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Insulin
Dependent
Diabetes
Trust

The GM 'Human' versus natural animal insulin debate

1. Choices – The Evidence

2. Evidence from people with diabetes

3. A little bit of history

4. Facts

5. Action and duration times of animal and GM 'human' insulins

6. Hypoglycaemia and loss of warnings

7. 'Dead in Bed' syndrome

8. The concerns of patients are justified

9. Availability of animal insulins in the UK

10. Changing your insulin

11. What to do if your consultant refuses to change your insulin

12. Availability of animal insulin if you admitted to hospital

13. Frequently asked questions

14. Allergic reactions to insulin

Insulin choices - how much more evidence do we need?

The NHS has always allowed patient to have an informed choice of treatment before they make their treatment decisions and this includes information about risks and benefits. In recent years, greater emphasis has been placed on informed choice as a result of NHS policy which puts patients at the centre of care and  encourages involvement in their treatment decisions so that in the ideal world, patients and their doctors make decisions jointly.

The treatment of diabetes is no exception and therefore people with insulin-requiring diabetes, whether Type 1 or Type 2 diabetes should have an informed choice of insulins and should be given information about risks and benefits.

IDDT has always argued that this should be the case and so if people have a preference for natural pork or beef insulins whether this is due to adverse reactions to GM synthetic insulins or simply personal preference, then their views should be respected. IDDT advocates the same principles should apply to of the newer insulin analogues.

The important of high quality evidence to inform our decisions

When new drugs, including new insulins, reach the market the research has been in limited numbers of people, often a highly selected group who are not necessarily typical of the general population with a condition such as diabetes. So at this stage there are many uncertainties about new insulins – are there any adverse effects, do they suit some categories of patient better than others, are they superior to their predecessors etc?

We must also remember that when a new insulin reaches the market, the manufacturers use the media to present it in the best possible light in order to maximise their sales and perhaps make exaggerated or unsubstantiated claims about its benefits and rarely admit to risks or drawbacks. So while it is important that we are aware of new insulins, it is also important to remember that our decisions should be made on the basis of good, high quality and independent research.

The best form of evidence is from good quality reviews, such as Cochrane Reviews, which examine all randomised controlled trials, assess their quality and draw conclusions from this information. Importantly, reviews may identify an absence of evidence and this too can help to inform our choices. For example, if research has not investigated the long-term safety of a type of insulin, then this is an uncertainty and treatment with it has associated risks which may influence our choice. Equally, if research has not compared the complication rates of different insulins, then this too is an unknown and without such information, our choices are not truly informed.

insulins

There are three types of insulin:

·         Natural animal insulins – derived from pancreases of pigs or cattle

·         Synthetic ‘human’ insulins – made in a laboratory by genetic modification.

·         Insulin analogues – the latest insulin made by genetically modifying GM ‘human’ insulin.

Let’s take a look at the evidence now in the public domain:

Human and animal insulins

·         Human insulins are not superior to animal insulin – Cochrane Review, 2002 

Rapid-acting insulin analogues

·         Rapid-acting insulin analogues have only minor benefit for the majority of patients - Cochrane Review, 2004

·         Rapid-acting insulin analogues are not superior to human insulin for the treatment of Type 2 diabetes - the Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG], July 2006

·         Rapid-acting insulin analogues are not superior to human insulin for the treatment of adults with Type 1 diabetes. The benefits for children and adolescents are unclear for lack of data - IQWiG, June 2007  

Long-acting insulin analogues

Long-acting analogue insulins can be used as an option for people with Type 1 diabetes but not for those with type 2 diabetes, except under special circumstances - NICE guidance, 2002.

·         Long-acting insulin analogues are not listed in Canada for treatment of Type 1 or Type 2 diabetes because they are not superior to NPH human insulin - Canadian Expert Drug Advisory Committee [CEDAC], June and Sept 2005.

·         Long-acting insulin analogues have only minor benefit, if at all, for the treatment of Type 2 diabetes - Cochrane Review, April 2007.

Details of the above Reviews can be found on our ‘Reviews and Reports’ pages: http://www.iddtinternational.org/reviewsandreports/index.htm

Note: IQWiG is carrying out a review of long-acting insulin analogues in Type 1 diabetes and then there will be reliable evidence to inform decision-making for all insulin analogues in both Type 1 and Type 2 diabetes.

The conclusions from the evidence are clear – GM insulins are not superior to their predecessors

There is no evidence that ‘human’ insulins are superior to animal insulin and it is reasonable to say that there is little evidence that insulin analogues are superior to ‘human’ insulin.

The decision about the choice of insulin should always be made on the basis of individual need, presence of adverse effects or personal preference. However, the importance of individual need and preference becomes very much greater when there is little evidence of superiority of the newer insulins.

For example, if an elderly person living on their own has always used a regime of two injections a day with ‘human’ or animal insulin, changing them to insulin analogues which means at least 4 injections a day can result a reduction in their quality of life, in confusion and even the danger of injecting the wrong insulin at the wrong time.

