Effects of the Novel Long-Acting GLP-1 Agonist, Albiglutide, on Cardiac Function, Cardiac Metabolism, and Exercise Capacity in Patients With Chronic Heart Failure and Reduced Ejection Fraction

Lepore, John J.; Olson, Eric J.; Demopoulos, Laura A.; Haws, Thomas F.; Fang, Zixing; Barbour, April M.; Fossler, Michael J.; Dávila‐Román, Víctor G.; Russell, Stuart D.; Gropler, Robert J.

doi:10.1016/j.jchf.2016.01.008

Cited by 107 publications

(91 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Findings of reduced numbers of total (fatal and nonfatal) MIs reported in liraglutide-treated subjects in LEADER (21) has heightened interest in identification of mechanisms linking GLP-1R signaling to ischemic cardioprotection. Although some studies demonstrate that GLP-1R agonism directly modulates cardiac fuel metabolism in normal or dysfunctional hearts from human subjects with or without T2D, the existing human data are inconclusive (58,59), and limited information is available regarding whether and how GLP-1 alters myocardial fuel metabolism in the ischemic or failing human heart. The accumulated evidence suggests that the GLP-1R is predominantly expressed in atria, and not ventricles, in hearts from mice and rats (3), indirectly localized via reporter gene expression to atrial cardiomyocytes and VSMs in mouse ventricle (34).…”

Section: Direct Glp-1 Action In the Heartmentioning

confidence: 99%

“…Reassuringly, no heart failure-related adverse outcomes were detected in studies examining the safety of GLP-1R agonists in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA), LEADER, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6), or EXSCEL (18-21), which collectively enrolled thousands of subjects with mild to moderate heart failure. Nevertheless, three smaller dedicated studies of more advanced heart failure, two with liraglutide (24 weeks) and one with albiglutide (12 weeks), failed to demonstrate functional improvement in human subjects, with or without T2D, with reduced ejection fraction and a history of hospitalization for heart failure (59,63,64). Indeed, rehospitalization for heart failure was numerically more common with liraglutide (63), and increased reports of arrhythmias, including supraventricular tachycardia, were noted in liraglutide-treated subjects in these trials (63,64), consistent with the localization of GLP-1R expression to the sinoatrial node.…”

Section: Heart Failurementioning

confidence: 99%

See 1 more Smart Citation

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Drucker

2018

Diabetes

View full text Add to dashboard Cite

Glucagon-like peptide 1 (GLP-1) was originally identified as a gut-derived incretin hormone that lowered glycemia through potentiation of glucose-dependent insulin secretion. Subsequent studies expanded the actions of GLP-1 to include inhibition of glucagon secretion, gastric emptying, and appetite, collectively useful attributes for a glucose-lowering agent. The introduction of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes was associated with questions surrounding their safety, principally with regard to medullary thyroid cancer, pancreatitis, and pancreatic cancer, yet cardiovascular outcome trials subsequently revealed reductions in rates of stroke, myocardial infarction, and cardiovascular death with a paucity of major safety signals. We discuss the controversies, unanswered questions, and established use of GLP-1R agonists from a mechanistic and clinical perspective. We highlight methods for detection and cellular sites of GLP-1R expression, key uncertainties, recent insights, and experimental caveats surrounding the use of GLP-1R agonists for the treatment of diabetes and the reduction of diabetes-related complications.

show abstract

Section: Direct Glp-1 Action In the Heartmentioning

confidence: 99%

Section: Heart Failurementioning

confidence: 99%

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Drucker

2018

Diabetes

View full text Add to dashboard Cite

show abstract

“…LePore et al [19] looked at the effects of 12 weeks of treatment of albiglutide, a long acting GLP -1 agonist in patients with stable, chronic heart failure with reduced LV EF <40% and NYHA functional class II to III symptoms. A 30mg dose was compared with placebo in 81 randomized patients.…”

Section: The Results Of Randomized Clinical Trialsmentioning

confidence: 99%

Metabolic Modulation with Incretins: Is the Bloom off the Rose?

