected adverse reactions

· without any long-term studies to compare complication and mortality rates or long-term safety.

However patients were not made aware of these facts or their rights to a choice of insulin treatment, so they are understandably concerned about the quality and validity of information they receive and the drug monitoring systems in place, supposedly for their protection.

Insulin analogues are the most recent biotechnology products used in the treatment of diabetes. They are artificial derivatives of the natural hormone human insulin. They were designed to have absorption profiles that more nearly mimic the action of normal insulin production by the body compared to artificial 'human' insulin. In short-acting 'human' insulin the individual insulin molecules clump together [aggregate], six at a time, to form a hexamer. Only individual insulin molecules are biologically active, so the body must first break the six pack into individual molecules [monomers]. But in analogues the hexamers bind together so weakly that they break apart much faster making the insulin molecules biologically active immediately.

However analogues also differ in their biological effects with unknown consequences, such as their effects on:

·         mitogenicity [promotion of division and proliferation of any cell, including tumour cells
·         apoptosis [see glossary]
·         glucose and lipid metabolism
·         thrombocyte function
·         protein degradation

The therapeutic effects of analogues have been extensively investigated and have shown negligible clinical benefit for patients but the biological effects have not been systematically studied. It is of special concern that the carcinogenic potential of insulin analogues remains to be determined on human carcinoma tissue in accordance with the recommendations issued by the European Agency for the Evaluation of Medical Products [EMEA] in their document, Points to consider CPMP/SWP/372/01.

While scientists have used analogues to study the insulin molecule, insulin manufacturers were more interested in their commercial potential and in 1988 Novo Nordisk announced the development of their prototype analogue, B10Asp. By virtue of a slight modification of the human insulin molecule B10Asp did not aggregate as much as regular 'human' insulin and was absorbed from the subcutaneous tissue 15minutes earlier. B10Asp was absorbed into the circulation significantly faster and with higher peak concentrations than 'human' insulin but a controlled trial failed to show that B10Asp had any benefit in terms of glycaemic control when compared to 'human' insulin.

From this study it was obvious by 1995 that manipulations of the subcutaneous absorption of rapid-acting [regular] insulin have only very little clinical impact on HbA1c and may explain why analogue insulin produces only less than 5% of the total variations in HbA1c. Much greater percentages of the total variation in HbA1c is accounted for by:

All clinical trials with B10Asp were stopped in 1992 when it was shown to promote breast cancer in rats. Nevertheless, in 1996 the first rapidly absorbed insulin analogue, lispro [Humalog], reached the market amidst warnings from Professor Stephanie Amiel [Diabetic Medicine, 1998;15;537-538] that "there remains a risk of unexpected problems with any new agent and we should remember that the structure of the new insulin is a little closer to IGF than the old insulin". The closeness to IGF-1 is important because it has broad range of effects including promotion of cell survival, cell proliferation of cells, inhibition of apoptosis, stimulation of metabolism.

In 2000 the first slowly absorbed long-acting insulin analogue, glargine [Lantus] was introduced. It has a flat, apparently peakless activity, and a duration of 24hours. This was followed in 2004 by the introduction of determir [Levemir], a once or twice daily long-acting insulin analogue.

Good control is not only the avoidance of high blood glucose levels [hyperglycaemia] but also the avoidance of low blood glucose levels [hypoglycaemia]. Hypoglycaemia is a daily fear of people with diabetes so a reduction in hypoglycaemic events can improve quality of life. It is therefore important to look at the effects of insulin analogues on hyper- and hypoglycaemia.

As could have been expected from the B10Asp study, Humalog and NovoRapid have barely shown any clinical benefits over GM 'human' insulin in terms of blood glucose levels as measured by HbA1c and daily blood glucose tests.

Studies comparing control of hypoglycaemia for Humalog and NovoRapid with GM 'human' insulin showed the following:

A Cochrane Review [2004] of short-acting analogues supported all the above findings and concluded that:

· short-acting insulin analogues have 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, a long-term follow-up study of large numbers of patients who use short acting insulin analogues is needed.

The clinical benefits of glargine [Lantus] as measured by HbA1c were small in comparison to GM 'human' insulin and when compared to twice daily long-acting [NPH] 'human' insulin there was no difference in hypoglycaemia.

At the time of writing, detemir [Levemir] has only been on the market a short time but manufacturers information shows little, if any, improvement in HbA1c and it is claimed that there is less weight gain when compared to 'human' insulin.

It is important to note that all clinical studies with insulin analogues have been conducted on carefully selected patient groups that have excluded all those with diabetic complications and any other conditions. So the effects of insulin analogues on people with these conditions is not known. Equally unknown are the effects of insulin analogues on mortality and other hard endpoints like blindness, amputation and end stage renal disease.

It is worth noting that the Drugs and Therapeutics Bulletin [Oct 2004 Vol 41;No10] reported on the use of insulin analogues as first line treatment: "In our view, this approach is not justified given that what still needs to established about the analogues - long-term benefits and safety. Also there is no convincing evidence to justify switching patients from existing conventional therapy to analogues if they have appropriate glycaemic control without troublesome hypoglycaemia."

As discussed, the rapid acting analogues B10Asp was shown to induce or promote breast cancer in Sprague-Dawley rats [type of rat used because it is most likely to produce breast cancer if a risk is present]. B10Asp was called the 'super-mitogen' and subsequent analogues reaching the market have been measured against this for their carcinogenic potential.

It was increasingly recognised that changing the physico-chemical properties of the GM 'human' insulin molecule will inevitably change its biological properties although manufacturers tried to play down the potential risks. Long before the European Medicines Evaluation Agency [EMEA] was asked to approve long-acting insulin analogue, glargine, it was found to be highly mitogenic [caused cell proliferation] on in-vitro testing with human osteosarcoma cells [cancerous cells from tissue surrounding bone]. On February 17, 2000 this information, still unpublished, was presented to the EMEA by the manufacturers, Aventis, in an oral explanation. The EMEA accepted the company's claim that this information was irrelevant and subsequently approved the drug. In June 2000, a paper publicly disclosed the mitogenicity of insulin glargine [Lantus] on osteosarcoma cells and in June 2001 Aventis publicly confirmed this information in an abstract presented to the American Diabetes Association.

Recently even more abnormal biological actions of insulin analogues as compared to 'human' insulin have been identified by various researchers:

· Humalog inhibits apoptosis in tumour (insulinoma) cells and protein degradation.

· A new insulin analogue, insulin Glusilin (Aventis) inhibits apoptosis in tumour (insulinoma) cells.

· Lantus, but not Humalog, increases serum IGF-1 concentrations in diabetic patients.

· On the receptor level eg of osteosarcoma cells, rat cardiomyocytes, human skeletal muscle cells, Lantus binds less to the insulin receptor and more to the IGF-1 receptor than does human insulin, and causes abnormal post-receptor signalling compared to human insulin.

In most instances, the animal toxicology experiments presented to the drug regulatory boards [the EMEA and the FDA] for the approval of insulin analogues were flawed. The experiments were not in accordance with the EMEA 2001 recommendations and are not suitable to rule out clinically relevant carcinogenicity of these insulins.

· Humalog was studied in rats which do not develop breast cancer (Fischer 344 rats

· Lantus was studied in dosages much lower than those of B10 Asp that induced breast cancer in cancer-prone rats

· the exposure time of the rats against Lantus was too short, as many rats died from hypoglycaemia before the end of planned 24-months observation period.

· Standard 2-year carcinogenicity studies in animals have not been performed or published to evaluate the carcinogenic potential of Humalog and NovoRapid/NovoLog.

Toxicology studies

Insulin analogue	Experimental design	Dosage	Duration	Outcome
B10 Asp	Sprague-Dawley rats	20-200 U/kg	12 months	breast cancer+++, dose-related
Humalog	344 Fischer rats	20-200 U7kg	12 months	no breast cancer
Lantus	Sprague-Dawley rats	5-12.5 U/kg	<24 months	malignant fibrohisticytoma++ malignant lymphoma (+)
NovoLog NovoRapid	Sprague-Dawley rats	10-200U/kg	12 months	breast cancer with 200 U/kg, significant difference to untreated controls, no significant difference to regular human insulin

Insulin analogues are new biotechnological products with unknown biological effects.

The actions of natural insulin in humans and animals has been brought about by evolution over millions of years and the delicate balance between its metabolic and mitogenic efficacy functions very well in every species in order to maintain survival. This cannot be said of artificial insulin analogues that interfere with this balance in unpredictable and unknown ways.

This lack of information prompted the EMEA [2001] to call for better pre-clinical testing of insulin analogues in order to definitely rule out any relevant carcinogenicity of these compounds. The 'Points to consider document CPMP/SWP/372/01 on the non-clinical assessment of the carcinogenic potential of insulin analogues states:

“Native human insulin has, in addition to its metabolic actions, a weak mitogenic effect. This effect has become important for the safety of insulin analogues,……since structural modifications of the insulin molecule could increase the mitogenic potency, possibly resulting in growth stimulation of pre-existing neoplasms...”

