Zusammenfassung
□ Hintergrund
Biguanide sind seitmehr als 30 Jahren fester Bestandteil der Therapie des Typ-II-Diabetes. Bei Mißachtung ernster Kontraindikationen und/oder sträflicher Mißachtung der empfohlenen Höchstdosen kam es Ende der 70er Jahre zu einer Häufung von Zwischenfällen mit Lactatacidose, die dazu geführt haben, daß die beiden in Deutschland hauptsächlich verbreiteten lipophilen Derivate Buformin und Phenformin vom Markt genommen wurden. Der Einsatz des hydrophilen Metformin war weiterhin erlaubt, da die Lactatacidosegefährdung 20fach geringer als die mit Phenformin und Buformin ist, was auf unterschiedliche pharmakokinetische Eigenschaften der Substanz zurückgeführt werden kann. In der Zwischenzeit hat der klinische Erfahrungsschatz mit Metformin enorm zugenommen, was sich in einer großen Zahl verläßlicher Langzeitstudien niederschlägt.
□ Untersuchungsergebnisse
Metformin senkt Nüchternblutzuckerspiegel durchschnittlich um 25% (17 bis 37%), die postprandiale Blutzuckersenkung liegt bei 44%, die Reduktion von HbA1c bei 1,5% (0,8 bis 3,1%). Metformin reduziert erhöhte endogene Insulinspiegel um etwa 30% und kann die „Insulinbedürftigkeit” übergewichtiger Typ-II-Diabetiker um 15 bis 32% senken. Im Gegensatz zu anderen oralen Antidiabetika hat es gut dokumentierte rheologische Effekte.
Bei übergewichtigen Typ-II-Diabetikern zeigt Metformin eine gleichstarke bzw. sogar ausgeprägtere hypoglykämische Wirkung im Vergleich zu Sulfonylharnstoffen, deren aktiver Mechanismus sich ausschließlich auf die Reduktion von Blutzuckerspiegeln konzentriert. Dieser Mechanismus trägt demnach nicht zu den anderen Risikokonstellationen, die mit der Insulinresistenz verbunden sind, Rechnung. Biguanide reduzieren die Hyperinsulinämie und haben damit positivere Effekte auf die Gewichtsreduktion im Vergleich zu Sulfonylharnstoffederivaten oder der endogenen Insulinzufuhr.
□ Schlußfolgerung
Das Risiko der Lactatacidose kann praktisch gänzlich eliminiert werden, wenn Dosisinstruktionen und Kontraindikationen sorgfältig beachtet werden. Die Ursache einer Nichtbeachtung dieser wichtigen Voraussetzungen war in 83% aller Zwischenfälle auf eine eingeschränkte Nierenfunktion zurückzuführen (Serumkreatinin größer als 1,5 mg%). Das Risiko der Morbidität und Mortalität einer Metformin-induzierten Lactatacidose ist nicht größer als das einer fatalen Hypoglykämie mit dem Sulfonylharnstoffderivat Glibenclamid.
Summary
□ Background and Objectivs
Biguanides have been used in treatment of diabetes mellitus for over 30 years now. Due to frequent occurrence of lactic acidosis, particularly in patients with serious contraindications to biguanide therapy and in cases of non-compliance with dosage instuctions, buformin and phenformin were taken off the market in most European countries at the end of the seventies. Metformin continued to be allowed, since the risk of lactic acidosis is 20 times less than with phenformin or buformin due to the different pharmacokinetic properties of the substance. Plenty of clinical experience has been gained with metformin, documented in a large number of reliable long-term studies.
□ Findings
Metformin lowers fasting blood glucose levels by an average of 25% (17 to 37%), postprandial blood glucose by up to 44,5% and HbA1c bei 1,5% (0,8 to 3,1%) Metformin reduces raised plasma insulin levels in cases of metabolic syndrome by as much as 30% and reduces the “insulin requirement” of type 2 insulin-treated diabetics by 15 to 32%. It has well documented effects on various rheological parameters. In overweight type 2 diabetics, metformin shows the same level of hypoglycaemic effect as all of the imporant sulfonylurea derivatives used in Europe. The active mechanism of these derivatives is, however, concentrated solely on reduction of blood glucose. This mechanism does not take into account the remaining risk constellation involved in insulin resistance. Biguanides, similarly to weight reduction, lead to a reduction of hyperinsulinaemia, which is by contrast exacerbated by sulfonylureas and, in particular, exogenous insulin.
□ Conclusion
The risk of lactic acidosis can probably be eliminated entirely if dosage instructions and contraindications are observed carefully. The cause of such neglect in 83% of all cases was limited on renal function (serum creatinine > 1,5 mg%). Regarding morbidity and mortality from lactic acidosis, metformin therapy is no riskier than treatment with the sulfonylurea derivative glibenclamide, taking into account the incidence of fatal hypoglycaemias with the latter.
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Haupt, E., Panten, U. Die Stellung der Biguanide in der Therapie des Diabetes mellitus. Med. Klin. 92, 472–479 (1997). https://doi.org/10.1007/BF03044916
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DOI: https://doi.org/10.1007/BF03044916