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GM Vs Animal Insulin

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Choices – The Evidence
Evidence from people with diabetes
A little bit of history
Facts
Action and duration times of animal and GM ‘human’ insulins
Hypoglycaemia and loss of warnings
‘Dead in Bed Syndrome’
The concerns of patients are justified
Availability of animal insulins in the UK
Changing your insulin
What to do if your consultant refuses to change your insulin
Availability of animal insulin if admitted to hospital
Frequently asked questions
Allergic reactions to insulin

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Choices – The Evidence

The NHS has always allowed patients 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 the newer insulin analogues.

The importance 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 this early research only involves a highly selected group of people who are not necessarily typical of the general population with a condition who will be using the new drug or insulin. 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? Is their long-term safety known?

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 they make exaggerated or unsubstantiated claims about its benefits and rarely admit to itd 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, 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

Rapid-acting insulin analogues

  • Rapid-acting insulin analogues have only minor benefit for the majority of patients.
    Cochrane Review, 2005
  • 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
  • Intermediate acting versus long acting insulin for Type 1 diabetes mellitus – not enough evidence to draw conclusions on benefits and risks.
    Cochrane Review July 2008
  • No proof that long-acting analogues outperform human insulin in Type 2 diabetes.
    IQWiG March 2009

Details of the above Reviews can be found on our ‘Reviews and Reports’ pages

The conclusions from the present 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 for the majority of people.

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]. Insulin analogues and cancer

So there are real grounds for people with diabetes to question whether these risks, however small, are worth taking when insulin analogues have not been demonstrated to be 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.

What Is Hypoglycaemia?

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What Is Hypoglycaemia?

In people without diabetes the level of glucose in the blood is controlled by insulin produced be the beta cells in the pancreas. This prevents the level of glucose in the blood from rising too high. In people with Type 1 diabetes, the body does not produce its own insulin and the blood glucose levels rise too high [hyperglycaemia] and so injections of insulin are given to prevent this. People with diabetes are advised to keep their blood glucose levels as near to the normal blood glucose levels as possible. If the blood glucose levels drop below normal, whatever the cause, then this is called hypoglycaemia [a hypo]. ‘Good’ control of diabetes is avoidance of both high and low blood glucose levels.

Normal blood glucose levels in non-diabetic people range between 4 and 7mmols/l. Hypoglycaemia is usually said to occur at 3.8mmols/l and so the recommended lower level is 4mmols/l – hence the recommendation to people with diabetes that “4 is the Floor”.

Note: Some publications say that hypoglycaemia does not occur until blood glucose levels are below 3.5 or even 3.0mmols/l. However, there is research that shows that the ability to function may be impaired by blood glucose levels of 3.8mmols/l and lower.

Useful definitions of hypoglycaemia
It is important that even mild hypos, or ‘lows’, are recognised as being hypoglycaemia and treated. This is also important so that all hypos can be reported to your doctor to provide a true picture of your diabetic control.

Hypos are generally defined as follows:

Mild: a hypo that is easily treated by the patient by the intake of a sugary drink or food, often referred to as ‘being low’.

Moderate: one where someone else, spouse, friend or parent, has to intervene and give the sugary food/drink because the person with diabetes is confused or even losing consciousness

Severe: one that usually means unconsciousness which may be accompanied by a convulsion/seizure.

Parent comment: ‘I am sure that I under-reported my daughter’s hypos at our clinic visits because I was never sure how to answer the question about how many hypos she had since the last visit. I didn’t know whether to class the lows before meals as a hypo or not.’

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For more information on hypoglycaemia, please visit the NHS Choices website:

NHS Choices: Hypoglycaemia

Tips For People With Visual Impairment

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Tips For People With Visual Impairment

Visual difficulties can affect people with or without diabetes but the one thing that insulin-treated people have to do is be able to inject the accurate amount of insulin. While visual difficulties may not prevent many activities, not being able to do your own injections [and blood glucose tests] results in a loss of independence, especially for people who live alone. There are also many everyday things that fully sighted people take for granted but these become difficult or impossible for people with visual impairment.

Alison Blackburn has had diabetes for many years and is visually impaired. She shares with us some of the tips she has picked up over the years that her sight was deteriorating. These have enabled her to maintain her independence and ability to do many of the everyday things in life.

Tips for injecting your insulin

Using an pen injection device

  • There are a variety of pens available and they have clicking devices so that you can count the clicks to know how many units you are injecting.
  • There are pre-filled disposable pens available for some brands of insulin and this means that you do not have to re-load the pen when a cartridge runs out. This can be easier for people with visual impairment [and for people with hand movement problems].
  • Magnifiers are available that fit on to the pen.

Using a syringe to inject
While a pen injector may seem ideal, not everyone likes to use them and some people still prefer to use syringes for their injections. Here are a few of Alison’s tips:

  • Syringe magnifiers that slot over a disposable syringe are available.
  • If you take the same dose of insulin regularly, score the outside of the syringe at your dose and then draw up to this mark. If you take two different doses, morning and evening, score two syringes but make sure you keep them in different places.
  • If seeing the clear insulin is difficult then hold a coloured card behind the syringe for a better contrast making sure that the colour is one that you can see well. If you ‘haven’t enough hands’ pin the card to the wall or a door.
  • Syringes are available in different sizes, 100ml, 50ml and 30ml. If your dose is small enough choose the smallest size syringe because the markings are further apart and easier to see – 30ml are easier to see than 50ml and 50ml easier than 100ml.
  • A nurse or relative can draw up a week’s supply of insulin in syringes and leave them in the fridge. Again if the dose or type of insulin is different at different times of the day, make sure that the morning syringes are stored on the top shelf and the evening ones on the bottom shelf. If using longer-acting cloudy insulin, then make sure that you roll the syringe about 20 times to ensure that the insulin is mixed properly before injecting.

Tips for the kitchen

  • If you make tea or coffee from leaves or powder then use the old-style sugar dispensers that were used in transport cafes. This way you get a limited amount of powder each time you tip up the dispenser. This is also a useful way of measuring custard powder, gravy etc.
  • For people with poor eyesight, powders can be stored in large clear coffee jars. If these are held up to the light, it is possible to see the colour of the powder.
  • If this doesn’t work then powders and foodstuffs can be stored in jars or canisters that are labeled with tactile buttons which you can feel. Self-adhesive, jelly like buttons can be purchased and you can stick different numbers of jars with different contents or place the buttons on a different part of the jar. Rubber bands work just as well and are cheaper! It is important that other members of the family don’t move the buttons or bands otherwise you may be making coffee with gravy powder!
  • When storing foods stack in a regular, particular way so that you know the order.
  • Always store cleaning materials well away from food stuffs.
  • If you keep cleaning fluids in the house, then smell ALL liquids before you use them for eating or drinking.
  • Liquid level indicators are available free to people who are registered blind or partially sighted. They are battery-operated gadgets that clip on the side of a cup or mug and they beep when the liquid is nearly to the top so preventing spilling.
  • If you have difficulty with mixing in a cooking bowl [because the contents fly on to the ceiling!] then put the contents into a plastic box with a lid. Fasten the lid well and shake vigorously.

Gas and electricity companies – If visual impairment is developing then gas and electric companies will fit tactile buttons to cookers and other household equipment, such as fires and microwaves. The larger companies are often happy to do this free of charge but if you are registered with Social Services, they should organise this for you.

Neuropathy Affecting The Feet

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Diabetic Neuropathy

What is Diabetic Neuropathy?
Neuropathy Affecting The Feet
Advice on Cutting Your Toenails
Symptoms of Neuropathy Affecting Your Feet and Hands
Heel Fissures
Charcot Foot
Wrong Sized Shoes
Neuropathy and Antidepressants
Diabetic Holiday Foot Syndrome
Patient and Family Carer Experience
Diabetes and Hearing Loss May be Due to Neuropathy
Gastroparesis

 

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Neuropathy Affecting The Feet

Care of the feet is very important for people with diabetes because of the risk of diabetic peripheral neuropathy. Systematic and regular foot care has been shown to reduce ulceration and limb loss by up to 50% and almost half of all diabetes related admissions to hospital are for problems related to the leg and foot.

Prevention is always better than cure and so obviously it is important to have regular checks of your feet by health professionals and to regularly examine your feet yourself.

The golden rules for looking after your feet.

