Insulin preparation

Various insulin preparations are available for insulin therapy for the treatment of diabetes in humans . This article describes what the insulin supplements are like, how they are made, and how they work.

For information on the hormone insulin, see insulin . The history of diabetology gives an overview of the milestones in the development of insulin preparations .

Injection solutions

The most important type of insulin preparation are the injection solutions. The types of insulin described in the following sections are described as injection solutions, but there are intermediate stages in the manufacture of most preparations in which the insulin is in crystalline form. These intermediate stages are relevant in the development of preparations for inhalation, which are described below. The following illustration of the types of insulin also shows a chronological sequence.

Animal insulins

The first insulin preparations were made from the pancreas of animals. It was also the only source of insulin production for several decades.

Canine insulin

The first research was carried out on dogs, and the insulin used for this was initially made from the pancreas of domestic dogs . The chemical structure of dog insulin is identical to that of the pig , rabbit and sperm whale . Dog insulin is of no importance for human therapy.

Bovine insulin

The first insulin preparations used to treat humans were made from the pancreas of domestic cattle . The protein structure of beef insulin differs from human insulin in three places: At position B30, as in pigs, the amino acid alanine is found instead of threonine . In the A chain there is alanine instead of threonine on A8, valine instead of isoleucine on A10 .

Bovines Insulin
          ┌─────────┐
G-I-V-E-Q-C-C-A-S-V-C-S-L-Y-Q-L-E-N-Y-C-N
            │                       ┌─┘
F-V-N-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-P-K-A

Porcine insulin

Pig pancreases were the second source of insulin extraction. Pig insulin differs from human insulin in only one amino acid: at position B30 there is alanine instead of threonine.

Porcines Insulin
          ┌─────────┐
G-I-V-E-Q-C-C-T-S-I-C-S-L-Y-Q-L-E-N-Y-C-N
            │                       ┌─┘
F-V-N-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-P-K-A

Biotechnologically produced insulins

Obtaining insulin from animal organs has several disadvantages. Therefore, ways were sought to produce insulin biotechnologically .

Human insulin

1976 succeeded the Frankfurt scientists Rainer upper Meier and Rolf Geiger at Hoechst first time to convert porcine insulin in an insulin that is chemically similar to the insulin produced in the human pancreas.

Since porcine insulin only differs from human insulin in one amino acid, the researchers exchanged alanine for threonine using biochemical methods. The name is a bit confusing in that it is not insulin from human pancreases, but a molecule that is chemically identical to that of humans. In 1983, this semi-synthetic human insulin was first brought onto the market by the Hoechst company .

Cloning of an industrially used GMO .

1979 succeeded Frankfurt scientists, using recombinant DNA , the gene to isolate insulin from human cells in plasmids to clone and means of gene transfer in micro-organisms such as bacteria ( Escherichia coli ) or yeast ( Saccharomyces cerevisiae ) to spend, so that in 1982 there was the possibility to produce human insulin in large quantities using these genetically modified organisms without using animal raw materials from pigs or cattle .

In 1984, considering the opportunities and risks of genetic engineering , the Hessian Ministry of the Environment refused to approve an operating permit for a test facility for the production of human insulin using bacteria. It was not until 1999 that the Aventis company, which emerged from the Hoechst company, brought this new human insulin onto the market in the USA.

Human insulin differs from pig insulin or from bovine insulin in one or three amino acids.

The protein structure of human insulin:

Humaninsulin
          ┌─────────┐
G-I-V-E-Q-C-C-T-S-I-C-S-L-Y-Q-L-E-N-Y-C-N
            │                       ┌─┘
F-V-N-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-P-K-T

Pump insulin

Velosulin ^® was a human insulin developed by Novo Nordisk specifically for use in insulin pumps . Contrary to the recommendation that all other insulin preparations should be stored at refrigerator temperature, the insulin carried in the pump must retain its effectiveness for several days at ambient temperature. It was genetically engineered from recombinant DNA in Saccharomyces cerevisiae . Auxiliary materials: zinc chloride , glycerol , m-cresol , disodium hydrogen phosphate dihydrate (as a buffer substance), sodium hydroxide and / or hydrochloric acid (to adjust the pH value), water for injection purposes.

