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.
What therapeutic approaches have been developed to overcome rapid degradation of GLP-1?
See more GLP-1 Agonist Resources.
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 .
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 . 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 . 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) . 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 . GLP-1 exerts beneficial effects on glucose homeostasis in regulating 1) islet hormone function (insulin and glucagon), 2) nutrient delivery, and 3) food intake.
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) .
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 . 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.
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.
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