  • Never go barefoot.
  • Wear good fitting shoes – not tight or worn.
  • Break in shoes gradually and make sure they don’t rub.
  • Keep your feet dry, especially between the toes.
  • If you need to use powder, use the unscented varieties.
  • Use lotion to keep the skin soft so that your feet do not get dry or cracked.
  • Cut your toenails straight across, not deep into the corners.
  • Wash your feet daily using luke warm water.
  • Do not use heating pads, hot water bottles, iodine, Epsom salts or alcohol.
  • Check your feet every day and if there are any problems see your doctor or chiropodist.

Treatment – Diet For People With Coeliac Disease and Diabetes

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Diabetes and Coeliac Disease

What is Coeliac Disease?
Symptoms of Coeliac Disease
Diagnosis
Diabetes and Coeliac Disease
Treatment – Diets For People With Coeliac and Diabetes
The Experiences of a Family With Diabetes and Coeliac Disease
Information Sources

 

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Treatment – Diet For People With Coeliac Disease and Diabetes

A strict gluten free diet is the only treatment that puts the intestine back to normal.

Diabetes requires a well balanced diet with plenty of carbohydrate but once coeliac disease has been diagnosed, providing carbohydrate becomes more difficult as many of the carbohydrates we eat and enjoy, such as bread, pasta, cereal, pastry, crackers, biscuits and cakes contain gluten which has to be avoided. This is particularly difficult for children. These foods can be replaced with gluten-free products, some of which are available on the NHS in the UK. But as there is no gluten in the flour, the products do not have the same consistency and taste and are often not so delicious.

Here are just some of the difficulties:

  • There is a lack of choice
  • Pre-prepared foods are much more difficult to obtain because many of them contain gluten eg the flour used to thicken sauces contains gluten.
  • It takes time to become familiar with the ‘hidden’ gluten eg wheat flour is often used as a carrier for flavouring in such things as crisps.
  • Buying gluten-free products is very expensive.

The Prostate and Diabetes

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Related Health Issues

Hypoglycaemia
The Eyes and Diabetes
The Kidneys and Diabetes
Weight and Diet
Exercise Your Heart
Diabetic Neuropathy
Diabetes and Coeliac Disease
Stress, Anxiety and Depression
The Prostate and Diabetes
Polycystic Ovarian Syndrome
Joint and Muscle Problems Associated With Diabetes
Impotence
Women, Sex and Diabetes
Osteoporosis – Is There A Link with Diabetes?
An experience of the menopause

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The Prostate and Diabetes

The prostate is a walnut-sized gland underneath the bladder in men that encircles the urethra [the tube that carries urine out of the body]. In adults the prostate often begins a new growth and tests have to be carried out to find out if this is benign or cancerous. If benign, it s called benign prostatic hyperplasia or BPH and if not, it is localised prostate cancer but to date no tests have been found to entirely reliable.
The pressure of the enlarged prostate may partially close the urethra causing various urinary problems, especially in older men.

A study published in the Journal of Urology, June 2000, shows that in men with diabetes the symptoms of BPH are worse than in men without diabetes. The research looked at the records of 1,290 men with diabetes and 8,566 men without diabetes all of whom were having drug treatment for BPH. They compared BPH symptoms before and after drug treatment and found that men with diabetes had more symptoms and slower urine flow rate than those without diabetes. It showed that men with diabetes have symptoms as severe as non-diabetic men eleven years older and a urine flow rate the same as non-diabetic men seven years older.

Facts about prostate cancer to put it in perspective

  • Prostate cancer is slow growing so most men will die of something else before the cancer becomes a problem.
  • It seems to occur in the majority of men as they get older but is not life threatening and remains localised in the prostate gland. Autopies have shown that 40% of men over the age of 50 have prostate cancer [and never knew] and the risk rises steadily with age so that by the age of 80 so that by 80, 70% of men have it.
  • Surveys show that for the average 50year old man with a reasonable life expectancy of a further 25years, there is a 10% chance that he will develop clinically significant prostate cancer but only a 3% chance that he will die of it.

Symptoms of BPH and prostate cancer

  • A weak or interrupted urine flow.
  • Frequent urination during the night.
  • Burning or painful urination.
  • Urgent need to urinateUrine leakage.
  • Feeling that the bladder is not empty even after urinating.

Ways to help the symptoms:

  • Limit the amount of fluids before bed.
  • Drink less alcohol and caffeine.
  • Completely empty your bladder.
  • Check with your GP that any other medicines you are taking are not aggravating the problems.

Treatment

Consult your doctor -It may be that if the symptoms don’t cause any problems, then there may be no need for treatment other than regular check ups.

Drug treatment – There are two different kinds of tablets that can help, all with side effects. One type of drug relaxes the prostrate muscles and lets the urine flow more easily and the other shrinks the prostate over several months.

Radiotherapy – Treatment is applied externally by Xrays or internally by using radioactive implants but a study has shown that it has limited efficacy [Int Joun of Radiat Oncol Bio Phys 2002, 53]. It also causes a range of unpleasant side effects.

Surgery – This is often recommended for men with serious BPH problems and prostate cancer. Surgery can have both severe and debilitating side effects that can include incontinence and impotence with a risk that both BPH and prostate cancer can return. A statement from the US National Cancer Institute in July 2001 says that the rate of recurrence rises to 40% 10 years after surgery.

Watchful waiting
Doing nothing does not sound like a treatment option but it is and it may be the best option and one that certainly should be discussed with your doctor. If BPH or prostate cancer is not causing effects or symptoms that markedly affect quality of life, then doing nothing may be the right choice. All the above treatments cause side effects that may be worse than the symptoms.

Screening for prostate cancer
Research to demonstrate whether or not screening for prostate cancer beneficial is far from conclusive. In 2000 the US National Cancer Institute stated ‘It is not known if the benefits of prostate cancer screening outweigh the risks, if surgery is a better option than radiation or if treatment is better than no treatment’.

The PSA screening test
This is the test used to screen for prostate and cancer and it measures the levels of prostate-specific antigen [PSA] in the blood. PSA is a protein produced by the prostate and when the prostate is enlarged the PSA blood levels tend to rise. However this tests produces a lot of false positives, suggesting that cancer is present when it is not, and false negatives giving the all clear when cancer is actually present
[Urologe A, 2000;39:22-6]

There is also disagreement about what level of PSA is significant and ‘normal’ levels can vary according to different factors.

If a PSA is positive, then further tests have to be carried out and these can have adverse effects that are worse than the condition itself as most prostate cancers are slow growing and may be present for years before they cause symptoms.

When considering being screened for prostate cancer, it is essential that the risks and benefits of the PSA and any subsequent procedures are carefully considered.

Treatment Options

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Impotence and Diabetes

General Information
Erectile Dysfunction and Diabetes
What to do if Erectile Dysfunction Develops
Treatment Options
Cochrane Review of Erectile Dysfunction Drugs For Men With Diabetes
Further Information

 

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Treatment Options

Psycho-sexual therapy
This may be recommended where psychological factors are considered to be an important part of the causes of erectile dysfunction. It may be recommended in combination with other treatments.

Cochrane Review of psychosocial interventions for erectile dysfunction
A meta-analysis was carried out looking at all the research for erectile dysfunction to compare the effectiveness of psychological treatment [therapy] and treatment with oral drugs, vacuum devices or other psychological interventions. The reviewers searched for randomised controlled trials carried out between 1966 and 2007 and found 11 trials involving 398 men. Their conclusions were:

  • Group psychotherapy therapy improves erectile dysfunction in selected patients.
  • Focused sex group therapy was more effective than no treatment.
  • Men who received group therapy and Viagra [sildenafil] showed significant improvement of erectile dysfunction and were less likely than those receiving only Viagra to drop out.
  • No difference was found when comparing the effectiveness of psychological interventions with local injection and vacuum devices.

Ref: Melnik T, Soares BGO, Nasselo AG. Psychosocial interventions for erectile dysfunction. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004825. DOI: 10.1002/14651858.CD004825.pub2

Hormone treatments
Only a small number of cases of erectile dysfunction are caused by hormonal imbalance – most often reduced levels of testosterone. If this is the case, testosterone replacement can then be used.

Oral medications
There are now three drugs in tablet form on the market used to treat erectile dysfunction

  • Viagra [Sildenafil, Pfzer]
  • Cialis [Tadafil, Lilly]
  • Vardenfil or Levitra [Bayer/GlaxoSmithKline]

They all act in the same way by helping the smooth muscles in the penis to relax so increasing the blood flow to the penis causing an erection. They will only work if the man is sexually stimulated. None of them should be taken in combination with each other.

