Looking after your Insulin and Injecting Devices

Storing Insulin
Insulin Pens Dribble
Needle Phobia
Needle Free Injection Device

 

Living with Diabetes

Needle Free Injection Device

The Insujet is an alternative to injections. For more information click here

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.

 

 

For further information contact:

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

tel: 01604 622837
e-mail: [email protected]
website: www.iddtinternational.org

© InDependent Diabetes Trust, 2017

Insulin – A Voice for Choice by Arthur Teuscher

Published by Karger Bern
ISBN-13: 978-3-8055-8353-4
August 2007

A thorough discussion of the controversy surrounding animal and "human" insulin

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

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

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

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

James Le Fanu, MD, FRCP, London Columnist for the Daily Telegraph and Sunday Telegraph.

"An important book for all who need insulin, and for their physicians to help them understand the message!"

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

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

Professopr Jim Mann, University of Otago, New Zealand

‘Insulin – A Voice for Choice’ can be obtained directly from IDDT, price £10.00 incl p&p – click here to order this book from the IDDT Book Shop.

tel: 01604 622837

e-mail: [email protected]

About Cochrane Reviews

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

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

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

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

Cochrane Review – ‘human vs. animal insulin’

July 2002

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

In order to have an informed choice of treatment, it is necessary to look at evidence from high quality systematic reviews. The following Cochrane Review comparing GM ‘human’ insulin and animal insulin provides just such high quality evidence.

"’Human’ insulin versus animal insulin in people with diabetes mellitus"

By Richter B, Neises G

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

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

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

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

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

Data collection and analysis: trial selection as well as evaluation of study quality was performed by two independent reviewers. The quality of reporting of each trial was assessed according to a modification of the quality criteria as specified by Schulz and by Jadad.

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

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

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

www.cochrane.org

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

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

• It can no longer be said that ‘human’ insulin is better than animal insulins, because there is no evidence for this.
• It can no longer be said that ‘human’ insulin gives better control and better HbA1cs, there is no evidence for this.
• It can no longer be said that ‘human’ insulin produces less antibodies, there is no evidence to support this.
• The existence of other adverse effects, apart from hypoglycaemia, was not even investigated, so their existence can no longer be denied.

Important issues for people treated with insulin have never been investigated

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

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

May 2004

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

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

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

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

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

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

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

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

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

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

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

The evidence from the review says:

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

Other information from the review:

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

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

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

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

About IQWiG

The Institute for Quality and Efficiency in Health Care [IQWiG] is an independent scientific institute that investigates the benefits and harms of medical interventions for patients. It regularly provides information about the potential advantages and disadvantages of different diagnostic and therapeutic interventions.

IQWiG: Rapid-acting analogues are not superior to ‘human’ insulin for Type 1 diabetes

June 2007

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

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

What did the review find?

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

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

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

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

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

• Why is the Dept of Health so unwilling to follow Germany’s lead and have all insulins assessed by NICE for risks/benefits and cost effectiveness?
• Why are Primary Care Trusts that are so obviously short of funds, spending unnecessary amounts on insulin analogues that have no proven benefits over less expensive human and animal insulins?
• Why are adults and children with diabetes being changed to insulin analogues when they have no proven benefit?
• Could all this be anything to do with heavy marketing of insulin analogues because they are the only insulins in patent, therefore more expensive and more profitable?

IQWiG: Short-acting insulin analogues are not superior to regular ‘human’ insulin in Type 2 diabetes

July 2006

Report from the Institute for Quality and Efficiency in Health Care [IQWIG]
This organisation is Germany’s equivalent to NICE in the UK and its final report on the use of rapid-acting analogues for the treatment of Type 2 diabetes resulted in the following recommendations:

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

The key points in the Report summary are:

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

• None of the studies were designed to investigate the effect of rapid-acting insulin analogues on the reduction of diabetic complications or total mortality.
• For hypoglycaemia, no clear advantage was shown with analogues compared to human insulin with regard to severe, symptomatic or nocturnal hypoglycaemia.
• Quality of life studies were limited but no clear advantage was shown with analogues compared to human insulin and no definite conclusions could be drawn about patient satisfaction as the studies were unsatisfactory.
• There was a tendency towards more people dropping out of the studies due to adverse reactions in those treated with analogues compared with those on human insulin.
• In so far as reported, there were similar weight increases for both patients receiving analogues and those receiving human insulin.
• As the maximum study period was 12months, no studies could show the safety of long-term use of analogues in people with Type 2 diabetes. Unless proved otherwise by adequately designed studies, the potential for mitogenic potency of insulin analogues [cell mutiplication and formation of tumours] as described in pre-clinical trials, is to be seen as a potential safety risk for long-term treatment of people with Type 2 diabetes.