At the beginning of May 2007, Novo Nordisk withdrew Velosulin from the market. As an alternative, switching to fast-acting insulin analogues was recommended, as these are better suited for optimal blood sugar control and have proven to be sufficiently stable for use in insulin pumps.

Insulin analogs

Normal or old insulin has a decisive disadvantage compared to insulin from the pancreas: the insulin molecules are arranged in groups of six ( hexamers ). After a few minutes these break down into groups of two ( dimers ). Only when these have finally broken down into individual molecules does the insulin take effect. The insulin in the pancreas is also stored there in hexamers, but individual molecules are released into the blood when necessary and take effect in the liver within seconds.

Therefore, an attempt was made to find insulins that take effect more quickly in order to get closer to the action curve of natural insulin. The short-acting insulin analogs flood in more quickly and have a shorter duration of action than normal insulin. One advantage is the elimination of the need for snacks between meals , which are often necessary when using regular insulin in order to compensate for the risk of hypoglycaemia caused by the "insulin overhang" several hours after a main meal.

A second area of ​​research is the development of analog insulins that work longer than NPH insulin. In both directions, attempts are made to achieve the goal by modifying the molecular structure.

Insulin lispro

Insulin lispro (sometimes also Lyspro, trade names Humalog ^® and Liprolog ^® ) was the first insulin to achieve this goal. It was brought onto the market by Lilly in 1996 under the trade name Humalog ^® and since the end of 2005 it has also been marketed by Berlin-Chemie under the trade name Liprolog ^® .

In insulin lispro, the amino acids at B28 and B29 are swapped. The new order leads to the name.

Insulin lispro
          ┌─────────┐
G-I-V-E-Q-C-C-T-S-I-C-S-L-Y-Q-L-E-N-Y-C-N
            │                       ┌─┘
F-V-N-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-K-P-T

The production is done by genetic engineering from recombinant DNA . As additives, m-cresol , glycerol , sodium monohydrogen phosphate , zinc oxide , water for injections , sodium hydroxide or hydrochloric acid are used to adjust the pH value . The preparation is approved for pump therapy.

Insulin lispro is transported faster through the subcutaneous fatty tissue and also breaks down into individual molecules more quickly. This results in a faster onset of action and a shorter duration of action. The drug can be prescribed.

Insulin aspart

Since 1999, Novo Nordisk sells its rapid-acting insulin analog under the name NovoRapid ^® (in some countries also NovoLog ^® ). At position B28, proline has been replaced by aspartic acid.

Insulin aspart
          ┌─────────┐
G-I-V-E-Q-C-C-T-S-I-C-S-L-Y-Q-L-E-N-Y-C-N
            │                       ┌─┘
F-V-N-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-D-K-T

It is produced by genetic engineering from recombinant DNA in Saccharomyces cerevisiae . Additives are glycerol , phenol , m-cresol , zinc chloride , sodium monohydrogen phosphate , sodium chloride , hydrochloric acid and water for injections.

The insulin aspart has almost the same effect as the insulin lispro and has a faster absorption and a faster breakdown into single molecules than human insulin.

NovoRapid is approved as a pump insulin. In autumn 2006 it was approved by the European Commission for insulin therapy in pregnant women.

Insulin glulisin

Insulin glulisin (trade name Apidra ^® ) is a fast-acting analog insulin from Sanofi-Aventis. It was approved by the EU Commission in September 2004.

"The replacement of the amino acid asparagine in position B3 in human insulin with lysine and that of lysine in position B29 with glutamic acid leads to faster absorption of insulin glulisine."

"Apidra ^® is the first insulin that, due to its structure (salt bridge between glutamate B29 and glycine A1), can do without zinc as a stabilizer. This should be the background for a rapid and consistent effect and means that it is independent of the BMI in patients , so it can work quickly in both slim and overweight or obese diabetics. "

Insulin glulisin
          ┌─────────┐
G-I-V-E-Q-C-C-T-S-I-C-S-L-Y-Q-L-E-N-Y-C-N
            │                       ┌─┘
F-V-K-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-P-E-T

It is produced by genetic engineering from recombinant DNA in Escherichia coli . Additives are m-cresol , sodium chloride , trometamol , polysorbate 20 , hydrochloric acid 36%, sodium hydroxide and water for injections .