“Although enhanced insulin-like growth factor 1(IGF-1) receptor activation and/or aberrant signalling through the insulin receptor have been implicated, the mechanism(s) responsible for the mitogenic activity of insulin analogues remain to be clarified...”

According to this same EMEA document, insulin analogues should be investigated on neoplastic [tumour] tissue rather than on non-neoplastic [normal] tissue, including in-vivo studies with tumour tissues transplanted on immunodeficient animals:

“Since there is evidence that receptor in neoplastic [tumour] tissues may react differently from those in normal tissues, it is desirable that the choice of test systems will cover testing of mitogenicity in non-neoplastic as well as neoplastic tissues.”

“Due to substantial background data on spontaneous tumour incidence, the rat may be considered a suitable species and in view of the responsiveness to AspB10....at present the Sprague-Dawley rat may be thought of as first-hand choice. ... other species or models, like the promotion of established human tumour cell lines grafted on immunodeficient animals might be considered.”

As evidence that IGF-1 promotes colonic-, breast-, prostatic-, and lung cancer growth is accumulating, it is mandatory that insulin analogues should be studied preferably on these neoplastic tissues. However, none of these investigations have so far been carried out or published.

In a public meeting on May 5, 2004 Professor Jürgen Eckel, Germany, announced that he is to carry out a systematic investigation of the mitogenic potency of insulin analogues. However, it will take years for the results of this investigation to be completed and published. Unless cancer growth promotion is properly excluded, the safety of insulin analogues will remain unknown and patients will be unable to assess their risks and benefits in order to make an informed choice of treatment. If patients safety is to be protected and their rights to an informed choice is to be respected, it is essential that patients are provided with the facts as they stand. When the clinical benefits of insulin analogues have proved to be negligible in terms of diabetes control, even a minimal carcinogenic risk could be classed as unacceptable by some patients.

Regulatory requirements for insulin analogues: weighing therapeutic benefits against potential carcinogenicity

Summary

Recent events with Cox-2 inhibitors have demonstrated that there is a need for greater effort into research before a new drug reaches the market and for improved post-marketing surveillance. There is a wide range of drugs available and the pattern of toxicity is likely to change with the introduction of new biotechnology products.

Insulin analogues are just such a product as they are artificial derivatives of the natural hormone insulin, designed to improve the absorption profiles compared to human insulins after subcutaneous injection. However, analogues also differ from human insulin in their biological effects such as, effects on mitogenicity, apoptosis, glucose and lipid metabolism, thrombocyte function and protein degradation, with unknown consequences. While the therapeutic effects have been investigated extensively and found to be negligible, the biological effects of insulin analogues remain to be systematically studied. Of special concern is that the carcinogenic potential of insulin analogues remains to be determined on human carcinoma tissue, according to the recommendations issued by the European Agency for the Evaluation of Medicinal Products (EMEA Points to consider document CPMP/SWP/372/01).

Introduction

Spontaneous adverse drug reactions reporting schemes, such as the Yellow Card Scheme in the United Kingdom, are the cornerstone of post-marketing drug safety surveillance and remain the only way of monitoring the safety of a drug throughout its life on the market. A problem with spontaneous reporting is that less than 10% of all serious and 2-4% of non-serious adverse reactions are reported (1). It must be hoped that the recent introduction in the United Kingdom of patients being able to report adverse drug reactions (2) will improve the number of reports and the post-marketing surveillance system, assuming that patients' reports carry the same weight as those from doctors and healthcare professionals.

Adverse events associated with the effects of the anti-depressant. paroxetine [Seroxat] highlighted in the BBC programme, Panorama, resulted in the Committee on Safety of Medicines [CSM] issuing a safety statement about the recommended dose (3) in March 2003. However, this statement was not based on new evidence but "on a review of the original dose finding studies carried out for the licensing of paroxetine". In other words, information the CSM hadthe information before the drug reached the market and once again lives were unnecessarily harmed or lost as a result of this system failure.

Pirmohamed et all point out (1) that there is a wide range of drugs available and the manifestations of drug toxicity may vary, may affect any organ system and that the pattern of toxicity is likely to change with the introduction of new biotechnology products. An early example of this was the introduction of genetically engineered tryptophan in 1988, withdrawn within months because it caused 37 deaths and 1500 people to be permanently disabled (4). Genetic engineering was implicated because the toxin responsible had never been shown to be present in non-genetically engineered tryptophan that had been used for many years without these adverse effects.

Human insulin was the first genetically engineered drug to be marketed in 1982. In common with tryptophan, regulatory authorities considered the method of production to be immaterial because natural animal insulin had one of the best safety profiles on the market with the only major side-effect being hypoglycaemia, technically caused by overdose (5). In effect regulatory authorities considered the new laboratory produced human insulin to be substantially equivalent to natural animal insulin used for more than 60 years. Patients were changed to the new 'human' insulin not for clinical reasons but on the assumption of superiority and not evidence of its superiority over its animal insulin predecessors.

An estimated 10% of patients reported, and continue to report, adverse effects when using genetically engineered human insulin. Despite awareness that genetic variability leads to differences in drug response between individuals (6) and that the clinical consequences of individual variation in drug response can be great, the adverse reactions with genetically engineered insulins have been largely ignored and they have become first-line treatment for people requiring insulin. However, there have been no large-scale studies to compare human and animal insulins and the vast majority of studies that have been carried out are classed as being of 'poor methodological quality' in a Cochrane Review (7). Not only was human insulin given marketing authorisation without consideration of the method of manufacture but post marketing studies have been of poor quality.

With this background for such a widely prescribed, and therefore highly profitable product as insulin, it is unsurprising that the rofecoxib and paroxetine situations have arisen. If patients are to be protected, regulatory bodies need to reconsider drugs that have already received marketing approval and this is particularly applicable to the more recently developed insulin analogues.

Hundreds of human insulin derivatives, nowadays called analogues have been designed by chemists since the molecular structure of human insulin became known in the 1960s (8,9). While scientists were using these compounds to study structure-function relationships of the insulin molecule, insulin manufacturers were interested in their commercial potential after recombinant DNA biotechnology had opened the way for industrial production. Novo Nordisk announced the production of insulin analogues for therapeutic purposes in 1988 (10). Their prototype analogue, B10Asp, was designed to aggregate less than regular human insulin in pharmaceutical preparations. Pharmaceutical regular human insulin molecules aggregate in the vial to hexamers which, after subcutaneous injection, must disintegrate to insulin monomers before they can enter the circulation. This process of hexamer disintegration takes about 10-15 minutes inside the subcutaneous fat tissue. There is no such time lag after intramuscular injection, perhaps due to the better vascularisation of muscular tissue, and hence faster wash-out of injected insulin. The analogue B10 Asp, by virtue of a slight modification of the native human insulin molecular structure, did not aggregate as much as regular human insulin and was absorbed from the subcutaneous tissue about 15 minutes earlier than human regular insulin.

However, a controlled trial failed to show any benefit in terms of blood glucose regulation of B10Asp versus regular human insulin, although B10Asp was absorbed into the circulation significantly faster and with higher peak concentrations than human insulin (11). From this study it was obvious in 1995 that manipulations of the subcutaneous absorption of rapid acting (regular) insulin have only very little clinical impact on HbA1c, and may explain only less than 5% of total variation in HbA1c. Much greater percentages of the total variation in HbA1c are accounted for by the size of the insulin dose, the amount and timing of carbohydrate intake, the timing of exercise in relation to the carbohydrate intake and/or the insulin application, effects from stress or intercurrent illness on insulin sensitivity, psychosocial aspects and residual ß-cell function (12).

All clinical trials with B10Asp were suspended in 1992, when this compound was shown to promote breast cancer in rats (13). Nevertheless, rapidly absorbed ‘monomeric‘ regular insulin analogue Lispro (Humalog®) was launched in 1996 and reached the UK market in 1998 when Amiel (5) warned that there remains a risk of unexpected problems with any new agent and "we should remember that the structure of the new insulin is a little closer to IGF structure than the old insulin".

Therapeutic potentials

Clinical superiority of Humalog® over human insulin in terms of blood glucose regulation with HbA1c and blood glucose daily profiles was barely detectable (14), as could have been expected from the B10Asp study (11). The same holds true for another insulin analogue, Aspart (Novolog®/ NovoRapid®) as despite its faster subcutaneous absorption, the effects on blood glucose regulation were very similar to those of regular human insulin. In 2000, Aventis launched a slowly absorbed insulin analogue, Glargine (Lantus®); again, the clinical benefits in comparison to human insulin were small (Table 1).

