Current challenges in the treatment of cardiac fibrosis: Recent insights into the sex‐specific differences of glucose‐lowering therapies on the diabetic heart: IUPHAR Review 33

Figures

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  FIGURE 1. Diabetes‐induced cardiac pathologies that contribute to the development of left ventricular (LV) remodelling in patients with diabetes and heart failure with preserved or reduced ejection fraction (HFpEF or HFrEF). (a) In the setting of diabetes, hyperglycaemia contributes to the formation and attachment of advanced glycation end products (AGEs) to myocardial collagen fibres. Alongside advanced glycation end products, endothelial cell dysfunction and hyperinsulinaemia promote pathological concentric remodelling whereby the LV thickens and there is increased interstitial and perivascular cardiac fibrosis. Consequently, patients develop HFpEF, a heart failure phenotype more common in women. (b) Diabetes‐induced increases in cardiac lipotoxicity, ROS formation and cardiomyocyte apoptosis contribute to the development of cardiac eccentric remodelling (LV expansion and myocardial wall thinning), ultimately resulting in HFrEF. There is also greater LV replacement fibrosis and scar formation. Men are more likely to develop eccentric cardiac remodelling and HFrEF. Red lightning bolts signify advanced glycation end products (AGEs). Red X's represents cellular dysfunction. Blue stars…

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  FIGURE 2. Mechanism of action of newer glucose‐lowering therapies and renin‐angiotensin‐aldosterone system inhibitors (RAASi), and their effects on the failing, diabetic heart. Target organs and actions of dipeptidyl peptidase 4 inhibitors (DPP4i), glucagon‐like peptide 1 receptor agonists (GLP‐1RAs), sodium‐glucose co‐transporter 2 inhibitors (SGLT2i), dual gastric inhibitory polypeptide receptor (GIPR)/ GLP‐1RAs and RAASi, are summarised above the coloured boxes. Effects of these treatments on the diabetic heart are summarised within the coloured boxes. Solid arrows indicate that effects of treatments on cardiovascular events and/or cardiac fibrosis are known. Dashed arrows indicate that the effects of the treatments on cardiovascular events and cardiac fibrosis are unknown. HF, heart failure; MACE, major adverse cardiovascular event. See text for references. Schema created using modifications to images provided by Servier Medical Art by Servier (https://smart.servier.com/), licensed under a Creative Commons Attribution 3.0 Unported Licence (https://creativecommons.org/licenses/by/3.0/)