Approval: Suitable as pump insulin. It may only be mixed with human NPH insulin. “There is insufficient experience with the use of Apidra in pregnant women.” (Package insert as of September 2004) “Caution is advised when used during pregnancy” (European approval 2006). Since June 2007 Apidra can be freely prescribed in Austria and together with Humalog and Novorapid it is in the “green box” of the reimbursement code. In comparison to normal human insulin, insulin glulisin has a faster onset of action and a shorter duration of action.

Insulin glargine

Insulin glargine , tradename Lantus ^® , is the first insulin analog with a long duration of action. It is manufactured by Sanofi-Aventis and was approved by the European Commission in June 2000 .

Delay mechanism

Insulin glargine is a human insulin analogue with a low solubility in the neutral pH range. It is completely soluble in the acidic pH range of the injection solution (pH 4). After injection into the subcutaneous tissue, the acidic solution is neutralized, which leads to the formation of microprecipitates from which consistently small amounts of insulin glargine are released. In humans, insulin glargine is partially broken down in the subcutaneous tissue on the carboxy group of the B chain. This creates the active metabolites 21A-Gly-insulin and 21A-Gly-des-30B-Thr-insulin.

At position A21, asparagine has been replaced by glycine and the B chain is extended by two arginines.

Insulin glargin
          ┌─────────┐
G-I-V-E-Q-C-C-T-S-I-C-S-L-Y-Q-L-E-N-Y-C-G
            │                       ┌─┘
F-V-N-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-P-K-T-R-R

It is produced by genetic engineering from recombinant DNA in Escherichia coli (K12 safety strain). Additives are zinc chloride , m-cresol , glycerol , hydrochloric acid, sodium hydroxide, polysorbate 20 and water for injections.

Approval: "In adolescents and children from 6 years of age, the tolerance and effectiveness of Lantus have been proven." "For insulin glargine, no clinical data on exposed pregnancies from controlled clinical studies are available. The clinical data are insufficient to rule out a risk. The use of Lantus during pregnancy can be considered if necessary."

Insulin glargine is a clear, colorless solution. In contrast to the delayed insulins available up to now, it does not need to be mechanically prepared before the injection. “Lantus must not be mixed with any other product. It must be ensured that the injection syringes do not contain any traces of any other material. "

Reimbursement rule for insulin glargine in Austria since July 1, 2007: For patients with diabetes mellitus, if treatment with insulins from the green range alone or in combination with other antidiabetic agents is not possible due to symptomatic, recurring nocturnal hypoglycaemia.

Insulin detemir

Insulin detemir (trade name Levemir ^® ) is the second long-acting analogue. It is manufactured by Novo Nordisk and was approved by the European Commission in June 2004. The C-terminal threonine (B30) was removed and a myristic acid molecule was condensed on the ε- amino function of the lysine on B29 . The pH of the preparation is 7.4. “The prolonged effect of insulin detemir is mediated by the strong self-association of insulin detemir molecules at the injection site and the albumin binding via the fatty acid side chain. Insulin detemir is released more slowly into the peripheral target tissue compared to NPH insulin. The combination of these delay mechanisms results in a more reproducible absorption and a more reproducible action profile of insulin detemir compared to NPH insulin. ”“ The time-action profile of insulin detemir is statistically significantly less variable and therefore more predictable than that of NPH insulin. ”

Detemir
          ┌─────────┐
G-I-V-E-Q-C-C-T-S-I-C-S-L-Y-Q-L-E-N-Y-C-N
            │                       ┌─┘
F-V-N-Q-H-L-C-G-S-H-L-V-E-A-L-Y-L-V-C-G-E-R-G-F-F-Y-T-P-K
                                                        │
                                                       HN-CO-C13H27

It is produced by genetic engineering from recombinant DNA in Saccharomyces cerevisiae . Additives are mannitol , phenol , m-cresol , zinc acetate , disodium hydrogen phosphate , sodium chloride , hydrochloric acid 2N (pH adjustment), sodium hydroxide 2N (pH adjustment), water for injections .