And what about risks?

The long-term safety of insulin analogues has not been established but it is known that they have the potential for carcinogenic effects with growing evidence of their mitogenic effects [cell multiplication which could lead to tumours]. So there are real grounds for people with diabetes to question whether these risks, however small, are worth taking when insulin analogies are not superior to older alternative insulins for which these risks do not appear to be present.

All the Cochrane Reviews of insulin analogues warn that a cautious approach to prescribing them should be adopted because of the lack of evidence of long-term safety, The 2005 International Diabetes Federation Position Statement on insulins, www.idf.org suggests that insulin analogues should only be used in patients where insulin analogues could be expected to help with specific problems.

Exercise your choice

Already 40% of people with diabetes have had their insulin changed to insulin analogues, an unnecessarily change according to the evidence and the newly diagnosed are automatically being treated with analogues. On what basis analogues are being so widely prescribed? From the above evidence of lack of superiority, it can only be on assumptions of benefit not evidence of benefit. This could be as a result of heavy marketing of the analogues as ‘designer’ or ‘modern’ insulins, both of which imply superiority or benefit. It is also worth noting that insulin analogues are the only insulins still in patent and therefore they can be sold at a higher price and greater profit for industry.  

Insulin analogues are significantly more expensive than ‘human’ and animal insulins and although the cost does not directly affect individual people in the UK, it does affect the overall NHS costs. Cost is less important than health risks, but Professor Edwin Gale questions whether people with diabetes are getting the best deal. He asks what choice people in the UK would make between treating 150-200 patients with long-acting analogues [rather than human insulin] or for the same cost, employing a full time specialist nurse to improve the education of people with diabetes so that they are better able to self-manage their diabetes. [Diabetologia (20070 50:1783-1790]

It is important that people with diabetes:

·         are involved in treatment decisions about their health

·         ask questions medications and about their insulin choices

·         ask for the evidence to support any recommendations that are being made, especially if it means changing their present insulin and regime.

Sadly in diabetes the choice of treatment has never truly rested with patients but if the intended discontinuations of some animal and human insulins go ahead, it will not be our doctors that are making our treatment decisions but drug companies. This is unacceptable, harmful and sets a dangerous precedent for healthcare generally. 

Evidence from people with diabetes

When IDDT formed in 1994 an important task was to collect information from people with diabetes and their family carers about their experiences with synthetic 'human' insulin. We sent questionnaires to everyone who contacted us and analysed the first 100 we received - the questionnaires that were received subsequently were all very similar to the first 100.

We received the following information from this group of people.

Analysis showed that on average the adverse effects did not appear until 13 months after treatment with GM 'human' insulin began.

• 41% - loss of warnings of hypos or 'I function on automatic pilot'.

• 34% - extreme tiredness or lethargy

• 9% - sleeping all the time

• 32% - weight increase of 1.5 stones [21 pounds] and above

• 28% - feeling unwell all the time

• 24% - memory loss or confusion

• 9% - blood glucose levels dipping and peaking erratically

• 8% - described by their families as 'not the same person'

• 5% - mood changes, described as difficult to live with

• 7% - pains, especially ion the legs and joints

• 4% - irregular or late periods

In addition to this 24% of those contacting IDDT said that their doctor was unwilling or reluctant to change their insulin to natural animal insulin and 3% told us their doctor didn't listen or said the problems were 'all in the mind'.

Other common statements were:

• 'I didn't know that there was such a thing as animal insulin.'

• 'I was never told there were alternatives'.

• I didn't realise that 'human' insulin was not derived from humans'.

Patient Experience

Interview with Beverley Freeman

Bev is 33 years old and has had diabetes since she was 5 years old. She used animal insulin for about eight years and was then changed to 'human' insulin. After several years on GM 'human' insulin, she insisted on changing back to animal insulin. She now uses short acting Hypurin porcine insulin and intermediate acting Hypurin bovine isophane twice a day with an injection of porcine neutral at lunch time if necessary.

Question: Although you were quite young when you first changed to GM 'human' insulin, were you aware of any changes in your diabetes?

Bev: No

Question: So what made you change back to animal insulin?

Bev: I didn't feel at all well and it was really a last resort. I seemed to be always visiting my GP and had lots of tests but he couldn't find anything wrong with me.

Question: What do you mean when you say that you weren't very well?

Bev: I felt constantly tired and depressed. I felt as though I had high blood sugars but they weren't. I had problems remembering things from one minute to the next and felt unable to hold a conversation. I felt inadequate and a sort of numbness and separate from what was going on around me. On top of this I put on a lot of weight very quickly.

Question: So what happened then?

Bev: Because I had heard rumours about 'human' insulin affecting people differently, as a last resort I changed back to animal insulin and at this point if it hadn't worked I don't know what I would have done. My GP was happy to change me back to pork insulin.

Question: How did things change then?

