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PHA407 Therapeutic Enquiry Explain The cardiovascular and renal effect of Sodium-glucose co-transporter 2 inhibitors   Introduction The sodium glucose co-transporter 2, commonly referred to as SGLT2 is a protein encoded in humans by the SLC5A2 gene.  It is a member of the family of sodium glucose co-transporter that is sodium dependent transport proteins facilitating movement of glucose. The primary role of the co-transporter is associated with reabsorption of glucose in the kidney. Sodium glucose co-transporter 2 inhibitors also referred to as gliflozin, belong to a medication class that are involved in inhibition glucose reabsorption, thereby reducing the blood sugar levels. These drugs primarily inhibit the SGLT2 that are specifically used for the treatment of type 2 diabetes (1). Apart from controlling the glycaemic index, gliflozins have also been found functional in bringing about significant cardiovascular benefits to all patients, diagnosed with T2D (2). This essay will discuss the mechanism of action of the group of drugs and will also elaborate on their role on cardiovascular and renal functioning. Mechanism Of Action SGLT2 is principally expressed on the epithelial cell linings of the kidneys (specifically the proximal convoluted tubule) and is accountable for an estimated 90% of the glucose reabsorption in the kidneys. In other words, sodium glucose co-transporter 2 inhibitors prevent the reuptake of glucose in the kidney from the glomerular filtrate, and thereby result in lowering the glucose levels in the blood stream. This in turn promotes the subsequent excretion of sugar or glucose in urine, in the form of glucosuria. Dapagliflozin is a highly selective and competitive inhibitor of SGLT2. The activities of the inhibitors are controlled by the kidney function, and underlie glucose control of the patient who is being administered the drug (3).  The effects of glucosuria also increase with a rise in the circulating blood sugar level. With an excretion of high glucose levels, the plasma levels in the patient drastically fall, thereby leading to an enhancement in the overall glycaemic parameters. In other words, the mechanism of action of these inhibitors is largely dependent on the blood sugar level, and contrasting action of thiazolidinediones, the popular oral antidiabetic drugs, the former are not dependent on the actions of the insulin hormone (4). Therefore, there is minimum potential for the onset of hypoglycaemia among the patients, thus reducing risks of beta cell overstimulation. Considering the fact that the mechanism of action principally depends on normal function of the renal cells, efficacy of the inhibitors are often reduced among person with complete renal impairment.     Cardiovascular Effect A study that investigated the effects of this inheritance on the cardiovascular outcomes of patients suffering from end stage renal disease and T2D found that use of the inhibitor was associated with a significant 57% and 24% reduced risk of mortality and myocardial infarction or ischemic stroke, among patients who underwent chronic dialysis. Furthermore, use of the inhibitors was also not significantly associated with an elevation in the susceptibility to heart failure among ESRD patients (5). Administration of empagliflozin was allied with a noteworthy decrease in risks related to cardiovascular death, when associated to patients who were subjected to placebo treatment (6). The inhibitors have been found to lower the blood pressure by promoting process of intravascular volume contraction and osmotic diuresis. Intravascular volume reduction stimulates the RAAS system and activates the type 1 angiotensin receptors. Owing to the fact that glycosuria results in excess of loss of water into the urine, with subsequent dehydration, the drug is directly responsible for onset of osmotic diuresis. Lower rates of adverse cardiac events observed in another study with patients were randomised to a group that received empagliflozin (7). The role of the SGLT2 inhibitors in improving cardiovascular outcomes can be related to their impacts in decreasing the overall levels of HbA1C, maintaining body weight, reducing blood pressure, and increasing the levels of HDL cholesterol in blood (8). Similar findings have also been presented in another study that elaborated on the fact that empagliflozin is responsible for lowering the composite primary cardiovascular end point, in T2D patients (9). Renal Effect The class of inhibitors is also responsible for providing renal protection and preventing onset of diabetic neuropathy, among diabetics. Upon increasing the reabsorption of sugar and sodium from the proximal convoluted tubule (PCT), the sodium delivery gets decreased to the juxtaglomerular apparatus. This is followed by an increase in production of angiotensin and renin. This results in contraction of the efferent arteriole and relaxation of the afferent arteriole. The inhibitors increase distribution of sodium to the juxtaglomerular apparatus, help in vasoconstriction of the efferent arteriole, and reduce interglobular pressure, thereby providing renal protection (10). In patients having reduced GFR, the amount of glucose that reaches the proximal convoluted tubule decreases. Further effects of SCLT2 inhibitors are related to a decrease in urine albumin, reduced progression to the condition microalbuminuria, improved albuminiuria, and an overall reduction in worsening of renal impairment condition (11). A study that investigated the impacts of dapagliflozin therapy on the kidney morphology and renal protection among T2D patients also found that the treatment significantly resulted in an improvement in glycaemic control and enhanced UACR, which in turn was related to a substantial decreasing mass of body fat, among the diabetes patients (12). The inhibitors are also responsible for improving the length of the kidney, radiation attenuation and enhancement of proximal fibula injury marker. Improvement in renal threshold related to glucose excretion is another significant effect of the inhibitors (10). Further evidences also suggest that empagliflozin is related to alterations in renal and myocardial metabolism, from fat oxidation to ketone body that consequently leads to an improvement in renal function and efficiency (6). Conclusion Thus, it can be concluded that sodium glucose co-transporter 2 inhibitors are a class of prescribed medications approved by the FDA, for usage with exercise and diet, in order to reduce blood glucose levels in adults suffering from type 2 diabetes. These inhibitors usually block the action of SGLT2 proteins that prevents reabsorption of glucose by the kidney, and help in removal of excess blood sugar from the body, in the form of urine. Besides lowering the level of sugar in the bloodstream, the drug is also responsible for improving the cardiovascular and renal outcomes.   References Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, Neal B. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. The lancet Diabetes & endocrinology. 2016 May 1;4(5):411-9. van Baar MJ, van Ruiten CC, Muskiet MH, van Bloemendaal L, IJzerman RG, van Raalte DH. SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management. Diabetes care. 2018 Aug 1;41(8):1543-56. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annual review of medicine. 2015 Jan 14;66:255-70. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium–glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015 Jan 1;75(1):33-59. Chan SY, Ou SM, Chen YT, Shih CJ. Effects of DPP-4 inhibitors on cardiovascular outcomes in patients with type 2 diabetes and end-stage renal disease. International journal of cardiology. 2016 Sep 1;218:170-5. Perrone-Filardi P, Avogaro A, Bonora E, Colivicchi F, Fioretto P, Maggioni AP, Sesti G, Ferrannini E. Mechanisms linking empagliflozin to cardiovascular and renal protection. International journal of cardiology. 2017 Aug 15;241:450-6. Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia. 2018 Aug 22:1-8. (4) Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes, Obesity and Metabolism. 2015 Dec;17(12):1180-93. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nature Reviews Nephrology. 2017 Jan;13(1):11. Hemmingsen B, Krogh J, Metzendorf MI, Richter B. Sodium?glucose cotransporter (SGLT) 2 inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2016(4). Seidu S, Kunutsor SK, Cos X, Gillani S, Khunti K. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis. Primary care diabetes. 2018 Jun 1;12(3):265-83. Sugiyama S, Jinnouchi H, Kurinami N, Hieshima K, Yoshida A, Jinnouchi K, Tanaka M, Nishimura H, Suzuki T, Miyamoto F, Kajiwara K. Impact of Dapagliflozin Therapy on Renal Protection and Kidney Morphology in Patients With Uncontrolled Type 2 Diabetes Mellitus. Journal of clinical medicine research. 2018 Jun;10(6):466.

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