Approval: "In children and adolescents, the efficacy and safety of Levemir has been shown in studies of up to 6 months in the age range 6-17 years." In December 2011 the admission was extended to children between the ages of 2 and 5 years.

"Treatment with Levemir can be considered during pregnancy [...]. Post-market data [...] do not indicate side effects of insulin detemir on pregnancy and do not indicate a risk of malformations or fetal / neonatal toxicity of insulin detemir."

“Levemir can be used in combination with… oral antidiabetic drugs… or as an add-on to liraglutide …. Levemir can also be used together with… fast-acting insulin products. ”“ When Levemir is mixed with other insulin products, the action profile of one or both of the components involved changes. Mixing Levemir with a fast-acting insulin analog such as insulin aspart results in an action profile with a lower and delayed maximum effect compared to single injections. Therefore, mixing fast-acting insulin with Levemir should be avoided. "

Extension of the duration of action of regular insulin

The duration of action of normal insulin is not sufficient for a longer-lasting supply of insulin. In order to get by with fewer injections in insulin therapy, ways of delaying the effect of the insulin were sought early on.

These insulin supplements are named differently:

• Delay insulin according to its delayed effect
• Depot insulin because they stay longer at the injection site
• Basic insulin because of its use for basal insulin supply

Zinc insulins

The binding of insulin molecules by zinc was the first method of making delay insulins; In 1934 the first zinc insulin became available. In 1945 Hallas-Møller developed the Lente insulins: the shorter-acting Semilente, the very long-acting Ultralente and a mixture of 30% Semilente and 70% Ultralente, called Lente.

There are two types of zinc insulins:

crystalline zinc insulin such as Ultratard HM from Novo Nordisk

Effect: very slow and long: onset of action approx. 180 min, duration of action up to 28 hours

amorphous zinc insulin such as Monotard HM, Novo Semilente MC, both from Novo Nordisk

Effect: slow and long: onset of action approx. 30–150 min, peak at approx. 6–8 hours, duration of action up to 24 hours, with Semilente duration of action up to 12 hours

Zinc insulins must be prepared very carefully (swirl and roll for 5 minutes, do not shake) and can only be injected with syringes, but not with pens. Due to these handling problems and the often irregular action, zinc insulins have become less and less important. At the beginning of 2006 the market share in Germany was only 0.05%, in the course of 2006 the last available zinc insulins from Novo Nordisk were also withdrawn from the market. As of the end of 2006, Ultratard and Monotard are no longer included in the Austrian reimbursement code .

NPH insulin or isophane insulin

In the case of NPH insulins , the delay effect is achieved by binding the insulin molecules to the basic protein body protamine (neutral protamine hawthorn = NPH).

Effect: medium-long: onset of action 45–60 minutes, peak at 4–6 hours, duration of action 8–12 hours, in higher doses up to 20 hours

NPH insulins must also be well prepared before the injection: The milky-cloudy sediment must be neatly slurried by carefully tilting and swiveling (at least 20 times, not shaking). NPH insulins can be mixed with old insulin. There are also prepared mixtures.

Surfing insulin

With these insulins surfing was used as a delay substance. They are no longer in use. An example of a preparation still available in 2002: Depot Insulin S Hoechst, a pig insulin.

Globin

This insulin was developed in the USA. In addition to zinc, the protein of hemoglobin, globin, was used as a delay substance. The duration of action was up to 24 hours. Globin insulin is no longer available.

Protamine Zinc Insulin (PZI)

This is a very slow and very long acting insulin. It was developed by Scott and Fisher in Toronto in the late 1920s. Effect: onset of action 240 min, duration of action 36–72 hours. PZI was widely used until the 1960s, but lost its importance. There is currently (2012) only one preparation left: Hypurin Bovine Protamine Zinc (FA Wockhardt / GB).

Mixed insulins

For conventional insulin therapy , ready-made mixtures of short-acting and long-acting insulins are used.

Use of injection solutions

Labelling

There is a recommendation by the International Diabetes Federation (IDF) to easily differentiate between insulins. The insulin packaging and ampoules are marked with colors.

effect

The following table provides an overview of the pharmacokinetics of some insulin supplements.

