Role of Glucagon Analogues in Cardiovascular disease

Role of Glucagon Analogues in Cardiovascular disease The Potential Role of Glucagon – Like Peptide – 1 (GLP-1) Analogues in Cardiovascular disease Introduction People who have a diagnosis of diabetes have a triple chance of developing cardiovascular disease (CVD) and unfortunately poorer clinical outcomes following myocardial infarction, angioplasty and bypass surgeries (Hausenloy and Yellon 2008). It is estimated that CVD is responsible for 65% of deaths in people with type 2 diabetes (Burge 2012). Management of diabetes includes identifying, preventing and managing CVD risk factors such as dyslipidaemia and hypertension (NICE 2014). Other risk factors for CVD include poor or inadequate consumption of fruits and vegetables, smoking, central obesity, psychosocial factors, altered lipids, inactivity and unsafe alcohol consumption (World Heart Federation 2014; Yusuf et al 2004). GLP-1 analogues indicated to treat diabetes have been shown to have cardiovascular benefits (Hausenloy and Yellon 2008). GLP – 1 GLP – 1 is an incretin naturally occurring in the body and is secreted due to the presence of food in the ileum, increasing endogenous insulin, inhibiting glucagon, thereby reducing post – prandial hyperglycaemia and is also responsible for controlling appetite and satiety (Hausenloy and Yellon 2008; Sheikh 2013). GLP -1 does not cause hypoglycaemia because its actions are inhibited when blood glucose is ≠¤ fasting levels (Hausenloy and Yellon 2008). GLP- 1 receptors are extensively distributed throughout the body: in the brain, lungs, intestines, stomach, pancreas, and heart. GLP-1 itself has a half – life of 1 – 2 minutes after secretion (Burge 2012; Zhao 2013). The presence of the receptors in the heart has been the focus of new research. Cardiovascular effects In animal studies GLP – 1 was seen to cause vasodilation (Brown 2012). An increase in heart rate and blood pressure were both observed in rats that were either conscious or sedated, but there is some controversy with the mechanism (Zhao 2013). When GLP-1 has been infused dogs with dilated cardiomyopathy showed improved cardiac performance after GLP – 1 infusion (Zhao 2013). Left ventricular systolic and diastolic functions were improved after GLP – 1 infusion in decompensated heart failure (Zhao 2013). Ban et al (2008) work on mouse heart as cited in Brown (2012) has shown that there are GLP – 1 receptors in the endothelium and cardiac myocytes. When GLP – 1 was administered during reperfusion studies cardiac damage was less likely (Brown 2012). Apart from the animal studies, there have been some phase 2 trials in humans with CVD (Zhao 2013). The first investigators to prove that infusing GLP – 1 for 3 days improved â€Å"global and regional left ventricular wall motion scores† in patients with dysfunction of the left ventricle after myocardial infraction was Shannon’s group (Zhao 2013). They also concluded that there was reduced hospital stay and mortality as an in – patient. Several weeks post discharge these effects remained. An experimental study of 14 people with coronary artery disease who were treated with GLP – 1 at a rate of 1.2pmol/kg/min resulted in improvement of left ventricular function (Zhao 2013). This was corroborated by another study of 172 patients who were treated with exenatide at a rate of 0.12 µg/min for 6 hours post elevation of ST – segment MI. A retrospective study of 420,493 people found that individuals who received treatment with exenatide were less likely to experience cardiovascular event, hospitalization due to CVD or all cause hospitalization when compared to non – exenatide treated people even though they were more likely to be obese, have prior CVD, high cholesterol and other co – morbidities at baseline (Best et al 2011; Brown 2012). The use of exenatide in patients with type 2 diabetes did not show an increase in cardiovascular disease and similarly liraglutide was not associated with any major adverse cardiac event in an analysis of phase 2 and 3 trials (Sheikh 2013). Hypertension Animal studies utilizing GLP – 1 have concluded a decrease in hypertension development in Dahl salt – sensitive rats (Zhao 2013). This decrease in blood pressure was also observed in human trials with the GLP – 1 agonists exenatide and liraglutide. A meta – analysis of 16 randomized controlled trials of 5860 people of which 3443 were randomized to a GLP – 1 agonist concluded that exenatide and liraglutide caused a fall in systolic and diastolic blood pressure by 1 – 5 mmHg when compared to other hypoglycaemic medication and placebo in patients with type 2 diabetes (T2DM) (Wang et al 2013). The LEAD trial concluded that liraglutide caused a reduction of systolic blood pressure ranging 3.6 – 6.7mmHg within 2 weeks of starting therapy (Burge 2012). This effect was seen for the full 26 weeks of the trial. The DURATION trial also reported reduction in systolic blood pressure (Burge 2012). Data from 6 trial concluded that subjects with T2DM who were treated for 6 months with exenatide saw a significant reduction in systolic blood pressure (Zhao 2013). There is also promising data from phase 3 trials of liraglutide which concluded that there may be reduction in systolic blood pressure when liraglutide is used with other agents such as metformin (Zhao 2013). Exenatide use reportedly cause a fall in systolic blood pressure in obese patients with T2DM who were also treated with insulin (Sheikh 2013). This decrease in systolic blood pressure was confirmed by an analysis of 2171 patients (Sheikh 2013). Liraglutide was also reported to cause a reduction in systolic blood pressure in Asian patients (Sheikh 2013). Conclusion The data from the use of GLP-1 in both animal and human studies show consistent reduction in systolic blood pressure a known risk factor for both cardiac disease and cerebrovascular accident (CVA). There have also been promising signs that there may be a GLP – 1 cardio protective effect post cardiac damage and improvement in left ventricular function. It is not clear whether the doses used to treat diabetes will provide the same level of reduction in systolic blood pressure and cardiovascular protection in the longer term. More clinical studies are required focusing the benefits of GLP-1 analogues on the cardiovascular system as the data will not only provide benefits to patients with T2DM but also patients who are at risk or suffer a CVD. References Best, J. H., Byron J. Hoogwerf, B. J. and Hussein, M. A. (2011) ‘Risk of Cardiovascular Disease Events in Patients With Type 2 Diabetes Prescribed the Glucagon-Like Peptide 1 (GLP-1) Receptor Agonist Exenatide Twice Daily or Other Glucose-Lowering Therapies’, Diabetes Care, 34(1), pp. 90 – 95. American Diabetes Association. [Online]. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005487/?report=reader (Accessed: 22 September 2014). Brown, N. (2012) ‘Cardiovascular Effects of Anti-Diabetic Agents: Focus on Blood Pressure Effects of Incretin-Based Therapies’, Journal of American Society of Hypertension, 6(3), pp. 163 – 168. [Online]. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422131/ (Accessed: 22 September 2014). Burge, T. (2012) The Effects of GLP-1 on Cardiovascular Health. Available at: http://www.diabetesincontrol.com/articles/54-feature/13201-the-effects-of-glp-1-on-cardiovascular-health (Accessed: 11 September 2014). Hausenloy, D. J. and Yellon, D. M. (2008) ‘GLP-1 Therapy: Beyond Glucose Control’, Circulation: Heartfailure, 1, pp. 147 – 149. [Online]. Available at: http://circheartfailure.ahajournals.org/content/1/3/147.full (Accessed: 11 September 2014). NICE (2014) Managing type 2 diabetes. Available at: http://pathways.nice.org.uk/pathways/diabetes#path=view%3A/pathways/diabetes/managing-type-2-diabetes.xmlcontent=view-index (Accessed: 17 September 2014). Sheikh, A. 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