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GLP-1 Agonist-based Therapies: An Emerging New Class of Antidiabetic Drug With Potential Cardioprotective Effects, Part 1

Melanie Sulistio, MD, Curtis Carothers, MD, Mandeep Mange, BS, Mike Lujan, BS, Rene Ofiveros, MD, and Robert Chilton, DO

Cardiovascular disease is a leading cause of death in the United States and across the world, and better therapies are constantly being sought to improve patient outcomes. Recent studies have brought our attention to the mechanisms of glucagon-like peptide 1 (GLP-1). Not only does it demonstrates beneficial effects in regard to cardiovascular risk factors (ie, diabetes, lipid management, and weight control), but it also has been shown in animal studies to have positive cardiac effects irrespective of its effects on glucose control and weight loss. This review discusses the biology of GLP-1 and its effects on cardiovascular risk factors, and it also elaborates on the positive direct cardiovascular outcomes of GLP-1 in animal studies.

PART 1: GLP 1 Agonist-based Therapies: How do they work?

What therapeutic approaches have been developed to overcome rapid degradation of GLP-1?

See more GLP-1 Agonist Resources.

Introduction

It has long been recognized that diabetes is a major risk factor for the development of cardiovascular disease. Cardiologists have aggressively treated dyslipidemia, hypertension, and smoking but have somewhat neglected diabetes. Many patients admitted for acute myocardial infarction have type 2 diabetes, and they are more likely to die during the acute episode or in follow-up [1].

Most patients with type 2 diabetes are overweight or obese. The excessive weight gain further fuels the disease by worsening insulin resistance, dyslipidemia, hypertension, and pancreatic a-cell failure, resulting in a downward spiral [2]. Weight loss should be a major treatment goal in overweight individuals with type 2 diabetes, but it is rarely achieved. Indeed, weight gain is expected and accepted with sulfonylureas, insulin, or the thiazolidinediones. Excessive weight gain associated with sulfonylureas and insulin treatment is not benign and results in worsening of well-known cardiovascular risk factors, potentially contributing to the increased macro-vascular risk. Additionally, the cardiovascular risk profile varies between antidiabetic agents. For example, the sul­fonylureas have little to no effect on insulin resistance, blood pressure, lipid profiles, or coagulant factors. In fact, large cohort-based studies have implicated sulfonylureas to potential harmful cardiovascular outcomes in patients with type 2 diabetes [3-5].

Better glycemic control is still the goal in diabetes to prevent microvascular disease. However, to impact macro-vascular disease, the drug chosen to lower blood glucose concentration may be more important [6]. This article reviews the glucagon-like peptide 1 (GLP-1) agonist—based therapies as a new class of antidiabetic and their potential effects beyond glucose control that may ultimately impact cardiovascular disease.

Understanding the Physiology of GLP-1

GLP-1 is derived from the proglucagon gene from the L cells of the ileum and colon. Two forms of GLP-1 are secreted in response to a meal: GLP-1(1-37) and GLP-1 (7-36), but the predominant form in the circulation is the truncated form GLP-1(7-36) [7]. GLP-1 levels increase within minutes of food intake, well before any food appears in the gut, suggesting a neural signal to the L cells [7]. GLP-1 exerts beneficial effects on glucose homeosta­sis in regulating 1) islet hormone function (insulin and glucagon), 2) nutrient delivery, and 3) food intake.

Image1

GLP-1 receptors are not only expressed in the pan­creas, but also in peripheral tissues, including the central nervous system, heart, kidney, lung, and gastrointestinal tract [8,9]. GLP-1 receptors are present on cardiomyocytes, endocardium, microvascular endothelium, and coronary smooth muscle cells [10.0]. In addition to glucoregula­tory and appetite-suppressant effects, GLP-1 appears to have neurotrophic, neuroprotective, and cardioprotective effects [11-16]. In cultured cells, GLP-1 mediates its effects through G proteins linked to adenylyl cyclase, resulting in increased intracellular circulating adenosine monophos­phate and activation of protein kinase A (PKA) [17].