Viagra – This was the first drug of its type on the market. It should be taken about an hour before sexual activity and on average takes 20 to 60 minutes to work and within a 4 to 6 hour period after taking the tablet, an erection should occur.

Side effects are usually mild and transient with the most common being headache and flushing. It should not be taken with other medicines unless the doctor says it is safe to do so.

Not to be taken by people who are taking medicines that contain nitrates, these are commonly prescribed for angina sufferers. Also people with the following conditions:

  • Severe heart or liver problems
  • Recent heart attack, stroke or low blood pressure
  • Certain rare eye diseases eg retinitis pigmentosa.

Cialis – This is a new drug and within 30 minutes of taking it, 50% of men can get an erection if sexually stimulated and its effects last for 24 hours. So the manufacturers say that it will allow men with erectile dysfunction to choose when they want to have sex and will allow couples greater spontaneity. The publicity material says that in clinical trials Cialis worked in four out of five men.

Side effects are usually mild and transient, the most common being headache and indigestion. Less common side effects include stuffy nose, flushing, myalgia, dizziness and backache.

It should not to be taken by people who are taking medicines that contain nitrates. It should also not be taken by men with the following:

  • Severe cardiac disease where sexual activity is inadvisable
  • Heart attack in the last 90 days or significant heart failure in the last 6 months
  • Stroke within the last 6 months
  • Unstable angina
  • Uncontrolled arrhythmias [irregular heart beat], low or untreated high blood pressure

Vardenafil or Levitra – The latest drug where clinical trials have shown that is effective and reliable in a wide range of men with erectile dysfunction. It normally works within 25-60 minutes and within a 5 hour period after taking.

Side effects are usually mild and transient with the most common being headache and flushing.

Not to be taken by people who are taking medicines that contain nitrates. It should also not be taken by men with the following:

  • Severe cardiac disease where sexual activity is inadvisable
  • Recent stroke, heart attack or low blood pressure
  • Unstable angina

Research among men with diabetes 73% taking 20mg Vardenfil/Levitra showed a significant improvement in erections. Most adverse events were mild to moderate and transient – headache, flushing, rhinitis dyspepsia, nausea and dizziness.

Vehicles You Can Drive

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Driving and Diabetes

Driving and the EU law
News release: EU changes night-time hypos driving rules for people with diabetes
Driving and hypoglycaemia – what are doctors being advised to do?
Test Strips – Department Of Health Warning For Doctors And Pharmacists
Vehicles You Can Drive
Insulin and Driving Taxis
Hypoglycaemia and Driving
Driving and Medicines
Driving and Visual Field Loss

 

Living with Diabetes
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Vehicles You Can Drive

On January 1st 1998, driving restrictions came into force in the UK to bring the UK in line with the other European countries.
People with insulin-treated diabetes have medically restricted driving licences issued for a maximum of 3 years. Diabetes is NOT specifically singled out – the regulations apply [i] to all conditions which require a medically restricted licence and [ii] to everyone applying for a licence for the first time whether young or old, with a normal licence or a restricted licence.

You ARE able to:

  • Drive a car or vehicle up to 3.5 tonnes with a trailer.
  • Tow a caravan, boat, horse box or broken-down vehicle.
  • Drive a minibus of less than 9 seats.
  • If you drive a non-commercial minibus on a voluntary unpaid basis you can apply for a special licence. This is bit complex and you can obtain information from the DVLA Swansea, Fact Sheet INF 28.

Driving a mini-bus
For many people there has always been some confusion over the DVLA regulations for driving a mini-bus.
You may be able to drive a mini-bus if you hold a car licence and follow certain conditions. Your driving licence will tell you what vehicles you can drive.  The DVLA states that you may be able to drive a minibus with up to 16 passenger seats using your current car driving licence as long as it’s not for ‘hire or reward’ – there is no payment from or on behalf of the passengers.

The conditions you must meet:

  • you’re 21 or older
  • the minibus is used for social purposes by a non-commercial body
  • you’ve had your driving licence for at least 2 years
  • you meet the Group 2’ medical standards if you’re over 70 – check with your GP if you’re not sure you meet the standards
  • you’re driving on a voluntary basis and the minibus is used for social purposes by a non-commercial body
  • the maximum weight of the minibus is not more than 3.5 tonnes – or 4.25 tonnes including specialist equipment for disabled passengers, eg a wheelchair ramp
  • you’re not towing a trailer.

Minibus permit – if you need to charge running costs

You can apply for a minibus permit if you need to charge passengers, as long as:

  • the vehicle can carry between 9 and 16 passengers
  • you’re driving it for a voluntary organisation that benefits the community – eg an educational, religious or sports organisation
  • the minibus service is only available for members of that organisation – not to the general public
  • any charges are to cover running costs and are not for profit

Apply for a minibus permit from your local authority, or contact DVSA (Driving Vehicle Standards Agency).

No blanket ban on driving 3.5 and 7.5 tonnes vehicles or for LGV drivers
There is no longer a blanket ban on driving these vehicles but people will be assessed on a individual basis. This includes the following:

  • The applicant needs to satisfy the DVLA that since commencing treatment with insulin ‘he has had sufficient experience in the driving of vehicles to make practicable an assessment of the risk posed by his driving vehicles in those classes.’ The qualifying condition for this purpose was set to require that the applicant has driven at least 4 hours a day 3 days a week during the 12 month period prior to the application.
  • Applicants must have had no hypoglycaemia attacks while driving.
  • They must undergo an annual examination by a diabetes specialist to enable the DVLA to assess that their diabetes is adequately controlled.
  • They must regularly monitor their condition and at least 2 months records will be required.

HGV licence applications process improved by the DVLA (2015)
The Driving and Vehicle Licensing Authority (DVLA) has made some improvements in the way people treated with insulin apply for their annual renewal to drive vehicles over 3.5 tonnes. This is to reduce the unreasonable delays people have been experiencing when renewing their licences.

  • The DVLA Drivers Medical Group has increased capacity to assess applications from people with diabetes.
  • The application form (D4) is being simplified so that it is easier to complete and will reduce the number of rejected applications.
  • The response time will be speeded up for any vocational drivers chasing up the whereabouts of their First Vocational Licence Application with the DVLA Contact Centre.

There are also plans to improve the whole process which includes:

  • Updating all DVLA literature to advise drivers not to send in their driving licence when applying for a renewal.
  • Changing legislation to allow drivers to apply for their licence 90 days before it is due to expire.
  • Recruiting and training more staff and medical professionals.

You can contact the DVLA Contact Centre about Vocational Medical Enquiries on 0300  790 6806

Glossary of Terms

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The glossary of terms is also available as a leaflet to download, or to order as a printed leaflet.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

A

Acetone: One of the chemicals called ketones. These are produced when there is too little insulin present and the body uses fat for energy. Acetone can be smelt on the breath when the level of ketones is raised. Acetone in the urine usually means that more insulin is needed.

Ace-inhibitors: Drugs that inhibit an enzyme (angiotensin converting enzyme) in the kidneys that increases the blood pressure.

Acidosis: Shifting of the pH in the blood towards being acidic.

Adrenal Gland: Small organ situated above the kidneys that produces a number of different hormones, including adrenaline and cortisol.

Adrenergic symptoms: Bodily symptoms of hypoglycemia caused mainly by adrenaline.

Albumin: a protein that is in most animal tissues. The presence of albumin in the urine may be a sign of kidney or bladder infection or early kidney damage.

Aldose reductace inhibitors: Drugs that can affect nerve damage caused by diabetes.

All Party Parliamentary Group for Diabetes: To study the condition of diabetes and its clinical and legal complexities.

Alpha cells: Cells in the Islets of Langerhans of the pancreas that produce the hormone glucagon.

Antibodies: Produced by the immune defense system to destroy viruses and bacteria.

Arteriosclerosis: Hardening, narrowing and eventually blocking of the blood vessels.

Aspartame: A low-calorie sweetener. This has some quiet dramatic side effects in some people.

Autonomic Neuropathy: Damage to the system of nerves which regulate many autonomic functions of the body such as stomach emptying, sexual function and blood pressure control.

Autonomic nervous system: The ‘independent’ part of the nervous system that is operated without having to give it a thought, including things like breathing and the movement of the intestines.