Bev: I did roughly the same doses of animal insulin and within 3 days felt a completely different person. I as able to get up in the mornings and feel awake for the first time in about 4 years! My depression went away, there was pinkness in my cheeks and I generally felt a lot fitter and healthier. My warnings of hypos came back and it was only then that I realised that they had gradually disappeared while I was on 'human' insulin.

Question: So what happened over a longer period?

Bev: I lost weight almost straight away and over 6 months lost nearly 3 stones [42 pounds] without dieting. My memory went back to normal or as it should be. I became more aware of what was going on around me and I felt able to include myself in this and could hold conversations with confidence again.

Question: So were there any other changes that happened that you wouldn't have put down to altering your insulin?

Bev: Yes. When I was on 'human' insulin I regularly got infections, frequent tonsillitis and cuts always went septic. I had regular stomach upsets and I suffered badly with constipation. I never had regular periods. All this has changed dramatically and I have none of these problems now I am on animal insulin.

Question: Finally, have you any comments you would like to make?

Bev: Yes. I'm fully aware that 'human' insulin agrees with some people but for me it was crippling. I lost my teenage years to 'human' insulin. People must have the choice of insulins and be given the information from the experiences of others that have suffered as a result of treatment with it.

A little bit of history

• For nearly 80 years people with diabetes who required insulin treatment used animal insulin, originally beef insulin. In the 1970s highly purified pork insulin became available. All insulin is now highly purified whether beef, pork or GM 'human'.
   

• In 1982 genetically modified insulin, so-called 'human' insulin, received marketing approval. Approval was given in five months, a remarkably short time when one realises that it was the first genetically produced drug to be licensed and used on people.
   

• It was claimed that GM 'human' insulin was better because it is an exact copy of the insulin molecule produced by the body and therefore it would produce less antibodies. It was also claimed that it would be cheaper, therefore more accessible to people in poor countries and that animal insulin supplies were likely to run out. None of this has proved to be the case.
   

• During the mid-1980s there were widely circulated but untrue rumours that animal insulins were being discontinued. This resulted in the over 80% of people in the UK being transferred from animal to GM 'human' insulin but in the majority of cases for no good clinical reasons.
   

• Within a year or so of the changeover people started were reporting loss or reduced warning symptoms of hypoglycaemia, more severe hypos and generally, more problems in controlling their diabetes safely. As time progressed other symptoms were being reported such as extreme tiredness, weight increases, feeling unwell and behavioural changes.
   

• The majority of people who reported these problems to their doctors were either ignored or not believed and they were even refused their right to change to the beef or pork insulin that had previously suited them. Nearly 3,000 people wrote to the then British Diabetic Association (now Diabetes UK) but little or no action was taken at this time.
   

• As a result of pressure from people with diabetes, in the early 1990s the British Diabetic Association (BDA) commissioned Dr Natasha Posner to carry out a study of only 384 of the 3,000 letters it had received. However, the study was never published because the BDA claimed that it was 'too alarmist'.
   

• In the early 1990s around 700 people attempted to take a class action against the manufacturers of 'human' insulin but failed for 'lack of scientific evidence'. IDDT has since discovered that during this period insulin manufacturer, Novo Nordisk employed a PR company, Key Communications, to "defend the safety profile of human insulin". Key communications described this as a crisis management programme and it included media training of UK medical spokespeople.
   

• The adverse effects experienced by some people have not disappeared over the years and nearly 20 years after the introduction of 'human' insulin, people are still battling for recognition of these problems. It is now evident that some more recently diagnosed people who have never used animal insulin also suffer the well-recognised adverse reactions to 'human' insulin. Once again these have been shown to regress with a change to natural animal insulin.

THE RESPONSE

The evidence from patients and their carers was not, and is not, listened to even though it is clear that for some people a change to animal insulin makes their symptoms disappear.

Most of the medical profession, healthcare professionals, researchers, the insulin manufacturers and, indeed, the UK Department of Health maintain that there is no scientific evidence to demonstrate a difference between animal and GM 'human' insulin. It has to be noted that there is equally no scientific evidence to prove that 'human' insulin does not cause the adverse effects of which patients complain. Indeed, some professionals go even further and declare that GM 'human' insulin is better than animal insulin although NO evidence is ever produced to justify this statement. The fact that there is no admittance of the adverse effects is surprising when both insulin manufacturers, Eli Lilly and Novo Nordisk, voluntarily included in Patient Information Leaflets the warning that:

"A change from animal insulins to human insulin may cause a loss of warnings."

FACTS

• GM synthetic ‘human’ insulin causes side effects for some people that largely disappear with a change to natural animal insulin. These problems do not just occur in people that have previously used animal insulin, however this is the group who are able to make comparisons.
   

• No large scale, long-term trials comparing GM ‘human’ and animal insulins have ever been carried out. The research that has been carried out has largely been in the laboratory situation and/or using small numbers of people, so the relevance of this research is questionable.
   