Insulin type	preparation	Onset of action (min)	Active peak (min)	Duration of action (min)	swell
fast acting insulin analog	Lispro = Humalog	15th	60	120-300	Karow / Roth-Lang: General and Special Pharmacology and Toxicology
fast acting insulin analog	Aspart = NovoRapid	10	40-50	180-300	Product information from the European Medicines Agency on NovoRapid
fast acting insulin analog	Glulisin = Apidra	10-20	60	105-300	Product information from the European Medicines Agency on Apidra; EPAR and specialist information

serves as a line break, please do not remove it

Storage and transport of injection solutions

Insulin in use

Opened insulin vials or pen ampoules should be stored at room temperature. They can then be used for up to 4 weeks.

Insulin supply

The supply of insulin that is not used immediately should be stored in the refrigerator at 2 to 8 degrees.

The shelf life with this storage is given until the date stated on the packaging.

Insulin becomes unusable when it freezes.

Insulin that has thawed again has also lost its effectiveness. It doesn't have to be clearly visible.

The insulin in the pen is also at risk, e.g. B. if it is not worn close enough to the body in winter.

When traveling by air, insulin should definitely be carried in hand luggage, as the temperatures in the hold can be very low.

The refrigerator used should be easily adjustable, the vegetable compartment is ideal.

Also temporarily turning down the refrigerator, e.g. B. for cooling larger quantities of drinks for parties, has already made the insulin unusable.

Insulin becomes ineffective with heat

If the food is exposed to extreme heat, spoilage can be seen through cloudiness. However, one must not rely on the fact that one always recognizes bad insulin.

Even the insulin that has been opened can become ineffective before the normal 4-week period has expired if it is exposed to temperatures above normal room temperature for a longer period of time.

Insulin will quickly become ineffective in a hot car.

For use in insulin pumps, where the insulin is close to body temperature, a shelf life of 3 days is usually specified.

The insulin in the pen must also be protected from extreme heat.

There are various cool bags for transport when traveling.

administration

dosage

Insulin preparations are available in various concentrated solutions. The International Unit (IU) is used for insulin to enable a comparison or a change between the various preparations . The blood sugar lowering effect of one unit of an insulin preparation should be the same as that of an IU of another preparation.

Subcutaneous, intravenous

Insulin should be subcutaneous and can be injected intravenously (iv). In the case of subcutaneous administration, it is essential to ensure that the correction factors are consistent with insulin (see insulin therapy ). In principle, it can also be injected intramuscularly , but this is considered a malpractice, as it can lead to muscle damage. The three types of administration have different onset of action. The standard statements about the effect of (old) insulin are always based on subcutaneous administration. Intramuscular administration usually accelerates the effect by 30% -50%. If injected into scarred muscle areas that have not yet regenerated, the effect may not be effective.

Intravenous insulin should only be injected with extreme caution (or through an infuser or pump that delivers very small amounts), because the effect occurs immediately. The blood sugar level begins to drop rapidly. However, a rapid drop, like a blood sugar that is too high, leads to cell damage. Therefore, intravenous insulin is only administered in an emergency and only in small doses.

In order to avoid deposits on the arteries (late damage) in the event of high levels of hyperglycaemia, intravenous insulin delivery can be used to accelerate the insulin effect significantly instead of subcutaneous insulin injection. Another advantage of intravenous insulin delivery is that the full effect is already completed after 50 minutes. Since no insulin action is absorbed in the adipose tissue, small doses (max. 5-7 i.e.) Are sufficient for intravenous administration.

The risk of hypoglycaemia as a result of the rapid action of insulin must be prevented by providing liquid or gel-form dextrose in advance. However, due to the low doses administered, the hypoglycaemia can be regulated with few carbohydrates. People who are not very sensitive to their own hypoglycaemia should only perform intravenous insulin under medical supervision and never without a trained backup person.

Intravenous insulin can be carried out with conventional insulin syringes. After the insulin has been dispensed, the patient briefly feels a “lazy” taste on the tip of the tongue, which is due to the preservative in the insulin.

