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.