Pleiotropic Effects of GLP-1. Cardiovascular Evidence of Effectiveness

Pedro Pujante Alarcón, Ana Belén Hernández Cascales, Alfonso López Ruiz, María Ángeles Ibañez Gil, Alicia Hernández Torres, María Dolores Hellín Gil

Endocrinology and Nutrition Service of the Hospital University Virgen de la Arrixaca, Murcia, Spain.
Endocrinology and Nutrition Service of the Hospital University Virgen de la Arrixaca, Murcia, Spain;.
Health Center Mariano Yago, Yecla, Murcia, Spain;.
Infectious Internal Medicine of the Hospital University Virgen de la Arrixaca, Murcia, Spain..
Pharmaceutical Care Research at the University of Granada, Granada, Spain;.

DOI: 10.4236/pp.2013.49091                

Abstract

Patients with diabetes are characterized by the development of cardiovascular complications: nephropathy, retinopathy, neuropathy, ischemia or hypertensive etc. Therefore, the cardiovascular involvement is the leading cause of death in patients with Diabetes Mellitus type 2 (DM2). Despite intensive treatment on classical factors of cardiovascular disease (blood pressure levels, LDL cholesterol, etc.), patients with diabetes have a high number of cardiovascular events and the onset and prognosis of these are related to glycemic control parameters, glycosylated hemoglobin (HbA1c). On the other hand, the question of the cardiovascular protective effect of some hypoglycemic treatments has been raised, asking what he has done to know more accurately about the safety and cardiovascular effects of the treatments we have today. The two most important incretin hormones are GIP (gastric inhibitory polypeptide) and GLP-1 (glucagon-like peptide-1). Treatment based on GLP-1 is a novel weapon in T2DM that achieves a reduction in HbA1c with other metabolic effects: weight loss and extra effect in dyslipidemia and blood pressure. In the last years other beneficial actions such a protector effect against myocardium ischemia and other actions in basals were reported. In this article we will try to explain the evidence of GLP-1 treatments and its cardiovascular effects.

 