Autoimmune system: Sometimes things go wrong and the cells of the body are attacked eg an infection and the autoimmune system is the body’s defence mechanism for fighting off the attack.

B

Basal insulin: A low level of insulin that covers the body’s need for insulin between meals and during the night. The insulin is given as intermediate or long-acting insulin.

Basal rate: With an insulin pump, a low dose of basal insulin is infused every hour of the day and night.

Beta cells: Cells in the Islets of Langerhans of the pancreas that produce the hormone insulin.

Blood Glucose Monitoring: A system of measuring blood glucose levels at home using special strips and a meter.

Brittle Diabetes: A term used to describe diabetes which is extremely unstable where blood glucose levels swing from very low to very high.

C

Capillary Blood: The capillaries are the very fine blood vessels between arteries and veins to allow the blood deliveries of oxygen to the tissues. Blood tests from fingers contain capillary blood.

Carbohydrate: A class of food which comprises of starches and sugar which are most easily available by the body for energy. Found in mainly plant foods eg rice, bread, potatoes, pasta and dried beans.

Coeliac disease: Illness where the person cannot tolerate gluten, a substance found in wheat, oats, barley and rye.

Coma: Unconsciousness. Can occur in people with diabetes when the blood glucose is very low (insulin coma) or very high (diabetes coma).

Control: Usually refers to blood glucose control.

C-peptide: ‘Connecting peptide’ a hormone produced together with insulin in the beta cells. By measuring C-peptide, the residual insulin production of the pancreas can be estimated.

Cortisol: Stress hormone that is produced in the adrenal gland.

Counter regulation: The body’s defense against low levels of blood glucose. The excretion of the counter regulating hormones (glucagon, adrenaline, growth hormone and cortisol) increase when the blood glucose level falls too low.

CSII: Continuous subcutaneous insulin infusion, treatment with an insulin pump.

Cystitis: Inflammation of the bladder causing frequent passing of urine and a burning sensation when passing urine. This should not be confused with frequent passing of urine due to high blood sugars.

D

Dawn phenomenon: The growth hormone level rises during the night, causing the blood glucose level to rise early in the morning.

Depot effect: Part of the insulin that is injected is stored in the fat tissue as a depot (a spare tank of insulin) – the longer the action of insulin, the larger the depot.

Dextrose: Pure glucose.

Diabetes/Diabetic Coma: Unconsciousness [coma] that occurs as a result of very high blood glucose levels [hyperglycemia] and is usually accompanied by ketoacidosis.  Also see ‘insulin coma’.

Diabetes Ketones: Ketones that are produced when the cells in the body are starved of insulin and therefore the blood glucose level is high.

Dialysis: The process of extracting harmful substances from the blood when the kidneys no longer can.

E

Exchanges: Portions of carbohydrate foods in the diabetic diet that can be exchanged for others.  One exchange is usually equal to 10gms of carbohydrate.

F

Fatty Acid: Substances produced when fat is broken down in the body.

Free Food: Foods that contain very little carbohydrate and so can be eaten in liberal amounts by people with diabetes without counting them in their diet. e.g. most vegetables, most salad ingredients, tea, coffee, meat and cheese. Note: meat and cheese are carbohydrate free but contain fats.

Fructose: A type of sugar found naturally in fruit and honey. It does not require insulin for its metabolism and so is often used as a sweetener in food for people with diabetes.

G

Gastroparesis: Slow stomach emptying, a complication of diabetes caused by neuropathy.

Galactose: Sugar molecule. Lactose consists of galactose and glucose.

Gestational diabetes: Diabetes occurring during pregnancy. The symptoms disappear after childbirth but the woman has an increased risk of acquiring type 2 diabetes later in life.

Gluconeogenesis: Production of sugar in the liver.

Glucagon: A hormone produced by the pancreas which causes a rise in blood glucose by freeing glycogen from the liver. It is available as an injection to treat a severe hypo when food or drink cannot be administered.

Glucose: A form of sugar made by digestion of carbohydrates. Absorbed into the bloodstream where it circulates and is used for energy.

Glucose tolerance test: Test to diagnose early stages of diabetes. Tells how much the blood glucose level rises after orally ingested or intravenously given glucose.

Gluten: Compound that makes dough sticky. Found in wheat, oats, rye and barley.

Glycaemic index: A method of classifying carbohydrates and foods according to how they affect the body glucose level. Abbreviates to GI.

Glycogen: The form in which carbohydrate is stored in the liver. It is often known as animal starch.

Glycogenolysis: The breakdown of the glycogen store in liver or muscles.

Glycosuria: Presence of glucose in the urine.

Goitre: Enlarged thyroid gland

Growth hormone: Hormone that is produced in the pituitary gland. Increased growth is the most important effect. It increases the blood glucose level.

H

HbA1c: Blood test that measures how much glucose binds to red blood cells over a 6 to 8 week period.

Haemoglobin A1: The part of the haemoglobin of the red blood cell to which glucose attaches. It is a test of ‘diabetes control’ as it measures the amount of haemoglobin A1 attached to the red cells so giving the average blood glucose levels over the 6 to 8 weeks.

Honeymoon Period: usually only a short time after diagnosis and the start of insulin treatment – the dose of insulin drops due to partial recovery of insulin secretion by the pancreas.

Hormone: Substance generated in a gland or organ which is carried by the blood to another part of the body to stimulate another organ into activity. Insulin is a hormone.

Hyperglycaemia: High blood sugars.

Hypoglycaemia: Low blood sugars

I

IDDM: Insulin dependent diabetes mellitus, former name for type 1 diabetes.

Immune defense: The defense in the body against foreign substances, such as bacteria and virus.

Insulin: A hormone produced by the beta cells of the pancreas which is responsible for the control of glucose in the blood. Insulin can only be given by injection because the digestive juices destroy its action if taken by mouth.

Insulin antibodies: Antibodies in the blood that bind insulin. The insulin that is bound has no function but can be released at a later time when the concentration of insulin in the blood is lower.

Insulin coma: Extreme form of hypoglycaemia associated with unconsciousness and sometimes seizures.

Insulin Dependent Diabetes (IDD): The type of diabetes that has to be treated with insulin because the body’s pancreas no longer produces it. Most common in younger people. It is also called type1 diabetes or juvenile-onset diabetes.

Insulin Pen: An injection device for insulin. The injection of insulin is given after dialing the dose and pressing a button.

Insulin Pump: Insulin is infused into the subcutaneous tissue through a thin tubing continuously during day and night.

Insulin Reaction: Another word for low blood sugars or hypoglycaemia, often called a hypo. In some countries it is called ‘insulin shock’ or ‘shock’.

Insulin receptor: Structure on the cell surface to which insulin binds. Initiates the signal that opens the cell membrane for glucose transportation.

Insulin resistance: Decreased insulin sensitivity. A higher level of insulin than normal is needed to obtain the same blood glucose lowering effect.

Intermediate-acting insulin: Insulin that has an effective time action of 8-12 hours, often given twice daily to provide 24 hour insulin cover.

Intradermal: Means ‘into the skin’. Usually refers to an injection given into the most superficial layer of skin. Insulin must not be given in this way as it will not be absorbed properly.

Intravenous injection: Injection directly into a vein.

Islet of Langerhans: the cells within the pancreas that produce insulin and glucagon.

J

Juvenile diabetes: Diabetes in childhood and adolescence, another term for type 1 diabetes.

K

Ketoacidosis: A serious condition due lack of insulin which results in body fat being used up to provide energy but dangerous ketones and acids are also formed. It is caused by high blood sugar levels which result in ketones in the urine, vomiting, drowsiness, heavy laboured breathing and breath smelling of acetone [pear drops].

Ketones: Acid substances formed when body fat is used up to provide energy.

Ketosis: Increase amounts of ketones in the blood.

Ketonuria: The presence of acetone and other ketones in the urine. Detected by testing with a special testing stick or tablets. Ketones in the urine are due to lack of insulin or periods of starvation.

L

Lactose: Milk sugar.

LADA: Latent Autoimmune Diabetes in the Adult. Onset of type 1 diabetes after the age of 35/40, usually with not so dramatic symptoms.

Langerhans: The scientist who discovered the islets of Langerhans in the pancreas in 1869.

Laser Treatment: A process in which laser beams are used to treat a damaged retina.

Lipoathrophy: Loss of fat from the injection sites. More common in the past when insulins were not highly purified.