The full report is available in English online at:

www.iqwig.de/index.media.538df941a1d274bea0b8b1f9ae06921b.pdf.

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

Cochrane Review – long-acting analogues vs NPH insulin in Type 2 diabetes

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

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

The authors’ conclusions are:

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

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

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

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

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

If this language is not plain enough, let’s make it plainer…

• We know that Lantus, Levemir and human long-acting insulins are the same in terms of blood glucose control as measured by HbA1s.
• We know that fewer people in the studies experienced symptomatic overall or night hypos with both the two analogues but we don’t know about the numbers of hypos without warnings [asymptomatic].
• We don’t know if treatment with Lantus and Levemir results in more or less complications over time or if there are any differences in death rates.
• We don’t know if Lantus causes higher rates of retinopathy – one study showed it did and one that it didn’t, so we don’t know if it’s safe or not.
• We don’t know if these insulins improve quality of life or not.
• We don’t know if they are cost-effective or not.
• We do know that the authors recommend a cautious approach to their use.

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

IQWiG: No proof long-acting insulin analogues outperform human insulin for Type 2 diabetes

This review by IQWiG concluded that it could find no proof long-acting insulin analogues are better than human insulin in long-term outcomes in people with type 2 diabetes.

IQWiG, was looking primarily at long-term outcomes, such as diabetes-related complications, heart and eye problems. It examined the available literature, concentrating in particular on longer-term studies. It also asked the two manufacturers concerned for additional information, which was supplied.

Of the 18 studies examined, nine compared glargine [Lantus] and Neutral Protamine Hagedorn (NPH) insulin, six compared detemir [Levemir] with NPH insulin, while the three others compared the two analogues against each other.

IQWiG commented that there was insufficient data to be able to be certain on the long-term implications, so there were indications, but no proof.  IQWiG’s statement said that although there was one five-year study on the use of glargine, it offered little information in terms of diabetes-related complications. Where heart disease was concerned, the comparison with NPH insulin showed no difference.

• Although the FDA had suggested that glargine could increase the risks of eye fundus damage, prompting Sanofi to conduct a long-term study, there was no indication this was the case.
• IQWiG also failed to find any proof of advantages in shorter-term effects, although there were some indications that, for example, under certain circumstances, mild hypoglycaemia appears to occur less frequently with insulin detemir.
• The report said the five-year-study shows some indication that serious hypoglycaemia occurs less frequently under glargine than with NPH insulin.
• In direct comparison to each other, neither of the two analogue insulins performed clearly better. People in the detemir [Levemir] group on average gained less weight than those in the glargine [Lantus] group. However, the differnce was only slight – between 0.9 and 1.3 kilos but as the studies were of short duration, between six and 12 months, it remained unclear how lasting this effect is.

  In the light of these findings, IQWiG has recommended that long-acting analogue insulins are not funded for people with Type 2 diabetes.

Novo Nordisk discontinue some GM ‘human’ insulins

June 29th 2005

‘Human’ Actrapid no longer available in cartridges for pens [from October 2005]

Novo Nordisk brought forward the discontinuation of some GM ‘human’ insulins to October 2005.  However, by 2009, the discontinuation of ‘human’ insulin that concerns most people is ‘human’ Actrapid in cartridges for pens. This means that people who want to continue to use ‘human’ Actrapid are being ‘forced’ to use a 10ml vial and syringe.

Of course, the Novo Nordisk recommended alternative is that people change to the newer short-acting insulin analogue, NovoRapid. Under these circumstances, changing your insulin is not being done clinical reasons to benefit you but because Novo Nordisk has made yet another commercial decision and it is this commercial decision which is dictating your treatment – something that must be deplored!

There are alternatives, you do not have to change to insulin analogues
If you do not want to change to GM analogue insulins but want to continue using pens for injection, then there are alternatives from other manufacturers. You should discuss with your doctor or health professional. The alternatives are:

• Humulin S made by Eli Lilly – a human insulin available in cartridges.
• Hypurin Porcine Neutral made by Wockhardt UK under the name of CP Pharmaceuticals – a short-acting natural pork insulin available in cartridges.

Changing insulin therapy
Novo Nordisk state that ‘any change of insulin therapy should be carried out by a suitably experienced healthcare professional’ . This is particularly so when changing to insulin analogues because they have a different speed of onset, peak of action and different duration of action from both ‘human’ and animal insulins.

