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Review Article KYAMC Journal Vol. 6, No.-1, July 2015 Review Article Glucuretics: A New Class of Drug for the Treatment of Type 2 Diabetes Hoque MA1, Rahman SMT 2, Islam MD 3, Akter N4 Abstract Type 2 diabetes is a common, chronic disease with a prevalence that is increasing at epidemic proportions. Management involves advice on lifestyle changes, oral anti-hyperglycaemic agents and/or insulin. The kidney plays an important role in glucose homeostasis via its production, utilization, and, most importantly, reabsorption of glucose from glomerular filtrate which is largely mediated via the sodium glucose co- transporter 2 (SGLT2). Competitive inhibition of SGLT2 induces glucosuria in a dose dependent manner and appears to have beneficial effects on glucose regulation in individuals with type 2 diabetes. Agents that inhibit SGLT2 represent a novel class of drugs, which has recently become available for treatment of type 2 diabetes. This article summarizes the rationale for use of these agents and reviews available clinical data on their efficacy, safety, and risks/benefits. Introduction pharmacological adjuncts are often required early in the Type 2 diabetes is a common, chronic disease and the management in the majority of patients. The choice of global prevalence of type 2 diabetes mellitus (T2DM) is drug depends on clinical and biochemical factors; as increasing at epidemic proportions1. It is a progressive with all pharmacological agents, anti-hyperglycaemic disease of the endocrine system with a significant therapy should only be initiated following careful economic burden, is estimated to affect more than 371 consideration of the possible benefits and risks of million people worldwide and close to one-fifth of all treatment for the individual patient. Antihyperglycaemic adults with diabetes in the world live in the South-East agents include metformin, sulphonylureas, meglitinides, Asia region. Current estimates-indicate that 8.3% of the alpha-glucosidase inhibitors, thiazolidinediones, DPP- adult population, or 71.4 million people, have diabetes IV inhibitors and GLP-1 analogues4. All of the oral in 20112. The number of people with diabetes in the anti-hyperglycemic drugs currently available are region will increase to 120.9 million by 2030, or 10.2% accompanied by some undesirable side effects or of the adult population2. The immediate purpose of problems with long term efficacy4. These agents are lowering blood glucose is to provide relief from osmotic effective initially, glucose-lowering effects are not symptoms (thirst, polyuria, nocturia and blurred vision). typically sustained long term as beta cell dysfunction There after, the aim is to prevent microvascular p rogresses. Historically, orally-active agents are usually complications: retinopathy, nephropathy and employed first line while insulin is reserved for patients neuropathy3. Modifications of diet habit and lifestyle are in whom tablets prove insufficient5. The majority of seldom sufficient to produce good, long-term, metabolic T2DM patients are overweight or obese, which control in patients with type 2 diabetes, so increases insulin resistance and complicates treatment6. 1. Md. Azizul Hoque, Assistant Professor, Department of Endocrinology, Sir Salimullah Medical College, Dhaka. 2. S M Tajdit Rahman, Intern Doctor, Sir Salimullah Medical College Mitford Hospital, Dhaka. 3. Md. Daharul Islam, Assistant Professor, Department of Medicine, Sir Salimullah Medical College, Dhaka. 4. Nazma Akter, Resident Physician, MARKS Medical College Hospital, Dhaka. Correspondance: Dr. Md. Azizul Hoque, Assistant Professor, Department of Endocrinology, Sir Salimullah Medical College, Dhaka. Mobile No. : +8801712622707, Email: [email protected] 592 KYAMC Journal Vol. 6, No.-1, July 2015 Hyperglycaemia along with hypertension and clear that the reabsorption of glucose is the most dyslipidaemia are associated with macrovascular important role that the kidneys play in glucose complications (myocardial infarction, stroke and homeostasis13. peripheral arterial disease). The effects of glucose- lowering therapies along with treatment of hypertension and dyslipidaemias have a major impact on cardiovascular morbidity and mortality7. Therefore, newer agents that are able to lower glucose long term without causing hypoglycemia, delay decline in beta cell dysfunction, assist with weight loss, and have beneficial effects on cardiovascular disease need to be developed. Several new classes of medications are currently in development. Anti-hyperglycaemic agents that act through inhibition of renal sodium glucose co- transporters are one of them and showing considerable potential8,9. The kidney plays an important role in glucose homeostasis and has recently become a target The transport