Inhalation preparations

According to the manufacturers, the administration of insulin by inhalation represents a major step forward : up to now the difficulties have mainly been the poorly controllable and therefore varying absorption of insulin in the lung tissue. One of the prerequisites for constant uptake is a defined granule size of the active ingredient. One of the technical difficulties lies in the fact that conventional inhalers (devices which release a defined amount of a drug into the respiratory tract under pressure ) are unsuitable for such an application of insulin.

The main advantages of inhalative use are said to be better patient acceptance. In type 1 diabetes patients, long-term insulin is still required, i. H. Injecting insulin is not completely unnecessary. Another theoretical advantage would be the reduced rate of late complications of diabetes, if it were better controlled by switching to insulin earlier.

A disadvantage of inhalation use, however, is that a 10-fold higher amount of insulin has to be supplied in order to achieve a comparable effect. Further disadvantages of the inhalation of insulin are the as yet insufficiently researched effects on the lungs and airways. Since insulin is also a growth hormone, there is a risk of lung cancer. Critical voices fear deposits on the lungs, which could eventually lead to pulmonary embolism after several years of use. Further disadvantages are the poorer dosage and the unwieldy and expensive inhaler.

Exubera

Exubera ^® was an inhaled human insulin from Pfizer; it was approved by the EU Commission in January 2006. A few days later, the American approval by the FDA followed. On October 18, 2007, Pfizer announced that it would take Exubera off the market. According to Pfizer, too few patients were using Exubera, making the preparation uneconomical.

It is produced by genetic engineering from recombinant DNA in Escherichia coli . Additives are mannitol , glycine , sodium citrate , sodium hydroxide .

Application: The white powder is offered in blister packs of 1 mg and 3 mg and may only be used with the associated inhaler.

A 1 mg blister pack of inhaled insulin corresponds to 3 IU of subcutaneously injected, fast-acting human insulin. A 3 mg blister pack of inhaled insulin corresponds to 8 IU of subcutaneously injected, fast-acting human insulin.

Approval: “There is no clinical experience with Exubera in pregnant women. Inhaled insulin often leads to the formation of insulin antibodies, the risk of which for the unborn child is unknown. Therefore Exubera must not be used during pregnancy. "

AIR by Lilly

Lilly, too, was developing a powdered insulin preparation called AIR together with Alkermes . On March 7, 2008 it was announced that the development, which had already reached phase III studies, will be discontinued. It was emphasized that there were no medical reasons, but primarily commercial considerations.

AER from Novo Nordisk

Novo Nordisk was testing the liquid inhalable insulin AERx ^® ; development was discontinued in early 2008.

Other inhalative insulins

Another development are the Technospheres from Mannkind under the name AFREZZA ^® .

Oral insulin preparations

Insulin as a pure substance is ineffective when given orally . The first problem is the low pH in the stomach, which denatures the protein molecules. Then they are broken down by digestive enzymes so that only very few insulin molecules in the blood can have their effect.

A “carrier system” is therefore necessary for the successful development of an oral insulin preparation: It must protect the insulin molecules from digestion and at the same time allow the insulin to pass through the intestinal wall into the bloodstream .

In Taiwan, in 2006, a liquid test preparation in which bovine insulin was enclosed in nanoparticles of chitosan and γ-PGA measuring just under 200 nm was successfully used on rats.

Insulin controversy

compatibility

There are various controversies about the tolerability of insulin preparations. These relate in particular to the compatibility of animal products, allergies to the ingredients of the products and the risk of diabetic retinopathies and cancer development .

The question of whether the use of insulin glargine can promote the growth of cancer cells is controversial. A very extensive study carried out in Germany in 2009 came to the conclusion that the use of insulin glargine probably increased the risk of cancer compared to patients treated with human insulin. The authors admitted, however, that this question could not be conclusively assessed on the basis of the documents available to them; further long-term studies are required. A study published at the same time that was carried out in Scotland found no increased risk of cancer in insulin glargine-treated diabetics due to the use of insulin glargine.