Table 1: Effect of insulin analogues on controlling hyperglycaemia

Aspart (NovoRapid® NovoNordisk) + NPH human insulin versus regular human insulin + NPH human insulin

(NovoNordisk, scientific information on NovoRapid®/NovoLog 1999, 2000 (15))

Glargine (Lantus®,Aventis) + regular human insulin versus NPH human insulin + regular human insulin

Glargine (Lantus®, Aventis) + insulin Lispro (Humalog®, Lilly) versus NPH human insulin + insulin lispro

Note: note that a -0.15% change in HbA1c translates into 5mg/dl (0.27mmol/l) change in blood glucose (18)

Table 2: Effect of insulin analogues on controlling hypoglycaemia

Glargine (Lantus®) once per day versus NPH human insulin twice per day

In summary, the beneficial effects of insulin analogues on control of hyper- and hypoglycaemia in diabetic patients were nearly nil. A previous review article (20), and a most recent Cochrane review have come to the same result (21). All clinical studies with insulin analogues had been performed in carefully selected patient groups, excluding those with diabetic complications and co-morbidity. Hence the effects of analogues on these conditions are not known, nor the effects on mortality and other hard endpoints like blindness, amputation, end stage renal disease.

After B10Asp was shown to induce or promote breast cancer (13) in Sprague-Dawley rats, which have a high spontaneous incidence rate of breast cancer and this insulin analogue was called "super-mitogen“ (22), it was increasingly recognised that changing the physico-chemical properties of the human insulin molecule will inevitably change its biological properties:

"Mutation of the insulin molecule through recombinant DNA technology has produced 'monomeric’ insulin, which does not form hexamers and is therefore more readily absorbed following subcutaneous injection. The pharmacokinetics and biological actions are thus altered... ” (23)

However, the manufacturers tried to play down potential risks with the manufacturers claiming that the biological differences of Humalog® to human insulin were not harmful:

"Insulin receptor binding: equipotent to insulin IGF-1 receptor binding: approx.160% as potent as insulin DNA synthesis: marginally more potent than insulin(approx.1-4x); possibly explained by enhanced IGF-1 receptor affinity“ (24).

Insulin Glargine (Lantus®) was found to be highly mitogenic on in-vitro testing with human osteosarcoma cells long before the EMEA had been asked for approval of the compound (25). On February 17, 2000 this information, still unpublished, was reported to the EMEA in an oral explanation by Aventis. The EMEA accepted the company’s claim that the finding was irrelevant, and subsequently approved the drug (24). A paper (26) in June 2000 publicly disclosed the mitogenicity of insulin Glargine on osteosarcoma cells and in June 2001, Aventis publicly confirmed this information in an abstract presented to the ADA (27):

"Lantus® binds more actively to IGF-1 receptors: In human hepatoma cells (Hep G2), Lantus® affinity for the IGF-1 receptor was 5-7 fold relative to human insulin...In human osteosarcoma cells, IGF-1 receptor affinity of Lantus® was 3.5-7.6 fold relative to human insulin....in a second study on osteosarcoma cells, IGF-1 receptor affinity of Lantus® was 14 fold relative to human insulin....and thymidine uptake (i.e. incorporation into DNA) in response to Lantus® was 6.1 fold higher compared with human insulin.. "(27)

Recently, even more abnormal biological actions of insulin analogues (as compared to human insulin) have been identified by occasional investigations of various researchers. Humalog® and NovoRapid®/NovoLog® inhibit thrombocyte function (28,29); Humalog® inhibits apoptosis in tumour (insulinoma) cells (30), and protein degradation(31). A new insulin analogue, insulin Glusilin (Aventis) inhibits apoptosis in tumour (insulinoma) cells (30). Lantus®, but not Humalog®, increases serum IGF-1 concentrations in diabetic patients (32,33). On the receptor level e.g. of osteosarcoma cells, rat cardiomyocytes, human skeletal muscle cells, Lantus® binds less to the insulin receptor and more to the IGF-1 receptor than does human insulin, and causes abnormal post-receptor signalling compared to human insulin (21,29,34). Published data on NovoRapid®/Novolog® are scarce (26,35,36).

The animal toxicology experiments, presented to the drug regulation boards, such as the FDA or EMEA, for approval of the insulin analogues (Table 3), in most instances were flawed, and not in accordance with the recommendations issued by the EMEA 2001. These experiments are not suitable to rule out clinically relevant carcinogenicity of these compounds. Humalog® was studied in rats which do not develop breast cancer (Fischer 344 rats (37)), while Lantus® was studied in dosages much lower than those of B10 Asp (13) that had induced breast cancer in cancer-prone rats(38). Furthermore, the exposure time of the rats against Lantus® was too short, as many rats died from hypoglycaemia before the end of planned 24-months observation period.

Table 3 Toxicology studies

Standard 2-year carcinogenicity studies in animals have not been performed or published to evaluate the carcinogenic potential of Humalog® and NovoLog ®(39).

Conclusion

Insulin analogues are new biotechnological pharmaceuticals with unknown biological effects. Natural insulin, be it human or animal insulin, has been brought about by evolution over millions of years; its delicate balance between metabolic and mitogenic efficacy is very well functioning in every species to maintain survival. This cannot be said of artificial insulin analogues, which interfere with this balance in an unpredictable way. This lack of information prompted the EMEA in 2001 to call for better pre-clinical testing of insulin analogues in order to definitely rule out relevant carcinogenicity of these compounds (40).

“Native human insulin has, in addition to its metabolic actions, a weak mitogenic effect. This effect has become important for the safety of insulin analogues, i.e. compounds derived from insulin with a molecular composition and/or structure that has been modified as compared to native human insulin, since structural modifications of the insulin molecule could increase the mitogenic potency, possibly resulting in growth stimulation of pre-existing neoplasms...”

According to the EMEA document (40), insulin analogues should be investigated on neoplastic rather than on non-neoplastic tissues, including in-vivo studies with tumour tissues transplanted on immunodeficient animals.

“Since there is evidence that receptor in neoplastic tissues may react differently from those in normal tissues, it is desirable that the choice of test systems will cover testing of mitogenicity in non-neoplastic as well as neoplastic tissues.”

Since evidence is accumulating that IGF-1 promotes colonic-, breast-, prostatic-, and lung cancer growth (41) it is mandatory that insulin analogues should be studied preferably on these neoplastic tissues. However, neither of these investigations have so far been carried out or published. In a public meeting on May 5,2004 Professor Jürgen Eckel, Germany (22,30) announced that he is about to start a systematic investigation of the mitogenic potency of insulin analogues. It will take years for the results of this investigation to be completed and published.

Unless cancer growth promotion is properly excluded, the safety of insulin analogues will remain unknown and patients will be unable to assess their risks and benefits in order to make an informed choice of treatment. If patients safety is to be protected and their rights to an informed choice is to be respected, it is essential that they are provided with the facts as they stand. As the clinical benefits of insulin analogues have proved to be negligible in terms of diabetes control, some patients may consider that even a minimal carcinogenic risk of insulin analogues may be unacceptable.

The long and short-term health of patients must be protected by greater effort being put into researching the safety of new drugs and by greater vigilance on the part of regulators before they reach the market. For physicians prescribing drugs and for patients' exercising their rights to an informed choice of treatment, decisions are made on the basis of weighing up the risks and benefits of the various therapies that are available to them. In order to truly achieve this, there needs to be greater transparency and more effort put into good quality clinical research before new drugs reach the market accompanied by more effective and more vigilant post-marketing surveillance.

1) Pirmohamed M, Breckenbridge AM, Kitteringham NR, Kevin Park B. Adverse Drug Reactions BMJ 1998;316:1295-1298 925 April)

4) Mayeno AN, Gleich GJ Eosinophilia-Myalgia syndrome and tryptophan production: a cautionary tale. TIBTECH, 12,346-352.1994

5) Amiel S. Learning to Use New Drug - the Fast-acting Insulin Analogues. Diabetic Medicine, 1998;15:537-538

7) Richter B, Neises G. Cochrane Review ‘Human’ insulin versus animal insulin in people with diabetes mellitus. July 2002 Cochrane Library

8) Brandenburg D, Gattner HG, Weinert M, Herbertz L, Zahn H, Wollmer A. Structure function studies with derivatives and analogs of insulin and its chains. Diabetes 1970-Proceedings of the Seventh Congress of the International Diabetes Federation.P.363-376. Excerpta Medica Amsterdam, International Congress Series No.231, 1971

9) Markussen J. New insulins: types and actions. In: J.R.Turtle,T.Kaneko and S.Osato (eds) Diabetes in the new millenium. The Endocrinology and Diabetes Research Foundation of the University of Sydney. Sydney 1999, pp 251-264

10) Brange J, Ribel U, Hansen JF, Dodson G, Hansen MT, Havelund S, Melberg SG, Norris F, Norris K, Snel L, Sorensen AR, Voigt HO. Monomeric insulins obtained by protein engineering and their medical implications. Nature 1988;333:679-682

11) Nielsen FS, Jorgensen LN, Ipsen M, Voldsgard AI, Parving HH. Long-term comparison of human insulin analogue B10Asp and soluble human insulin in IDDM patients on a basal/bolus insulin regimen. Diabetologia 1995;38:592-598

12) Bott U, Bott S, Hemmann D, Berger M. Evaluation of a holistic treatment and teaching programme for patients with type-1 diabetes who failed to achieve their therapeutic goals under intensified insulin therapy. Diabetic Med 2000;17:635-643

13) Jorgensen LN, Dideriksen LH, Drejer K. Carcinogenic effect of the human insulin analogue B10Asp in female rats. Abstract. Diabetologia 1992;35/Suppl.1: A3

14) Gale EAM for the UK Trial Group. A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with Type-1 diabetes on intensified insulin therapy. Diabetic Med 2000;17:209-214

16) Pieber TR et al. Efficacy and safety of HOE 901 versus NPH insulin in patients with type-1 diabetes. Diabetes Care 2000;23:157-162

17) Raskin p, Klaff L, Bergenstal R, Halle JP, Donley D, Mecca T. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care 2000;23:1666-1671

18) Nathan DM, Singer DE, Hurxthal K, Goodson TD. The clinical information value of the glycosylated hemoglobin assay. New Engl J Med 1984;310:341-346

19) Heinemann L. Hypoglycemia and insulin analogues: is there a reduction in the incidence ? J Diabetes Complications 1999;13:105-114

20) Berger M, Heinemann L. Are presently available insulin analogues clinically beneficial? Diabetologia 1997;40:S91-S96

21) Siebenhofer A. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester UK: John Wiley & Sons Ltd.