• The link between GM ‘human’ insulin, hypoglycaemia, loss of warning symptoms and unexplained, sudden death or ‘dead in bed syndrome’, has not been satisfactorily explained. However small the number of deaths, any avoidable death is unacceptable and this issue needs further investigation. Equally any increase in frequency or severity of hypoglycaemia is unacceptable.
   

• The first research in 1980 using GM ‘human’ insulin, by Professor Harry Keen, involved 17 healthy non-diabetic men and in 1982 ‘human’ insulin was given a licence for general use. This is a remarkably short time for a new drug, especially as ‘human’ insulin was the first ever genetically engineered drug to be used on people.
   

• There is no evidence to show that synthetic ‘human’ insulin has any advantages over natural animal insulins. No formal post-marketing research was ever carried out despite the fact that ‘human’ insulin was the first genetically produced drug to ever be used on people. For this reason alone, the experiences of patients using it should have been, and still are, of vital importance in the development and use of other genetically produced drugs.
   

• GM ‘human’ insulin has been shown to be more aggressive with a faster action and a higher peak of action than the equivalent porcine or bovine insulins.
   

• In July 2002 the Cochrane Review comparing 'human' and animal insulin was published and it showed that there is no evidence that 'human' insulin is superior to animal insulin. It also showed that the majority of the research carried out was 'methodologically poor' and that many patient-oriented outcomes like health-related quality of life or diabetes complications and mortality were never investigated in high quality randomised clinical trials. So the introduction of synthetic 'human' insulin was never backed up by sufficient proof of its  advantages and safety. In the years since its introduction, this proof has never been obtained because the research has not been carried out. Click here to go to Cochrane Review in 'Reviews and Reports'

Action and duration times of animal and GM 'human' insulin

This chart shows the relative activity curves of GM 'human' and animal insulin. This is the information that the American Diabetes Association provide. It must be noted that these times are a very rough guide of peak activity and duration as they have not differentiated between beef and pork insulins. Beef insulin is longer acting with a smoother action than pork insulin.

In addition the action peaks and duration of action will vary in different people.

Note: Multi-dose insulin regimes only appeared as a form of treatment after the introduction of 'human' insulin. Prior to this many people had controlled their diabetes well using twice daily mixtures of soluble and isophane animal insulin. The shorter duration of GM 'human' insulin does not give as good basal 24hour cover as animal insulin and therefore more doses of short-acting 'human' insulin became necessary.

Hypoglycaemia and loss of warnings

For more information on HYPOGLYCAEMIA AND LOSS OF WARNINGS CLICK HERE

Hypoglycaemia and loss or reduced warning symptoms of an impending hypoglycaemic attack are the most common reported adverse reactions to GM synthetic 'human' insulin. The fact that this happens to some people is not denied by regulatory authorities or the insulin manufacturers and warnings are issued in all GM 'human' insulin Patient Information Leaflets. Despite this, unfortunately many of the medical and nursing professionals are either unaware of this or do not accept it and this often can result doctors refusing to change people to animal insulin or even consider this as an option when their patients have lost their hypo warnings.

Note: In a book written by Charles Fox and Anthony Pickering for GPs, Diabetes in the Real World, the advice is "If a patient is showing signs of unhappiness over problems with hypos, it is always worth offering a change to the porcine equivalent of the insulin being used." As 'human' insulin has never been demonstrated to have any advantages over animal insulin, this advice is welcomed but unfortunately GPs often will not change the species of insulin without approval of the hospital consultant and it is usually here that the refusal to prescribe animal insulin occurs.

Understanding the effects of living with hypos and loss of warnings

As an organisation we wonder if healthcare professionals do not or cannot understand the effects of hypos and loss of warnings on the daily life of those of us who live with diabetes. Perhaps this offers one explanation of the refusal to change people to pork or beef insulin.

Hypoglycaemia itself, or the avoidance of it, is an acute daily problem for people with diabetes but when accompanied by loss or partial loss of warnings, it can have a dramatic effect on the lives of the person with diabetes and their families. There can be a marked reduction in the quality of life for all concerned.

Information gathered in 1997 by IDDT from the experiences of people with diabetes and their carers says that loss of warnings may result in the following:

• A feeling of insecurity and loss of independence.

• Embarrassment.

• Being a danger to oneself and others.

• Aggressive or violent behaviour.

• Family conflict, breakdown of relationships.

• Loss of driving licence - it is illegal to drive with loss of warnings.

• Loss of job

• A deliberate raising of blood glucose levels to avoid such situations.

Even more worrying is the condition of hypoglycaemia automatism when in a hypo the person is unaware of their actions, often described as 'functioning on auto-pilot'.