Lipohypertrophy: Fatty swelling usually caused by repeated injections of insulin into the same place.

Long-acting insulin: Insulin with a prolonged action, up to 24 hrs.

M

Macroangiopathy: Diabetes complications in the large blood vessels.

Metabolism: Process by which the body turns food into energy.

Microalbuminuria: Small amount of protein in the urine. The first sign of kidney damage which can be caused by long term diabetes.

Microaneurysm: Small protuberances on the retinal vessels. The first stage of eye damage which can be caused by long-term diabetes.

Microangiopathy: Diabetes complications in the small blood vessels of the eye, kidney and nerves.

Millimoles: Unit for measuring the concentration of glucose and other substances in the blood. Blood glucose is measured in millimoles per litre (mmol/l).

Multiple injection treatment: Treatment with injections of short or rapid- acting insulin before meals and intermediate or long acting insulin to cover day and night.

N

Necrobiosis lipoidica diabeticorum: A special type of skin lesion that can be seen in people with diabetes.

Nephropathy: Kidney damage. In the early stages this makes the kidneys leaky so that albumin appears in the urine. At the later stage it may affect the function of the kidney and in severe cases lead to kidney failure.

Neuroglycopenic symptoms: Symptoms of brain dysfunction caused by a low blood glucose level.

Neuropathy: Damage to the nerves. This may be peripheral or autonomic and is usually caused by long-term diabetes,

NICE: This is the National Institute for Health and Clinical Excellence. NICE is an independent organisation responsible for providing national guidelines for the treatment of various conditions, the use of medicines and on the promotion of good health. www.nice.org.uk

P

Pancreas: A gland lying behind the stomach which secretes digestive fluid and also contains the islets of Langerhans that produce insulin.

Pituitary gland: Small gland situated in the brain where many of the most important hormones in the body are produced.

Pre-meal injection: Injection with short or rapid acting insulin prior to a meal.

Protamine: A protein from salmon that is added to insulin to extend its action time.

Polydipsia: Being excessively thirsty and drinking too much. Also a symptom of untreated diabetes.

Polyuria: The passing of large quantities of urine due to excess glucose in the bloodstream. It is a symptom of untreated diabetes.

Primary Care Trust [PCT]: PCT’s cover all parts of England. All PCT’s receive budgets directly from the Department of Health. Since April 2002, PCT’s have taken control of local health care and decide how the funding is distributed.

Proteinuria: Protein or albumin in the urine.

R

Rapid-acting insulin: A fast-acting insulin analogue used to cover carbohydrate content of meals. It works rapidly and is of short duration.

Receptor: A special structure on the cell surface that fits with a hormone. The hormone must fit into the receptor for it to have its effect on the cell.

Rebound phenomenon: After a hypo episode, the blood glucose may rise to high levels. This is caused both by the secretion of counterregulatory hormones and by eating too much when feeling hypo.

Renal Threshold: The level of glucose in the blood above which it will begin to spill into the urine. The renal threshold for glucose in the blood is about 10 mmol/l but this can vary amongst individuals.

Retinopathy: Damage to the retina, the sensitive area at the back of the eye providing sight.

S

Short-acting insulin: Soluble insulin without additives to prolong its action.

Somogyi phenomenon: A special type of rebound phenomenon after a night hypo resulting in high blood glucose levels in the morning.

Sorbitol: Sugar alcohol, a sweetener that gives energy.

Starch: Complex carbohydrates found in potatoes, corn, rice and wheat.

Subcutaneous Injection: An injection beneath the skin into the layer of fat which lies between the skin and muscle – where insulin should be injected.

Sucrose: Cane or beat sugar, brown sugar, table sugar, powder sugar, and saccharose.

T

Type 1 Diabetes: Another name for insulin dependent diabetes, the type that is always treated with insulin.

Type 2 Diabetes: Another name for non-insulin dependent diabetes which may be treated with diet only, diet and tablets and/or eventually insulin if the other treatments fail.

U

U 100: The standard strength of insulin in the UK and many other countries.

Unaware hypo: A hypo without having had warning symptoms associated with decreasing blood sugar.

V

Visual acuity: the measurement of vision by reading letters on a chart.

Visual field: the measurement of the area that can be seen while the eyes are looking straight ahead – important for driving.

 

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For further information contact:

InDependent Diabetes Trust [IDDT]
PO Box 294
Northampton
NN1 4XS

tel: 01604 622837               
fax: 01604 622838
e-mail: enquiries@iddtinternational.org
website: www.iddtinternational.org

© InDependent Diabetes Trust, 2017

The Safety of Insulin Analogues – should patients be concerned?

By Uncategorized

The Safety of Insulin Analogues – should patients be concerned?

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 5th 2005
The Influence of the Pharmaceutical Industry

What are insulin analogues?
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:
  3. Those who require assistance from a carer or healthcare professional to administer their insulin.
  4. Those whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemic episodes.
  5. Those who would otherwise need twice daily basal insulin injections in combination with oral anti-diabetic drugs.

Cost
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.

Note: Determir [Levemir] is a similar cost to glargine.

Glossary of Terms

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.

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

Name of insulin

Brand Name

Insulin glargine

Lantus

Insulin aspart

NovoRapid [NovoLog in the US]

Insulin lispro

Humalog

Insulin determir

Levermir

 

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.

Version One – using layman’s language
Regulatory requirements for insulin analogues: weighing therapeutic benefits against potential carcinogenicity

Authors:

Prof. Dr. med. Ernst Chantelau
Department of Endocrinology, Diabetes and Rheumatology
Diabetesambulanz MNR-Klinik
PO Box 10 10 07
D- 40001 Dusseldorf
Germany

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

Background
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.

Drug toxicity

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.

Drug Toxicity:

  • May vary
  • May affect and organ system
  • The different genetic make up leads to different drug responses between people
  • The clinical consequences of individual drug response can be great
  • New biotechnology products are likely to have different patterns of toxicity compared to the more predictable ones of chemically produced drugs.

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
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.

Introduction of genetically engineered insulin
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
  • with little attention paid to the quality of the post-marketing studies
  • 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.

Introduction of insulin analogues
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:

  • the size of the insulin dose
  • the amount and timing of carbohydrate intake
  • the timing of exercise in relation to carbohydrate intake and/or insulin administration
  • the effects of stress or intercurrent illness
  • psychosocial aspects
  • residual beta cell function [the amount of insulin that is still produced by the body’s own cells].

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.

Treatment Goals
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.

Short-acting insulin analogues
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:

Type of hypoglycaemia

Number of studies analysed

Effects of using Humalog or Novolog/NovoRapid

Frequency of mild hypoglycaemia

22 studies

Reduction in 5 studies

Frequency of severe hypoglycaemia

12 studies

No change in 10 studies

Frequency of nocturnal hypoglycaemia

24 studies

Reductions in 6 studies (19)

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.

Long-acting insulin analogues
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.

Studies carried out on selected patient groups
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."

Safety issues – the potential for carcinogenic effects
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 and NovoRapid /NovoLog inhibit thrombocyte function
  • 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.
[Published data on NovoRapid/Novolog are scarce].

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

Conclusions
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.

 

Version two – 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

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

Number of patients in studies

Changes in HbA1c measurements

1070 Type 1 diabetic patients in Europe:

HbA1c – 0.12% within 6 months

884 Type 1 diabetic patients in USA:

HbA1c – 0.15% within 6 months, – 0.14% within 12 months

 

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

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

Number of patients in study

Changes in HbA1c measurement

333 Type 1 diabetic patients

HbA1c – 0.14% versus NPH human insulin (15,16)

 

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

Number of patients in study

Changes in HbA1c measurement

619 Type 1 diabetic patients

HbA1c no statistically significant difference (17)

 

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

Humalog® or Novolog®/NovoRapid®, versus regular human insulin

Type of hypoglycaemia

Number of studies analysed

Effects of using Humalog® or Novolog/NovoRapid®

Frequency of mild hypoglycemia

22 studies

Reduction in 5 studies

Frequency of severe hypoglycaemia

12 studies

No change in 10 studies

Frequency of nocturnal hypoglycaemia

24 studies

Reductions in 6 studies (19)

 

 

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

No difference in hypoglycaemia (16)

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.

