Is the Way to Someone’s Heart Through Their Stomach?
2017; Lippincott Williams & Wilkins; Volume: 10; Issue: 10 Linguagem: Inglês
10.1161/circheartfailure.117.004551
ISSN1941-3297
Autores Tópico(s)Diabetes Management and Research
ResumoHomeCirculation: Heart FailureVol. 10, No. 10Is the Way to Someone's Heart Through Their Stomach? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBIs the Way to Someone's Heart Through Their Stomach?The Cardiorenal Paradox of Incretin-Based Hypoglycemic Drugs in Heart Failure Milton Packer, MD Milton PackerMilton Packer From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX. Originally published11 Oct 2017https://doi.org/10.1161/CIRCHEARTFAILURE.117.004551Circulation: Heart Failure. 2017;10:e004551Incretins 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 DrugsAn 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 cardiac metabolic effects.10,11Download figureDownload PowerPointFigure. Contrasting effects of antihyperglycemic drugs on cAMPin the heart and sodium excretion in the kidney. Insulin and many drugs that act through insulin (ie, thiazolidinediones) exert positive inotropic effects experimentally and can lead to sodium retention. Glucose-like peptide-1 (GLP-1) receptor agonists exert both positive inotropic and positive chronotropic effects by increasing intracellular cAMP. Such an action has been demonstrated to have deleterious effects in patients with heart failure. This may explain why GLP-1 receptor agonists (such as liraglutide) can worsen heart failure, even though they act to increase sodium excretion in the kidney. SGLT2 (sodium-glucose cotransporter 2) inhibitors have natriuretic effects without increasing cardiac contractility or heart rate, and they reduce the risk of new-onset heart failure. DPP-4 indicates dipeptidyl peptidase-4.Drugs that have natriuretic effects typically reduce the risk of new-onset heart failure when given to patients at increased cardiovascular risk.12 Therefore, in light of their shared natriuretic capability, we might anticipate a reduced risk of heart failure with both incretin-based drugs and SGLT2 inhibitors. In large-scale studies with empagliflozin and canagliflozin in diabetes mellitus, SGLT2 inhibition markedly reduced the risk of new-onset heart failure; the effect size was large when compared with the minimal effects on myocardial infarction and stroke.13,14 In contrast, although GLP-1 receptor agonists (but not DPP-4 inhibitors) reduce the risk of atherosclerotic ischemic events, neither incretin-based treatment ameliorates the likelihood of heart failure.15–20 In diabetes mellitus, the risk of hospitalization for heart failure was not decreased in large-scale studies with liraglutide and lixisenatide15,17 or with sitagliptin, saxagliptin, and alogliptin.18–20Furthermore, in patients with existing cardiac dysfunction, both incretin-based treatments have been associated with worsening heart failure. In a trial in moderate-to-severe heart failure,21 treatment with liraglutide was associated with more hospitalizations for heart failure and significant worsening of renal function. In a trial in diabetes mellitus,22 saxagliptin was associated with a significant increase in the risk of hospitalization for heart failure, which was seen primarily in patients with biomarker evidence for elevated cardiac filling pressures at study entry. Admittedly, the findings in the saxagliptin trial were based on post hoc analyses that focused only on admissions that required intravenous therapy and have inconsistently confirmed in a meta-analysis of clinical trials22 or in observational studies of community use.23–25 Nevertheless, worsening heart failure is an established risk of many antidiabetic drugs that act through insulin,26–30 although this injurious effect has long been ascribed to the antinatriuretic actions of these agents.2,3,31Uncertainty About the Actions of Incretin-Based Drugs on the HeartWhy are the natriuretic and metabolic benefits of incretin-based treatments insufficient to prevent heart failure, in contrast to SGLT2 inhibitors? In experimental and clinical studies, GLP-1 receptor agonism produces positive inotropic and chronotropic effects by increasing intracellular cAMP (Figure).32–37 This action is qualitatively similar to that produced by β-adrenergic agonists and phosphodiesterase inhibitors, which are known to exert serious adverse effects in chronic heart failure, particularly in those with advanced disease.38 Increases in cAMP underlie the increases in ejection fraction and heart rate seen with infusions of GLP-1 in patients with heart failure,39–41 as well as the increase in heart rate in those with diabetes mellitus.42,43 Unfortunately, drugs that increase heart rate enhance the risk of major cardiovascular events in patients with glucose intolerance.44 Similarly, drug-induced changes in heart rate have important influences on the morbidity and mortality in heart failure.45,46 Interestingly, DPP-4 inhibitors also increase cAMP and may increase heart rate,43,47–49 but their cardiac effects are poorly characterized, possibly because they augment and diminish endogenous peptides with opposing effects on the heart.1,50,51 Nevertheless, it is noteworthy that antidiabetic drugs that act through insulin and have led to worsening heart failure in clinical studies26–30 can be shown to exert positive inotropic actions experimentally (Figure).52–55 In contrast, SGLT2 is not expressed in the heart and cannot mediate changes in cardiac inotropy or chronotropy.56We know that the effects of a drug before the onset of heart failure may differ from its effects after overt symptoms ensue. Statins can prevent heart failure,57 but they do not alter the course of patients with established heart failure.58 Drugs that lower blood pressure reduce the onset of heart failure in patients with hypertension,59 but most antihypertensive agents do not benefit patients with established heart failure.60,61 α-Adrenergic blockers increase the risk of heart failure when used to treat hypertension,62 but they do not adversely affect patients with manifest heart failure.63 Therefore, studies of the cardiovascular safety of incretin-based drugs in patients without heart failure may tell us little about their effects in those with established symptoms.64After the reporting of large-scale trials, physicians have become concerned about the cardiovascular safety of DPP-4 inhibitors but sanguine about the cardiovascular actions of GLP-1 receptor agonists. However, we know little about the benefits and risks of incretin-based drugs in chronic heart failure. Only a small fraction (<15%) of the patients enrolled in the major trials of GLP-1 receptor agonists and DPP-4 inhibitors had heart failure during their baseline evaluation. Yet, diabetes mellitus and heart failure frequently coexist and share many pathophysiological derangements;10 thus, the prescribing of incretin-based treatments in patients with a reduced ejection fraction will increase in the coming years, and our lack of understanding of this potential drug–disease interaction is discomforting. New studies may yet challenge the proverbial assumption that broken hearts are gladdened by a seductive gastronomic hormonal event.DisclosuresDr Packer has recently consulted for Amgen, AstraZeneca, Bayer, BioControl, Boehringer Ingelheim, Cardiorentis, Celyad, Daiichi Sankyo, Relypsa, Sanofi, Takeda, and ZS Pharma.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circ Heart Fail is available at http://circheartfailure.ahajournals.org.Correspondence to: Milton Packer, MD, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N Hall St, Dallas, TX 75226. E-mail [email protected]References1. Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies.Circ Res. 2014; 114:1788–1803. doi: 10.1161/CIRCRESAHA.114.301958.LinkGoogle Scholar2. Tiwari S, Riazi S, Ecelbarger CA. 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October 2017Vol 10, Issue 10 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.117.004551PMID: 29021350 Originally publishedOctober 11, 2017 Keywordsdiabetes mellituscyclic AMPheart failureincretinsantidiabetic drugsPDF download Advertisement SubjectsHeart FailureMetabolic Syndrome
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