Research into the relationship between hypoglycaemia and crime that has shown that hypoglycaemia has resulted in the following crimes:

Person

• Disorderly conduct

• Resisting arrest

• Assault

• Murder

Property

• Wilful destruction

• Shoplifting

• Petty larceny

• Embezzlement

• Driving violations

Behaviour

• Exhibitionism

• Blasphemy

• Slander

• Sexual perversion

• Sadism

[David Kerr and Joan Everett, Journal of Nursing Vol 1: N0 4 1997]

Repeated hypoglycaemia in children has been shown to cause a slight reduction in their IQ and cognitive functioning and so avoidance of hypos and loss of warnings is very important in children.

It is for these reasons, and many more, that IDDT believes that every possible option should be tried to reduce the risk of hypos and loss of warnings. Therefore if a person/child has unaccountable hypos, reduced or loss of warnings of hypoglycaemia, they should be offered a change to pork or beef insulin for a trial period of at least 6 months.

Sudden unexplained deaths or 'dead in bed syndrome'

Unfortunately IDDT has also received reports from the relatives of young people with diabetes who have died suddenly in their sleep. Some reports from the families show that some of the above symptoms were already occurring. These deaths have become known as 'dead in bed syndrome', and are thought to be caused by hypoglycaemia although this is difficult to confirm in a post mortem. While this appears to be a very small number of deaths, an estimated 6% of all deaths in people with diabetes under 40, there are particular circumstances that surround them:

• The person is found dead in an undisturbed bed.

• The person was observed to be in good health before going to bed.

• It seems to happen most commonly in young people, especially those living alone.

'Dead in bed syndrome' and the association with GM 'human' insulin.

In 1989 Dr Patrick Toseland, then a senior and well-respected pathologist at Guy's Hospital, London, was asked to investigate 19 deaths reported by doctors in the previous 18 months that had occurred in young people with diabetes. The deaths were unusual - they all happened suddenly, they all appeared to follow a rapid decline in blood sugar levels and the deceased were all using 'human' insulin. Dr Toseland thought that this sort of sudden death in young diabetics was something new.

Sadly IDDT still receives reports of such deaths in young people and in the cases we have received, all of the deceased had been using GM 'human' insulin. Very little research has been done in this area, despite the recommendations from those who have carried out studies. Much of the evidence may be circumstantial and there may be a combination of causes but hypoglycaemia is strongly linked with these deaths and 'human' insulin is linked to loss of warning symptoms and a subsequent increased risk of hypoglycaemia.

Research related to 'dead in bed syndrome'

Prior to 1993, no records were kept for the category of death from hypoglycaemia, so it is impossible to make comparisons of before and after the introduction of 'human' insulin by this method. The following studies are interesting:

• Dead in Bed Syndrome in Young Diabetic Patients in Norway
  Diabetic Medicine 1995 vol.12 H Thordensen et al

The authors collected data from 1981 to 1990 and the cause of death examined in people under the age of 40.

• 16 cases of dead in bed syndrome were found, 6 females and 10 males the age ranged from 7 to 35 years

• The duration of diabetes was from 2 months to 26 years. 9 were on multi-dose regimes.

• Frequent episodes of hypoglycaemia were mentioned in 12 cases, 10 of these having night hypos.

12 of the total 16 deaths occurred during the years 1988,1989 and 1990. These years coincide with the introduction of 'human' insulin. They also coincide with the introduction of tighter diabetic control when there is a threefold increased risk of severe hypos. [Diabetes Control and Complications Trial Study Group N.Eng.J.Med 1993; 329, 977-86] The authors suggest that hypoglycaemia may play a part in these deaths. However, it is possible that 'human' insulin was the cause as it is known to cause loss of hypo warning signs and more frequent hypos. It may also be a combination of tight control and 'human' insulin.

• Unexplained Deaths in Type 1 Diabetic Patients
  Diabetic Medicine 1991 vol.8 R B Tattersall and G V Gill

This study looked at 50 deaths of young people with diabetes that were collected in an ad hoc way. 22 of the deaths fitted into the 'dead in bed' category and 14 of these cases reportedly had night hypos. All were using 'human' insulin.

• GM 'human' and animal insulin compared - A review carried out by Prof Rhys Williams et al, Nuffield Institute for Health, Leeds. Date of original Review 1998 presented to the BDA Medical Conference in May 1999.

Page 5 of 'Human and animal insulin compared', 29 July 1998 says:

"The following observations can be made from this body of evidence:

• Increased frequency of hypoglycaemia and reduced awareness of impending hypoglycaemia do occur when people are transferred from animal to "human" insulin.

• In some cases (probably a small number) these phenomena may lead to death.

• It is not possible to determine, from the evidence available, how commonly these phenomena occur.

• From mortality data it is likely that any association with sudden death is uncommon.

It is not possible to say whether these phenomena are specific to "human" insulin or an effect resulting from tighter glycaemic control perhaps compounded, in some cases, by neurological complications in long standing-diabetes."