Safety issues: carcinogenic potential
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

Insulin analogue

Experimental design

Dosage

Duration

Outcome

B10 Asp (6)

Sprague-Dawley rats

20-200 U/kg

12 months

breast cancer+++, dose-related

Humalog® (29)

344 Fischer rats

20-200 U7kg

12 months

no breast cancer

Lantus® (30)

Sprague-Dawley rats

5-12.5 U/kg

<24 months

malignant fibrohisticytoma++

malignant lymphoma (+)

NovoLog® (31)

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

 

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…"

"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…"(40)

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."

"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." (39)

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.

References

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  2. www.yellowcard.gov.uk
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  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
  6. Wolf CR, Smith G, Smith RL. Pharmacogenetics, BMJ 2000;320:987-90
  7. Richter B, Neises G. Cochrane Review ‘Human’ insulin versus animal insulin in people with diabetes mellitus. July 2002 Cochrane Library
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  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
  15. Fuchs B, Morck M, Schulz M, Thesen R. Die Insulinanaloga Insulin Aspart und Insulin Glargin.Pharmazeutische Zeitung 2002. http://www.pharmazeutische-zeitung.de/pza/2002-10/pharm3.htm, accessed 24.1.2004
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  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
  23. LeRoith D, DiMarchi RD.Introduction. Horm Res 1994;41/Suppl.2:49-50
  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
  25. EMEA. Scientific Discussion Lantus 2000. CPMP/615/00.
  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
  39. FDA Patient information on NovoLog®(Insulin Aspart) NovoNordisk
  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

Carers and Diabetes

By Uncategorized

Carers and Diabetes

We are well aware that for many people the effects of living with diabetes do not seem to put a strain on relationships but we are also aware that for others it does, either sometimes or all the time. Just as diabetes is different in everyone, so is the day to day living with it – we all have different ways of coping with it. Many people with diabetes would not consider themselves in need of a ‘carer’ and see themselves as totally independent, but that may not be how their partner sees the situation.

Quote from a carer: “Independence is fine, but who picks up the pieces when they have a bad hypo? Who wakes up in the morning with only a bad headache, knowing nothing about the 3.00am battle with food – certainly not me!”

Partners can feel:

  • Excluded from their partner’s diabetes even though this exclusion may be quite unintentional on the part of the partner who may be unaware of how their partner feels. They may also feel that their knowledge of diabetes is very limited because they have not been included by their partner or included in the education sessions at the diabetes clinic.
  • They may feel frightened both on a day to day basis and for the future health of their partner. They may feel alone with their worries and fears with no one to talk to about their own feelings. Talking to an ‘outsider’, even a friend, can make them feel guilty and disloyal to their partner.
  • They may feel angry. Diabetes has altered everything and the life they expected may no longer seem possible which in turn, can lead to feelings of guilt and selfishness.
  • They may feel that diabetes and the welfare of their partner is a huge responsibility for them and feel unable to cope with this responsibility that has suddenly been thrust upon them. 
  • They cannot talk to their partner about their concerns because they do not want to upset them.

While people with diabetes live healthy and independent lives, we have to remember they get older just like everyone else. Unfortunately they may also get the complications of diabetes and so the partner can be placed in the role of caring for 24 hours a day with little or no help and support. This can be stressful and tiring!

Research
These studies are not recent but demonstrate the type of feelings that carers may have. If you are a carer and you feel any or all of these things, then don’t worry you are just like the rest of us.

The impact of severe hypoglycaemic episodes in patients with IDDM on spouses psycho social status and marital relationships.

Diab Care 1997; 20: 1543-1546

This study found that spouses of people with frequent severe hypos had more fear of hypos, more marital conflict about diabetes management and more sleep disturbance worrying about night hypos than did spouses whose partners with diabetes had not had recent severe hypoglycaemia.

Spouse’s worries concerning diabetic partner’s possible hypoglycaemia

Diab Med 1998; 619-622

In this study spouses of people who were treated in emergency for severe hypoglycaemia were interviewed and the results showed the following:

When the partner is late home, for nearly 1/5 of their spouses their first concern was the possibility of a severe hypo.

Severe hypoglycaemia was a source of concern for nearly 2/3 of the spouses.

For nearly 10% of the spouses the possibility of severe hypoglycaemia was ‘always’ a burden.

IDDT Triumphs in Australia

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IDDT Triumphs in Australia

The Insulin Dependent Diabetes Trust (IDDT) – after many years of lobbying – has at last succeeded in facilitating supplies of pork insulin into Australia.  Previously, people with diabetes in Australia who wished to use porcine animal insulin were forced to import it via the UK, but with the intervention of IDDT, pork insulin is now available from Aspen Pharmacare Australia.

IDDT Chair, Jenny Hirst commented, ‘We are so pleased that at last people in Australia have choice.  This has taken years of lobbying and although in the past it was possible for Australians to import some animal insulins from the UK, this proved to be extremely problematic.  This was largely because insulin doesn’t travel well in high temperatures and is adversely affected, and the cost of importation was extremely high.

Although the pork insulin (Hypurin Porcine) is not a registered product it is available through a government Special Access Scheme (SAS) on a case-by-case basis.   It is a Category B product and applications for its supply can be made by registered medical practitioners.

Ian Kershaw, IDDT’s Australian campaign officer said, ‘This is a real breakthrough for us here in Australia.  Prior to this new supply route it was almost impossible for people here to use porcine animal insulin.  However, thanks to everyone’s hard work we now have easy access to this insulin here in Australia.’

In order to make the supply as simple and fast as possible for both patients and healthcare professionals, Aspen Pharmacare have prepared very clear instructions on how to order Hypurin Porcine Insulin with prices and SAS forms, all of which are available by telephone, fax or on their website (details below).

Notes to Editors

For further information on the supply of pork insulin in Australia, please contact:

Aspen Pharmacare
tel: 02 8436  8300
fax: 02 9901 3540
website: www.aspenpharma.com.au

Ian Kershaw – IDDT Australia
tel: 03 6334 7552
e-mail: iddta@aapt.net.au

Press Contact
Veronica Wray (London, UK)
tel: 0011 44 20 8568 8546 or 0011 44 7710 624454
e-mail: veronicawray@aol.com

IDDT in New Zealand

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IDDT International

An umbrella organisation
Canada
Germany
New Zealand
United States

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IDDT in New Zealand

IDDT does not have a formal group in New Zealand but we do have members who live in New Zealand and we are aware that some people suffer the same adverse effects of ‘human’ insulin that are experienced by people in other countries. So some people in New Zealand need beef and pork insulins.

Insulin Availability in New Zealand
People are automatically treated with genetically produced human or analogue insulins as animal insulins are not available in New Zealand. Pork insulin can be imported on the ‘importation for personal use basis’, as used by people in other countries.

The details of how to import pork insulins can be found by visiting Wockhardt’s website: www.wockhardt.co.uk

Or you can contact Wockhardt UK as follows:
Wockhardt UK Ltd
Ash Road North
Wrexham Industrial Estate
Wrexham LL13 9UF
UK
tel: +44 1978 661261
fax: +44 1978 660130

Avandia suspended

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Avandia suspended – 23.09.10

The European Medicines Agency has recommended the suspension of the marketing authorisation for Avandia [rosiglitazone] and Avandamet – medicines used to treat Type 2 diabetes. This is as a result of accumulating evidence that Avandia increases the risk of heart disease and stroke to a point where its risks now outweigh its benefits.

These medicines will stop being available in the UK from October 21st 2010 and from this date all stocks will be recalled.

Any adverse side effects experienced by someone taking Avandia or Avandamet should be reported to the Medicines and Healthcare Products Regulatory Agency (MHRA).

People who are currently taking these medicines should make an appointment with their doctor to discuss suitable alternative treatments. You are advised not to stop these medicines without speaking to your doctor.

Doctors should stop prescribing Avandia and Avandia -containing medicines. People who are currently taking Avandia should be reviewed to have their treatment changed.

The suspension will remain in place unless the marketing authorisation holder can provide convincing data to identify a group of patients in whom the benefits of the medicines outweigh their risks. The Committee’s recommendation has now been forwarded to the European Commission for the adoption of a legally binding decision.

The U.S. Food and Drug Administration [FDA] also announced that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications.

The FDA will require that the manufacturers, GSK, develop a restricted access program for Avandia under a risk evaluation and mitigation strategy. This will require Avandia to be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so.

Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The FDA anticipates that this strategy will significantly limit use of Avandia.

 

 

Background to the Safety of Avandia

There has been intense media coverage over the last few weeks of the scandal emerging around Avandia – a drug used to treat Type 2 diabetes, manufactured by drug giant GlaxoSmithKline (GSK).

