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Diabetologie und Stoffwechsel 2017; 12(04): 294-306
DOI: 10.1055/s-0043-112658
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Empagliflozin reduziert das Risiko für Mortalität sowie makro- und mikrovaskuläre Komplikationen bei Patienten mit Typ-2-Diabetes und bestehender kardiovaskulärer Erkrankung

Empagliflozin Reduces the Risk of Mortality, Macro- and Microvascular Events in Patients with Type 2 Diabetes and Established Cardiovascular Disease
Jochen Seufert
1   Abteilung Endokrinologie und Diabetologie, Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg
,
Jan-Christoph Galle
2   Klinik für Nephrologie und Dialyseverfahren, Märkische Kliniken GmbH Klinikum Lüdenscheid, Germany
,
Martina Manning
3   Medizinische Abteilung, Lilly Deutschland GmbH, Bad Homburg, Germany
,
Volkmar Schmid
4   Medical Affairs Deutschland, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
Michael Lehrke
5   Medizinische Klinik I, Klinik für Kardiologie, Pneumologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum Aachen, Germany
› Author Affiliations
Further Information

Publication History

13 February 2017

30 May 2017

Publication Date:
01 September 2017 (online)

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Zusammenfassung

Patienten mit Typ-2-Diabetes mellitus haben auch bei optimierter Lipidsenkung, Blutdruckkontrolle und Blutzuckereinstellung ein erhöhtes Risiko für kardiovaskuläre Ereignisse. Zur Abbildung der kardiovaskulären Sicherheit neu zugelassener Antidiabetika verlangen die Arzneimittelbehörden FDA und EMA den Nachweis für Nichtunterlegenheit bezüglich kardiovaskulärer Sicherheit gegenüber Placebo in Endpunktstudien. Während für verschiedene neuere Antidiabetika bisher die Nichtunterlegenheit in kardiovaskulären Sicherheitsstudien gezeigt wurde, konnte mit Empagliflozin erstmals in der EMPA-REG OUTCOME®-Studie und nachfolgend mit Liraglutid in der LEADER-Studie eine präspezifizierte kardiovaskuläre Überlegenheit im Vergleich zu Placebo demonstriert werden; auch mit Semaglutid wurde in der SUSTAIN-6-Studie eine statistisch signifikante Reduktion kardiovaskulärer Ereignisse erreicht. Die Gabe von Empagliflozin, einem Hemmer des Natrium-Glukose-Cotransporters 2 (SGLT-2), zusätzlich zur antidiabetischen und kardiovaskulären Standardtherapie führte zu einer signifikanten relativen Risikoreduktion des primären kombinierten Endpunkts aus kardiovaskulärem Tod, nicht tödlichem Myokardinfarkt oder nicht tödlichem Schlaganfall um 14 % gegenüber Placebo. Diese Risikoreduktion wurde maßgeblich durch die Senkung der kardiovaskulären Mortalität um 38 % erreicht. Zudem zeigten sich gegenüber Placebo relative Risikoreduktionen von 35 % bzw. 39 % für stationäre Aufnahmen wegen Herzinsuffizienz bzw. für das Neuauftreten oder die Verschlechterung einer Nephropathie. Empagliflozin reduzierte die Gesamtmortalität relativ um 32 %. Welche Mechanismen den nachgewiesenen Risikoreduktionen zugrunde liegen, ist Gegenstand weiterer Untersuchungen. Diskutiert werden vor allem eine Entlastung des Herzens durch Ausscheidung von überschüssigem Natrium, Glukose und Wasser, hämodynamische Effekte an der Niere über eine Normalisierung des tubulo-glomerulären Feedbacks oder auch eine durch Ketonkörper energetisch günstigere Substratnutzung im vorgeschädigten Herzen. Empagliflozin war, mit Ausnahme einer erhöhten Rate an Genitalinfektionen, die generell mit dem Wirkmechanismus von SGLT-2-Hemmern assoziiert sind, gut verträglich.

Abstract

Patients with type 2 diabetes mellitus face an increased risk of cardiovascular events, even under conditions of optimal lipid reduction, blood pressure and blood glucose control. To ensure cardiovascular safety of novel antidiabetic drugs, FDA and EMA regulations require evidence of non-inferiority compared to placebo in cardiovascular outcome studies for approval. Previously, cardiovascular safety of various newer antidiabetic drugs was observed in dedicated non-inferiority trials. In contrast, the EMPA-REG OUTCOME® study was the first trial to demonstrate for empagliflozin, followed by the LEADER trial for liraglutide, prespecified cardiovascular superiority of an individual antidiabetic medication versus placebo. Subsequently, semaglutide showed a significant reduction in cardiovascular events in the SUSTAIN 6 trial. Administration of empagliflozin, a sodium glucose-linked cotransporter (SGLT-2) inhibitor, in addition to antidiabetic and cardiovascular standard of care medication led to a significant relative risk reduction by 14 % of the primary composite endpoint composed of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke as compared to placebo. This overall risk reduction was mainly driven by a significant 38 % reduction in cardiovascular death. Furthermore, empagliflozin reduced the relative risk of hospitalisations for heart failure, or incident or worsening nephropathy by 35 % and 39 %, respectively. Empagliflozin reduced the relative risk of all-cause mortality by 32 %. The underlying mechanisms for the observed risk reductions are not yet completely understood. Specifically, relieving the heart from excess glucose, sodium and water, effects on renal hemodynamics and restored tubuloglomerular feedback as well as a substrate shift towards ketone bodies resulting in better energy consumption in the diabetic heart are considered. Empagliflozin was well tolerated but associated with an increased incidence of genital infections, which are generally associated with the mode of action of SGLT-2 inhibitors.

Schlüsselwörter

Empagliflozin - SGLT-2-Inhibitor - Diabetes mellitus - Mortalität - Kardiovaskuläre Endpunktstudie

Key words

cardiovascular outcome trial - empagliflozin - SGLT-2 inhibitor - diabetes mellitus - mortality
 

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