Zyban – Safety precautions from the Committee on Safety of Medicines

30 May 2002

Zyban is a drug licensed to help people to stop smoking. Since it was first on the market it is estimated that 419,000 people have used Zyban. But the Committee on Safety of Medicines [CSM] have received over 5,000 Yellow card reports of adverse reactions. 126 of these reports were of people having seizures.

The CSM have issued warnings to doctors:

• Changes in the recommended dose
• They have warned that the use of Zyban is contraindicated in people with certain conditions where there is already a risk of seizures.
• They have stated that there are certain conditions where Zyban must NOT be prescribed and these include people treated with oral hypoglycaemic and those treated with insulin. Clearly this means that people with Type 1 and Type 2 diabetes should NOT be prescribed Zyban. They state that the exception to this is where there is compelling clinical justification that the potential benefit of stopping smoking outweighs the increased risk of seizure.for prescribing Zyban.

Warnings about ‘human’ insulin from the manufactuers, Novo Nordisk and Aventis

July 7 2000

Jenny Hirst, Co-Chairman
In September 1999 Novo Nordisk, one of the three major suppliers of insulin in the world, issued a press statement that included the following:

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

But of even greater concern is a statement from Aventis, another large insulin manufacturer, dated April 24th 2000 that includes the following:

"Human insulin therapy may be associated with hypoglycaemia, worsening of diabetic retinopathy, lipodystrophy, skin reactions (such as injection-site reaction, pruritus, and rash), allergic reactions, sodium retention and oedema."

The statements were put in the public domain by the insulin manufacturers and not by IDDT. They cause us concern because the adverse reactions that may occur with ‘human’ insulin therapy, as listed by Aventis and Novo Nordisk, are very much in line with the evidence from a large number of patients in various countries. These reactions largely regress with a change to animal insulins.

IDDT contacted Health Ministers and the Regulatory Bodies within the Department of Health – May 5th 2000

As a result of the above statements, we once again contacted the Department of Health [DoH]. We requested that the position in relation to ‘human’ and animal insulin is investigated by the Department so that people with diabetes may now given the full facts and evidence on which to base the choice of insulin species. In addition we asked that they consider the implications of these statements for Health Care Professionals. Our concerns appeared to be well justified by the publication of an article in Pulse, May 20th, quoting a helpful statement by the Medical Defence Union:

"The data sheets for human insulin specify the potential for lowered hypoglycaemia awareness but doctors should take care to discuss this with their patients." They further explain that provided they do this (and the patient is happy with this) any litigation would not be directed at them.

We made the Department aware of IDDT’s commitment to provide information about risks, benefits and alternatives to enable people with diabetes to make informed choices about their treatment. We pointed out that:

• IDDT has tried never to cause alarm or panic about the problems we know exist for a so far unidentifiable sub-group of people using ‘human’ insulin, but that we have a duty and commitment to people with diabetes.
• Our approach to this latest information has to be the same. We have to make this information available to people with diabetes through our Newsletter to be published July1st, our web site and other methods, otherwise we are guilty of withholding information that could affect the health and welfare of our client group.
• We are aware that it may, not unjustifiably, cause alarm as visual impairment and blindness are major fears for people with diabetes. We are equally aware that there may well be a desire on the part of some people to change to natural animal insulins.

We had hoped that the Department of Health would be able to make some response or guidance prior to publication of our Newsletter so that doctors and healthcare professionals would be prepared for any patients wishing to discuss or reconsider their insulin treatment options. However, some two months later the DoH has still made no response at all and therefore IDDT issued notices to consultants, GPs with a special interest in diabetes, diabetes specialist nurses and pharmacists.

IDDT also made known the following points of concern:
It is 18 years since ‘human’ insulin was introduced there is still no evidence of any clinical benefit for patients and considerable evidence of adverse reactions. With the reservation that the decisions to prescribe ‘human’ insulin and to change people from the animal insulin that suited them were not, and still are not evidence based, IDDT has always fully acknowledged that the vast majority of people with diabetes appear to be satisfactorily treated with ‘human’ insulin. However, these public statements now made by two manufacturers of ‘human’ insulin have very serious implications for everyone treated with ‘human’ insulin and for prescribing doctors.

