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DPP-4-Hemmer und GLP-1-Rezeptor-Agonisten

Kardiovaskuläre Effekte

DPP-4 inhibitors and GLP-1 receptor agonists

Cardiovascular effects

  • Leitthema
  • Published:
Der Diabetologe Aims and scope

Zusammenfassung

Hintergrund

Inkretinbasierte, den Glukosespiegel senkende Medikamente (IBGSM) wirken ausschließlich (GLP-1-RA [GLP: „glucagon-like peptide“, RA: Rezeptoragonist]) oder vorwiegend (DPP-4-Inhibitoren [DPP: Dipeptidylpeptidase]) über eine vermehrte Stimulation von GLP-1-Rezeptoren. Sie unterscheiden sich von herkömmlichen, den Glukosespiegel vermindernden Medikamenten dadurch, dass sie weder zu einer Körpergewichtssteigerung noch zu Hypoglykämieepisoden führen. Damit verbindet sich die Hoffnung, mit IBGSM das erhöhte kardiovaskuläre Risiko bei Typ-2-Diabetes günstig beeinflussen zu können. GLP-1-Rezeptoren wurden auch im kardiovaskulären System nachgewiesen.

Effekte von IBGSM

In klinischen Studien wurden eine Senkung des Körpergewichts, des systolischen Blutdrucks, eine leichte Pulsbeschleunigung (GLP-1-RA) und eine günstige Beeinflussung der Lipoproteinparameter beschrieben (alle IBGSM). Vorläufige Ergebnisse einer tendenziell reduzierten kardiovaskulären Ereignisrate konnten in eigens durchgeführten kardiovaskulären Sicherheitsstudien nicht bestätigt werden. Bislang wurden durchweg neutrale Ergebnisse hinsichtlich erheblicher kardiovaskulärer Ereignisse (Herzinfarkt, Schlaganfall, kardiovaskulärer Tod [MACE]) erzielt. Bezüglich der DPP-4-Inhibitoren ergab sich für Saxagliptin eine nominell signifikante Erhöhung der Rate von Krankenhausaufnahmen wegen Herzinsuffizienz, die sich mit Alogliptin tendenziell und mit Sitagliptin gar nicht bestätigte, ebenfalls nicht mit Lixisenatid (GLP-1-RA).

Schlussfolgerung

Wahrscheinlich sind Studien mit weniger vorgeschädigten Patienten, längerer Laufzeit und deutlichen Unterschieden in der Glukosekontrolle zur Vergleichsmedikation notwendig, um einen möglichen kardiovaskulären Benefit von IBGSM sinnvoll zu untersuchen und ggf. nachzuweisen.

Abstract

Background

Incretin-based glucose-lowering medications (IBGLM) exert their effects exclusively (GLP-1-RA [GLP: glucagon-like peptide, RA: receptor agonist]) or mainly (DPP-4 inhibitors [DPP: dipeptidylpeptidase]) by enhancing the stimulation of GLP-1 receptors. In contrast to established glucose-lowering drug classes, they are less likely to increase body weight or to provoke hypoglycaemic episodes. These properties promoted the hope that incretin-based glucose-lowering medications will have a positive effect on the elevated cardiovascular risk in patients with type 2 diabetes. GLP-1 receptors have also been found in the cardiovascular system.

Effects of IBGSM

Clinical studies have described weight loss, lowering of systolic blood pressure, a slightly increased heart rate (GLP-1-RA) and a favourable influence on serum lipoproteins (all IBGLM). Initial results of a slightly reduced rate in cardiovascular events could not be confirmed in dedicated cardiovascular safety studies, in which mainly “neutral” results concerning cardiovascular events (myocardial infarction, stroke, cardiovascular death [MACE]) were reported for DPP-4 inhibitors and GLP-1-RA so far. Regarding DPP-4 inhibitors, treatment with saxagliptin showed a significant, with alogliptin a trend towards an elevation in hospitalization rates for congestive heart failure, while this was not confirmed for sitagliptin or for lixisenatide (GLP-1-RA).

Conclusion

Most likely, studies including patients with less advanced cardiovascular damage at baseline, with a longer diabetes duration, and allowing for significant differences in glucose control between the drugs that are to be compared will probably be needed to meaningfully analyze and, possibly, confirm a cardiovascular benefit of IBGLM .

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Authors and Affiliations

  1. Abteilung für Diabetologie, Medizinische Klinik I, St. Josef Hospital (Ruhr-Universität Bochum), Gudrunstraße 56, 44791, Bochum, Deutschland

    M. A. Nauck, M. S. Abd El Aziz & J. J. Meier

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  1. M. A. Nauck
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  3. J. J. Meier
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Correspondence to M. A. Nauck.

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Interessenkonflikt

M.A. Nauck hat bei Advisory Boards für Berlin Chemie, Amylin Pharmaceuticals, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, MSD, Novo Nordisk, Sanofi, Intarcia mitgewirkt; er hat Beraterhonorare von Amylin Pharmaceuticals, AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Hoffman La Roche, Intarcia Therapeutics, MSD, Novartis, Janssen, Novo Nordisk und Sanofi, Unterstützung für Forschungsvorhaben von Berlin Chemie, Boehringer Ingelheim, Novartis, MSD, AstraZeneca, GlaxoSmithKline, Hoffmann La Roche, Novo Nordisk und ToleRx sowie Honorare für Vorträge von AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Diabate, Eli Lilly & Co., Incretin Expert Program, Medscape, MSD, Novartis und Novo Nordisk erhalten.

M.S. Abd El Aziz hat eine Reisekostenerstattung von MSD erhalten.

J.J. Meier hat Vortragshonorare von AstraZeneca, Berlin Chemie, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Novo Nordisk, Novartis, Roche, Sanofi-Aventis, Beraterhonorare von AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novo Nordisk und Sanofi-Aventis sowie Unterstützung für Forschungsprojekte von Novo Nordisk, MSD, Sanofi-Aventis, Eli Lilly und Novartis erhalten.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Additional information

Dieses Manuskript wurde geschrieben, bevor eine Pressemeldung zur LEADER-Studie (kardiovaskuläre „Outcome“-Studie mit Liraglutid, einem GLP-1 Rezeptor-Agonisten) eine signifikante Reduktion der Kombination aus nicht-tödlichem Herzinfarkt, nicht-tödlichem Schlaganfall und kardiovaskulärem Tod berichtet hat.

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Nauck, M.A., Abd El Aziz, M.S. & Meier, J.J. DPP-4-Hemmer und GLP-1-Rezeptor-Agonisten. Diabetologe 12, 184–194 (2016). https://doi.org/10.1007/s11428-016-0083-8

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