Glitazone

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Glitazones , also known as insulin sensitizers and (based on the chemical structure, a thiazole-2,4-dione) thiazolidinediones , are a group of active ingredients that are used in the therapy of type 2 diabetes mellitus . They belong to the group of orally effective antidiabetic agents . The name of the group already indicates the mode of action, a sensitization of the tissue to insulin . The body's own insulin is then able to lower high blood sugar levels again. In June 2011 only the active ingredient pioglitazone was still on the market, but the Federal Institute for Drugs and Medical Devices advises against taking it.

Mechanism of action

Glitazones activate the cell nucleus receptor PPAR ( peroxisome proliferator-activated receptors ) of type γ as a transcription factor . By inducing a large number of genes, PPARγ regulates various metabolic pathways in carbohydrate and fat metabolism. Activation increases the sensitivity of the cells of the liver, muscles and adipose tissue to insulin (lowering of insulin resistance ). Fatty acids and glucose are increasingly absorbed into the cells and converted into metabolism. In the liver, the formation of new glucose is also reduced. The effect of supplied insulin is also increased. The simultaneous administration of insulin and insulin sensitizers should only be carried out in exceptional cases because the risk of heart failure is increased. Pioglitazone and rosiglitazone increase body weight through increased water retention, which is visible in the increase in peripheral edema . The risk of heart failure increases.

application

Glitazones are indicated in patients whose blood sugar levels can not be adequately lowered through weight loss and diet control, or through treatment with metformin or sulfonylureas . Due to the different points of attack of the insulin sensitizers, the effects add up when combined with other oral antidiabetic agents. In the meantime, however, the drugs in this group have also been approved for monotherapy.

In contrast to other drugs that are available for diabetes therapy, the effect of the glitazones does not start immediately, but only after two weeks or later.

Pharmacokinetics

The glitazones are characterized by a very high oral bioavailability . They are almost completely absorbed from the gastrointestinal tract into the blood , where 99% of them are bound to plasma proteins. The breakdown takes place via the cytochrome P450 system of the liver, which can lead to interactions with other drugs that affect this system (e.g. rifampicin, trimethoprim, methotrexate). It is partly excreted via the kidneys and partly via the stool.

Active ingredients

The group of substances includes, for example, ciglitazone , balaglitazone , darglitazone , englitazone , netoglitazone , pioglitazone , rivoglitazone , rosiglitazone and troglitazone .

Discussions

Security aspects

Since the two commercially available active ingredients rosiglitazone ( Avandia ) and pioglitazone ( Actos ) are only available for a relatively short time, there is lively discussion in specialist circles about their benefits and advantages over other antidiabetic agents, especially since the first active ingredient in this group (troglitazone) due to liver-damaging effects in some countries or was never approved in Germany. The two approved representatives also show a diverse side effect profile (see individual articles).

In May 2005 the BfArM published that studies found an increased risk of fractures in women; the product information was supplemented and the medical profession was informed by red hand letter .

In a meta-analysis published in the New England Journal of Medicine in June 2007 , an approximately 40% increased heart attack rate was reported with rosiglitazone intake. In September 2010, the European Medicines Agency decided to withdraw approval of all rosiglitazone-containing drugs, as data suggests that the drugs' risks outweigh the benefits. The manufacturer Glaxo Smith Kline announced this in a Rote-Hand-Brief dated September 23, 2010. Medicines containing rosiglitazone should no longer be prescribed immediately.

The FDA investigated a possible but not yet proven connection between pioglitazone and bladder cancer.

Cost-benefit ratio

Glitazones have a proven blood sugar lowering effect. With regard to this blood-sugar-lowering effect, they are not superior to the established oral antidiabetic agents ( metformin , sulfonylureas ) at higher costs and with a high potential for side effects. At the request of the Federal Joint Committee, from October 2010, without exception, they should no longer be reimbursed by the statutory health insurance .

Therapeutic potential in multiple sclerosis

In 2008, US researchers described a mechanism of action of PPAR-gamma agonists in a mouse model in multiple sclerosis . In order to be able to use the mechanism therapeutically, however, it is first necessary to eliminate the blood sugar-lowering effect of the substances.

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  1. ↑ Diabetes: Pioglitazone goes off the market due to cancer risk ( Memento of the original from June 18, 2011 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , Deutsches Ärzteblatt, June 10, 2011. @1@ 2Template: Webachiv / IABot / www.aerzteblatt.de
  2. ↑ arznei-telegram 2008: Do not prescribe - oral antidiabetic agent rosiglitazone (AVANDIA) .
  3. ↑ Glitazone (rosiglitazone, pioglitazone): Increased risk of fractures in women. BfArM , May 10, 2007, accessed on March 9, 2017 .
  4. ↑ Nissen SE, Wolski K: Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007 May 21, PMID 17517853 .
  5. ↑ Spiegel online: Heart attack risk - study causes dispute over blockbuster drug .
  6. ↑ akdae.de: Suspension of the marketing of medicinal products containing rosiglitazone (PDF; 243 kB), September 23, 2010.
  7. ↑ FDA: Actos (pioglitazone): Ongoing Safety Review - Potential Increased Risk of Bladder Cancer .
  8. ^ Institute for Quality and Efficiency in Health Care (IQWiG): Final Report A05-05A - Glitazones for the Treatment of Diabetes Mellitus Type 2. 2008 (pdf, 430 kB).
  9. ^ Resolution of the Federal Joint Committee on an amendment to the Drugs Directive (AM-RL): Glitazone for the treatment of type 2 diabetes mellitus (PDF; 285 kB) from June 17, 2010.
  10. ↑ Paul D. Drew, Jihong Xu, Michael K. Racke: PPAR-γ: Therapeutic Potential for Multiple Sclerosis. In: PPAR Research. 2008, 2008, pp. 1–9, doi: 10.1155 / 2008/627463 , PMC 2441778 (free full text)