22) Rakatzi I, Ramrath S, Ledwig D, Dransfeld O, Bartels T, Seipke G, Eckel J. A novel insulin analog with unique properties. Diabetes 2003;52:2227-2238

24) L.J.Slieker: In vitro studies with Lys(B28),Pro(B29) human insulin (LY275585), Des 64,65 human proinsulin (LY197535) and Asp(B10)human insulin. Unpublished. Data on file.Lilly Comp. 1992

26) Kurtzhals P, Schäffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C,Trüb T. Correlations of Receptor Binding and Metabolic and Mitogenic Potencies of Insulin Analogs Designed for Clinical Use. Diabetes 2000;49:999-1005

27) Sandow J, Seipke G. In Vitro Pharmacology Studies with Insulin Glargine and Human Insulin: IGF-1 Receptor Binding and Thymidine Incorporation. Abstract. Diabetes 2001;50/Suppl.1: A 429

28) Russo I, Massucco P, Mattiello L, Cavalot F, Anfossi G, Trovati M. Comparison between the effects of the rapid recombinant insulin analog aspart and those of human regular insulin on platelet cyclic nucleotides and aggregation. Thrombosis Research 2002;107:31-37

29) Russo I, Massucco P, Mattiello L, Anfossi G, Trovati M. Comparison between the effects of the rapid recombinant insulin analog Lispro(Lys B28,Pro B29) and those of human regular insulin on platelet cyclic nucleotides and aggregation. Thrombosis Research 2003;109:323-327

30) Rakatzi I, Seipke G, Eckel J. [LysB3,GluB29]insulin: a novel insulin analog with enhanced ß-cell protective action. Biochemical and Biophysical Research Communications 2003;310:852-859

31) Fawcett J, Hamel FG, Bennet RG, Vajo Z, Duckworth WC. Insulin and analogue effects on protein degradation in different cell types-Dissociation between binding and activity. Journal of Biological Chemistry 2001;276:11552-11558

32) Slawik M, Petersen KG. Effects of Basal Insulin Treatment on IGF-1: Glargine – vs. NPH-Insulin. Abstract. Diabetes 2002;51/Suppl.2: A297

33) Hedman CA, Orre-Pettersson AC, Lindström T, Arnqvist HJ. Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-1 and IGFBP-1 in type-1 diabetes. Clinical Endocrinology 2001;55:107-112

34) Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR. Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: Comparisons to insulin and IGF-1. Journal of Clinical Endocrinology and Metabolism 2001;86:5838-5847

35) Jorgensen LN, Dideriksen LH. Preclinical studies of rapid acting insulin analogues. In:M.Berger, F.A.Gries (eds) Frontiers in Insulin Pharmacology. pp.110-117. Georg Thieme Verlag Stuttgart-New York 1993

36)Medline research 1996-2003, key words „aspart or detemir and safety“ ,aspart or detemir and toxicity‘. Accessed 18.3.2004

37) Zimmermann JL, Truex LL. 12-month chronic toxicity study of LY275585 (human insulin analog) administered subcutaneously to Fischer 344 rats. Int J Toxicol 1997;16:639-657

38) Stammberger I, Bube A, Durchfeld-Meyer B, Donaubauer H, Troschau G. Evaluation of the cacinogenic potential of insulin glargine(LANTUS) in rats and mice. Int J Toxicol 2002;21:171-179

40) European Agency for the Evaluation of Medicinal Products (EMEA). Committee for proprietary medicinal products(CPMP): Points to consider document on the non-clinical assessment of the carcinogenic potential of insulin analogues. Issued in London 15 November 2001. Internet: CPMP/SWP/372/01

41) LeRoith D(Ed.)Insulin-like growth factors and cancer.Horm Metab Res 2003;35:649-872

Insulin - A Voice for Choice

INSULIN - A Voice For Choice
Arthur Teuscher
Published by Karger Bern
ISBN-13: 978-3-8055-8353-4
August 2007

In the early 1980' synthetic "human" insulin produced by recombinant DNA technology came onto the market. Despite an acknowledgment by the manufacturers regarding the potential dangers of "human" insulin they soon began to withdraw bovine and porcine insulin from markets all over the world, and promoted more expensive "human" insulins as a superior replacement. Diabetics had no option but to effectively switch to the new synthetic insulins and often they received little or no information about their potentially life-threatening side effects.

In the first part of this book the author provides fundamental information about insulin therapy and its history. A detailed discussion of the hazards confronting some diabetic patients when using "human" insulin follows. Due to more pronounced hypoglycemia symptoms animal insulin can be regarded as safer than "human" insulin for 10-20% of diabetic patients. The last part of this publication looks at the pharmaceutical industry's decision to withdraw animal insulin from the market and describes the struggles of a new global movement to secure its continued availability.

This book not only provides potentially vital background information for those who depend on insulin, but also deserves the attention of professionals who prescribe or distribute this medication. It can also serve as a reference for patient advocates, relevant government departments and pharmaceutical companies.

“Arthur Teuscher’s lucid analysis of the saga of human insuilin should be compulsory reading for patients and professionals alike. This is a cautionary tale of how an overmighty pharmaceutical industry has, under the guise of progress, adversely influenced the best interests of those with diabetes. But it also tells the important story of how an alliance between physicians and patients has successfully campaigned to bring this issue to public attention and thus guaranteed for those who need it, continued access to the mot appropriate treatment for their needs.”

“An important book for all who need insulin, and for their phyd=sicians to help them understand the message.!

Andrew Herxheimer, MB, FRCP, London, Emeritus Fellow of the UK Cochrane Cntre, Co-Founder of the International Society of Drug Bulletins and DIPEx

“It is a masterpiece which clearly describes the unfortunate saga and cause which Arthur Teuscher has expounded for 20 years. It is in many ways a sad story but at least there is some cause for optimism, as there is a reasonable chance that the groundswell of public opinion will ensure that animal insulin becomes more widely available.”

‘Insulin – A Voice for Choice’ can be obtained directly from IDDT, price Cost £13.50 incl p&p.

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

Cochrane Database Syst Rev. 2004;2:CD003287

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:

Human insulin has a weak mitogenic effect. [Mitogenic effect mean cell division 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.
More information can be found by visiting:

http://www.emea.eu.int/pdfs/human/swp/037201eu.pdf

We will be happy to send copies of this to people without internet access. It is also worth looking at the EMEA approval documents for each analogue insulin on their website www.emea.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.

A Cochrane Review April 2007
K Horvath, K Jeitler, A Berghold, SH Ebrahim, TW Gratzer, J Plank, T Kaiser, TR Pieber, A Siebenhofer Cochrane Database of Systematic Reviews 2007 Issue 2 (Status: New)

Insulin analogues are the latest form of GM synthetic insulin and this review compares long-acting analogues glargine [Lantus] and determir [Levemir] with long-acting 'human' isophane [NPH] insulin for Type 2 diabetes. For us to have an informed choice of treatment, it is necessary to look at evidence from high quality systematic reviews and Cochrane Reviews provide just such evidence.

"If at all there is only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2 treated with "basal" insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with insulin glargine or detemir."

Below is the 'Plain Language Summary' but the full review can be found on the Cochrane Database www.cochrane.org

Plain language summary
No unambiguous clinical benefits of treatment with long acting insulin analogues in the majority of people with type 2 diabetes mellitus demonstrated
NPH (Neutral Protamine Hagedorn) insulin is the current standard for basal insulin in the blood glucose lowering therapy in people with type 2 diabetes mellitus. The mode of action of this insulin is highly variable, which may be the cause for the difficulties some people with diabetes have to achieve current goals for long-term metabolic control. Therefore, new insulins which are thought to show more favourable properties of action have been developed: insulin glargine and insulin detemir. Because of their theoretical advantages, it is thought that treatment with these new insulin analogues might lead to a beneficial effect, for example less hypoglycaemia or a better metabolic control, possibly resulting in higher quality of life and treatment satisfaction less late diabetic complications such as problems with eyes, kidneys or feet and myocardial infarction, stroke or death.

