Cardiovascular Effects of Glucagonlike peptide–1 Agonists

doi:10.1016/j.amjcard.2011.03.046

The American Journal of Cardiology

Volume 108, Issue 3, Supplement, 2 August 2011, Pages 33B-41B

https://doi.org/10.1016/j.amjcard.2011.03.046 Get rights and content

Type 2 diabetes mellitus is acknowledged as a major risk factor for the development of cardiovascular disease (CVD). Advancing treatment options for person with diabetes beyond glucose control to prevent microvascular and macrovascular complications and ultimately have an impact on CVD development holds great significance for the growing number of persons with diabetes. Glucagonlike peptide–1 (GLP-1) is an incretin secreted in response to nutrient ingestion that inhibits glucagon secretion and gastric emptying, resulting in reduced postprandial glycemia. GLP-1 has insulinomimetic, insulinotropic, and antiapoptotic properties. GLP-1 agonists (exenatide and liraglutide) are a class of drugs approved for the treatment of diabetes that have significant cardiovascular (CV) effects. These CV effects potentially provide an opportunity for clinicians to address the multifactorial issues involved in the increased CV morbidity and mortality associated with diabetes. This article presents an overview of the CV effects of GLP-1 agonists, highlighting implications for the management of patients with diabetes and heart disease.

Section snippets

Incretin Effect

GLP-1 agonists address an important metabolic deficit in type 2 diabetes known as the incretin effect. In individuals with normal glucose tolerance, the ingestion of glucose involves a much larger insulin response than observed after an isoglycemic intravenous glucose infusion. This enhancement in insulin secretion called the “incretin” effect is markedly reduced to <50% in patients with diabetes compared with individuals with normal blood glucose. The incretin effect is mediated by the

Glucagonlike peptide–1 and the Cardiovascular System

Upon binding of GLP-1 to the GLP-1R receptor in the myocardium mediated by the production of cyclic adenosine monophosphate (cAMP) and activation on protein kinase A (PKA) there is increased inotropic action and glucose uptake. GLP-1 appears to also have GLP-1R–independent effects. Based on animal model experiments, the GLP-1R–independent effects include modest glucose uptake and vasodilatation through a nitric oxide/cyclic guanosine monophosphate (cGMP) pathway (endothelial independent) (

Effects of Glucagonlike peptide–1 on Models of Atherosclerosis

In addition to the effects GLP-1 agonists have on the CV system mediated by activation of the GLP-1R on the cardiomyocytes or the endothelium, GLP-1 may also have effects on the atherosclerotic process through direct actions involving interaction with monocytes/macrophages. Macrophages contain GLP-1 receptors, and upregulation of cAMP is a well-recognized mechanism to enhance cholesterol efflux and promote reverse cholesterol transport. Treatment with exendin-4 significantly inhibited monocytic

Glucagonlike peptide–1 Therapy and Improvement in Cardiovascular Risk Factors

GLP-1R agonists have a positive impact on CV risk factors that are not specifically addressed by standard diabetes therapies. Both liraglutide and exenatide have been demonstrated to have an impact on CV risk factors, including promoting weight loss and reducing systolic blood pressure. The use of exenatide, an injectable GLP-1 receptor agonist, in patients with type 2 diabetes has been demonstrated to result in reduction in hypertension, dyslipidemia and lower risk of CVD events (MI, ischemic

Conclusions

GLP-1 has been demonstrated to have a number of CV effects that potentially provide an opportunity for clinicians to address the multifactorial issues involved in the increased CV morbidity and mortality associated with diabetes. The recent CV outcome trials with drugs to lower elevated glucose levels have been disappointing. In part, the disappointing results may relate to the adverse effects of specific glucose-lowering drugs such as weight gain, fluid retention and hypoglycemia and the

Author Disclosures

The author of this article has disclosed the following industry relationships:

Michael H. Davidson, MD, is a member of the Speakers' Bureau for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, and Merck & Co., Inc.; has worked as a consultant to Abbott Laboratories, Aegerion Pharmaceuticals, Inc., Amgen Inc., AstraZeneca, Atherotech, Daiichi-Sankyo Co. Ltd., Esperion Therapeutics, Inc., KineMed, Inc., LipoScience Inc., Merck & Co., Inc., Novo Nordisk A/S, Hoffman-La Roche Ltd, sanofi-aventis,

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Cited by (75)