Studies have shown that Avandia [also called rosiglitazone] causes an increased risk of stroke and heart failure. Manufacturer, GSK, continue to defend the drug despite already paying out millions of dollars in settlements to patients or their relatives in the US. Several more studies, published this year, have again demonstrated that Avandia causes an increased risk of stroke and heart failure.

IDDT has tried to keep Newsletter readers up to date with news about the safety of Avandia but decisions have taken too long and patients have been put at risk.

Avandia has been prescribed for the last ten years but now it has emerged that GSK knew that there were cardiac risks associated with the drug but chose to downplay these risks, before it became public knowledge.

It has been reported that the UK drug regulator, the Medicines and Healthcare Products Regulatory Authority was advised by the Commission on Human Medicines to withdraw Avandia last July because its “risks outweigh its benefits.” However, it remains on the market because the European Medicines Agency, which licenses drugs across Europe, has yet to reach a decision. The situation is similar in the United States.

This news is highly alarming and IDDT has already been contacted by several people taking Avandia, who have been deeply worried and have wanted to change their medication. The advice IDDT is giving is not to stop taking your medication but to go to see your doctor to discuss alternative treatment options. It may also be worth bearing in mind that one option you may be offered is Actos (pioglitazone). This comes from the same family of drugs as Avandia and concerns have also been expressed about the safety of Actos.

 

 

European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim

Anti-diabetes medication to be taken off the market

The European Medicines Agency today recommended the suspension of the marketing authorisations for the rosiglitazone-containing anti-diabetes medicines Avandia, Avandamet and Avaglim. These medicines will stop being available in Europe within the next few months.

Patients who are currently taking these medicines should make an appointment with their doctor to discuss suitable alternative treatments. Patients are advised not to stop their treatment without speaking to their doctor.

Doctors should stop prescribing rosiglitazone-containing medicines. Patients taking rosiglitazone-containing medicines should be reviewed in a timely manner to amend their treatment.

The current review of rosiglitazone by the Agency’s Committee for Medicinal Products for Human Use (CHMP) was initiated on 9 July 2010 following the availability of new studies questioning the cardiovascular safety of the medicine.

Since its first authorisation, rosiglitazone has been recognised to be associated with fluid retention and increased risk of heart failure and its cardiovascular safety has always been kept under close review. Consequently, the use of rosiglitazone was restricted to a second-line treatment and contra-indicated in patients with heart failure or a history of heart failure when it was first granted a marketing authorisation as Avandia in 2000.

Data from clinical trials, observational studies and meta-analyses of existing studies that have become available over the last three years have suggested a possibly increased risk of ischaemic heart disease associated with the use of rosiglitazone. Further restrictions on the use of these medicines in patients with ischaemic heart disease were introduced.

The availability of recent studies has added to the knowledge about rosiglitazone and overall, the accumulated data support an increased cardiovascular risk of rosiglitazone. In view of the restrictions already in place on the use of rosiglitazone, the Committee could not identify additional measures that would reduce the cardiovascular risk. The Committee therefore concluded that the benefits of rosiglitazone no longer outweigh its risks and recommended the suspension of the marketing authorisation of the medicines.

The suspension will remain in place unless the marketing authorisation holder can provide convincing data to identify a group of patients in whom the benefits of the medicines outweigh their risks.

The Committee’s recommendation has now been forwarded to the European Commission for the adoption of a legally binding decision.

 

PERSPECTIVE

FDA Regulatory Action on Rosiglitazone
September 23, 2010 | J. Woodcock, J.M. Sharfstein, and M. Hamburg | DOI: 10.1056/NEJMp1010788

Because of cardiovascular risk, the FDA is requiring the sponsor of the diabetes drug rosiglitazone to submit a Risk Evaluation and Mitigation Strategy (REMS). Under the REMS, the drug will be available to patients not already taking it only if they are unable to achieve glycemic control using other medications and, in consultation with their health care professional, decide not to take pioglitazone for medical reasons.

For Immediate Release: Sept. 23, 2010
Media Inquiries: Karen Riley, 301-796-4674; karen.riley@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA significantly restricts access to the diabetes drug Avandia
Makes regulatory decisions on RECORD and TIDE trials

The U.S. Food and Drug Administration today announced that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia.

“The FDA is taking this action today to protect patients, after a careful effort to weigh benefits and risks,” said FDA Commissioner Margaret A. Hamburg, M.D. “We are seeking to strike the right balance to support clinical care.”

Rosiglitazone also is available in combination with other diabetes medications, metformin under the brand name Avandamet or glimepiride under the brand name Avandaryl.

Avandia, manufactured by GlaxoSmithKline (GSK), is in a class of drugs known as thiazolidinediones, or TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose (blood sugar) control in patients with Type 2 diabetes mellitus.

The FDA will require that GSK develop a restricted access program for Avandia under a risk evaluation and mitigation strategy, or REMS. Under the REMS, Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so.

Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the REMS will limit use of Avandia significantly.

“Allowing Avandia to remain on the market, but under restrictions, is an appropriate response, given the significant safety concerns and the scientific uncertainty still remaining about this drug,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

Also today, the FDA ordered GSK to convene an independent group of scientists to review key aspects of the company’s clinical trial known as RECORD, which studied the cardiovascular safety of Avandia compared to standard diabetes drugs. During the course of the FDA’s review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events. The FDA is requiring this independent review to provide additional clarity about the findings.

In addition, the agency halted the GSK’s clinical trial known as TIDE and rescinded all of the regulatory deadlines for completion of the trial. The TIDE trial compares Avandia to Actos and to standard diabetes drugs.

NICE not recommending Lucentis for treatment of diabetes macular oedema

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NICE not recommending Lucentis for treatment of diabetes macular oedema

The National Institute for Clinical Excellence [NICE] issued final draft guidance on the use of Lucentis [Ranibizumab] in England and Wales. It has decid4ed not to recommend its use on the basis that it is ‘not a cost effective use of NHS resources’. Lucentis is a new treatment for diabetic macular oedema, which affects around 50,000 people with diabetes and leads to visual impairment and blindness if not treated.

Diabetic macular oedema is a swelling in the area of the retina that gives detailed vision. Laser treatment has been the standard treatment on the NHS for diabetic macular oedema for the last 25 years and while this does stop deterioration, it has not been shown to improve vision. Over time laser treatment can cause damage to the surrounding area of the retina. Lucentis can improve vision and improve quality of life.

NICE has rejected the use of Lucentis on the grounds of cost. The injections cost £742 per eye and some people will need several monthly injections. Ultimately the cost of looking after people with sight loss is far greater, not to mention the effect on people’s lives.

People already being treated with Lucentis should have the option to continue with their treatment until they or their doctor decide it is appropriate to stop. NICE has not yet issued final guidance and there is the opportunity for registered stakeholders to appeal against the decision. Final guidance is expected in August 2011.

National Carers Week

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National Carers Week 18th – 24th June 2012

Most people with diabetes do not need carers but some people have diabetes and other conditions and they may well require a carer. IDDT is supporting National Carers Week by providing useful links which give information on Charities that can offer support to reduce the isolation that many carers experience.

A carer can be someone of any age who provides unpaid support to family or friends who could not manage without this help due to illness, disability, mental ill-health or a substance misuse problem.

Being a carer may mean:

  • Facing a life of poverty, isolation, frustration, ill health and depression.
  • Many carers give up an income, future employment prospects and pension rights to become a carer.
  • Many carers also work outside the home and are trying to juggle jobs with their responsibilities as carers.
  • The majority of carers struggle alone and do not know that help is available to them.
  • Carers say that access to information, financial support and breaks in caring are vital in helping them manage the impact of caring on their lives.

If you are a carer or know someone that is, these are organisations can offer support and information:

IDDT’s leaflet ‘For Family Carers’ for people living with diabetes
https://www.iddt.org/wp-content/uploads/2009/10/for-family-carers.pdf

Finance and Benefits:

http://www.direct.gov.uk/en/caringforsomeone/moneymatters/carersallowance/index.htm

http://www.carers.org/carers-allowance

http://www.carersuk.org/help-and-advice/help-with-money

Organisations that can help:

Carers Trust
http://www.carers.org

Carers UK
http://www.carersuk.org/

http://www.carersuk.org/help-and-advice

Carers Matter
http://www.carersmatters.co.uk/

Community Care – Care Matters
http://www.communitycare.co.uk/Articles/21/06/2007/104895/essential-information-on-time-for-change-care-matters.htm

The National Carers Strategy is available here:
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4006522

Hypurin pork insulin – assurance of continued availability

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IDDT Canada

Welcome to IDDT Canada
Global systematic withdrawal of animal insulins
Wockhardt UK pork insulin’s are available in Canada
Hypurin pork insulin – assurance of continued availability

 

Back to IDDT International
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Hypurin pork insulin – assurance of continued availability

From December 2018, people in the US will not be able to import pork insulin from Wockhardt UK.  