No such statements have had to be issued about either bovine or porcine insulins. It may be that these adverse reactions are as a result of increased hypoglycaemia and reduction in hypoglycaemia awareness, the most frequently reported adverse reactions by people using ‘human’ insulin, but this remains unknown. Our attempts to obtain information from Aventis have received no response. However, it now appears that the risk/benefit ratio for first line treatment may have shifted from ‘human’ insulin in favour of animal insulin and that the present prescribing habits may be putting some people with diabetes at risk of unnecessary and avoidable complications to which they are already susceptible.

Hypoglycaemia is an acute daily problem for those living with diabetes especially when accompanied by loss of warnings and any increased risks of this not only make ‘human’ insulin therapy less safe but reduce the quality of life of those with diabetes and that of their families. Hypoglycaemia may also cause all the adverse reactions quoted in the Aventis statements. Recent statistics show that between 4 and 13% of deaths in people with diabetes are now caused by hypoglycaemia.

The ‘worsening of retinopathy’ is an example of how serious these problems are. The implication of the wording is that for patients who already have retinopathy, ‘human’ insulin therapy could make it worse so leading to earlier visual impairment or blindness. While there are screening programmes for retinopathy, these and other services for people with diabetes, are very variable. Many patients have early retinopathy of which they are unaware because there are no signs or symptoms and many have early retinopathy at diagnosis. As there is no way of knowing which patients have retinopathy in its various forms, all patients may be at risk of worsening of retinopathy if ‘human’ insulin is prescribed. However small this increased risk may be, the risk of visual impairment and blindness is one that most people would consider unacceptable especially when there are alternative insulins that have never been said to carry such risks.

Oedema is an equally serious adverse reaction and now explains the large weight increase that happens to some people when they use ‘human’ insulin with the subsequent weight loss on changing to animal insulin.

IDDT remains committed to ensuring that the adverse reactions that some people experience with ‘human’ insulin are fully recognised and that their health and well being is not put at risk by the discontinuation of the animal insulins they need. We remain committed to the view that there is a need for research so that insulin treatment is based on evidence of benefit rather than assumption of benefit. No large-scale, long-term trials comparing ‘human’ and animal insulins, have ever been carried out and to assume that absence of evidence of adverse reactions is the same as evidence of absence of them is unacceptable to people with diabetes.

Health Select Committee – IDDT gives evidence

December 2004

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

Further information is available on Parliament’s website:
http://www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/cmhealth.htm

IDDT’s written evidence presented to the Health Committee:

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

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

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

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

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

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

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

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

From our experience, we have to raise the following points:

1. The quality of studies carried out by the pharmaceutical companies wishing to market and promote a new drug.
2. The lack of independent studies to inform decision making and the bias that may be introduced, especially publication bias that is likely to occur if the majority of the studies are carried out by industry who are unlikely to publish negative studies
3. The quality and efficiency of the marketing approval process whereby drugs are approved for use on the basis of largely poor quality research.
4. The post marketing surveillance system which does not appear to require evidence from research carried out independently of the pharmaceutical industry.
5. In view of the lack of evidence of benefit of synthetic GM insulins, it is surprising that NICE has never evaluated insulin prescribing, assessed cost effectiveness and issued guidelines on insulin prescribing.

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

The provision of drug information and promotion

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

We cite the following examples:

• Using the press and celebrities to indirectly advertise. For example, the press covered TV chef Anthony Worall Thompson cooking for the staff of Novo Nordisk to launch their new analogue insulin Levermir [ref 4].
• Industry sponsorship of medical charities occurs frequently and while the agreement may be for sponsorship and not endorsement of their products, the perception of the charities’ membership may well be different and the products seen as acceptable and even preferable by the charity associating itself with the company. Examples include an advertisement in Readers Digest May 2002 Diabetes UK supported by Novo Nordisk and the Sexual Dysfunction Association advertising in the March/April edition of consumer magazine, Balance has with Pfizer prominently on an advertisement.
• The direct marketing to patients of insulin injection devices that can only be used with a particular company’s insulin brand indirectly advertises and promotes the use of that particular insulin. [Complaint referred to and upheld by the ABPI complaints body

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

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

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

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

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

6. The provision of drug information can be incomplete
We are concerned that in the UK patients and physicians are not provided with full information about risks and benefits and that this must in part be due to the actions of both industry and the regulatory authority in the UK.

Patients and physicians involved in diabetes care receive restricted information compared to the United States.

For example: Journals in the US make reference to the potential carcinogenic effects of insulin analogues in advertisements to both patients and professionals patients [ref 6] but in the UK published journals have less information and do not include the potential for carcinogenic effects [ref 7 & 8]. The result is that treatment choices of both physicians and patients are not fully informed and there could be long-term health damage. The lack of this information cannot be explained as a matter of commercially sensitive information as all insulin analogues have this potential.

