Is the Way to Someone’s Heart Through Their Stomach?
The Cardiorenal Paradox of Incretin-Based Hypoglycemic Drugs in Heart Failure
This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Incretins are endogenous insulin secretagogues that are synthesized in the gastrointestinal tract and released by eating. Incretin mimetics (glucagon-like peptide-1 [GLP-1] receptor agonists) cause prolonged stimulation of the GLP-1 receptor, whereas incretin enhancers (DPP-4 [dipeptidyl peptidase-4] inhibitors) intensify the action of endogenous GLP-1 by blocking its degradation. The responses to these 2 incretin-based classes of drugs are both overlapping and distinct.1 The supraphysiological stimulation of GLP-1 receptors produced by agonists (eg, exenatide and liraglutide) is greater than that after the modest potentiation of GLP-1 that results from inhibition of DPP-4. Conversely, the actions of DPP-4 inhibitors (eg, sitagliptin and saxagliptin) may be modulated by the augmentation of endogenous peptides in addition to GLP-1.
Paradoxical Cardiorenal Effects of Incretin-Based Drugs
An intriguing feature of incretin-based drugs is their effect on the kidney. Whereas insulin and thiazolidinediones cause sodium retention,2,3 both GLP-1 receptor agonists and DPP-4 inhibitors increase urinary sodium excretion, which underlies their action to decrease blood pressure (Figure).4,5 Natriuresis leading to smaller ventricular volumes may explain the reportedly favorable effects of these drugs on cardiac remodeling.6,7 Both GLP-1 receptor agonists and DPP-4 inhibitors may also enhance cardiac function by optimizing the use of metabolic fuels by the heart.8,9 This spectrum of cardiorenal actions closely resembles that of SGLT2 (sodium-glucose cotransporter 2) inhibitors, which also exert natriuretic, antihypertensive, and beneficial …