Mechanisms of Cardiorenal Protection of Glucagon-Like Peptide-1 Receptor Agonists

Kalie L Tommerdahl, Kristen J Nadeau, Petter Bjornstad, Kalie L Tommerdahl, Kristen J Nadeau, Petter Bjornstad

Abstract

The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel antidiabetic agents, diabetic kidney disease and cardiovascular disease remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate postprandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of antihyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual- and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.

Keywords: Cardiovascular disease; Diabetic kidney disease; GLP-1 receptor agonists; Type 2 diabetes.

Conflict of interest statement

Disclosure summary: PB has acted as a consultant for Bayer, Bristol-Meyers Squibb, Boehringer Ingelheim, Sanofi, Astra Zeneca, Novo Nordisk, and Horizon Pharma. PB serves on the advisory boards of XORTX and Boehringer Ingelheim. No potential conflicts of interest relevant to this article were reported from any of the authors.

Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.
Figure 1.
Proposed Mechanisms of Cardiorenal Protection of Glucagon-Like Peptide-1 Receptor Agonist Therapies Key: BG – blood glucose, IR – insulin resistance, LDL – low density lipoprotein, TG –triglyceride, BP – blood pressure, ATP – adenosine triphosphate, GFR – glomerular filtration rate
Figure 2.
Figure 2.
Hypothesized Mechanisms of Synergy for Combination GLP-1/GIP/Glucagon Receptor Agonist Therapies Key: GLP-1 – glucagon-like peptide-1, GIP – glucose-dependent insulinotropic polypeptide

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