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

References

Ref 1 Cochrane Collaboration Database, 2002. ‘Human’ insulin versus animal insulin in people with diabetes mellitus

Ref 2. Cochrane Database 2004. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.

Ref 3 Professor Edwin Gale. Diabetes Digest; Vol 2 Number 4, 2003

Ref 4 Crawley Observer. 30.6.04 Top chef cooks at town firm

Ref 5 Practical Diabetes International; Sept 2003 Vol 20 No7

Ref 6 Diabetes Health, June 2004

Ref 7 Practical Diabetes, July/August 2004

Ref 8 Diabetic Medicine, July 2004

Jenny Hirst
Co-Chairman
Insulin Dependent Diabetes Trust

The Bellagio Report

1996

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

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

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

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

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

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

1. That this latest information be relayed to those living with insulin dependent diabetes. This will enable those experiencing impaired or reduced warning symptoms of hypoglycemia or reduced feelings of well-being and safety to re-examine their choice oh human or animal insulin. This choice will then be based on both scientific evidence and the reported experiences of patients;
2. That this information be reported to Government Health Departments, WHO, IDF, Diabetes Associations, Physicians and all diabetes health care professionals throughout the world;
3. That when insulin is needed, animal insulin should be considered as first choice treatment for all those where hypoglycaemia may be of special concern. This may include the following:
   • Children
   • The elderly
   • Those reporting severe and/or frequent hypoglycaemia
   • Those with severe cardiovascular disease or long term complications
   • Those who do not have access to frequent blood-glucose monitoring, e.g. in developing countries.
4. That animal insulin:
   • remain available in all countries which presently have that facility
   • is re-introduced into countries in which it is no longer available or in which it is no longer available through the normal prescribing mechanism;
   • for insulin pens becomes available, again to provide equal choice for patients and physicians
5. That in future greater recognition should be given to the value of patient experiences in relation to adverse drug reactions.

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

April 8, 1996

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

Scientific Information for the Bellagio Report, April 1996

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

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

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

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

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

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

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

• Patients who have experienced difficulties with human insulin are mainly those who keep good or tight control 12 (observations).
•  A recent study concludes that the uptake of glucose in the brain during hypoglycaemia, is a major mechanism for inducing hypoglycaemia unawareness, more so with tight than intermediate or poor control 10. Boyle 10 showed that in two patient groups with less well controlled diabetes with elevated blood glucose concentration (HbA1c 8.5 and 10.2%), the glucose uptake in the brain dropped during hypoglycaemia so sparking off the counter-regulatory hormones and producing early warning symptoms of the impending hypoglycaemia10. However, in patients with good or tight control (HbA1c 7.2%) and in patients who had experienced a recent "hypo", the intra-cerebral glucose did not drop during hypoglycaemia and the brain did not react to peripheral ongoing hypoglycaemia. This inappropriate response suggests that counter-regulatory hormones, like adrenalin, were lacking. The study was performed with human insulin.
• Another part of the explanation comes from the molecular differences between human and animal insulin. These show that animal insulin is more lipophilic than human insulin which is more hydrophilic 13,14, resulting in a faster cerebral accumulation of porcine insulin 15. One can therefore make the logical assumption that the intra-cerebral concentration is higher, thus reducing brain glucose during hypoglycaemia at an equivalent peripheral blood glucose level. A consequence of this will be a reduction or loss of awareness of hypoglycaemia with human insulin in some patients.
• Evidence to support this view comes from research, some of which has not been referenced frequently in the large reviews done on this subject. This research shows differences in neurophysiological 15,16 and higher sensory function between human and animal insulin 17. Auditory and visual responses, as well as auditory brain stem, responses were significantly weaker during the first 20 minutes of hypoglycaemia induced by human insulin, than with animal insulin 17. Kern et al. concluded that "… human and pork insulin induced hypoglycaemia differ in their actions". The differences in awareness of human and porcine insulin induced hypoglycaemia are very likely a consequence of differential processing signals within the nervous system.
• The above area of research demonstrates a mechanism which explains the differences in awareness of hypoglycaemia between human and animal insulin found in clinical studies 1,18,19,20,21,22,23,24. 
• Many other studies showing a reduction in counter-regulatory hormone response in hypoglycaemia comparing human and animal insulin give further support to this explanation 25,26,27,28. Of particular importance are those studies demonstrating a greater adrenergic response with animal insulin in hypoglycaemia 29,30. This in effect is showing change from clearly recognised adrenergic to neuroglycopenic symptoms with primary or secondary human insulin treatment, which explains the experiences of patients.
• Heller and Cryer 31 found that one single episode of hypoglycaemia could trigger the loss of warning mechanism of hypoglycaemia and Mitrakou et al. 32 showed that hypoglycaemia itself can induce unawareness of hypoglycaemia and a decrease in the counter-regulatory hormones.