Keywords

GLP-1; T2DM; Myocardium Ischemia

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	H. King, R. E. Aubert and W. H. Herman, “Global Burden of Diabetes, 1995-2025: Prevalence, Numerical Estimates and Projections,” Diabetes Care, Vol. 21, No. 9, 1998, pp. 1414-1431. http://dx.doi.org/10.2337/diacare.21.9.1414
[2]	R. S. Clements Jr. and D. S. Bell, “Complications of Diabetes. Prevalence, Detection, Current Treatment and Prognosis,” American Journal of Medicine, Vol. 79, No. 5, 1985, pp. 2-7. http://dx.doi.org/10.1016/0002-9343(85)90503-0
[3]	Scandinavian Simvastatin Survival Study Group, “Randomised Trial of Cholesterol Lowering in 4444 Patients with Coronary Heart Disease: The Scandinavian Simvastatin Survival,” Lancet, Vol. 344, No. S4, 1994, pp. 1383-1389.
[4]	M. Davidson, “Cardiovascular Effects of Glucagonlike Peptide-1 Agonists,” American Journal of Cardiology, Vol. 108, No. 3, 2011, pp. 33B-41B. http://dx.doi.org/10.1016/j.amjcard.2011.03.046
[5]	The ADVANCE Collaborative Group, “Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes,” New England Journal of Medicine, Vol. 358, No. 24, 2008, pp. 2560-2572. http://dx.doi.org/10.1056/NEJMoa0802987
[6]	J. Hsai, J. D. Otvos, J. E. Rossouw, L. Wu, S. Wassertheil-Smoller, S. L. Hendrix, J. G. Robinson, B. Lund, L. H. Kuller and Women’s Health Initiative Research Group, “Lipoprotein Particle Concentrations May Explain the Absence of Coronary Protection in the Women’s Health Initiative Hormone Trials,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 28, No. 9, 2008, pp. 1666-1671. http://dx.doi.org/10.1161/ATVBAHA.108.170431
[7]	M. J. Perley and D. M. Kipnis, “Plasma Insulin Responses to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects,” Journal of Clinical Investigation, Vol. 46, No. 12, 1967, pp. 1954-1962. http://dx.doi.org/10.1172/JCI105685
[8]	D. J. Drucker, “The Biology of Incretin Hormones,” Cell Metabolism, Vol. 3, No. 3, 2006, pp. 153-165. http://dx.doi.org/10.1016/j.cmet.2006.01.004
[9]	M. Nauck, F. Stockmann, R. Ebert and W. Creutzfeldt. “Reduced Incretin Effect in Type 2 (Non-Insulin-Dependent) Diabetes,” Diabetologia, Vol. 29, No. 1, 1986, pp. 46-52. http://dx.doi.org/10.1007/BF02427280
[10]	D. J. Grieve, S. C. Roslyn and B. D. Green, “Emerging Cardiovascular Actions of the Incretin Hormone Glucagon-Like Peptide-1: Potencial Therapeutic Benefits beyond Glycaemic Control?” British Journal of Pharmacology, Vol. 157, No. 8, 2009, pp. 1340-1351. http://dx.doi.org/10.1111/j.1476-5381.2009.00376.x
[11]	T. J. Moretto, D. R. Milton, T. D. Ridge, et al., “Efficacy and Tolerability of Exenatide Monotherapy over 24 Weeks in Antidiabetic Drug-Naive Patients with Types 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study,” Clinical Therapeutics, Vol. 30, 2008, pp. 1448-1460. http://dx.doi.org/10.1016/j.clinthera.2008.08.006
[12]	R. A. De Fronzo, R. E. Ratner, J. Han, D. D. Kim, M. S. Fineman and A. D. Baron, “Exenatide (Exendín-4) on Glycemic Control and Weight over 30 Weeks in Methformin-Treated Patients with Type 2 Diabetes,” Diabetes Care, Vol. 28, 2005, pp. 1092-1100. http://dx.doi.org/10.2337/diacare.28.5.1092
[13]	J. B. Buse, R. R. Henry, J. Han, D. D. Kin, M. S. Fineman and A. D. Baron, “Exenatide-113-Clinical Study Group. Effects of Exenatide (Exendín-4) on Glycemic Control over 30 Weeks in Sulfonylurea-Treated Patients with Type 2 Diabetes,” Diabetes Care, Vol. 27, 2004, pp. 2628-2635. http://dx.doi.org/10.2337/diacare.27.11.2628
[14]	D. M. Kendall, M. C. Riddele, J. Rosenstock, et al., “Effects of Exenatide (Exendín-4) on Glycemic Control over 30 Weeks in Patients with Type 2 Diabetes Treated with Metformin and Sulfonylurea,” Diabetes Care, Vol. 28, No. 5, 2005, pp. 1083-1091. http://dx.doi.org/10.2337/diacare.28.5.1083
[15]	D. M. Klonoff, M. C. Riddle, J. Rosenstock, et al., “Exenatide Effects on Diabetes, Obesity Cardiovascular Risk Factors and Hepatic Biomarkers in Patients with Type 2 Diabetes Treated for at Least 3 Years,” Current Medical Research and Opinion, Vol. 24, 2008, pp. 275-286.
[16]	A. Garber, R. Henry, R. Ratner, et al., “Liraglutide versus Glimepiride Monotherapy for Type 2 Diabetes (LEAD-3 Mono): A Randomised 52 Weeks, Phase III, Double-Blind, Paralle-Treatment Trial,” Lancet, Vol. 373, No. 9662, 2009, pp. 473-481. http://dx.doi.org/10.2337/diacare.28.5.1083
[17]	M. Nauck, A. Frid, K. Hermansen, et al., “Efficacy and Safesty Comparison of Liraglutide, Glimpiride and Placebo All in Combination with Metformin in Type 2 Diabetes,” Diabetes Care, Vol. 32, No. 1, 2009, pp. 84-90. http://dx.doi.org/10.2337/dc08-1355
