Pioglitazone

Structural formula
1: 1 mixture of ( S ) -Pioglitazon (left) and ( R ) -Pioglitazon (right)
General
Non-proprietary name	Pioglitazone
other names	Pioglitazonum ( RS ) -5- { p - [2- (5-Ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione
Molecular formula	C 19 H 20 N 2 O 3 S (pioglitazone) C 19 H 20 N 2 O 3 S HCl (pioglitazone hydrochloride)
External identifiers / databases
CAS number 111025-46-8 (pioglitazone) 112529-15-4 (pioglitazone hydrochloride ) EC number 601-029-7 ECHA InfoCard 100.114.441 PubChem 4829 ChemSpider 4663 DrugBank DB01132 Wikidata Q417765
Drug information
ATC code	A10 BG03
Drug class	Insulin sensitizer
properties
Molar mass	356.4 g · mol -1 (pioglitazone) 392.90 g · mol -1 (· pioglitazone hydrochloride)
Melting point	183-184 ° C (pioglitazone) 193–194 ° C (pioglitazone hydrochloride)
solubility	soluble in DMF (hydrochloride) bad in ethanol , acetone and acetonitrile (hydrochloride) insoluble in water and diethyl ether (hydrochloride)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Pioglitazone is a drug from the group of glitazones (insulin sensitizer) that is used in the form of tablets to treat type 2 diabetes mellitus . The principle of action is a sensitization (increase in sensitivity) of the tissue to insulin, the effect of which is reduced in the typical insulin resistance of this form of diabetes. The body's own insulin or insulin supplied by injections is consequently able to lower increased blood sugar levels more effectively.

application

In overweight patients, pioglitazone is used in combination with metformin . The drug is administered orally. In patients who cannot tolerate metformin or for whom metformin is contraindicated, pioglitazone can be used in monotherapy (pioglitazone only) or in combination with a sulphonylurea . It is also possible to use pioglitazone in a triple therapy (together with metformin and sulfonylureas), and the combination with insulin is also possible. The tablets can be taken regardless of meals. The effect of pioglitazone does not take effect immediately, but takes about 4 weeks to fully develop. The combination with insulin is an exception, as this directly intensifies the effect of the insulin. The blood sugar values ​​should be checked closely in order to avoid hypoglycaemia (low blood sugar levels).

According to a decision by the Federal Joint Committee, since April 2011 pioglitazone can only be prescribed in justified exceptional cases at the expense of the statutory health insurance .

Mechanism of action

In the body's cells, pioglitazone activates the PPARγ receptor (peroxisome proliferator-activated receptor gamma) in the cell nucleus . This receptor is involved in the regulation of various mechanisms in carbohydrate and fat metabolism. The activation of this receptor increases the sensitivity of the cells of the liver, muscles and adipose tissue to insulin . As a result, fat building blocks and glucose are increasingly absorbed into the cells and metabolized. The formation of new glucose in the liver is reduced.

Blood sugar levels drop both when fasting and after meals. Increased insulin concentrations after meals are also reduced. Due to the increased effect of the existing insulin, the body only needs smaller amounts of insulin. Any existing insulin resistance therefore decreases with the administration of pioglitazone.

The active ingredient pioglitazone reduces, according to the same mechanism as all glitazones , the insulin resistance ( insulin resistance ) of adipose tissue, muscles and the liver and thus lowers the blood sugar level. Pioglitazone can also reduce sugar production in the liver and improve sugar utilization in the body, for example in the muscles. This also optimizes the sugar metabolism.

In addition to improving the effect of the body's own insulin, pioglitazone also increases the effect of the insulin that is added. The onset of action of pioglitazone, which can be delayed around two to three weeks with individual therapy, occurs much faster in combination with insulin. When taking pioglitazone, the patient may have to lower their insulin dose by up to 30 percent in order to prevent hypoglycaemia. Sometimes it is even possible to stop taking insulin altogether. However, the switch to the combination should only be done under the supervision of a doctor who is experienced in the treatment of diabetes and with very frequent follow-up examinations.

Contraindications

Patients with liver problems should not use pioglitazone. In addition, patients with heart failure, i.e. heart failure, should not receive pioglitazone. This also applies if the heart failure was present in the past.

There is no experience with the use of pioglitazone in pregnant women and nursing mothers. The use of the substance in these patients must therefore be avoided. There is currently insufficient experience with the use of pioglitazone in patients with severe renal impairment, in dialysis patients and in children and adolescents under 18 years of age. Pioglitazone should therefore not be used in these patient groups either.

