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The Effects of GLP-1 on Cardiovascular Health

Tina Burge, Doctor of Pharmacy Candidate, FAMU College of Pharmacy

Reviewed by Dave Joffe, BSPharm, CDE

It’s well-known that patients with diabetes have an increased risk of cardiovascular disease when compared to patients without diabetes.

Diabetes type 2 has a high prevalence in the obese (BMI ³ 25kg/m2) and overweight (BMI ³ 30kg/m2) population, and these patients tend to have poor diets and sedentary lifestyles. Characteristics such as unhealthy nutrition habits, sedentary lifestyle as well as visceral obesity, in combination with diabetes, can contribute to other metabolic disorders.

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Metabolic disorders such as hypertension and dyslipidemia are considered to be risk factors that put the patient at an increased risk for cardiovascular disease. These cardiovascular factors increase the patient’s overall risk of mortality and morbidity due to potential cardiovascular events such as a myocardial infarction or stroke1. In fact approximately 65% of all deaths in patients with type 2 diabetes are a result of a cardiovascular disease2. Management for diabetes must therefore be multifaceted, besides simply controlling glucose. Guidelines recommend aggressive treatment to decrease cardiovascular risk factors, by providing weight, blood pressure and lipid management2.

Not many anti-diabetic agents have the potential to decrease the patient’s risk factors for cardiovascular disease and some may even cause the patient to gain weight leading to other co-morbidities.

Incretin based therapies, such as glucagon-like peptide-1 (GLP-1) receptor agonists mimic the hormone that originates from the small intestine and is released in response to nutrition intake.

These analogs are beneficial to diabetes patients in numerous ways as they work by enhancing glucose-dependent insulin secretion, suppressing elevated glucagon secretion, slowing gastric emptying, and suppressing appetite.

GLP-1 receptors are also found in the lungs, kidney, intestine and several locations in the central nervous system. Additionally, GLP-1 receptors are widely expressed in the heart and therefore studies have shown that the benefits exceed glucose control and are also helpful in the cardiovascular system. Some specific locations of these receptors are in the vascular smooth muscle, cardiomyocytes, endocardium and coronary endothelium/smooth muscle.

Studies have shown that GLP-1 receptors play important roles in the cardiovascular system such as adjusting of the heart rate, blood pressure, vascular tone and myocardial contractility3.

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Protective Cardiovascular Effects of GLP-1
As seen in the figure above, there are several pathways that lead to the cardiovascular effects seen with GLP-1. Once GLP-1 binds to its receptor in the heart it induces activation of cyclic adenosine monophosphate (cAMP) and phosphatidylinositol 3-kinase (PI3K). This pathway helps with ischemic preconditioning and decreases the myocyte apoptosis.

There are also GLP-1 receptors in the brain which help activate nitric oxide synthase, causing vasodilatation to control blood pressure4.

N. Brown notes that in a large retrospective study, patients who were treated with exenatide were less likely to be hospitalized for CVD even though they were more likely to have CAD & risk factors then those patients not treated with exenatide4. Another study done with mice by Forst and colleagues, showed that binding of GLP-1 to the GLP-1 receptor in the myocardium leads to an increase in production of cAMP and activation of protein kinase A, which yields an increase in glucose uptake and the inotropic effects of the heart. In addition, GLP-1 treatments showed an improvement on left ventricular function as well as reducing the levels of the brain natriuretic peptide (BNP), which is a hormone associated with heart failure.

The hypothesis is that there are two pathway mechanisms for the protective cardiovascular action of GLP-1. One depends on the GLP-1 receptor mediated action with inotropic, glucose uptake stimulating, and ischemic preconditioning effects, and secondly that the GLP-1 receptor independent pathway causes vasodilatation that is mediated by nitric oxide5.

GLP-1 Effect on Dyslipidemia

Weight is a contributing factor in increasing patients’ cardiovascular risk, and many antidiabetic agents available are associated with weight gain or other cardiovascular problems. As stated above, GLP-1 receptor agonists work by slowing gastric emptying and increasing the feeling of satiety, which can be related to the weight loss seen with this agent. As we know, any weight loss could be beneficial to the patient’s lipid profile. Measures of cardiovascular risk factors were evaluated in the DURATION trials; these trials compared diabetic agents to one another. Conclusions of the DURATION trials, showed that exenatide weekly had positive improvements on weight loss with an average of 4-5kg and also demonstrated significant improvement in total cholesterol in three of the four-comparator DURATION trials. Exenatide weekly was also associated with improvements in low-density lipoprotein (LDL) within two of the trials and no other drug in the trial saw these improvements6.

GLP-1 Effect on Hypertension

It’s not yet certain whether the additional benefits seen with the GLP-1 receptor agonist such as improving lipid profile and reductions in systolic blood pressure are related to the weight loss or the drug itself. However, according to the Liraglutide Effect and Action in Diabetes (LEAD) the reduction in systolic blood pressure of 3.6-6.7mmHg occurred within 2 weeks, which resulted prior to any substantial weight loss, this effect lasted throughout the entire 26-week trial7. Also in the DURATION trial, exenatide weekly had beneficial reductions of -3 to -5mm Hg in systolic blood pressure6.

Numerous studies show that the GLP-1 receptor agonists have favorable benefits on the lipid panels, as there were decreases in total cholesterol, and LDL. Besides the benefit in the lowering of cholesterol, GLP-1 receptor agonists also have been implicated to reduce systolic blood pressure in patients8.

It is now even more important that treatments for type 2 diabetes should be selected not just solely on their glucose lowering capability but also on their overall ability to lower mortality.

References: 
  1. Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. Journal of Diabetes.4 (2012) 55-67
  2. Kurukulasuriya LR, Sowers JR. Therapies for type 2 diabetes: lowering A1C and associated cardiovascular risk factors. Cardiovascular Diabetology. 9:45, 2010
  3. Grieve DJ, Cassidy RS, Green BD. Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycemic control. British Journal of Pharmacology. 157: 1340-1351. 2009
  4. Brown Nancy. Cardiovascular effects of antidiabetic agents: focus on blood pressure effects on incretin-based therapies. Journal of the American Society of Hypertension. 6(3). 2012 163-168
  5. Forst T, Weber MM, Pfutzner A. Cardiovascular Benefits of GLP-1-Based Therapies in Patients with Diabetes Mellitus Type 2: Effect on Endothelial and Vascular Dysfunction beyond Glycemic Control. Experimental Diabetes Research. 2012
  6. Stonehouse A, Walsh B, Cuddihy, R. Exenatide Once-Weekly Clinical Development: Safety and Efficacy Across a Range of Background Therapies. Diabetes Technology & Therapeutics. 13:10. 2011
  7. Cariou B. Harnessing the incretin system beyond glucose control: Potential cardiovascular benefits of GLP-1 receptor agonists in type 2 diabetes. Diabetes & Metabolism. 2012
  8. Addison D, Aguilar D. Diabetes and Cardiovascular Disease: The Potential Benefit of Incretin-Based Therapies. Curr Atherscler Rep. 13(2): 115-122. 2011
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