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The Use of GLP-1 Analogs and Lifestyle Changes

Alan Mathis PharmD Candidate 2013 University of Florida

GLP-1 analogs not only improve plasma glucose levels and reduce HbA1c, but also improve metabolic effects such as reduction in BMI, waist circumference, and improve cardiovascular health.

Diabetic patients, especially with type 2 diabetes, tend to have poor diets and sedentary lifestyle leading to a high prevalence of overweight and obesity. The characteristics of unhealthy nutrition habits, sedentary lifestyle, and visceral obesity, with diabetes, contribute to metabolic disorders such as hypertension and dyslipidemia which increase the patient’s risk for cardiovascular disease. Lifestyle changes such as increasing activity and altering eating behaviors are important in the treatment of type 2 diabetes. In fact, the American Diabetes Association recommends patients diagnosed with type 2 diabetes start lifestyle changes and metformin.

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In addition to traditional therapies for type 2 diabetes, incretin mimetics are valuable new options that help target patients that may have GLP-1 deficits. Two strategies that accomplish this are replacement of GLP-1, glucagon-like peptide-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 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. Exenatide was the first GLP-1 analog to be produced followed by liraglutide. Exenatide is a twice daily injection that should be administered one hour before breakfast and supper while liraglutide is once daily and can be injected anytime during the day. Most recently, a once weekly injection formulation called Bydureon® has been produced.

GLP-1 is a hormone produced mainly through the entero-endocrine L-cells of the small intestine that is secreted in response to food intake and is a component of the gut phenomenon known as the incretin effect. GLP-1 also plays a role to reduce slow gastric emptying.  GLP-1 binds to GLP-1 receptors, which are G-protein coupled receptors, found not only in the GI tract, but also in the pancreas, brain, and other tissues including the heart. In the pancreas, GLP-1 acts to enhance glucose dependent insulin release in the beta-cells and also inhibit inappropriate glucagon secretion from the α-cells. Type 2 diabetics may release inappropriate amounts of glucagon resulting in increased plasma glucose levels despite hyperglycemia. These are the primary mechanisms for which GLP-1 analogs have been approved for type 2 diabetes.1

As mentioned above, 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.2

In the brain, GLP-1 receptors are found in the hypothalamus region and act to reduce appetite and regulate body weight. The effects of GLP-1 in the brain are not limited to satiety and weight reduction, but GLP-1 may also increase energy expenditure and alter the body’s preference for fuel consumption from carbohydrates to fat. A small cross-sectional study with 46 human participants found that higher fasting levels of GLP-1 was associated with increased energy expenditure and higher rates of fat oxidation.3

GLP-1 receptors in the heart, once activated by GLP-1, induce activation of cyclic adenosine monophosphate (cAMP) and phosphatidylinositol 3-kinase (PI3K). This helps ischemic preconditioning and decrease myocyte apoptosis. There are two theories regarding the cardiovascular effects of GLP-1. The first regards the GLP-1 receptor mediated effects regarding ischemic preconditioning and glucose uptake stimulation. The other is independent of GLP-1 receptors and regards vasodilation mediated by nitric oxide, as the following figure illustrates.4

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Lifestyle modifications, including increasing physical activity and decreasing caloric intake, are an effective way of preventing or delaying type 2 diabetes in high risk patients. Increased physical activity helps muscle cells increase glucose uptake and decrease plasma glucose levels. There are cardiovascular and metabolic advantages as well. In addition to lifestyle modification, a strategy to slow the progression of type 2 diabetes is by preserving beta-cell function. Not only do GLP-1 analogs increase glucose dependent insulin secretion from beta-cells, they also have been shown to have effects on beta-cell growth and survival leading to increased beta-cell mass.

Lifestyle modification together with GLP-1 analogs can not only help treat patients with type 2 diabetes by reducing HbA1c and plasma glucose levels, they may also help prevent the onset of type 2 diabetes in high risk patients.

References: 
  1. Powers AC, DAlessio D. Chapter 43. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia. In: Chabner BA, Brunton LL, Knollman BC, eds.Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com.lp.hscl.ufl.edu/content.aspx?aID=16674366.  Accessed September 5, 2012.
  2. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824_830.
  3. Pannacciulli N, Bunt JC, Koska J, Bogardus C, Krakoff J. Higher fasting plasma concentrations of glucagon-like peptide 1 are associated with higher resting energy expenditure and fat oxidation rates in humans. Am J Clin Nutr. 2006;84:556–560.
  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

Copyright © 2012 Diabetes In Control, Inc.