• Is undetected autonomic dysfunction responsible for sudden death in Type1 diabetes? The 'dead in bed' syndrome revisited -
  Diab Med. Aug 1999 Vol 16, Simon Heller et al

The authors explored the details of all the papers recording the syndrome to formulate a possible cause and they also did a literature review of nocturnal hypoglycaemia and autonomic dysfunction. The results showed that nocturnal hypoglycaemia is strongly implicated in being present prior to death but the death is sudden and probably arrhythmic. [Arrhythmic means any variation of the normal regular heartbeat.] They point out that dysrhythmias can occur with early autonomic neuropathy, with relative sympathetic overactivity, in young people with diabetes. They conclude that the ventricular dysrhythmias will be compounded by nocturnal hypoglycaemia which may be associated with an increase in the electrocardiograph Q-T interval and Q-T dispersion. This could lead to sudden death in an undisturbed bed. They say that further research in this area is urgently needed. 

The concerns of patients are justified

While many medical and health professionals chose to dismiss the evidence from patients of side effects when using 'human' insulin, the following statements support the concerns of patients:

British National Formulary [BNF] No 30, September 1995 page 280 (and also in the current edition ) states:

Preparations of human sequence of insulin should theoretically be less immunogenic, but in trials no real advantage has been shown ….Some patients have reported loss of warnings of hypoglycaemia after transfer to human insulin. Patients should be warned of this possibility and if they believe that human insulin is responsible for their loss of warnings it is reasonable to transfer them back to porcine insulins. When prescribing insulin great care should be taken to specify whether a human or an animal insulin is required. Indications for changing from animal to human preparations must be carefully considered in the light of these reported problems. Beef insulins are still available for patients who specifically request them.

Mims - the monthly index of medical specialities (current)
Patients transferred to human insulin should be advised that the early warning symptoms of hypoglycaemia may be less pronounced than with insulins from an animal source.  

Novo Nordisk prescribing information for GM insulins 2003
Contraindications - Hypoglycaemia; hypersensitivity to human insulin or any of the excipients 

Food and Drug Administration [FDA] Patient Information Leaflet
The warning in these leaflets in bold type in the insulin packs says:

"A few patients who have transferred from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycaemia were less pronounced or different."

NICE Clinical Guidelines on Glycaemia Control in Type 2 diabetes April 2002
The final draft guideline on Type 2 diabetes - glycaemiac control, is currently on the NICE website. Page 59 in the section on the use of insulin in the treatment of Type 2 as an adjunctive treatment, states the following:

"Despite the lack of an evidence-base to support current practice, the group recognised that usual insulin therapy both for people with diabetes starting and continuing insulin now utilised human species insulin rather than beef or pork. However the purified forms of these latter species of insulin are appropriate options for clinical and patient choice."  

Aventis Pharmaceuticals, April 24^th 2000 Press Release
"Human insulin therapy may be associated with hypoglycaemia, worsening of diabetic retinopathy, lipodystrophy, skin reactions (such as injection-site reaction, pruritus, and rash), allergic reactions, sodium retention and oedema." 

Pulse, May 20^th 2000
A spokeswoman for the Medical Defence Union is quoted as saying: "The data sheets for human insulin specify the potential for lowered hypoglycaemic awareness but GPs should take care to mention this to patients. Provided they did this, any legal claims in connection with human insulin would be directed against the manufacturers under product liability." 

Department of Health September 2000
As a result of the adverse reactions to 'human' insulin and all the above statements, IDDT again entered into correspondence with the Medicines Control Agency and Lord Hunt, then Minister of State for Health. This resulted in the following statement from the Medicines Control Agency in Current Problems in Pharmacoviglance, Volume 25 Sept 2000:

HUMAN INSULIN

The Insulin Dependent Diabetes Trust, a patient representative group, has recently circulated a letter to some health professionals entitled 'Important Safety Information on Human Insulin' which suggests that there are concerns about the safety of human insulin.

A considerable number of scientific studies have been performed comparing animal and human insulin and the CSM has considered the available evidence on a number of occasions.

Although some patients have experienced problems on transferring from animal to human insulin, there is no evidence of a specific safety problem with human insulin, which is well tolerated by most patients.

We would like to reassure health professionals that there are no concerns regarding the safety of human insulin.

NB. It is notable that this latest statement from the Committee on Safety of Medicines differs from the 1998 CSM conclusion that "some patients ……were better suited to continuing their treatment with animal insulins."

Press Release, Sept 9^th 1999, Novo Nordisk,
'human' insulin manufacturers

………Historically improving glycaemic control with soluble human insulin has been associated with an increased risk of hypoglycaemia. 

Committee on Safety of Medicines (CSM), August 19^th 1998
A letter from Baroness Hayman, Parliamentary Under Secretary of State at the Dept of Health said:

"The CSM concluded that some patients did experience problems with human insulins, particularly when initially transferred from animal insulins and were better suited to continuing their treatment with animal insulins. However, the CSM no evidence of a safety problem specific to human insulin. Indeed most patients respond well on it…. To ensure that patients continue to have a choice of treatment both animal and human insulin will remain available." 

