The gut incretin hormone GLP-2 is a novel risk marker and potential therapeutical target for atherosclerotic cardiovascular disease

Maximilian Sausen (Aachen)1, M. Reugels (Aachen)1, R. W. Mertens (Aachen)1, L. B. Quintana Selek (Aachen)1, M. Rückbeil (Aachen)1, P. Idel (Aachen)1, N. Tabaza (Aachen)1, N. Ganesh (Aachen)1, M. Neuhaus (Aachen)1, K. M. Schneider (Aachen)2, S. Just (Aachen)1, M. C. Arrivas (Aachen)1, J. Möllmann (Aachen)1, J. Spießhöfer (Aachen)3, B. Kurt (Aachen)1, C. V. Schneider (Aachen)2, M. Biener (Heidelberg)4, E. Giannitsis (Heidelberg)4, H. A. Katus (Heidelberg)4, D. J. Drucker (Toronto, Ontario)5, N. Marx (Aachen)1, M. Lehrke (Aachen)1, F. Kahles (Aachen)1

1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; 2Uniklinik RWTH Aachen Med. Klinik III - Gastroenterologie und Stoffwechselkrankheiten Aachen, Deutschland; 3Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; 4Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; 5Mount Sinai Hospital: Sinai Health Lunenfeld-Tanenbaum Research Institute Toronto, Ontario, Kanada


Background: The incretin hormones GLP-1 and GLP-2 (glucagon-like peptide-1/2) are co-secreted from intestinal L-cells in response to food intake. While GLP-1 is known to induce postprandial insulin secretion and to improve cardiovascular outcomes in patients with diabetes, GLP-2 is a local intestinal growth factor enhancing intestinal lipid absorption. GLP-2 agonists are clinically used for the treatment of patients with short bowel syndrome. The relevance of GLP-2 beyond the gut is not well understood. The aim of this study was to study the role of GLP-2 in cardiovascular disease (CVD).


Methods: Total GLP-2 levels were assessed at time of admission in 1929 patients (cohort 1: n=1011 patients; cohort 2: n=918 patients) admitted to the emergency department with myocardial infarction. The primary outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-P-MACE). To induce experimental atherosclerosis, Glp2r−/− or WT mice were injected with PCSK9 virus and fed a diet high in cholesterol (HCD) for 12 weeks. Experimental myocardial infarction was induced by LAD-ligation in mice.


Results: In the derivation cohort (n=1011) Kaplan-Meier survival plots (separated by tertiles of GLP-2; low: < 2.79 pM, medium: 2.79 - 4.74 pM, and high GLP-2: > 4.74 pM) and univariable Cox regression analyses found circulating GLP-2 levels to be associated with 3-P-MACE (HR: 1.87, 95% CI: 1.47 - 2.37; p<.0001) in patients with acute myocardial infarction. After adjustment for traditional CV risk factors, creatinine and hs-Troponin T the adjusted standardized HR remained significant at 1.34 (95% CI: 1.01 - 1.78; p = 0.043). We found similar results for all-cause death. Addition of GLP-2 on top of the GRACE risk score improved risk discrimination and model performance (delta c-index 0.06). These findings were confirmed in an independent validation cohort of 918 patients with myocardial infarction. To investigate whether GLP-2 plays a causal role in ASCVD, we performed experimental myocardial infarction and found no difference in left ventricular function (analyzed by millar catheter) 4 weeks after LAD-ligation in Glp2r−/− vs. WT mice. To explore direct vascular effects of GLP-2 we induced atherosclerosis by PCSK9 virus and HCD. After 12 weeks Glp2r−/− mice compared to WT littermates presented with a significant reduction in plaque volume and lesion size. While body weight and circulating leukocyte numbers (FACS analysis) were unaffected, Glp2r−/− mice had lower total cholesterol levels. Consistently higher GLP-2 levels were associated with hypercholesterolemia in patients with ASCVD admitted due to myocardial infarction.  


Conclusion: GLP-2 is an independent cardiovascular risk marker in partients with ASCVD while activation of the GLP-2 receptor increases total cholesterol and aggravates atherosclerosis in mice. Future studies are needed to investigate whether GLP-2 could be a novel therapeutic target for patients with ASCVD. 

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