economics

In the German health care system there is a discussion as to whether the significantly higher costs of analog insulins are offset by greater benefits. In this context, the Federal Joint Committee (G-BA) commissioned the Institute for Quality and Efficiency in Health Care with the review. Among other things, this could not show any clear advantages in the use of short-acting analogs in type I diabetes and type II diabetes, in inhaled insulin preparations, or in the use of long-acting preparations in type II diabetes. These reports aroused criticism and protests from the pharmaceutical industry, patient organizations and professional societies. In June 2010, the Federal Ministry of Health (BMG) backed the value-added contracts that the Lantus manufacturer Sanofi-Aventis has concluded with several health insurers in a dispute about the exclusion of long-acting insulin analogues from reimbursement. This also rejected the view of the Federal Joint Committee, according to which a health fund may not apply any other criteria for assessing economic efficiency than the G-BA. Also, Novo Nordisk has for its product Levemir closed appropriate contracts with health insurance companies. With effect from July 15, 2010 (published in the Federal Gazette on July 14, 2010), insulin glargine (Lantus ^® , Sanofi-Aventis) and Detemir (Levemir ^® , Novo Nordisk) may only be prescribed for type II diabetes at the expense of the health insurers if there are no additional costs compared to human insulin.

effectiveness

The opinion on the use of short-acting insulin analogs in the treatment of type 1 diabetics, which was negative for the analogs, was contested by the BMG. The benefit of short-acting insulin analogues in children and adolescents is currently being examined in a follow-up order.

literature

• Helmut Schatz (Ed.): Diabetology compact. 4th edition, 2006, ISBN 3-13-137724-0 .
• Gerhard-W. Schmeisl (ed.): Training book for diabetics. 4th edition, 2002, ISBN 3-437-47270-4 .
• Charles Wassermann: Insulin. The struggle for a discovery. Ullstein, 1991. ISBN 3-548-34769-X .
• Eva Fritzsche & Sabine Hancl (eds.): Animal insulin - a proven drug in modern diabetes therapy. Trafo-Verlag, 2006, ISBN 3-89626-616-0 .
• Arthur Teuscher: Insulin - A Voice for Choice. Karger Verlag, Bern 2007, ISBN 978-3-8055-8353-4 .

Web links

• Type 1 diabetes - information at Gesundheitsinformation.de (online offer from the Institute for Quality and Efficiency in Healthcare )
• Type 2 diabetes - information at Gesundheitsinformation.de (online offer of the Institute for Quality and Efficiency in Healthcare )