Symposium on Childhood and Adolescent Diabetes, Scandinavia 1998
Individualised Insulin Therapy in Children and Adolescents
with Type 1 Diabetes - Acta Paediatr Suppl 425: 20-41, 1998

This paper was presented at a symposium in Scandinavia and the author's group based in the US usually prefers to use pork insulin in the treatment of children with Type 1 diabetes. It cites a study in children under 5 years where HbA1cs were considerably lower with conventional therapy on pork compared to 'human' insulin. Also that in older children HbA1cs were no different but blood glucose levels were less erratic and easier to control on pork insulin. Insulin antibody production was no different for pork and 'human' insulin over a 5year period. 

The Lancet, 1998; Vol 352: 502-3
Professor Stephanie Amiel "Severe confusional hypoglycaemia in its extreme forms can destroy confidence, relationships and livelihoods, if not lives…….The newer more purified insulins* probably compound the problem [of night hypos] by being just that little bit shorter acting than their predecessors."

*The reference to this statement is dated 1983 when the newer insulins referred to could only 'human'. 

The Lancet, 1998; Vol 352: 1549
Response to Professor Amiel - F Wolff, Hypoglycaemia Avoidance
This response in The Lancet pointed out that when insulin is extracted from the beta cells of the pancreas of pigs or cattle, small amounts of glucagon are also extracted from the alpha cells by the process itself and are therefore present in animal insulins. The author points out that the newer insulins ['human'] do not contain glucagon. The significance of this is that glucagon is a counter-regulatory hormone and these hormones provide protection from hypoglycaemia by triggering the warning signs of an impending hypo.

Medical Monitor, September 9^th 1996 Professor Harry Keen
Discussing Humalog at the European Association for the Study of Diabetes 1996 Professor Keen is quoted as saying "No one wants a repeat of the problems that occurred when human insulin was introduced. We want to be absolutely sure that there is no repetition of that feeling among patients that they are being submitted to a new insulin which has not been carefully tried in all situations."

US Report of Post Market Adverse Drug Effects,1995, FDA
The 1995 table for reported post-market adverse drug effects in the US shows the top 10 suspect drugs. Humulin, 'human' insulin produced by Eli Lilly, is ranked number eight and is one of only three non-prescription drugs to be on this list. The Medicines Control Agency in the UK does not make public their reported adverse drug reactions.

Drug and Therapeutics Bulletin, March 1989,
This government sponsored safety bulletin, reported that 'human' insulin is no better than conventional insulin treatment and may hold dangers for people with diabetes. The Bulletin also said that 'human' insulin may cause loss of early warning symptoms of hypoglycaemia. (The Bulletin has continued to maintain this stance.)

Availability of natural animal insulins in the UK

GM 'human' insulins are supplied in the UK by three major pharmaceutical companies: Eli Lilly, Novo Nordisk and Aventis Pharmaceuticals. Information about the availability of insulins by these companies is readily available from your GP or diabetes clinic.  However, information about natural animal insulins is not so readily available and all too frequently patients are not informed of their availability despite their right to an informed choice of treatment. Even when suffering unaccountable symptoms and loss of warnings of hypoglycaemia, most people are not given the opportunity to try animal insulin. Many patients do not realise there are other options or that they are being prescribed a genetically modified drug. Some believe that 'human' insulin is actually insulin obtained from man. It is not, it is produced genetically from bacteria or yeast. Animal insulins are extracted from the pancreases of pigs and cattle.

Animal insulins in the UK are supplied by two companies:

• CP Pharmaceuticals Ltd - supply pork and beef insulins in both vials and cartridges. The following are available.

• PORK Insulin

 BEEF Insulin

Future availability:

CP Pharmaceuticals are committed to supplying beef and pork insulins in the future and are prepared to expand their production to supply people in other countries if necessary.

CP 's website is http://www.cppharma.co.uk

IMPORTANT WARNING!

In the UK Novo Nordisk Pharmaceuticals Ltd will discontinue their pork insulins, Actrapid, Insulatard and Mixtard 30/70 at the end of 2007.

This is part of their strategy to globally remove all animal insulins and they have already been discontinued in most other countries. In October 2002 Novo Nordisk confirmed to IDDT that they supply 20,000 people in the UK with pork insulin but despite this need, they made the decision to cease supplying at the end of 2007. The company gave assurances that they would inform all relevant parties at least 18 months in advance of the withdrawal in the UK and that they will issue information about availability of equivalent available pork insulins, including those made by other companies.

Changing your insulin

In the UK insulin is a prescription only drug and therefore you will need to discuss your wishes to change your insulin type with your GP and/or clinic doctor.

The following guidelines are an extract from a talk given by Dr Laurence Gerlis, IDDT's Medical Adviser.

• Any change of insulin, type and brand, can alter your control in the first few days or weeks and so it is important to monitor your blood glucose levels more frequently.
   

• Dose changes should be made in only 1 or 2 units at a time.
   

• Dose changes should be kept to a minimum by altering the amount of exercise and the food at the next meal to cope with the odd high blood sugar.
   

