The Cardiovascular Biology of Glucagon-like Peptide-1 Daniel J. Drucker  Cell Metabolism  Volume 24, Issue 1, Pages 15-30 (July 2016) DOI: 10.1016/j.cmet.2016.06.009 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Mechanisms Linking GLP-1 to Modulation of Inflammation GLP-1 secretion from EECs is alternatively stimulated or inhibited by pro-inflammatory stimuli. GLP-1 in turn may control inflammation locally in the intestine through engagement of GLP-1 receptors on intestinal intraepithelial lymphocytes (IELs). GLP-1 may also reduce inflammation in different peripheral organs indirectly through weight loss or improved glucose control, or by targeting GLP-1Rs expressed on populations of circulating immune cells. Alternatively, GLP-1R activation may directly reduce inflammation in organs and cell types expressing the GLP-1R. The dashed line linking GLP-1 to anti-inflammatory actions in distinct organs reflects current uncertainty as to whether these actions are possibly direct or largely indirect. Cell Metabolism 2016 24, 15-30DOI: (10.1016/j.cmet.2016.06.009) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Direct and Indirect Actions of GLP-1 in the Heart and Blood Vessels The GLP-1R is expressed predominantly in the atrium of the heart. The localization of GLP-1R expression in blood vessels is less well understood. Some blood vessels express the GLP-1R within vascular smooth muscle, whereas potential GLP-1R expression in endothelial cell populations is less completely defined. The actions of GLP-1 on heart and blood vessels are shown, and may be direct or indirect, depending on the species and specific experimental paradigm examined. Cell Metabolism 2016 24, 15-30DOI: (10.1016/j.cmet.2016.06.009) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 GLP-1 Modifies CV Risk through Direct and Indirect Actions in Multiple Organs The targets for GLP-1 that may impact the risk of developing CV disease, and the consequences of GLP-1 action in specific tissues and cell types with CV implications, are shown. Cell Metabolism 2016 24, 15-30DOI: (10.1016/j.cmet.2016.06.009) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 4 The CV Safety of GLP-1R Agonists Based on results from the LEADER trial, sustained GLP-1R agonism in subjects with T2D at high risk for CV events produced a reduction in MACE events and CV mortality, balanced by gastrointestinal side effects, and lingering uncertainty about any possible associated increased risk of cancer. The CV benefit of GLP-1R agonists in obese non-diabetic subjects has not been established. Cell Metabolism 2016 24, 15-30DOI: (10.1016/j.cmet.2016.06.009) Copyright © 2016 Elsevier Inc. Terms and Conditions