The main therapeutic drawback of GLP-1 is the short half-life of the compound (< 2 minutes). GLP-1 is rapidly cleaved by the widely expressed dipeptidyl-peptidase-IV (DPP-IV), which removes two N-terminal amino acids, resulting in GLP-1(9-36) with little glucoregulatory prop­erties but with potential cardiovascular effects [18]. To overcome the rapid degradation of GLP-1, two approaches have been developed: 1) GLP-1 receptor agonists resistant to DPP-IV metabolism, and 2) DPP-IV inhibitors to aug­ment the effect of native/endogenous GLP-1. The most extensively studied compounds are exenatide (Byetta [Amylin Pharmaceuticals, San Diego, CA], which has been approved by the US Food and Drug Administration [FDA] for the treatment of type 2 diabetes), liraglutide (Victoza [Novo Nordisk, Princeton, NJ], which has been submitted to the FDA for approval), sitaglitptin (Januvia [Abbott Laboratories, Abbott Park, IL], which has been approved by the FDA for type 2 diabetes), and vildagliptin (Galvus [Novo Nordisk, Princeton, NJ], which has been submitted to FDA). The most common adverse effects of the GLP-1 agonists (exenatide and liraglutide) are nausea and vomiting. No changes in electrocardiogram or wors­ening of liver or kidney function have been reported. Both agents result in significant weight loss over time. Rare cases of pancreatitis have been reported with exenatide, at an incidence rate similar to the background rate observed in the type 2 diabetes population. Alone or combined with metformin or a thiazolidinedione, exenatide or liraglutide do not cause hypoglycemia. Sitagliptin and vildagliptin are both DPP-IV inhibitors that restore physiologic levels of GLP-1 with a similar adverse effect profile as GLP-1 agonists. Rare cases of Stevens-Johnson’s syndrome have been reported with sitagliptin.

Overview:
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Next week, Part 2 will include sections describing the effect of phar­macologic GLP-1 levels achieved via a continuous infusion of GLP-1 or via the two GLP-1 agonists exena­tide or liraglutide.

References and Recommended Reading
  1. Muller C, Neumann 9, Ferenc M, et al.: impact of diabetes mellitus on long-term outcome after unstable angina and non-ST-segment elevation myocardial infarction treated with a very early invasive strategy. Diabetologia 2004, 47:1188-1195.
  2. Jung RT: Obesity as a disease. Br Med Bull 1997, 53:307-321.
  3. Johnson JA, Majumdar SR, Simpson SH, Toth EL: Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabe­tes. Diabetes Care 2002, 25:2244-2248.
  4. Johnson JA, Simpson SH, Toth EL, Majumdar SR: Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabetes Med 2005,22:497-502.
  5. Evans JM, Ogston SA, Emslie-Stnith A, Morris AD: Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonyl­ureas and metformin. Diabetologia 2006,49:930-936.
  6. Simpson SH, Majumdar SR, Tsuyuki RT, et al.: Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. Can Med Assoc J 2006, 174:169-174.
  7. Drucker DJ, Nauck MA: The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006, 368:1696-1705.
  8. Bullock BP, Heller RS, Habener JF: Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996, 137:2968-2978.
  9. Brubaker PL, Drucker DJ: Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Receptors Channels 2002, 8:179-188.
  10. Ban K, Noyan-Ashraf MH, Hoefer J, et al.: Cardioprotec­tive and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 2008, 117:2340-2350. This article discusses the effects of GLP-1 receptor-mediated effects on arterial flow, contractility, and intracellular signaling. The authors also suggest a second potential pathway independent of GLP-1 for some of the cardiovascular effects.
  11. Perry T, Greig NH: Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer’s disease. Curr Alzheimer Res 2005, 2:377-385.
  12. Nikolaidis LA, Doverspike A, Hentosz T, et al.: Gluca­gon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J Pharmaco! Exp Ther 2005,312:303-308.
  13. Nikolaidis LA, Elahi D, Hentosz T, et al.: Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 2004, 110:955-961.
  14. Nikolaidis LA, Mankad S, Sokos GG, et al.: Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004, 109:962-965.
  15. Bose AK, Mocanu MM, Carr RD, et al.: Glucagon-like
    peptide 1 can directly protect the heart against ischemia/ reperfusion injury. Diabetes 2005, 54:146-151,
  16. Bose AK, Mocanu MM, Carr RD, Yellon DM: Glucagon like peptide-1 is protective against myocardial ischemia/ reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs The, 2005, 19:9-11.
  17. Mayo KE, Miller LJ, Bata ate D, et al.: International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 2003, 55:167-194.
  18. Deacon CF, Nauck MA, Toft-Nielsen M, et al.: Both subcutaneously and intravenously administered glucagon­like peptide I are rapidly degraded from the NH2-terminus in type lI diabetic patients and in healthy subjects. Diabetes 1995, 44:1126-1131.
Corresponding author:
Robert Chilton, DO
University of Texas Health Science Center, 27971 Smithson Valley,
San Antonio, TX 78261, USA.

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