Although epidemiological studies indicate that high concentrations of blood glucose carry a higher risk for these late complications, evidence for a beneficial effect of glucose-lowering therapy is conflicting. Following from the different results of large clinical trials, interventions seem to carry different substance specific beneficial or adverse effects. As a consequence, conclusions on the effects of different blood glucose lowering interventions on these outcomes can not be drawn from their effect on blood glucose concentration alone.
Methodological quality of all the studies was rated low ("C"). Eight studies investigated altogether 2293 people. Trials lasted between 24 and 52 weeks. Our analysis of the currently available long-term trials comparing long acting insulin analogues with NPH insulin showed that insulin glargine and insulin detemir were almost identically effective compared to NPH insulin in long-term metabolic control (HbA1c). Fewer people experienced symptomatic overall or nocturnal hypoglycaemic episodes with treatment with either of the two analogues. No conclusive information on late complications or on possible differences in the number of fatalities exists. For insulin glargine one study found a higher rate of progession of diabetic retinopathy in patients treated with insulin glargine, while in another investigation the opposite result was found. It was thus not possible to conclude for certain whether insulin glargine treatment is safe or not.

From the retrieved trials it was also not possible to draw firm conclusions on the effects of these new insulins on quality of life or their cost effectiveness. Until long-term data on benefit and risk are available, we suggest a cautious approach to treatment with insulin glargine or insulin detemir.

· We know that Lantus, Levemir and human long-acting insulins are the same in terms of blood glucose control as measured by HbA1s.

· We know that fewer people in the studies experienced symptomatic overall or night hypos with both the two analogues but we don't know about the numbers of hypos without warnings [asymptomatic].

· We don't know if treatment with Lantus and Levemir results in more or less complications over time or if there are any differences in death rates.

· We don't know if Lantus causes higher rates of retinopathy - one study showed it did and one that it didn't, so we don't know if it's safe or not.

From this review we know two things - there are an awful lot of uncertainties about long-acting analogues and the authors' recommendation for a cautious approach to prescribing these insulins is not being adopted in the UK and many other countries.

Yet again we are reliant on Germany for another review that helps to inform our decisions about insulin treatment. Unlike the UK where the Dept of Health has refused our lobbying request for a National Institute of Clinical Excellence [NICE] assessment of all insulins, the German Federal Joint Committee actually commissioned IQWiG to compare the benefit of rapid-acting insulin analogues versus human insulin for Type 1 diabetes. So one has to wonder why this doesn’t happen in the UK?

The insulins investigated were, Humalog [lispro], NovoRapid [aspart] and Apidra [glulisine].

· Adults - there is currently no evidence available to demonstrate a superiority of rapid-acting insulin analogues in the treatment of adults with Type 1 diabetes. The value of the evidence and design of studies so far are inadequate and do not allow conclusions regarding most important patient goals, such as the reduction in long-term complications or overall mortality.

· Children and adolescents – due to lack of data, the benefit of rapid-acting insulin analogues in children and adolescents is unclear [an uncertainty!]. Novo Nordisk has carried out long-term comparative studies in this group of patients but they are withholding some of the results.

· Pump therapy – no long-term studies were available therefore it remains unclear whether adults would benefit and what advantage patients would have by using analogues with insulin pumps [an uncertainty!]. The same applies to children and adolescents as only fully published short-term studies are available. Novo Nordisk sponsored 2 long-term studies in children and adolescents but to date, both studies have only been partially published and unlike Sanofi-Aventis and Lilly, Novo Nordisk were not prepared to provide the information needed for the review.

· Quality of life, not a fair comparison – in some studies patients treated with insulin analogues assessed their quality of life as higher and they were more satisfied with treatment than those using human insulin. IQWiG did not evaluate this finding as evidence of an additional benefit, because it was not based on a fair comparison – patients in the human insulin group were asked to adhere to a fixed injection-meal regimes but the analogue group were not. [As we know, it is quite possible to use a flexible regime with all types of insulin.] So it is unclear whether the patient satisfaction was due to the insulin or to the more flexible regime prescribed by the physicians.

Basically it is simple, there is no evidence that rapid-acting insulins are any better than human insulins for adults with type 1 diabetes. It is unclear whether they are of any benefit to children and adolescents. It is also unclear whether they are of benefit any groups of pump users. They are, of course, significantly more expensive to the NHS! So once more, we this review raises big questions:

· Why is the Dept of Health so unwilling to follow Germany’s lead and have all insulins assessed by NICE for risks/benefits and cost effectiveness?

· Why are Primary Care Trusts that are so obviously short of funds, spending unnecessary amounts on insulin analogues that have no proven benefits over less expensive human and animal insulins?

· Why are adults and children with diabetes being changed to insulin analogues when they have no proven benefit?

· Could all this be anything to do with heavy marketing of insulin analogues because they are the only insulins in patent, therefore more expensive and more profitable?

It is the patient's right to have an informed choice of treatment, with information about risks and benefits, including any adverse effects. People with diabetes have a right to an informed choice of insulin treatment and should be told of their choices. All too often they are not given information about the different species of insulin and are automatically prescribed GM synthetic insulin without being told that natural beef and pork insulins are available. Even when people are adversely affected by GM insulin, rarely are they advised to try natural animal insulin.

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 GM 'human' insulin and animal insulin provides just such high quality evidence.

“ ‘Human’ insulin versus animal insulin in people with diabetes mellitus”

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

Background: Human insulin was introduced for the routine treatment of diabetes mellitus in the early 1980s without adequate comparison of efficacy to animal insulin preparations. First reports of altered hypoglycaemic awareness after transfer to human insulin made physicians and especially patients uncertain about potential adverse effects of human insulin.

Objectives: To assess the effects of different insulin species by evaluating their efficacy [in particular glycaemic control] and adverse effects [mainly hypoglycaemia].

Search Strategy: A highly sensitive search for randomised controlled trials combined with key terms for identifying studies on human versus animal insulin was performed using the Cochrane Library [Issue 2, 2002], Medline [1966 to May 2002]. We also searched reference lists and databases of ongoing trials. Date of last search: May 2002

Selection criteria: We included randomised controlled trials with diabetic patients of all ages that compared human to animal [for the most part purified pork] insulin. Trial duration had to be at least one month in order to achieve reliable results on the main outcome parameter glycated haemoglobin.

Data collection and analysis: trial selection as well as evaluation of study quality was performed 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 by Jadad.

Main results: Altogether 2156 participants took part in 45 randomised controlled studies that were discovered through extensive search efforts. Though many studies were of a randomised, double-blind design, most studies were of poor methodological quality. Purified porcine and semi-synthetic insulin were most often investigated. No significant differences in metabolic control or hypoglycaemic episodes between various insulin species could be elucidated. Insulin dose and insulin antibodies did not show relevant dissimilarities.

Reviewers’ conclusions: A comparison of the effects of human and animal insulin as well as of the adverse reaction profile did not show clinically relevant differences. Many patient-oriented outcomes like health-related quality of life or diabetes complications and mortality were never investigated in high quality randomised clinical trials. The story of the introduction of human insulin might be repeated by contemporary launching campaigns to introduce pharmaceutical and technological innovations that are not backed up by sufficient proof of their advantages and safety.

The full version of this Cochrane Review can be found at:

www.cochrane.org

People in England, Wales, Ireland, Norway & Australia can gain free access.

What does this review of ‘human’ and animal insulin mean for people with diabetes?

It provides us with information to make truly informed choices about the species of insulin we wish to use. Our choices are simple - animal insulins with a history of 70 years research and post marketing surveillance [being used in the real life situation for over 70 years] or ‘human’ insulin with an absence of meaningful research and an ongoing history of reported adverse reactions.

The review has dispelled many of the myths that are told to people with diabetes.

· It can no longer be said that ‘human’ insulin is better than animal insulins, because there is no evidence for this.

· It can no longer be said that ‘human’ insulin gives better control and better HbA1cs, there is no evidence for this.

· It can no longer be said that ‘human’ insulin produces less antibodies, there is no evidence to support this.

· The existence of other adverse effects, apart from hypoglycaemia, was not even investigated, so their existence can no longer be denied.

Important issues for people treated with insulin have never been investigated

Perhaps the greatest importance of this review is that it highlights the research that has NEVER been carried out. This absent research is essential for us to know that we are being treated with the insulin that produces the best effects on our health, our wellbeing and indeed our lives and even our life expectancy. These are very basic requirements for any drug but perhaps especially so for ‘human’ insulin - the first ever genetically produced drug to be used on human beings. Twenty years after its arrival on the market with indecent haste, ‘human’ insulin has never been subjected to essential, quality post marketing research to answer the questions that must now be asked by people who are prescribed it.

It is an international non-profit organisation that aims to help people make informed decisions about health care by reviewing and promoting the best available evidence from research on the effects of various treatments. The Collaboration also aims to influence what the direction of future research by identifying areas where more research is needed.