[18]	B. Zinman, J. Gerich, J. B. Buse, et al., “Efficacy and Safety of the Human GLP-1 Analog Liraglutide in Combination with Metformin and TZD in Patients with Type 2 Diabetes (LEAD-4-Met + TZD),” Diabetes Care, Vol. 32, 2009, pp. 1224-1230. http://dx.doi.org/10.2337/dc08-2124
[19]	D. Russell-Jones, A. Vaag, O. Schmitz, et al., “Liraglutide vs Insulin Glargine and Placebo in Combination with Metformin and Sulphonylurea Therapy in Type 2 Diabetes Mellitus: A Randomised Controlled Trial(LEAD-5 met + SU),” Diabetología, Vol. 52, No. 10, 2009, p. 2046. http://dx.doi.org/10.1007/s00125-009-1472-y
[20]	J. Buse, J. Rosenstock, G. Sesti, et al., “A Study of Two Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes: Liraglutide Once Daily Compared with Exenatide Twice Daily in a Randomised 26 Weeks, Open-Label Trial(LEAD-6),” Lancet, Vol. 374, 2009, pp. 39-47. http://dx.doi.org/10.1016/S0140-6736(09)60659-0
[21]	T. Okerso, P. Yan, A. Stonehouse and R. Brodows, “Effects of Exenatide on Systolic Lood Pressure in Subjects with Type 2 Diabetes,” American Journal of Hypertension, Vol. 23, No. 3, 2010, pp. 334-339. http://dx.doi.org/10.1038/ajh.2009.245
[22]	L. Blonde and D. Russell-Jones, “The Safety and Efficacy of Liraglutide with or without Oral Antidiabetic Drug Therapy in Type 2 Diabetes: An Overview of the LEAD 1-5 Studies,” Diabetes, Obesity and Metabolism, Vol. 11, Suppl. 3, 2009, pp. 26-34. http://dx.doi.org/10.1111/j.1463-1326.2009.01075.x
[23]	M. Arakawa, T. Mita, K. Azuma, C. Ebato, H. Goto, T. Nomiyama, Y. Fujitani, T. Horise, R. Kawamori and H. Watada, “Inhibition of Monocyt Adhsion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4,” Diabetes, Vol. 59, No. 4, 2010, pp. 1030-1037. http://dx.doi.org/10.2337/db09-1694
[24]	A. Basu, N. Charkoudian, W. Schrage, R. A. Rizza, R. Basu and M. J. Joyner, “Benefial Effects of GLP-1 on Endothelial Function in Humans: Dampening by Glyburide but Not by Glimepiride,” Endocrinology and Metabolism—American Journal of Physiology, Vol. 293, 2005, pp. E1289-E1295.
[25]	T. Nystrom, M. K. Gutniak, F. Zhan, J. J. Holst, B. Ahrén and A. Sjoholm, “Effects of Glucagon-Like Peptide-1 on Endothelial Function in Type 2 Diabetes Patients with Stable Coronary Artery Disease,” Endocrinology and Metabolism—American Journal of Physiology, Vol. 287, 2004, pp. E1209-E1215.
[26]	S. Ozyazgan, N. Kutluta, S. Afsar, S. B. Ozdas and A. G. Akkan, “Effect of Glucagon-Like Peptide-1(7-36) and Exendin-4 on the Vascular Reactivity in Streptozotocin/ Nicotinamide-Induced Diabetic Rats,” Pharmacology, Vol. 74, No. 3, 2005, pp. 119-126.
[27]	Y. Ishibashi, T. Matsui, M. Takeuchi and S. Yamagishis, “Glucagon-Like Peptide-1 (GLP-1) Inhibits Advance Glycation End Product (AGE)-Induced Up-Regulation of VCAM-1 mRNA Levels in Endothelial Cells by Suppressing AGE Receptor (RAGE) Expression,” Biochemical and Biophysical Research Communications, Vol. 391, No. 3, 2010, pp. 1405-1408. http://dx.doi.org/10.1016/j.bbrc.2009.12.075
[28]	D. P. Sonne, T. Engstrom and M. Treiman, “Protetive Effects of GLP-1 Analogues Exendin-4 and GLP-1 (9-36) Amide against Ischemiareperfusion Injury in Rat Heart,” Regulatory Peptides, Vol. 146, No. 1-3, 2008, pp. 243-249. http://dx.doi.org/10.1016/j.regpep.2007.10.001
[29]	L. A. Nikoladis, D. Elahi, Y. T. Shen and R. P. Shannon, “Active Metabolite of GLP-1 Mediates Myocardial Glucose Uptake and Improve Left Ventricular Performance in Conscious Dogs with Dilated Cariomyopathy,” Heart and Circulatory Physiology—American Journal of Physiology, Vol. 289, 2005, pp. H2401-H2408.
[30]	L. Timmer, J. P. Henriques, D. P. De Klein, J. H. Devries, H. Kemperman, P. Steendijk, et al., “Exenatide Reduces Infarcts Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury,” Journal of the American College of Cardiology, Vol. 53, No. 6, 2009, pp. 501-510. http://dx.doi.org/10.1016/j.jacc.2008.10.033
[31]	G. G. Sokos, H. Bolukoglu, J. German, T. Hentosz, G. J. Magovern, T. D. Maher, D. A. Dean, S. H. Bailey, G. Marrone, D. H. Benckart, D. Elaine and R. P. Shannon, “Effect of Glucagon-Like Peptide-1 (GLP1) on Glycemic Control and Left Ventricular Function in Patients Undergoing Coronary Artery Bypass Grafting,” American Journal of Cardiology, 2007, pp. 824-829.
[32]	M. H. Noyan-Ashraf, M. A. Momen, K. Ban, A. M. Sadi, Y. Q. Zhou, A. M. Riazi, L. L. Baggio, R. M. Henkelman, M. Husain and D. J. Drucker, “GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes after Experimental Myocardial Infaction in Mice,” Diabetes, Vol. 58, No. 4, 2009, pp. 975-983. http://dx.doi.org/10.2337/db08-1193