Individual evidence

1. ↑ Oliver Reiser: Chemistry in Everyday Life, Milestones in Chemistry - Medicines , accessed on April 8, 2011.
2. ↑ Product information (PDF) from the European Medicines Agency on Velosulin.
3. ↑ Novo Nordisk's announcement page about the discontinuation of Velosulin ( Memento from August 15, 2007 in the Internet Archive ).
4. ↑ Product information from the European Medicines Agency on Humalog ( Memento from January 24, 2010 in the Internet Archive ).
5. ↑ ^{a b} Product information from the European Medicines Agency on NovoRapid ( Memento from January 14, 2010 in the Internet Archive ).
6. ↑ pluses for insulin analog in pregnant women with diabetes. In: Diabetes Austria - Emergency Aid Initiative for People with Diabetes. October 31, 2006, archived from the original on October 31, 2006 ; accessed on November 23, 2015 . 
7. ↑ ^{a b c} Product information from the European Medicines Agency on Apidra .
8. ^ Information page from Sanofi-Aventis .
9. ^ Product information from the European Medicines Agency on Lantus ( Memento from February 14, 2010 in the Internet Archive ).
10. ↑ Product information from the European Medicines Agency on Levemir ( Memento from March 15, 2010 in the Internet Archive ).
11. ↑ Extension of approval for insulin analog . Pharmaceutical newspaper online; Retrieved December 5, 2012.
12. ↑ APPENDIX I: Summary of Product Characteristics Levemir 100 units / ml solution for injection in a cartridge. (PDF; 2.6 MB) EMA, p. 6 , accessed on February 14, 2012 . 
13. ↑ APPENDIX I: Summary of Product Characteristics Levemir 100 units / ml solution for injection in a cartridge. (PDF; 2.6 MB) In: Package insert. EMA, accessed February 14, 2012 . 
14. ↑ 24th amendment to the refund Codex, see avsv.at .
15. ↑ medicines.org.uk EMC Datapharm, accessed March 20, 2012.
16. ^ F. Bonnici: Making insulin usage safer - the universal color code. In: South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. Volume 94, Number 5, May 2004, pp. 343-344, PMID 15211949 .
17. ↑ European Medicines Agenxy: Exubera. European Public Assessment Report ( Memento from May 31, 2010 in the Internet Archive )
18. ↑ exubera.com .
19. ↑ Lilly Announces Termination of AIR Insulin Program ( Memento of March 4, 2016 in the Internet Archive ) (accessed March 22, 2008).
20. ↑ NovoNordisk press release ( Memento of June 28, 2008 in the Internet Archive ), January 14, 2008.
21. ↑ Helmut Schatz (Ed.): Diabetology compact. 4th edition 2006, ISBN 3-13-137724-0 .
22. ↑ Lin, YH et al. (2007): Preparation and Characterization of Nanoparticles Shelled with Chitosan for Oral Insulin Delivery. In: Biomacromolecules. 8 (1): 146-152. PMID 17206800 doi: 10.1021 / bm0607776 .
23. ↑ Harro Albrecht: Insulin shock. The analog insulin Lantus, injected millions of times, is suspected of stimulating the growth of cancer cells . In: Die Zeit , No. 28/2009
24. ↑ LG Hemkens, U. Grouven, R. Bender, C. Günster, S. Gutschmidt, GW Selke and PT Sawicki: Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study . In: Diabetologia . 2009, p. 1732-1744 , doi : 10.1007 / s00125-009-1418-4 .
25. ↑ HM Colhoun and SDRN Epidemiology Group: Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group . In: Diabetologia . 2009, p. 1755-1765 , doi : 10.1007 / s00125-009-1453-1 .
26. ^ Institute for Quality and Efficiency in Health Care (IQWiG): Short-acting insulin analogues for the treatment of type 1 diabetes mellitus . (PDF) Final report A05-02, Version 1.0, Cologne, March 2007.
27. ^ Institute for Quality and Efficiency in Health Care (IQWiG): Short-acting insulin analogues for the treatment of type 2 diabetes mellitus . (PDF) Final report A05-04, Version 1.0, Cologne, December 2005.
28. ↑ Institute for Quality and Efficiency in Health Care (IQWiG): Inhalative insulin (Exubera) . (PDF) Rapid Report A05-22, Version 1.0, Cologne, April 2006.
29. ^ Institute for Quality and Efficiency in Health Care (IQWiG): Long-acting insulin analogues for the treatment of type 2 diabetes mellitus (PDF) Final report A05-03, Version 1.1, Cologne, February 2009.
30. ↑ V. Zylka-Menhorn, p Rabbata: insulin analogues: a precedent for the industry . Dtsch Arztebl 2006; 103 (30): A-2005 / B-1723 / C-1667.
31. ↑ Désirée Kietzmann: Long-acting insulin analogues: BMG defends value-added contracts . ( Memento from July 5, 2010 in the Internet Archive ) Report in apotheke-adhoc.de from July 1, 2010.
32. ↑ Udo Barske: AOK concludes contracts for long-acting insulin analogues.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. ddp direct, July 12, 2010.  
33. ↑ Insulin analogues: TK also bypasses G-BA decision. ( Memento from July 15, 2010 in the Internet Archive ) apotheke-adhoc.de, July 13, 2010.
34. ↑ Novo Nordisk's long-acting insulin analog still eligible for prescription. ( Memento of August 22, 2011 in the Internet Archive ) (PDF; 188 kB) Press release from Novo Nordisk of July 5, 2010
35. ↑ G-BA: Insulin analogues finally out ( Memento from August 4, 2010 in the Internet Archive ).
36. ↑ IQWiG: A05-02 - Short-acting insulin analogues for the treatment of type 1 diabetes mellitus
37. ↑ The Cologne pill inspectors, Frankfurter Allgemeine Sonntagszeitung , September 3, 2006 (Issue 35/2006, p 31).
38. ↑ IQWiG: A08-01 - Short-acting insulin analogues in children and adolescents with type 1 diabetes mellitus ( Memento from July 27, 2009 in the Internet Archive ).

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !