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The Effects of GLP-1 Agonists — A Review of the Drug Class

Sep 21, 2012

Amanda Zell, PharmD Candidate, Mercer University College of Pharmacy

Glucagon-like peptide-1 (GLP-1) is part of a family of peptide hormones known as incretins. Incretins, such as GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are secreted by entero-endocrine cells of the gastrointestinal tract to stimulate glucose-dependent insulin secretion and beta-cell proliferation. GLP-1 receptor agonists have been shown to decrease glucagon production, improve insulin secretion, increase satiety, and help decrease food intake. They have also been shown to have other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk and beta-cell mass and function….


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In addition to traditional therapies for type 2 diabetes, GLP-1 agonists are valuable options that help patients who may have GLP-1 deficits. Two strategies that accomplish this are replacement of GLP-1 with long-acting analogs or inhibition of DPP-4, the enzyme responsible for GLP-1 degradation. By inhibiting DPP-4, the patients endogenous GLP-1 is able to have a longer effect.  This can increase beta-cell production but does not have any effect on gastric emptying or weight loss. On the other hand, the addition of a long acting GLP-1 analog creates plasma levels 5-7 times higher than normal physiologic levels which allow the effects of decreased gastric emptying, increased satiety, and weight loss to be seen.

Glucagon and GLP-1 are important regulators for glucose homeostasis. The role of glucagon in the body is to maintain an adequate supply of glucose even in the fasting state. The mechanisms responsible for hyperglycemia found in type 2 diabetes include not only a decline in beta-cell function and insulin resistance, but also increased levels of glucagon found in the blood. Because of elevated amounts of glucagon in the blood, type 2 diabetic patients have increased production in hepatic glucose and therefore, significantly higher postprandial and fasting plasma glucose levels. GLP-1 has been shown to counter the effects of both mechanisms responsible for type 2 diabetes by stimulating glucose dependent pancreatic beta-cell function, as well as inhibiting the effects of pancreatic alpha-cells.

GLP-1 agonists have a role at suppressing glucagon production which allows lower postprandial and fasting glucose levels, and they also have very significant glucagon suppressive effects at normal and elevated plasma glucose levels.

There are several incretin hormones, but GLP-1 appears to be the major player in type 2 diabetes and is best understood. The primary actions are to regulate insulin and glucagon secretion only when plasma glucose exceeds normal fasting levels. GLP-1 stimulates insulin secretion and augments the insulin-releasing effects of glucose on the pancreatic beta-cell. GLP-1 agonists may also have beneficial effects on beta-cell function as their glucose-dependent mechanism limits the risk for hypoglycemia.

GLP-1 receptors are in high concentrations on the beta-cells within the pancreas, and they have many functions. A few of these functions include increasing beta-cell proliferation, neogenesis, and beta-cell mass. GLP-1 receptors are also found in the lungs, kidney, intestines, and several locations in the central nervous system. Additionally, GLP-1 receptors are widely expressed in the heart, and studies have shown that the benefits exceed glucose control and are also beneficial 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 contractility. There are also GLP-1 receptors located in the brain which help activate nitric oxide synthase, causing vasodilatation to help control blood pressure.

Another study 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, treatment with a GLP-1 agonist 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.

As previously mentioned, GLP-1 receptor agonists work by slowing gastric emptying and increasing the feeling of satiety, which can be related to the decrease or weight gain and/or weight loss seen with these agents. As we know, any positive effect on weight could be beneficial to a patient’s lipid profile. Numerous studies show that the GLP-1 agonists have favorable effects on lipid panels, as there were decreases in total cholesterol and LDL cholesterol.

GLP-1 receptor agonists are a great option for type 2 diabetes to help control postprandial and fasting plasma glucose levels, not only through sensitizing beta-cells to plasma glucose and its effects on satiety and gastric emptying, but also suppressing glucagon production to decrease hepatic glucose production. They have also been shown to have other extraglycemic benefits such as weight loss and improvements in cardiovascular health and beta-cell mass and function. GLP-1 analogs have the potential to truly make a difference in diabetes management.

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