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

• More erratic blood glucose levels experienced by some patients when using human insulin can be explained by the faster absorption and shorter duration 34. An explanation of the other reported adverse cognitive brain effects of human insulin by family members and colleagues (depression, anxiety, other psychological events, aggressive tendencies, personality changes) is now necessary.
• Pharmacological studies clearly demonstrate that human insulin is absorbed faster than animal insulin, thus increasing the serum insulin concentration (up to significant differences) during the first hours after subcutaneous injections 35.

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

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

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

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

1. Most commonly not recognising the effect study conditions have on changing the diabetic patients’ level of care they take with their control – this is often subconscious. This practical effect may be difficult for researchers to understand and it is probably only truly understood by those living with the condition.
2. Patients entered into a trial are often not representative of the population with the disorder 36. Numbers of registered participants in research studies, the reasons for non participation and the real drop-out rates are either not published or under-reported 37,38.
3. Unawareness studies involving self reporting of hypoglycaemia symptoms without recording of self measured blood glucose levels can only be of limited value as the patients may already have some degree of unawareness. Studies which include family members’ observations have more value but symptomless hypoglycaemic episodes can still be missed e.g. nocturnal hypoglycaemia which goes unnoticed 37,39,40. 
4. Studies which are obviously atypical of everyday life:
   • Where the follow up visits to the diabetic clinic are every 2 to 4 weeks 37,38,40. In normal life visits are commonly every 26 to 52 weeks. Recording study events by questionnaire can increase the usual consultation time compared to routine visits.
   • Where the number of home blood glucose tests are increased by up to 50% per week 40.
   • Where the insulin species is randomly changed every 4, 6 or 12 weeks 38,41,42. In addition to this, IDDT’s analysis of case reports show that the adverse reactions to human insulin took on average 1.1 years to be recognised after starting to use human insulin 12,43.
   • Where acute hypoglycaemia is induced by intravenous infusion, with the patient being maintained in a prone position anticipating hypoglycaemia and with an intravenous canula maintained in their arm, the symptoms of hypoglycaemia are then recorded under these conditions. Hypoglycaemia in everyday life is where the patient is preoccupied with work or pleasure and the "hypo" is neither gradual nor predictable 41,42.
   • Perhaps the most significant error is the failure to realise that hypoglycaemia itself has been shown to produce loss of warnings for several days or longer, therefore hypoglycaemia occurring before the study (of which the patient may be unaware) or indeed slow hypoglycaemia induced by the study itself, may cause loss of warnings, regardless of insulin species 33.
   • It is not wholly surprising that these studies show no difference between human and animal insulin. Common sense suggests that if patients complain of loss of awareness in everyday conditions 43 then a study must test for this under these conditions.

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

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

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

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

Suggestions (in addition to those already written in the Bellagio Report).

1. Animal insulin should be used as the first line treatment in most newly diagnosed diabetic patients including the elderly. Exceptions may be made in those requiring pens i.e. poorly sighted, and some children, or those with previous insulin resistance.
2. If patients on human insulin have unexplainable symptoms such as depression, aggressive behaviour, psychological changes, lethargy, muscle cramps, it may well be worth trying a change to animal insulin for at least 6 months.
3. Human and animal insulin must remain available in all countries. Patients who are well- controlled on human insulin and do not suffer from unaccountable problems should not routinely be changed to animal insulin.
4. Drug companies should produce animal insulin in pen injectors to give both doctors and patients an equal choice of insulin 46.
5. Drug companies should again start producing a long acting animal insulin (e.g. Ultralente) which has a much longer tradition for smoother control compared to similar human products (e.g Ultratard HM) and would enable non-insulin-dependent diabetic patients to have one injection a day. A plea for animal Ultralente has been brought forward also in the United States48.
6. All governments should assist all drug companies to ease re-licensing of animal insulin, especially the ultra-long acting insulins.
7. In countries where animal insulin has been completely removed, government health departments should assist with the reintroduction of animal insulin as soon as possible.

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

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