MD Conference Express ADA 2011 - (Page 22)

n SELECTED UPDATES IN NOVEL T2DM THERAPIES Novel Diabetes Treatments: New and Future Developments Written by Rita Buckley Current treatment of hyperglycemia in type 2 diabetes mellitus (T2DM) is often ineffective and has unwanted side effects. Therefore, novel antidiabetic drugs are under development to address this problem. Sodium glucose cotransporter 2 (SGLT2) inhibitors are currently being tested for safety and efficacy [DeFronzo R et al. Endcorinology Rev 2011]. Ernest M. Wright, DSc, David Geffen School of Medicine, UCLA, Los Angeles, California, USA, discussed the SGLT gene family, the molecular dynamics of Na+ glucose cotransport, genetic disorders of SGLTs, and the mechanism of action of SGLT2 inhibitors. There are two classes of glucose transporters that are involved in glucose homeostasis in the body—the facilitated transporters, or uniporters (GLUTs), and the active transporters, or symporters (SGLTs). The energy for active glucose transport is provided by the sodium gradient across the cell membrane, the Na(+) glucose cotransport hypothesis first proposed in 1960 by Crane [Wright EM et al. Physiol Rev 2011]. The human SGLT (SLC5) gene family is made up of 12 members. They belong to a structural class of membrane proteins from unrelated gene families of antiporters and Na(+) and H(+) symporters [Wright EM et al. Physiol Rev 2011]. Membrane cotransport proteins that use a fivehelix inverted repeat motif have emerged as one of the largest structural classes of secondary active transporters [Watanabe et al. Nature 2010]. Watanabe et al. identified a cascade of events that were initiated by sodium release that ensure proper timing of ion and substrate release. Once set in motion, these molecules weaken substrate binding to the transporter and allow galactase to readily enter the intracellular space [Watanabe A et al. Nature 2010]. The human Na(+)/D-glucose cotransporter (hSGLT2) is believed to be responsible for the bulk of glucose reabsorption in the kidney proximal convoluted tubule. Since blocking reabsorption increases urinary glucose excretion, hSGLT2 has become a novel drug target for T2DM treatment. Results from hSGLT1 research suggest that it may also play a significant role in the reabsorption of filtered glucose in the late proximal tubule [Hummel CS et al. Am J Physiol Cell Physiol 2011]. According to Dr. Wright, SGLT1 is essential for normal intestinal absorption of glucose. The kidney contributes to glucose homeostasis through gluconeogenesis and the use and reabsorption of glucose 22 August 2011 from the glomerular filtrate [Gerich JE. Diabet Med 2010]. Dr. Wright noted that diabetes is a disorder of glucose homeostasis. One of the earliest symptoms is a loss of glucose to urine due to hyperglycemia, overwhelming the reabsorption capacity of SGLTs in the proximal tubule. There is a growing interest in alternative therapies to manage diabetic patients, and one is to control blood glucose by inhibiting SGLT2 in the kidney. The pharmaceutical industry has been encouraged by 1) studies that have demonstrated that intravenous phlorizin decreases blood glucose levels without producing hypoglycemia in diabetic animals and that this is accompanied by an improvement in insulin resistance; 2) reports that familial renal glucosuria is a benign disorder with no long-term renal abnormalities; and 3) cloning of the “renal” SGLTs, enabling in vitro studies [Wright et al. Physiol Rev 2011]. The strategy has been to develop oral SGLT2 inhibitors. Oral phlorizin does not fit the bill, as it blocks gastrointestinal absorption of glucose and thus produces osmotic diarrhea. Furthermore, phlorizin is hydrolyzed to glucose and phloretin by the intestinal brush border lactasehydrolase; so, little of the intact molecule is absorbed. Yet, most SGLT2 inhibitors in the drug pipeline have exploited the same chemical space as phlorizin, and many of these compounds are in Phase 1 to Phase 3 clinical trials. Several SGLT2 inhibitors are undergoing development, including dapagliflozin, canagliflozin, ASP1941, LX4211, and B1I10773 [Chao EC, Henry RR. Nat Rev Drug Discov 2010]. Dapagliflozin reduces fasting and postprandial plasma concentrations of glucose and HbA1C, as well as body weight, with low risk of hypoglycemia [Tahrani AA et al. Lancet 2011]. Safety studies of dapagliflozin in healthy human subjects indicate that the drug is well tolerated, with minimal adverse events and no clinically relevant changes in vital signs relative to the placebo controls. The drug is currently under review by the Food and Drug Administration for treatment of diabetes (Figure 1). Dr. Wright concluded his presentation by making six key points about SGLTs: • • Those in the small intestine and kidney are drug targets for diabetes SGLT2 in the kidney is the major focus of pharmaceutical companies www.mdconferencexpress.com http://www.mdconferencexpress.com http://www.mdconferencexpress.com

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MD Conference Express ADA 2011

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