GLP-1 agonists: A review for emergency clinicians
2024, American Journal of Emergency Medicine
Glucagon-like peptide 1 (GLP-1) based therapies, including GLP-1 agonists, are currently in use for treatment of diabetes and obesity. However, several complications may occur with their use.
This narrative review provides a focused evaluation of GLP-1 agonist therapy and associated complications for emergency clinicians.
GLP-1 agonists potentiate insulin release and reduce gastric emptying and food intake. These agents have demonstrated significant improvements in glucose control in diabetics and weight loss in obese patients. The two most common agents include subcutaneous semaglutide (Ozempic, approved for type 2 diabetes, and Wegovy, approved for weight loss) and liraglutide (Saxenda, approved for weight loss, and Victoza, approved for type 2 diabetes), though an oral formulation of semaglutide is available (Rybelsus). While these drugs are associated with improved long-term outcomes, there are a variety of associated adverse events. The most common include gastrointestinal (GI) adverse events such as nausea, vomiting, diarrhea, and abdominal pain. Pancreatitis and biliary disease may also occur. Hypersensitivity including injection site reactions have been associated with use, with reports of anaphylaxis and other rashes. Renal adverse events are most commonly associated with severe GI losses. Hypoglycemia may occur when these agents are used with sulfonylureas or insulin. There is also an increased risk of diabetic retinopathy. Due to the current shortage and expense of these medications, many patients have attempted to obtain these medications from non-licensed and unregulated agents, which may be associated with increased risk of serious complications.
An understanding of the indications for GLP-1 agonist use and associated adverse events can assist emergency clinicians.
Cardioprotective properties of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus patients: A systematic review
2021, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citation Excerpt :
This weight loss effect from GLP-1 RA also demonstrated by other studies [23–25]. Better results were found in exenatide therapy, that significantly reduced body weight, waist circumference, and total body and fat truncal fat mass [26]. This effect will be helpful for T2DM patients in reducing the risk of cardiovascular disease, because excess fat accumulation triggered cardiovascular disease through supporting premature atherosclerosis formation in large arteries and causing abnormality in coronary microvasculature.
Cardiovascular disease is one of the main contributors for the mortality in type 2 diabetes mellitus (T2DM) patients. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) had shown cardiovascular benefits which may be advantageous to reduce mortality in T2DM patients. This systematic review focused on analyzing the effects of GLP-1 RAs on cardiovascular outcomes.
We conducted an extensive search through JSTOR, PubMed, Scopus, EBSCohost, and CENTRAL. All related studies assessing the use of GLP-1 RAs in T2DM patients from inception up to October 2020 were screened. Any cardioprotective properties as the outcomes were obtained.
A total of six studies (4 randomized, 2 observational) with a total of 182.205 patients were included in this review. The GLP-1 RAs used were either liraglutide or exenatide in combination with antihypertensive or antilipidemic drugs. All studies showed that GLP-1 RA significantly caused weight loss and improved cardiac functional capacity by increasing left ventricular ejection fraction and reducing end-systolic and end-diastolic left ventricle volume. GLP-1 RA also improved myocardial blood flow without affecting myocardial glucose uptake. However, GLP-1 RA failed to show its effect in reducing blood pressure and improving lipid profiles.
Despite the limited number of studies, consistent data showed that GLP-1 RA has several cardioprotective properties.
Exenatide alleviates adriamycin-induced heart dysfunction in mice: Modulation of oxidative stress, apoptosis and inflammation
2019, Chemico-Biological Interactions
Citation Excerpt :
It is reported that GLP-1 could directly protect the heart against myocardial ischaemia injury via suppressing oxidative stress and apoptosis, while this change can be reversed by GLP-1 receptor antagonist [35]. Also, GLP-1R stimulation in cardiomyocytes has been shown to enhance survival through the activation of the RISK pathway [36,37], indicating that this protective action is at least partly dependent on GLP-1 receptors. Of interest, researcher found that liraglutide can also exert similar beneficial effect on animal and H9c2 cells [34,38].
Adriamycin (ADR) is an effective antineoplastic drug; the clinical application of ADR is limited due to fatal heart dysfunction. Exenatide has antioxidant, anti-apoptotic and anti-inflammatory properties. It can alleviate heart damage induced by ischaemia-reperfusion injury. Thus, we assumed that exenatide would produce protective effects on ADR-induced heart dysfunction.
Mice were treated with exenatide 1 h prior to every ADR treatment for 20 days. Left ventricular function and performance were assessed by echocardiography. Additionally, H9c2 cells were pretreated with exenatide followed by ADR, and intracellular reactive oxygen species (ROS) and cell viability, as well as the lactate dehydrogenase (LDH) and the creatine kinase MB (CK-MB), were subsequently measured. Flow cytometry and TUNEL staining were applied to assess the effect of exenatide on cardiac damage caused by ADR. Western blot and RT-PCR were performed to detect the effect of exenatide on apoptosis-related genes (Bcl-2 and Bax) and inflammation-related genes and/or proteins (tumour necrosis factor-α, interleukin-6, nuclear factor-κB, and p53).
Echocardiography showed that cardiac dysfunction caused by ADR was significantly improved by treatment with exenatide. ADR mice had harmful changes in the levels of ROS and CK-MB/LDH production, as well as the targeted apoptotic and inflammatory molecules, and these effects were also reversed by exenatide. In vitro, exenatide mitigated ADR-induced oxidative stress and CK-MB/LDH production, as well as Annexin V⁺/PI⁺ and TUNEL⁺ apoptosis in H9c2 cells.
In conclusion, our research demonstrated the potential protective effects of exenatide on ADR-induced heart dysfunction through suppressing oxidative stress, apoptosis and inflammation.
Cardiovascular safety of GLP-1 receptor agonists for diabetes patients with high cardiovascular risk: A meta-analysis of cardiovascular outcomes trials
2018, Diabetes Research and Clinical Practice
To show long-term cardiovascular safety of the GLP-1 receptor agonists for diabetes patients with cardiovascular risk.
For cardiovascular outcomes, the association between treatment and outcomes was estimated using the odds ratio and 95% confidence interval. I² test was adopted to assess the magnitude of heterogeneity between studies, with values more than 25%, 50%, and 75% defined as low, moderate, or high heterogeneity.
We combined data from four cardiovascular outcomes trials and prospectively blinded endpoint adjudication. 4105 cardiovascular events including cardiovascular death, acute MI or stroke experienced during the trials. And the odds ratios of the cardiovascular outcomes were 0.90 (95% CI 0.81, 1.00) for the cardiovascular outcome, 0.93 (95% CI 0.85, 1.02) for nonfatal myocardial infarction, 0.88 (95% CI 0.76, 1.03) for nonfatal stroke, 0.94 (95% CI 0.84, 1.05) for heart failure hospitalization, 0.89 (95% CI 0.63, 1.27) for pancreatitis, 0.98 (95% CI 0.92, 1.05) for any hypoglycemic events, 0.92 (95% CI 0.83, 1.01) for the severe hypoglycemic events, 0.96 (95% CI 0.83, 1.01) for serious adverse events. Significant differences showed in mortality parameters: 0.88 (95% CI 0.81, 0.95) for all-cause mortality, 0.87 (95% CI 0.79, 0.97) for cardiovascular mortality. CV benefits were obtained in the male, black, Asian patients and patients with BMI ≥ 30 kg/m².
Additional GLP-1 receptor agonists treatment did not increase cardiovascular outcomes in diabetes patients with high cardiovascular risk or established cardiovascular disease.
The Medical Treatment of Stable Angina
2018, Chronic Coronary Artery Disease: A Companion to Braunwald's Heart Disease
The Medical Treatment of Stable Angina
2017, Chronic Coronary Artery Disease: A Companion to Braunwald's Heart Disease