We are all aware that some health care treatments make you better, some don’t and sometimes the treatment can be even worse than the condition. Sometimes it seems as though a drug/treatment worked, but really the benefit came from something else or maybe you would have just got better anyway. So both patients and doctors need good evidence from research to know the effects of a drug or treatment in order to decide whether we should try it. This also applies to decision-making bodies, such as the NHS.

However good individual studies maybe, they are often carried out on specific groups of people or on small numbers so the results cannot be extended to assume that the effects of the treatment will be the same for everyone with a particular condition. Publication bias also creeps in as a great deal of good research is not published and so we are not receiving the complete picture.

Cochrane groups carry out systematic searches for all the studies on a topic and then sort out which are the good quality studies [randomised controlled trials or RCTs]. Conclusions can then be drawn that give a much more complete picture of whether or not a drug/treatment is effective. A review may show that there is no evidence to support a particular drug/treatment or that little or no good quality research has been carried out. This is equally important because it means that the use or prescribing of that drug/treatment is not based on proven benefit from research.

HEALTH SELECT COMMITTEE - IDDT gives evidence
December 2004

New Inquiry - The Influence of the Pharmaceutical Industry on Health

The Health Committee is a Select Committee of the House of Commons appointed to examine the expenditure, administration and policy of the Dept of Health and associated public bodies. It has the power to send for persons, papers and records holding an Inquiry into the influence of the pharmaceutical industry on health.
In mid 2004 The Health Committee announced a new inquiry into the influence of the pharmaceutical industry to health. On behalf of IDDT, Co-Chairman Jenny Hirst presented written evidence to the Committee and subsequently was called to give oral evidence to the Committee on November 25th 2004.

Further information is available on Parliament's website www.parliament.uk/parliamentary_committees/health_committee.cfm

IDDT's written evidence presented to the Health Committee:

Introduction
The Insulin Dependent Diabetes Trust is a registered charity offering information and support to people with diabetes and their families. The Trust formed in 1994 as a direct result of the adverse effects experienced by a significant number of people to synthetic insulin made by genetic modification, introduced in 1982.

Synthetic GM 'human' insulin was introduced into the market without long-term safety data and as shown in the Cochrane Review [ref 1], without scientific proof of advantage over existing purified animal insulins with their long history of safety and efficacy. Nevertheless, the significantly more expensive synthetic GM insulin became first line treatment for insulin requiring diabetes and the adverse effects experienced by at least 10% of patients [30,000] have been largely ignored or disputed by both the medical profession and the regulatory authorities.

The vast majority of patients have not, and are not, given the treatment choice of animal or synthetic GM insulin which should be theirs by right and nor have they been provided with information about the risks and benefits of all insulin types so that their choice is informed.

It is difficult to find an explanation for this situation which may have an effect on the health of patients, on their ability to have an informed choice of treatment and on the overall cost of diabetes to the NHS. We believe that in part the explanation must be due to the influence of the pharmaceutical industry.

In their conclusion, the Cochrane reviewers [ref 1] expressed concerns that the story of the introduction of synthetic GM 'human' insulin might be repeated by contemporary launching campaigns to introduce pharmaceutical and technological innovations that are not backed up by sufficient proof of their advantages and safety. It is for this reason that the Inquiry may wish to consider this 'story' as an example of the influence of the pharmaceutical industry over health outcomes and health policies.

The conduct of medical research
We are concerned about the quality of industry sponsored research. The Cochrane Review of animal and synthetic GM 'human' insulin showed no evidence of benefit and a lack of research to compare mortality and diabetic complication rates which are very important issues for people with diabetes wishing to make treatment choices. However, it also showed that the research that was carried out was "methodologically poor". Yet despite this poor quality research, lack of evidence of benefit and no long-term safety data, synthetic 'human' insulin became first line treatment with over 84% of patients transferred to it, too often for no clinical reason.

Our concerns were compounded in 2004, when a further Cochrane Review [ref 2] comparing the more recently developed insulin analogues with synthetic 'human' insulin, also showed that the research was "methodologically poor". As many as 81% of the studies were sponsored by the analogue insulin manufacturers themselves and the remaining studies had no sponsor stated. Insulin analogues are now taking over as first line treatment so no lessons have been learnt.

From this we have concluded that the quality of industry research has not improved and nor have the demands of the regulatory authorities become more vigilant in requiring better quality research.

From our experience, we have to raise the following points:
[a] the quality of studies carried out by the pharmaceutical companies wishing to market and promote a new drug.

[b] the lack of independent studies to inform decision making and the bias that may be introduced, especially publication bias that is likely to occur if the majority of the studies are carried out by industry who are unlikely to publish negative studies

[c] the quality and efficiency of the marketing approval process whereby drugs are approved for use on the basis of largely poor quality research.

[d] the post marketing surveillance system which does not appear to require evidence from research carried out independently of the pharmaceutical industry.

[e] in view of the lack of evidence of benefit of synthetic GM insulins, it is surprising that NICE has never evaluated insulin prescribing, assessed cost effectiveness and issued guidelines on insulin prescribing.

Our concerns are summarised by Edwin Gale, Professor of Diabetic Medicine in Bristol, [ref 3] writing about the marketing of troglitazone, a Type 2 diabetes drug which had to be withdrawn for safety reasons 6 weeks after gaining marketing approval in the UK:
"Big pharmaceutical companies see clinical studies as a means of satisfying the regulators and promoting sales, not of providing information. Published reports are not designed to help clinicians persuade us to use the new agent effectively: they are selected and slanted in such a way as to persuade us to use the new agent. Hence the huge amount of junk literature of irrelevant and badly reported studies with misleadingly optimistic titles. No one will ever know how many people it [troglitazone] killed, perhaps between 200-1000, yet the culture of secrecy protected the industry from full and timely disclosures of the mounting evidence of risk."

The provision of drug information and promotion
1. Advertising and promotion
While direct to consumer advertising of drugs [DTCA] is not allowed in the UK, we are concerned at the subtle ways in which industry circumvents this situation to reach the general public.
We cite the following examples:

2. Influencing and advertising to physicians
We are concerned at the close links between industry and the medical profession. After failing to obtain recognition of the adverse effects to synthetic GM insulin, some patients attempted legal action against the manufacturer Novo and attracted media attention as a result of sudden unexplained deaths. Novo employed a public relations company to defend the safety profile of genetically modified human insulin. They recommended a reactive strategy of a issues/crisis management programme that spanned three years and involved media training of company headquarters staff and UK medical spokespeople. The litigation collapsed and the PR company's description of the results was that Novo's reputation remaining intact among patients, health professionals and media, that sales continued to grow and the medical professionals accepted that human insulin has an excellent safety profile. While such action may have been in the best interests of the company and the promotion of their insulin, it has to be noted that the insulin could not be defended on the grounds of scientific evidence. It also demonstrates that there was unacceptable influence used to influence the medical profession and patients in favour their product.

To further quote Professor Edwin Gale [ref 3] on the issue of troglitazone, but which could equally apply to synthetic GM insulins: "Not one physician stood up to say that the evidence base was inadequate and that no drug for diabetes is worth dying for……..Our profession did nothing to protect the public. No one wants to remember troglitazone. It is treated as an unfortunate aberration of the system. It was not. It was a consequence of the system. Finding that out certainly changed my life."

3. Selective advertising
Industry stops advertising the drugs they no longer wish to promote in favour new more expensive drugs. While this is understandable from the company's perspective, it adversely affects patients being given an informed choice of treatment or alternatives if they experience adverse effects from the new product. For example animal insulins have not been advertised to physicians for many years and there is a perception amongst physicians and healthcare professionals that they are no longer available as a result of which they misinform patients.

4. Pharmaceutical company promotional materials
Promotional materials to medical and nursing staff affect prescribing habits. A survey [ref 5] examining the influences on 227 diabetes specialist nurses showed that regardless of their lack of legal status to prescribe and patients' right to a an informed choice of treatment, 96% felt that they predominantly chose the insulin type. While this choice was primarily influenced by their personal experience of a given insulin type, the second influence was literature and pharmaceutical promotion of a particular insulin type and notably not scientific evidence of benefit.

5. Local pharmaceutical contracts
In some areas drug prescribing is influenced by prescriptive protocols and local pharmaceutical contracts for the exclusive use of a particular insulin brand. While this may reduce overall costs, it removes the right of choice from both patients and doctors.

6. The provision of drug information can be incomplete
We are concerned that in the UK patients and physicians are not provided with full information about risks and benefits and that this must in part be due to the actions of both industry and the regulatory authority in the UK.
Patients and physicians involved in diabetes care receive restricted information compared to the United States.
For example: Journals in the US make reference to the potential carcinogenic effects of insulin analogues in advertisements to both patients and professionals patients [ref 6] but in the UK published journals have less information and do not include the potential for carcinogenic effects [ref 7 & 8]. The result is that treatment choices of both physicians and patients are not fully informed and there could be long-term health damage. The lack of this information cannot be explained as a matter of commercially sensitive information as all insulin analogues have this potential.

Professional and patient education
We do not believe that pharmaceutical companies should be involved in patient or professional education as they have a vested interest in promoting their own products or company name. In our experience, industry's record to date in the provision of the required high quality evidence to inform treatment decisions leaves much to be desired as has been demonstrated by the issues raised throughout this document.
If industry wish to be magnanimous and support patient education programmes, then a system should be devised whereby they can donate to a central fund that then allocates funding to specific education programmes not necessarily in a specific company's particular section of the market.

References
Ref 1 Cochrane Collaboration Database, 2002. ‘Human’ insulin versus animal insulin in people with diabetes mellitus
Ref 2. Cochrane Database 2004. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.
Ref 3 Professor Edwin Gale. Diabetes Digest; Vol 2 Number 4, 2003
Ref 4 Crawley Observer. 30.6.04 Top chef cooks at town firm
Ref 5 Practical Diabetes International; Sept 2003 Vol 20 No7
Ref 6 Diabetes Health, June 2004
Ref 7 Practical Diabetes, July/August 2004
Ref 8 Diabetic Medicine, July 2004

Jenny Hirst
Co-Chairman
Insulin Dependent Diabetes Trust

This organisation is Germany's equivalent to NICE in the UK and its final report on the use of rapid-acting analogues for the treatment of Type 2 diabetes resulted in the following recommendations:

"For patient relevant outcomes, there is no convincing evidence of a superiority of rapid-acting insulin analogues compared to regular human insulin [short-acting] in diabetes mellitus type 2 therapy. Rapid acting insulin analogues have not been sufficiently investigated with regard to their potential long-term beneficial and harmful effects."

· No relevant and fully published study was found on insulin aspart [NovoRapid] only an abstract in 1999 and Novo Nordisk was not prepared to provide study data if these data were to be published in this report. No relevant studies were found on pre-mixed formulations of rapid-acting insulin analogues or short-acting human insulin combined with longer-acting insulins. [Important lack of research considering Novo Nordisk's removal of pre-mixed human insulins in the UK!]

· None of the studies were designed to investigate the effect of rapid-acting insulin analogues on the reduction of diabetic complications or total mortality.

· For hypoglycaemia, no clear advantage was shown with analogues compared to human insulin with regard to severe, symptomatic or nocturnal hypoglycaemia.

· Quality of life studies were limited but no clear advantage was shown with analogues compared to human insulin and no definite conclusions could be drawn about patient satisfaction as the studies were unsatisfactory.

· There was a tendency towards more people dropping out of the studies due to adverse reactions in those treated with analogues compared with those on human insulin.

· In so far as reported, there were similar weight increases for both patients receiving analogues and those receiving human insulin.

· As the maximum study period was 12months, no studies could show the safety of long-term use of analogues in people with Type 2 diabetes. Unless proved otherwise by adequately designed studies, the potential for mitogenic potency of insulin analogues [cell mutiplication and formation of tumours] as described in pre-clinical trials, is to be seen as a potential safety risk for long-term treatment of people with Type 2 diabetes.

As a result of this review and the significant additional cost of insulin analogues, health providers in Germany made the decision not to fund rapid-acting insulins for people with Type 2 diabetes. This resulted in the insulin manufacturers lowering the price to that of short-acting ‘human’ insulin.

by the International Team Residency supported by the Rockefeller Foundation, New York, USA

"The need to enable people requiring insulin to have an informed choice of insulin treatment"

The welfare of people with diabetes depends on their active participation in their care. To achieve this active participation the patient must have information about benefits, risks and alternatives concerning treatment and must have appropriate facilities available to make a free choice. New research has made possible an overall understanding concerning differences in warning symptoms of hypoglycaemia when using genetically produced human insulin and natural animal insulin.

The debate on these differences has continued since the introduction of treatment with human insulin and, unfortunately, very often the patients’ experiences have been classed as "only anecdotal" and of little value. Evidence supporting these experiences demonstrates neurophysiological differences during hypoglycaemia in human and animal insulins.

Research has already demonstrated that human insulin has no clinical advantage for patients and that it has a faster absorption and consequently a shorter duration of action, so accounting for the greater fluctuations in blood-glucose levels. However, it has been the general view that because of its exact similarity to endogenous insulin, human insulin should be the insulin of choice for all.

Based on the new understanding of the information from the neurophysiological studies which clearly support the reported adverse reactions to human insulin by many patients, we recommend:

1. That this latest information be relayed to those living with insulin dependent diabetes. This will enable those experiencing impaired or reduced warning symptoms of hypoglycemia or reduced feelings of well-being and safety to re-examine their choice oh human or animal insulin. This choice will then be based on both scientific evidence and the reported experiences of patients;

2. That this information be reported to Government Health Departments, WHO, IDF, Diabetes Associations, Physicians and all diabetes health care professionals throughout the world;

3. That when insulin is needed, animal insulin should be considered as first choice treatment for all those where hypoglycaemia may be of special concern. This may include the following:

5. That in future greater recognition should be given to the value of patient experiences in relation to adverse drug reactions.

Rockefeller Study & Conference Center
I-22021 Bellagio (Como), Italy

April 8, 1996

Prof. Arthur Teuscher, MD (Switerland)
Dr. Pier Luigi Barbero, MD (Italy)
Nina Bollhalder Sureskumaran (Switerland)
Jenny Hirst, FBCO (UK)
Dr. Matthew Kiln, MB.BS/DRCOG (UK)
Scott King, Editor-in-Chief (USA)
Dr. Kristian Midthjell, MD (Norway)
Dr. Deo Mtasiwa, MD/PhD (Tanzania)
Dr. Shiva Murugasampillay, MB.BS/MSc (Zimbabwe, unable to attend)
Prof. Malina Petkova, MD (Bulgaria)

"Human Insulin Hypoglycaemia Unawareness: Accumulated Evidence on the Phenomenon"

A debate on the well-known topic of hypoglycaemia unawareness has been going on since the introduction of animal insulin 75 years ago. A few patients, mainly insulin-dependent, have suffered from insulin hypoglycaemia unawareness (abrupt severe hypoglycaemia without warning symptoms) over all these years. This debate has risen sharply since the first publication of an apparent sudden rise of this hypoglycaemia syndrome linked to human insulin in 1987 ^1,2, later confirmed by controlled studies with so called human (HI) vs porcine (PI) insulin from various diabetes centres. ^3,4,5.

Many diabetes care professionals around the world do continuously observe differences between human and animal insulin in clinical practice: unawareness of hypoglycaemia symptoms, unstable diabetes control, increased severity of hypoglycaemic episodes without warning symptoms. Human insulin is still one possible explanation for the so called "dead in bed syndrome" (approximately 50 sudden unexplained deaths in young insulin-dependent diabetics, going to bed in apparently good health and later found dead in an undisturbed bed) ^6,7,8. The full explanation still remains unanswered.

Since the introduction of human insulin of recombinant DNA origin in 1982 the official FDA (USA) labelling carries a warning ⁹. In 1991 the warning was highlighted by the FDA’s mandate imposing the use of bold print. "A few patients who experienced hypoglycaemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycaemia were less pronounced or different from these experienced with their previous insulin."

Recent research has shown important new evidence in hypoglycaemia effects in the brain explaining the loss of awareness of hypoglycaemia in insulin requiring diabetic patients ¹⁰. It also provides another very important piece of the jigsaw puzzle in understanding the specific loss of hypoglycaemia awareness in a subset of human insulin consumers.

We are pleased to report that now there is also a logical neurophysiological and pharmacodynamic explanation for the phenomenon of "human insulin hypoglycaemia unawareness". We hope all health care professionals will be able to accept that these new findings show a mechanism to explain differences between these two species of insulin, and that these are significant for a substantial number of insulin users - "that the awareness of changes in central nervous stimulus processing (being stronger after PI than HI) may serve as a first subjective cue for an acute impending hypoglycaemia"¹¹.

Relevant research demonstrating a mechanism for the difference in hypoglycaemic awareness between human and animal insulin (and practical information).

· Patients who have experienced difficulties with human insulin are mainly those who keep good or tight control ¹² (observations).

· A recent study concludes that the uptake of glucose in the brain during hypoglycaemia, is a major mechanism for inducing hypoglycaemia unawareness, more so with tight than intermediate or poor control ¹⁰. Boyle ¹⁰ showed that in two patient groups with less well controlled diabetes with elevated blood glucose concentration (HbA1c 8.5 and 10.2%), the glucose uptake in the brain dropped during hypoglycaemia so sparking off the counter-regulatory hormones and producing early warning symptoms of the impending hypoglycaemia10. However, in patients with good or tight control (HbA1c 7.2%) and in patients who had experienced a recent "hypo", the intra-cerebral glucose did not drop during hypoglycaemia and the brain did not react to peripheral ongoing hypoglycaemia. This inappropriate response suggests that counter-regulatory hormones, like adrenalin, were lacking. The study was performed with human insulin.

