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Diabetes - Ursachen und Behandlung

Orale Antidiabetika: Glitazone

Hinweis
Glitazone (Thiazolidindione) und sind oral eingenommene Medikamente, die bei Typ-2-Diabetikern die Wirkung des Insulins steigern und damit einer Insulin-Resistenz entgegenwirken.

Glitazone werden auch Insulin-Sensitizer oder PPAR-γ1)-Liganden genannt. Die beiden in Deutschland derzeit (2010) zugelassenen Wirkstoffe Pioglitazon (Handelsname Actos®) und Rosiglitazon (Avandia®) wirken auf die Expression einer ganzen Reihe von Genen, die an der Glucose-Aufnahme in Muskel-, Leber- oder Fettzellen und am Energiestoffwechsel beteiligt sind. Der Glucose-Spiegel im Blut sinkt langfristig.

Den Namen "Insulin-Sensitizer" tragen diese Wirkstoffe durchaus zu Recht, denn Glitazone verstärken die Wirkung des körpereigenen Insulins, auf das viele Typ-2-Diabetiker im Verlauf der Erkrankung zunehmend weniger reagieren (Insulin-Resistenz).

Abb.1
Pioglitazon
Abb.2
Rosiglitazon

Der PPAR-γ und PPAR-γ-regulierte Gene

Nebenwirkungen

Eine Therapie mit Glitazonen führt oft in den ersten sechs Monaten dosisabhängig zu einer Gewichtszunahme - es gibt mehr reife Fettzellen (Adipocyten). Diese neu entstandenen Fettzellen wandeln vermehrt aufgenommene Glucose in Fett um und speichern dieses. Glitazone fördern auch die Zurückhaltung von Wasser im Gewebe (Ödembildung), was ebenso zu einer Gewichtszunahme beiträgt.

Als Nebenwirkungen werden gelegentlich Schwindel, Kopfschmerzen und leichte Blutarmut genannt. Bei Herzproblemen oder Leberfunktionsstörungen, in der Schwangerschaft und in der Stillzeit sind diese Medikamente nicht zu empfehlen. Glitazone sind für eine Kombinationstherapie mit Sulfonylharnstoffen oder Metformin bei Typ 2 Diabetes zugelassen, sollten aber nicht mit einer Insulin-Therapie kombiniert werden.

Das erste, 1997 in den USA zugelassene Troglitazon-Präparat (Rezulin®) wurde im Jahr 2000 sehr schnell vom Markt genommen, nachdem sich die Fälle von Leberschäden mit tödlichem Leberversagen häuften. Bei den heutigen Glitazon-Präparaten ist diese Komplikation nicht zu befürchten, trotzdem ist eine Kontrolle der Leberwerte (Transaminasen) bei einer Glitazon-Therapie ratsam. Das Rosiglitazon-Präparat Avandia® sorgte im Februar 2010 für negative Schlagzeilen, es soll neueren Studien zufolge in den USA für Hunderte von Todesfällen durch Herzversagen verantwortlich sein (Spiegel Online, Feb. 2010, Juli 2010).

Hinweis
Der Insulin-Sensitizer Troglitazon wurde als Antidiabetikum zwar vom Markt genommen, zeigt aber gute Erfolge in der Krebstherapie. Dieses Medikament bewirkt, dass bei Tumorzellen leichter der so genannte programmierte Zelltod (Apoptose) ausgelöst wird. Bei bestimmten Tumorarten ist dieses zelluläre Signalprogramm blockiert, das normalerweise im Körper eine Art Selbstmord der Zelle einleitet, sobald sich eine Zelle verändert.
Im Juni 2011 hat Frankreich Pioglitazon vom Markt genommen. Die Zulassung wurde zurückgenommen, nachdem es Hinweise auf ein erhöhtes Blasenkrebsrisiko bei Männern gab (C. Piccinni et al.).