of glucose across the proximal tubular for treatment of diabetes. The majority of glucose epithelium along with the main molecular participants is reabsorption from glomerular filtrate is mediated via a now well described. Glucose enters eukaryotic cells via transporter protein called sodium glucose co- two different types of membrane associated carrier transporter2 (SGLT2). Pharmacological inhibition of proteins, the faciliative glucose transporters (GLUTs) SGLT2 increases urinary glucose excretion (UGE) and and the Na+-coupled glucose co-transporters decreases plasma glucose levels in insulin-independent (SGLTs)14,15. SGLTs couple the transport of glucose manner11. SGLT2 inhibitors represent a novel class of against a concentration gradient with the simultaneous drugs that has recently become available for treatment transport of Na+ down a concentration gradient16. Two of T2DM. Glucose Homeostasis: Role of Kidney important SGLT isoforms (SGLT1 and SGLT2) have During the fasting state, the plasma glucose level is been cloned and identified. SGLT1 is located primarily predominantly maintained by endogenous glucose in small intestinal cells but is also present in the kidney production by the liver specially through glycogenolysis and the heart17. SGLT1 is a high-affinity, low-capacity and gluconeogenesis10. The kidney contributes to transporter and therefore accounts for only a small glucose homeostasis by the consumption of glucose to fraction of renal glucose reabsorption; it serves meet its own metabolic requirements, gluconeogenesis, predominantly as a sodium-glucose co-tranporter18. In plus filtration and reabsorption of filtered glucose11. contrast, SGLT2 is a lowaffinity, high capacity SGLT located exclusively at the apical domain of the epithelial In the 1930s, Bergman and Drury first demonstrated cells in the early proximal convoluted tubule (S1 that interfering with kidney function in hepatectomized segment) (Figure-1). 90% of filtered glucose is rabbits, either by ligation of the vascular pedicles or the reabsorbed by SGLT2; rest 10% is reabsorbed by ureters, resulted in an increase in glucose utilization SGLT1 in the late proximal straight tubule14,15. rates12. Glucose remains unbound within the circulation and is filtered freely at the glomerulus. Under Therapeutic implications of SGLTs physiological circumstances, approximately 180 gm of inhibition glucose is filtered in a 24hr period11. To prevent such Phlorizin, a non-specific SGLT1 and SGLT2 inhibitor large losses in glucose, the kidney reabsorbs all filtered first isolated from the root bark of the apple tree in glucose. With increases in the filtered load either by a 1835,19 was found to increase glucosuria, reduce rise in plasma glucose concentration or an increase in hyperglycemia, and normalize insulin sensitivity in a glomerular filtration rate, the rate of reabsorption partial pancreatectomized animal model of T2DM20. increases to prevent increased excretion of glucose. However, it was not developed as a treatment for Glucosuria results when the filtered load overwhelms diabetes because of a number of practical shortcomings. the reabsorptive capacity of the kidney. Given that the It is non-selective and inhibits SGLT1 at the intestinal kidney typically consumes 25–35 gm per day and brush border, which is responsible for absorption of produces between 15 and 55 gm of glucose per day, it is dietary glucose21. Inhibition of SGLT1, therefore, 593 KYAMC Journal Vol. 6, No.-1, July 2015 has the potential to result in glucose–galactose induced by dapagliflozin monotherapy in patients with malabsorption and thus diarrhea, as occurs in naturally T2DM has been reported in one study to be associated occurring SGLT1 deficiency23. Furthermore, phlorizin is with weight reduction of 2.5–3.4 kg in 12 weeks and a poorly absorbed in the intestine and is readily net loss of 200– 300 kcal/day33. Modest blood pressure hydrolyzed to phloretin, a compound that blocks the reduction is consistently noted in clinical trials of facilitative glucose transporter, GLUT1. This might lead SGLT2 inhibitors34. The mechanism of that is not to interference with glucose uptake in a number of entirely clear. The natriuretic effect of SGLT2 inhibitors, tissues23. To overcome phlorizin short-comings, highly due to sodium-dependent co-transport mechanism of specific inhibitors of SGLT2 were developed24. Early SGLT2, in addition to glucose-induced osmotic diuresis SGLT2 inhibitor candidates, remogliflozin25 and may be contributing. There is also a suggestion that sergliflozin26, were selective for SGLT2 versus SGLT1 some inhibition of the renin– angiotensin–aldosterone (296- and 395-fold, respectively) but remained system, secondary to increased sodium delivery to the susceptible
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