This is due to stringent Regulatory Controls, leaving Wockhardt UK with no choice but to discontinue supply of Hypurin Porcine & Bovine insulin which is directly supplied to the patients in the USA on a “Name Patient basis”.

On November 30th 2018, Wockhardt issued the following statement which offers reassurance to people in the UK who use Hypurin® porcine insulin.

Wockhardt UK Ltd – Supporting Diabetic Patient Choice

Wockhardt UK has been committed to the provision of Hypurin® Porcine Insulin for many years, recognising the medical needs and preferences of patients with diabetes.

At Wockhardt UK, we firmly believe that maintaining freedom of choice for diabetic patients is important and we are committed to continue the supply of our Hypurin® Porcine Insulin range to the UK and Canada for the foreseeable future.

Hypurin® Porcine Insulin is available in 10ml vials and 3ml cartridges and are an alternative to human or analogue insulins.

Here is the link on Wockhardt’s website:
http://www.wockhardt.co.uk/about-wockhardt/wockhardt-news/hypurin%C2%AE-porcine-insulin-uk-canada-commitment-301118.aspx

Facts About Diabetes

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Diabetes is a chronic disease that affects around 2.2 million people in the UK of whom 85 to 90% have Type 2 diabetes and 10 to 15% have Type 1 diabetes. In the UK there are about 20,000 children with Type 1 diabetes under the age of 15 years.

The number of people with diabetes is increasing throughout the world with Type 2 diabetes reaching epidemic proportions.

There are two forms of diabetes:

Type 1 diabetes:

  • This type accounts for 10 to 15% of the total number of people with diabetes in the UK. Also referred to as insulin dependent diabetes or juvenile diabetes, Type 1 diabetes affects children and adults up to the age of about forty. The number of children diagnosed under the age of 5 is markedly increasing.
  • Type 1 diabetes is caused by the body’s immune system attacking the insulin producing cells in the pancreas. The body no longer produces insulin and glucose levels rise. Treatment with insulin injections is always required for survival. It is usually diagnosed as an acute condition.
  • Around 20,000 people are treated with animal insulin and the remainder with synthetic ‘human’ or analogue insulin.
  • There is no cure for Type 1 diabetes and cause has not been established. It is thought that there may be several causes with a genetic link in some people. Recent research shows that a common virus may trigger the body’s immune system to attack its own insulin producing pancreatic cells.

Type 2 diabetes:

  • This type of diabetes affects 85% to 90% of the total number of people with diabetes in the UK – over 2 million people and it is thought that there could be a further 1 million people undiagnosed.
  • Type 2 is also referred to as non-insulin dependent diabetes and it occurs mainly in people over the age of 40 although with the rise in obesity, it is now occurring in children.
  • In Type 2 diabetes, the pancreas still often produces some insulin but either not enough or it not used properly by the various organs in the body (so there can be too much insulin in the system).
  • Type 2 diabetes can be treated with diet and exercise alone, oral blood glucose lowering drugs and if this still fails to reduce blood glucose levels sufficiently, then treatment with insulin is necessary. On average, people with Type 2 diabetes start to take insulin 7 years after diagnosis.
  • Type 2 diabetes can remain undiagnosed for several years during which time the blood glucose levels are too high, causing  and some of the complications of diabetes. People with Type 2 diabetes are often diagnosed as a result of having complications rather than because they suspect they have diabetes.
  • There is a tendency for Type 2 diabetes to run in families but a sedentary lifestyle and being overweight or obese are also causes, so it is preventable for many people.
  • The number of people affected by Type 2 diabetes is expected to double by the year 2010 due to the effects of lack of exercise, the increase in obesity and an ageing population.

The complications of diabetes
Type 1 and Type 2 diabetes are different diseases in cause, in effect and in treatment but the same long-term complications can arise in both types of the condition. The complications affect:

The eyes
Diabetes can affect the blood vessels at the back of the eye [retinopathy] and this can lead to visual impairment or blindness. Diabetes is the leading cause of blindness in the working population.

The heart and vascular system
Diabetes can affect the heart and the vascular system making people more susceptible to heart disease and stroke. It can also cause blood clots in the vessels in the legs which may result in amputation. Amputations are 50-80 times higher in people with diabetes than the general population.

Kidney damage
Diabetes can affect the kidneys resulting in damage or kidney failure [nephropathy].

Nerve damage
Diabetes may cause nerve damage [neuropathy]. The most common form of nerve damage is in the extremities leading to pain or loss of sensation in the feet and ulceration of the legs. Again this can lead to amputation.

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For more information on Type 1 and Type 2 diabetes, please visit the NHS Choices website:

NHS Choices: type 1 diabetes

NHS Choices: type 2 diabetes

The Causes and Treatment of Hypoglycaemia

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The Causes and Treatment of Hypoglycaemia

The simplistic explanation is that hypoglycaemia is caused by too much insulin hence the statement that hypoglycaemia is not caused by diabetes itself but by the treatment of it. The other way of looking at this is that there is not enough food for the exercise taken so there is too much insulin present.

Information leaflets often describe the causes of hypoglycaemia as follows:

  • Missing or postponing a meal or eating less than the correct amount of carbohydrate.
  • Taking more exercise than usual
  • Injecting the wrong dose of insulin
  • Emotional upset or stress
  • Alcohol consumption
  • No apparent reason

From a patient/family carer perspective this may seem like an underestimate of the complexities of hypoglycaemia in everyday life. Many leaflets for patients list these causes of hypos in a way that seems to place responsibility and blame on the patient and/or the family carer. All too often this can add to their feelings of guilt and failure for ‘not having managed their diabetes properly’! This is especially the case for parents of children with diabetes.

Treatment of hypoglycaemia

  • Hypoglycaemia in its early stages [mild hypo] is treated with a sugary drink or sugary food. This should then be followed with some longer-acting carbohydrate [eg a sandwich] to prevent another hypo.
  • If the hypo is not treated at this stage then there may be confusion, behavioural changes, helplessness and an inability to function properly occurs [moderate hypo].
  • If not treated at this stage with glucose, GlucoGel or Hypo-Fit then coma occurs and this may or may not be accompanied by seizures [severe hypo]. Severe hypos need treating with glucagon or intravenous glucose and this may mean admission to hospital.

Note: Both GlucoGel and Hypo-Fit can be squeezed into the mouth around the cheeks and gums. They MUST NOT be given if the person is unconscious or unable to swallow because they could choke. They are both available on a doctor’s prescription in the UK.

Some Golden Rules:

  • Always have some form of quickly absorbed glucose with you.
  • Never drive while hypo. If warning signs come on while driving, always stop the car and get into the passenger seat so that you are not seen to be in control of a car while hypoglycaemic.
  • When driving always keep glucose or sweets in an accessible place – the glove compartment is not very accessible.
  • If it is difficult to make the person eat or drink, then GlucoGel can be used, which is easier than the more old-fashioned method of rubbing jam around the cheeks and gums!
  • People with diabetes are renowned for denying that they are hypo when they actually are. If you are suspicious that they are hypo, always treat with sugary food or drink.
  • If you are a family carer and are unable to treat an unconscious hypo, call emergency services or your GP.
  • If the hypo is accompanied by vomiting, drowsiness and difficulty breathing, then a doctor is needed and admittance to hospital.

IDDT Newsletter Available on Tape

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Quarterly Newsletter and Type 2 & You for blind and visually impaired people

Until December 2013 we recorded our Newsletter and ‘Type 2 & You’ on tape to send to members through the post. However, tapes are soon no longer going to be available, so we have put the publications on our website so that they can be listened to from your computer or from a computer in your local library.

We hope that this change does not cause inconvenience but if you do need help with this, please don’t hesitate to get in touch with IDDT by calling 01604 622837 or email enquiries@iddtinternational.org

InDependent Diabetes Trust
IDDT