Side effects

The increased uptake of fat building blocks from the blood has the undesirable consequence that more body fat and adipose tissue are formed, which leads to excess weight . Body weight may therefore increase during treatment with pioglitazone and should be checked regularly. In addition, pioglitazone can increase the amount of water in the body and also lead to increased water retention in the tissue.

An increased risk of fractures has also been reported in randomized controlled trials of long-term use. Accordingly, the drug lowers the bone density in the lumbar spine and the hip, especially in women, which is why the authors advise against treatment with glitazones in women with an increased risk of fractures.

In September 2010, the US Food and Drug Administration initiated a review of pioglitazone with regard to the risk of inducing bladder cancer . An increased incidence of bladder cancer with pioglitazone had previously been observed in two clinical studies . A review initiated by the Committee for Medicinal Products for Human Use of the European Medicines Agency followed in March 2011 . In France, the responsible authority Afssaps ordered drugs containing pioglitazone to be withdrawn from the market in June 2011 after the completion of a cohort study which had also shown a tendency towards an increased risk of bladder cancer. In the same month, the German Federal Institute for Drugs and Medical Devices advised against recruiting patients to a drug containing pioglitazone, and the manufacturer issued a corresponding red-hand letter . The European Medicines Agency found that there was a slightly increased risk of developing bladder cancer, which justifies carefully controlled therapy, and only advises against treatment with pioglitazone in patients who are appropriately disposed. In July 2011, the manufacturer Takeda published another Rote-Hand-Brief.

Stereoisomerism

Pioglitazone is chiral and contains a stereocenter, so there are two enantiomers , the ( R ) form and the ( S ) form. The commercial preparations contain the drug as a racemate in the form of the hydrochloride.

Trade names

The pharmaceutical company Takeda launched the insulin sensitizer with the active ingredient pioglitazone in 1999 together with Eli Lilly under the trade name Actos on the US market. The market launch in Europe follows in 2000.

• Monopreparations : Actos (D, A, CH and other EU countries), Glustin (A)
• Combination preparations: Competact (D, A, CH and other EU countries), Tandemact (D, A), Actoplus Met (USA), Duetact (USA)

Web links

• Onmeda health portal: Oral anti-diabetic drugs
• European Public Assessment Report (EPAR) for Glustin (Pioglitazone) (PDF; 65 kB) European Medicines Agency website

Individual evidence

1. ↑ ^{a b c d e} The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition, 2006, p. 698, ISBN 978-0-911910-00-1 .
2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
3. ↑ Resolution on an amendment to the Drugs Directive (AM-RL): Glitazones for the treatment of type 2 diabetes mellitus (PDF; 285 kB) from June 17, 2010.
4. ↑ onmeda.de: pioglitazone .
5. ↑ Meier, Juris J .; Nauck, Michael A .; Schmidt, Wolfgang E .; Gallwitz, Baptist: Diagnosis of limited glucose tolerance and diabetes prevention: Can the diabetes epidemic be stopped? Dtsch Arztebl 2002; 99 (47): A-3182 / B-2685 / C-2500.
6. ↑ FDA Safety Alerts: Actos (pioglitazone): Ongoing Safety Review - Potential Increased Risk of Bladder Cancer .
7. ↑ Deutsches Ärzteblatt, September 20, 2010: Pioglitazone: FDA examines possible risk of bladder cancer ( memento of the original from December 3, 2010 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. . 
8. ↑ Fiche Médicament sous surveillance renforcée: Actos, Competact - Traitement du diabète de type 2 of June 9, 2011.
9. ↑ The BfArM currently advises against the use of drugs containing pioglitazone. BfArM , June 10, 2011, archived from the original on April 13, 2012 ; Retrieved September 13, 2013 . 
10. ↑ Red Hand Letter from Takeda Pharma on June 10, 2011. (PDF; 94 kB) Retrieved June 15, 2011 . 
11. ↑ EMA press release of July 21, 2011; available as html ; last accessed on July 22, 2011.
12. ↑ European Medicines Agency recommends new contraindications and warnings for drugs containing pioglitazone due to a slightly increased risk of bladder cancer. BfArM , July 22, 2011, accessed on July 22, 2011 . 
13. ↑ Red Hand Letter from Takeda Pharma on July 28, 2011. (PDF; 138 kB) Retrieved on August 1, 2011 . 

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 !