Literatur

Komajda, M.; McMurray, J. J.; Beck-Nielsen, H.; Gomis, R.; Hanefeld, M.; Pocock, S. J.; Curtis, P. S.; Jones, N. P.; Home, P. D. (2010): Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. In: Eur. Heart. J.. 31 (7) , 824-831
Titel des Artikels
Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial
Abstract
AIMS: Thiazolidinediones are insulin sensitizers, and are associated with fluid retention and increased risk of heart failure (HF) in people with type 2 diabetes. We assessed fatal and non-fatal HF events and their outcome, and identified HF predictors in the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial population. METHODS AND RESULTS: In a multicentre, open-label study, we randomized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA(1c) of 7.9% to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227) and followed them over 5.5 years on average. Heart failure hospitalizations and deaths were adjudicated by a Clinical Endpoint Committee using pre-specified criteria. Independent predictors of HF events were identified out of a group of 30 pre-specified clinical, demographic, and biological variables. In the rosiglitazone group, the risk of HF death or hospitalization was doubled: HR = 2.10 (95% CI, 1.35-3.27): the excess HF event rate was 2.6 (1.1-4.1) per 1000 person-years. An excess in HF deaths was observed (10 vs. two), including four HF deaths as first HF events. By contrast, there was no increase in cardiovascular mortality or hospitalization (HR = 0.99, 95% CI, 0.85-1.16) or in cardiovascular deaths (60 vs. 71). Independent predictors of HF were rosiglitazone assignment, age, urinary albumin : creatinine ratio, body mass index, and systolic blood pressure at baseline. A history of previous cardiovascular disease was not predictive of HF. Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups. CONCLUSION: These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication. Close follow-up for the risk of HF should be offered to elderly people, people with markedly increased body mass index, people with microalbuminuria/proteinuria, and people with increased systolic blood pressure.
Jaeschke, H. (2007): Troglitazone Hepatotoxicity: Are We Getting Closer to Understanding Idiosyncratic Liver Injury?. In: Toxicol. Sciences. 97 , 1-3
Titel des Artikels
Troglitazone Hepatotoxicity: Are We Getting Closer to Understanding Idiosyncratic Liver Injury?
Abstract
Troglitazone, a first-generation thiazolidinedione antidiabetic drug, was withdrawn from the market due to an unacceptable risk of idiosyncratic hepatotoxicity. Troglitazone does not cause hepatotoxicity in normal healthy rodents, but it produces mitochondrial injury in vitro at high concentrations. The aim of this study was to explore whether genetic mitochondrial abnormalities might sensitize mice to hepatic adverse effects of troglitazone. We used heterozygous superoxide dismutase 2 (Sod2(+/-)) mice as a model of clinically silent mitochondrial stress. Troglitazone was daily administered for 4 weeks (0, 10 or 30 mg/kg/day, ip). We found that troglitazone caused overt liver injury in the high-dose group, manifested by increased serum alanine aminotransferase activity (> twofold) and midzonal areas of hepatic necrosis, in Sod2(+/-) but not in wild-type mice. No signs of hepatotoxicity were apparent at 2 weeks of treatment. Hepatic mitochondria isolated from troglitazone-treated mice exhibited decreased activities of aconitase (by 45%) and complex I (by 46%) and increased (by 58%) protein carbonyls, indicative of enhanced mitochondrial oxidant stress. This was paralleled by compensatory increases in mitochondrial glutathione levels. Finally, in hepatocytes isolated from untreated Sod2(+/-), but not wild-type mice, troglitazone caused a concentration-dependent increase in superoxide anion levels as demonstrated with a selective mitochondria-targeting fluorescent probe. In conclusion, prolonged administration of troglitazone can superimpose oxidant stress, potentiate mitochondrial damage, and induce delayed hepatic necrosis in mice with genetically compromised mitochondrial function. These data are consistent with our hypothesis that inherited or acquired mitochondrial abnormalities may be one of the contributing determinants of susceptibility to troglitazone-induced idiosyncratic liver injury.
Piccinni, C.; Motola, D.; Marchesini, G.; Poluzzi, E. (2011): Assessing the Association of Pioglitazone Use and Bladder Cancer Through Drug Adverse Event Reporting. In: Diabetes Care. 34 (6) , 1369-1371
Titel des Artikels
Assessing the Association of Pioglitazone Use and Bladder Cancer Through Drug Adverse Event Reporting
Abstract
OBJECTIVE To analyze the association between pioglitazone use and bladder cancer through a spontaneous adverse event reporting system for medications.RESEARCH DESIGN AND METHODS Case/noncase bladder cancer reports associated with antidiabetic drug use were retrieved from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) between 2004 and 2009 and analyzed by the reporting odds ratio (ROR).RESULTS Ninety-three reports of bladder cancer were retrieved, corresponding to 138 drug-reaction pairs (pioglitazone, 31; insulin, 29; metformin, 25; glimepiride, 13; exenatide, 8; others, 22). ROR was indicative of a definite risk for pioglitazone (4.30 [95% CI 2.82–6.52]), and a much weaker risk for gliclazide and acarbose, with very few cases being treated with these two drugs (6 and 4, respectively).CONCLUSIONS In agreement with preclinical and clinical studies, AERS analysis is consistent with an association between pioglitazone and bladder cancer. This issue needs constant epidemiologic surveillance and urgent definition by more specific studies.

Zugang zur PubMed-Datenbank

1)PPAR-γ: Peroxisomen-Proliferator-aktivierter Rezeptor, γ-Subtyp
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