· Another part of the explanation comes from the molecular differences between human and animal insulin. These show that animal insulin is more lipophilic than human insulin which is more hydrophilic ^13,14, resulting in a faster cerebral accumulation of porcine insulin ¹⁵. One can therefore make the logical assumption that the intra-cerebral concentration is higher, thus reducing brain glucose during hypoglycaemia at an equivalent peripheral blood glucose level. A consequence of this will be a reduction or loss of awareness of hypoglycaemia with human insulin in some patients.

· Evidence to support this view comes from research, some of which has not been referenced frequently in the large reviews done on this subject. This research shows differences in neurophysiological ^15,16 and higher sensory function between human and animal insulin ¹⁷. Auditory and visual responses, as well as auditory brain stem, responses were significantly weaker during the first 20 minutes of hypoglycaemia induced by human insulin, than with animal insulin ¹⁷. Kern et al. concluded that "... human and pork insulin induced hypoglycaemia differ in their actions". The differences in awareness of human and porcine insulin induced hypoglycaemia are very likely a consequence of differential processing signals within the nervous system.

· The above area of research demonstrates a mechanism which explains the differences in awareness of hypoglycaemia between human and animal insulin found in clinical studies ^{1,18,19,20,21,22,23,24}.

· Many other studies showing a reduction in counter-regulatory hormone response in hypoglycaemia comparing human and animal insulin give further support to this explanation ^25,26,27,28. Of particular importance are those studies demonstrating a greater adrenergic response with animal insulin in hypoglycaemia ^29,30. This in effect is showing change from clearly recognised adrenergic to neuroglycopenic symptoms with primary or secondary human insulin treatment, which explains the experiences of patients.

· Heller and Cryer ³¹ found that one single episode of hypoglycaemia could trigger the loss of warning mechanism of hypoglycaemia and Mitrakou et al. ³² showed that hypoglycaemia itself can induce unawareness of hypoglycaemia and a decrease in the counter-regulatory hormones.

Note: Perfectionists may wish to see this fully logical theory tested out by a repeat of Boyle’s study using animal and human insulin in controlled settings. But there seems little point in subjecting more patients to experimental insulin hypoglycaemia when there are risks of consequent loss of awareness that inevitably follow it ³³.

· More erratic blood glucose levels experienced by some patients when using human insulin can be explained by the faster absorption and shorter duration ³⁴. An explanation of the other reported adverse cognitive brain effects of human insulin by family members and colleagues (depression, anxiety, other psychological events, aggressive tendencies, personality changes) is now necessary.

· Pharmacological studies clearly demonstrate that human insulin is absorbed faster than animal insulin, thus increasing the serum insulin concentration (up to significant differences) during the first hours after subcutaneous injections ³⁵.

Although it is difficult for many of us to understand this, in two large collections of data held by the British Diabetic Association and the Insulin Dependent Diabetes Trust, cognitive symptoms like these were reported with remarkable consistency, either by patients or by their families, and the majority of these subjects (or carers) reported these difficulties resolving when the patient changed back to animal insulin, irrespective of the duration of treatment with human insulin (Posner T.R.: 3000 letters (384 analyzed) British Diabetic Association 1992. London)

Whether we fully understand these phenomena or not, we must listen to these opinions as patients have very little reason to lie and patient satisfaction, well-being and safety are key factors in diabetes care. Finally because the numbers are quite large, these reports and the ongoing research are very unlikely to have no foundation.

Fundamental practical design mistakes in many published scientific studies comparing human and animal insulin.

We need to examine how reliable scientific research is to account for the differences that seem to occur between insulin-research and every day use of insulin.

1. Most commonly not recognising the effect study conditions have on changing the diabetic patients’ level of care they take with their control - this is often subconscious. This practical effect may be difficult for researchers to understand and it is probably only truly understood by those living with the condition.

2. Patients entered into a trial are often not representative of the population with the disorder ³⁶. Numbers of registered participants in research studies, the reasons for non participation and the real drop-out rates are either not published or under-reported ^37,38.

3. Unawareness studies involving self reporting of hypoglycaemia symptoms without recording of self measured blood glucose levels can only be of limited value as the patients may already have some degree of unawareness. Studies which include family members’ observations have more value but symptomless hypoglycaemic episodes can still be missed e.g. nocturnal hypoglycaemia which goes unnoticed ^37,39,40.

i. Where the follow up visits to the diabetic clinic are every 2 to 4 weeks ^37,38,40. In normal life visits are commonly every 26 to 52 weeks. Recording study events by questionnaire can increase the usual consultation time compared to routine visits.

ii. Where the number of home blood glucose tests are increased by up to 50% per week ⁴⁰.

iii. Where the insulin species is randomly changed every 4, 6 or 12 weeks ^38,41,42. In addition to this, IDDT’s analysis of case reports show that the adverse reactions to human insulin took on average 1.1 years to be recognised after starting to use human insulin ^12,43.

iv. Where acute hypoglycaemia is induced by intravenous infusion, with the patient being maintained in a prone position anticipating hypoglycaemia and with an intravenous canula maintained in their arm, the symptoms of hypoglycaemia are then recorded under these conditions. Hypoglycaemia in everyday life is where the patient is preoccupied with work or pleasure and the "hypo" is neither gradual nor predictable ^41,42.

v. Perhaps the most significant error is the failure to realise that hypoglycaemia itself has been shown to produce loss of warnings for several days or longer, therefore hypoglycaemia occurring before the study (of which the patient may be unaware) or indeed slow hypoglycaemia induced by the study itself, may cause loss of warnings, regardless of insulin species ³³.

vi. It is not wholly surprising that these studies show no difference between human and animal insulin. Common sense suggests that if patients complain of loss of awareness in everyday conditions ⁴³ then a study must test for this under these conditions.

The last place one can expect a result that is valid for extrapolation to everyday life is from a slow glucose clamp technique procedure under laboratory conditions.

Human insulin is a useful insulin formulation and many people with diabetes can happily use it. However, a substantial minority of people with diabetes feel safer, have better hypoglycaemia warning symptoms with animal insulin and fewer abrupt hypoglycaemic episodes.

A transfer back to animal insulin brings relief in most instances from severe hypoglycaemic events due to loss of warning symptoms ⁴⁴. Patients who have always been on human insulin may find advantages if they are allowed to change to animal insulin ⁴⁵. At the Liverpool Symposium of human insulin and hypoglycaemia (1992) there was general agreement for carefully designed large field studies. Until such scientific evidence can be available, "the simple practical advice must be that patients who wish to use animal insulin should be able to have the insulin of their choice" ⁴⁶. The balance of scientific data confirms that there are differences between human and animal insulin. Several show advantages with animal insulin in controlled studies also in the elderly despite an intact counter-regulatory response ⁴⁷ and in numerous case histories. No studies show any clinical advantages of human compared to animal insulin.

Review of literature shows altered cognitive function and reduced autonomic nervous stimulation with human insulin. These observations are in agreement with the recent studies of brain glucose uptake in well-controlled diabetic patients ¹⁰ and offer an explanation for reduced awareness in some patients experiencing hypoglycaemic events from human insulin treatment. This explanation comes as a relief to many doctors and patients. Adding to this the many case reports from patients or their families who have experienced or witnessed practical problems with human insulin (Insulin Dependent Diabetes Trust, Draft Report. Feb. 1996) means that the case for saying that human insulin should not be the automatic first line choice insulin for most insulin-dependent or insulin-requiring diabetic patients is proven beyond reasonable doubt. (The International Team Residency, Rockefeller Foundation Center Bellagio, April 1996) This is in agreement with the rules and ethics of careful surveillance control as proposed by health governments and drug control agencies.

1. Animal insulin should be used as the first line treatment in most newly diagnosed diabetic patients including the elderly. Exceptions may be made in those requiring pens i.e. poorly sighted, and some children, or those with previous insulin resistance.

2. If patients on human insulin have unexplainable symptoms such as depression, aggressive behaviour, psychological changes, lethargy, muscle cramps, it may well be worth trying a change to animal insulin for at least 6 months.

3. Human and animal insulin must remain available in all countries. Patients who are well- controlled on human insulin and do not suffer from unaccountable problems should not routinely be changed to animal insulin.

4. Drug companies should produce animal insulin in pen injectors to give both doctors and patients an equal choice of insulin 46.

5. Drug companies should again start producing a long acting animal insulin (e.g. Ultralente) which has a much longer tradition for smoother control compared to similar human products (e.g Ultratard HM) and would enable non-insulin-dependent diabetic patients to have one injection a day. A plea for animal Ultralente has been brought forward also in the United States⁴⁸.

6. All governments should assist all drug companies to ease re-licensing of animal insulin, especially the ultra-long acting insulins.

7. In countries where animal insulin has been completely removed, government health departments should assist with the reintroduction of animal insulin as soon as possible.

Note: The Bellagio Report was circulated to ALL national and international diabetes associations and the departments of health in many countries.

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8. 450 case reports of adverse effects experienced on human insulin from patients and their partners. Insulin Dependent Diabetes Trust UK. Data still being collected. To be published in due course. Abstracts available.

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Authors: Prof. Dr. med. Ernst Chantelau