• There is nothing wrong with what is called conventional therapy, twice daily doses of short and longer acting insulins, and it is quite possible to achieve 'good' control on this regime.
   

• Insulin is a delicate protein and small but subtle changes in the insulin molecule, such as the difference between the insulin molecule in pork and 'human', can affect diabetic control in some patients.
   

• Both doctors and patients tend to raise the dose of insulin and rarely lower it. For example, if the morning blood sugars are high as a result of the body's reaction to a hypo in the night, then raising the insulin dose will only make this situation worse. This leads to a vicious circle of increasing insulin doses to cope with highs, leading to more hypos and so it goes on.  

What to do if your consultant refuses to change you to animal insulin

Unfortunately IDDT continues to receive reports from people that their consultant is refusing to change their insulin from GM 'human' to animal. People also report that they are too nervous to ask their doctor to change them. Some specialist nurses are also refusing to allow people to change insulin. The reason for this refusal is hard to understand especially now the Cochrane Review [July 2002] has shown that GM 'human' insulin is not superior to animal insulin and has no clinical advantages over animal insulin. There is nothing to be gained by this refusal for either the consultant or the patient and it merely serves to hinder the doctor/patient relationship because the patient feels not listened to, not understood, frustrated and angry.

IDDT's advice in this situation:

• Before your appointment with the doctor, make a list of your reasons for wanting to change so that you don't forget anything.
   

• Discuss your desire to change with your GP, he/she may well write to your consultant or just make the change for you.
   

• Take your spouse or partner with you to the clinic so that they can back you, especially if they recognise the changes in you or have to deal with your hypos.
   

• Discuss your concerns with your consultant in a non-aggressive way and ask to change to animal insulin.
   

• Be calm and forceful. Remember there was probably no good reason for prescribing 'human' insulin for you in the first place other than accepted policy and there is no research that shows it to be better than animal insulin. So if your doctor says 'there is no difference' take the opportunity and say 'Well then, I'll try animal insulin for 6 months, thank you.'
   

• If all else fails, your rights as a patient include the right to be given a clear explanation of any treatment proposed, including risks and alternatives BEFORE YOU decide whether YOU will agree to the treatment. Your alternatives are GM 'human' insulin or natural animal insulin.  

NB. If your doctor has failed or fails to give you this choice and information then he/she is actually in breach of his/her NHS contractual rights.

Availability of animal insulin if you are admitted to hospital

Many of our members who use animal insulin have expressed real concerns about if they are admitted to hospital, especially in emergency or if they are unconscious. They report that they have had to argue to remain on their usual animal insulin or they have been changed to GM 'human' insulin, even against their expressed wishes. Some people have felt that a hospital admission was seen as the opportunity to change this 'non-compliant' patient to GM 'human' insulin. It may be because the hospital doesn't stock animal insulin.

Note: All major pharmaceutical wholesalers in the country stock CP Hypurin insulins and they should be available to any hospital within 4 hours, except at weekends.

IDDT advice:

• If it is a pre-planned stay in hospital, then ensuring that you remain on your usual insulin should be organised before you go into hospital and you should always take your own insulin with you.
   

• The difficulties arise if you enter hospital in emergency, unconscious and unable to speak for yourself. If possible, make prior arrangements to try to ensure that a member of your family speaks for you and takes your usual insulin to the hospital as soon as possible. 

IDDT has taken action on this matter:

IDDT supplies special stickers for hospital and GP notes for people who are concerned about 'human' insulin being administered without their consent. The stickers say: 'This patient does not consent to the administration of 'human' insulin.'

Contact IDDT for your supply of stickers.

In April 2000 IDDT wrote to the Chief Executives of all hospitals in the UK to request that their pharmacy departments stock beef and pork insulins, especially for emergency hospital admissions. We pointed out that around 30,000 people in the UK are still choosing to use animal insulins and at any time any of these people could be admitted to hospital and need animal insulin. There were mixed responses to this request, some were very supportive and made a policy decision to stock animal insulins but some were dismissive!

IDDT wrote to the General Medical Council [GMC] and their general advice was:

"We always expect doctors to act in the best interests of their patients and to listen and respect their views and their right to be fully involved in decisions about their care. We also expect doctors to be satisfied that, wherever possible, the patient has understood what is proposed, and consents to the treatment.

We advise that in an emergency, where consent cannot be given, the doctor provides medical treatment to anyone who needs it, provided the treatment is limited to what is immediately necessary to save life or avoid significant deterioration in the patient's health. However, the doctor must still respect the terms of any valid advance refusal which he/she knows about or has been drawn to his/her attention. The patient must be told what has been done and why as soon as he/she is sufficiently recovered to understand."

So applying this advice to treatment with animal insulin, the GMC recommend that your wishes should be respected. However, if animal insulin is unavailable, and you need insulin in emergency, eg if you were hyperglycaemia, then 'human' insulin could be administered to save your