Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future

James P. Psaltis
Adelaide Medical School, The University of Adelaide, Adelaide, Australia

Jessica A. Marathe
Adelaide Medical School, The University of Adelaide, Adelaide, Australia
Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical
Research Institute, Adelaide, Australia
Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia

Mau T. Nguyen
Adelaide Medical School, The University of Adelaide, Adelaide, Australia
Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical
Research Institute, Adelaide, Australia
Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia

Richard Le
Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical
Research Institute, Adelaide, Australia
College of Medicine and Public Health, Flinders University, Adelaide, Australia

Christina A. Bursill
Adelaide Medical School, The University of Adelaide, Adelaide, Australia
Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical
Research Institute, Adelaide, Australia

Chinmay S. Marathe
Adelaide Medical School, The University of Adelaide, Adelaide, Australia
Department of Endocrinology, Central Adelaide Local Health Network, Adelaide, Australia

Adam J. Nelson
Adelaide Medical School, The University of Adelaide, Adelaide, Australia
Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical
Research Institute, Adelaide, Australia
Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia

Peter J. Psaltis
Adelaide Medical School, The University of Adelaide, Adelaide, Australia
Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical
Research Institute, Adelaide, Australia
Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia

Abstract

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or over- weight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose- dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2 % and weight loss exceeding 15 % from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease.

Key words: atherosclerosis, diabetes, incretins, obesity, tirzepatide

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2024

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James P. Psaltis, Jessica A. Marathe, Mau T. Nguyen, Richard Le, Christina A. Bursill, Chinmay S. Marathe, Adam J. Nelson, Peter J. Psaltis (2024). Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future 13(5), (8-38)