Patterson¹

2017

J Cardiovasc Disord

View full text Add to dashboard Cite

For the better part of a half century, cardiovascular physiologists have recognized that the failing heart is characterized by perturbations in myocardial metabolism whether or not heart failure is accompanied by myocardial ischemia. These metabolic derangements have long been a target of therapeutic intervention but with little or no evidence of therapeutic benefit. Attempts to drive substrate uptake, oxidation, or utilization have all proven ineffective in altering the natural history and clinical symptoms in heart failure. The shift in substrate preference from fatty acid to glucose oxidation as a means to achieve oxidative efficiency has led to a focus on driving glucose metabolism. Early efforts to employ supplemental insulin, glucose and potassium (GIK) inadvertently exacerbated heart failure due to the volume requirements. These early failure led to a consideration of agents which further impair fatty acid oxidation as an intrinsic means of driving glucose utilization but to no avail. Thus, the emergence of incretin based therapies as an intrinsic insulin dependent means to increase glucose uptake and disposal were heralded as a next generation of metabolic adjuvants. There emergence on the scene corresponded to a period in which modifying cardiovascular outcomes in diabetes has become an equally compelling clinical objective particularly given the occurrence of diabetes and heart failure in the world's population. Here we review what has been learned regarding the cardiovascular effects of incretin based therapies and their impact on the progression of heart failure. At this point, effective metabolic modulation with incretins in heart failure remains elusive.Keywords: Heart Failure; Myocardial Metabolism; Incretins; GlucagonLike-Peptide-1; Metabolites advanced heart failure have been plagued by the requirements of simultaneous infusion of dextrose to avoid hypoglycemia, further exacerbating underlying volume overload [4,5]. Thus, the promissory note remains unfulfilled with respect to metabolic modulation in heart failure as a new therapeutic approach. The Allure of Incretin Based TherapyFor these reasons, there was a great deal of enthusiasm when incretin therapies emerged as an effective treatment for Type 2 diabetes. Glucagon-Like Peptide-1 (GLP-1 7-36 amide)is a naturally occurring incretin peptide released from intestinal L cells that enhances cellular glucose uptake by stimulating insulin secretion. The insulin stimulating actions of GLP-1 cease at glucose levels below 4 mmol/L, mitigating the risk of hypoglycemia and the need for dextrose infusion. GLP-1 also promotes increased glucose uptake in target tissues via mechanisms independent of insulin action. GLP-1 receptors have been identified in myocardium and in vascular and endocardial endothelium making GLP-1 administration a putative pharmacologic intervention in heart failure and ischemic heart disease as a means to favorably influence myocardial metabolism.Native GLP-1 (7-36) amide requires continuous infusion due to rapid hydrolysis...

show abstract

“…In addition, a recent study performed in T2D patients with HF (New York Heart Association II or III) and LVEF < 40% showed that treatment with the new GLP-1RA albiglutide (30 mg once a week for 12 weeks) compared with a placebo did not significantly improve LVEF, the 6-min walk test, or myocardial glucose or oxygen use [32].…”

Section: Glp-1 and Cardiac Functionmentioning

confidence: 99%

GLP-1 receptor agonists and heart failure in diabetes

Scheen

2017

Diabetes & Metabolism

View full text Add to dashboard Cite

The prevalence of heart failure (HF) is increasing in patients with type 2 diabetes (T2D), and glucose-lowering agents have distinctive effects on the risk of developing HF that requires hospitalization. Such an increased risk has been consistently reported with thiazolidinediones (glitazones) and perhaps also with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin (at least in SAVOR -TIMI 53), whereas a markedly decreased risk was highlighted with the sodium -glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin in EMPA-REG OUTCOME. Yet, the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on myocardial function remain controversial. Whereas some promising observations have been reported in various animal models, the effects of GLP-1RAs on myocardial function in humans are more heterogeneous, while the positive effect on left ventricular ejection fraction (LVEF), if any, appears to be inconsistent and rather modest in most patients with HF. However, no increased risk of hospitalization for HF has been reported with GLP-1RAs in meta-analyses of phase-II/III trials (exenatide, albiglutide, dulaglutide, liraglutide), demonstrating the safety of this pharmacological class, and such findings have been confirmed by three large prospective cardiovascular outcome trials (ELIXA with lixisenatide, LEADER with liraglutide and SUSTAIN-6 with semaglutide). In particular, LEADER reported a trend towards a reduction in HF hospitalization (-13%, P = 0.14), together with a significant reduction in cardiovascular and all-cause mortality in patients with T2D at risk of cardiovascular disease. These results are reassuring in the face of the somewhat negative results of the FIGHT trial, which evaluated the effects of liraglutide in patients with advanced HF and low LVEF, such that further studies and caution are now required when using this agent to treat such patients in clinical practice.

show abstract

Effects of the Novel Long-Acting GLP-1 Agonist, Albiglutide, on Cardiac Function, Cardiac Metabolism, and Exercise Capacity in Patients With Chronic Heart Failure and Reduced Ejection Fraction

Cited by 107 publications

References 24 publications

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Metabolic Modulation with Incretins: Is the Bloom off the Rose?

GLP-1 receptor agonists and heart failure in diabetes

Contact Info

Product

Resources

About