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: Publication of this supplement was supported by funding from Novo Nordisk. Editorial support was provided by Dr. Ruth Kleinpell and Mary Lou Briglio.

: Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

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Cardiovascular Effects of Glucagonlike peptide–1 Agonists

Section snippets

Incretin Effect

Glucagonlike peptide–1 and the Cardiovascular System

Effects of Glucagonlike peptide–1 on Models of Atherosclerosis

Glucagonlike peptide–1 Therapy and Improvement in Cardiovascular Risk Factors

Conclusions

Author Disclosures

Cell Metab

Regul Pept

J Card Fail

Am J Cardiol

Regul Pept

Biochem Biophys Res Commun

Lancet

Lancet

Effects of intensive glucose lowering in type 2 diabetes

N Engl J Med

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes

N Engl J Med

Lipoprotein particle concentrations may explain the absence of coronary protection in the women's health initiative hormone trials

Arterioscler Thromb Vasc Biol

A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia

Diabetes Care

Glucose control and vascular complications in veterans with type 2 diabetes

N Engl J Med

GLP-1 agonist-based therapies: an emerging new class of antidiabetic drug with potential cardioprotective effects

Curr Atheroscler Rep

Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the Lifelink database

Diabetes Care

Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury

Diabetes

Exenatide as a treatment for diabetes and obesity: implications for cardiovascular risk reduction

Curr Atheroscler Rep

Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts

J Pharmacol Exp Ther

Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure

Diab Vasc Dis Res

Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion

Circulation

Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor dependent and independent pathways

Circulation