SGLT-2 Inhibitors: a New Mechanism for Glycemic Control
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FEATURE ARTICLE SGLT-2 Inhibitors: A New Mechanism for Glycemic Control Edward C. Chao, DO ype 2 diabetes is a progres- or death.7 Diabetes also exacts a in muscle, brain, and liver; increased sive, chronic metabolic disease tremendous economic burden; in the glucagon secretion in α-cells; characterized by hypergly- United States, direct and indirect increased lipolysis in adipose tissue; T1 cemia. Beyond being a diagnostic costs totaled $174 billion in 2007.3 incretin deficiency and resistance marker, elevated glucose is a key Meeting treatment goals is elusive in the gastrointestinal (GI) tract; factor in the two abnormalities that for many people with diabetes.8–10 and increased glucose reabsorp- are at the core of type 2 diabetes: Data from the National Health and tion in the kidney.11 Other obstacles pancreatic β-cell failure and insulin Nutrition Examination Survey from include clinical inertia, or the failure resistance. Chronic hyperglycemia 2003 to 2006 showed that only 57.1% to start or intensify therapy when can induce apoptosis of β-cells that of adults with diagnosed diabetes clinically indicated.12 There is some is not countered by a compensatory achieved an A1C < 7%, 45.5% had a evidence that patients with type 2 increase in β-cell neogenesis and blood pressure level < 130/80 mmHg, diabetes who have lower medication can lead to decreased insulin gene and 46.5% had an LDL cholesterol adherence are less likely to undergo transcription. The detrimental effect level < 100 mg/dl.10 Only 12.2% of treatment intensification.13 Reaching of excessive glucose concentrations is people with diabetes reached all glycemic targets may also be ham- referred to as “glucotoxicity.”2 three goals.10 pered by aversion to adding insulin Despite therapeutic advances, the There are multiple barriers to or implementing lifestyle changes. incidence and prevalence of diabe- achieving optimal glycemic control. Barriers such as cost and formulary tes continue to surge. An estimated The pathophysiology of diabetes restrictions also present challenges. 25.8 million people in the United is complex and involves multiple Current medications for type 2 States have diabetes.3 The incidence defects: β-cell failure (decreased diabetes have potential adverse could triple to one in three by 2050.4 insulin secretion); insulin resistance effects; sulfonylureas and insulin, for Worldwide, the number of individu- example, can cause hypoglycemia als with diabetes is projected to rise IN BRIEF and weight gain.14 Thus, the search from 366 million in 2011 to 552 mil- continues for novel therapeutic lion by 2030, which is the equivalent Glucosuria, the presence of agents that can help patients avoid of approximately three new cases glucose in the urine, has long these limiting side effects while being diagnosed every 10 seconds.5 been regarded as a consequence providing glycemic control. Type 2 diabetes doubles the of uncontrolled diabetes. Although the concept of the risk of cardiovascular disease,6 However, glucose excretion can be kidney playing a significant role in and macrovascular complications induced by blocking the activ- glucose balance is not new, only (myocardial infarction and stroke) ity of the renal sodium-glucose recently has this organ been con- cotransporter 2 (SGLT-2). This are a common cause of death in sidered a potential therapeutic mechanism corrects hyperglyce- patients with type 2 diabetes.3 The target. Sodium-glucose cotrans- mia independently of insulin. This U.K. Prospective Diabetes Study porters (SGLTs), namely SGLT-1 article provides an overview of the showed that every 1% absolute and SGLT-2, facilitate reabsorption paradigm shift that triggered the decline in mean A1C was associ- of glucose back into the plasma. development of the SGLT-2 inhibi- ated with a 37% reduction in the Inhibiting this process promotes tor class of agents and summarizes risk of microvascular complications glucosuria and thus reduces blood the available evidence from clinical and a 21% reduction in the risk of glucose. This review describes the studies to date. any diabetes-related complication mechanism of action of this new 4 Volume 32, Number 1, 2014 • CLINICAL DIABETES FEATURE ARTICLE class of treatment for type 2 diabe- tes, as well as published data on its efficacy and safety. Role of the Kidney in Glucose Homeostasis Despite wide fluctuations in the daily supply of glucose and the body’s demand for it, homeostatic mecha- nisms maintain plasma glucose levels within a narrow range, with average levels of ~ 90–100 mg/dl in a 24-hour period.15,16 The kidney’s crucial role in maintaining glucose balance was first described as early as 1938.17 Along with the liver, the kidney supplies glucose during periods of fasting. The renal contribution to gluconeogenesis Figure 1. Renal glucose handling. In healthy individuals, the vast majority of the is ~ 15–55 g/day, or 20–25% of the glucose filtered by the kidney is reabsorbed by SGLT-2 in the S1 and S2 segments of glucose released into the circulation the proximal convoluted tubule, and the remaining glucose is reabsorbed by SGLT-1 20 after an overnight fast.17,18 in the S3 segment. The reabsorption of glucose active extrusion of sodium across the 260–350 mg/min/1.73 m2. The renal filtered into the glomerular filtrate is basolateral surface into the intracel- glucose threshold (RTG) is the the primary mechanism by which the lular fluid (Figure 2).20 Facilitated plasma glucose concentration above kidney influences glucose homeosta- glucose transporters (GLUTs) carry which the SGLT capacity becomes sis.18 Glucose excretion in urine is the glucose across the basolateral mem- saturated and urinary glucose excre- net difference between the amount brane by facilitated diffusion.20 tion (UGE) occurs. It is estimated to of glucose filtered by the kidney and Glucose reabsorption in the PCT occur at a plasma glucose concen- the amount reabsorbed. In healthy increases with rising plasma glucose tration of ~ 200 mg/dl (Figure 3).15,16 individuals, the kidney contributes levels until the transport maximum The actual threshold is not abrupt significantly to glucose homeostasis for glucose (T ) is reached. The and differs from the theoretical by reabsorbing essentially all of the max Tmax is usually considered to occur threshold for both the reabsorption ~ 180 g of glucose that it filters per at a glomerular filtration rate of and excretion curves (Figure 3). One day.19 Individuals without diabetes thus have very little or no glucose present in the urine. Reabsorption occurs in the proximal convoluted tubule (PCT) and is carried out by two isoforms of SGLT. 20 SGLT-2 is located in the S1 and S2 segments of the PCT and has a high capacity but low affinity for glucose transport. In healthy indi- viduals, it reabsorbs ~ 90% of filtered glucose (Figure 1).20 SGLT-1 governs glucose transport in the S3 segment Figure 2. SGLT-2 mediates glucose reabsorption in the kidney. SGLT-2 catalyzes and is a low-capacity, high-affinity the active transport of glucose (against a concentration gradient) across the luminal glucose transporter that reabsorbs membrane by coupling it with the downhill transport of Na+. The inward Na+ gradi- the remaining 10% of the filtered ent across the luminal epithelium is maintained by active extrusion of Na+ across glucose.20 The active transport of the basolateral surface into the intracellular fluid. Glucose diffuses out of the cell glucose is linked to downhill sodium down a concentration gradient via the basolateral facilitative transporter GLUT2.20 transport, which is maintained by Adapted from Ref. 20. CLINICAL DIABETES • Volume 32, Number 1, 2014 5 FEATURE ARTICLE Phlorizin was not developed for use in humans because of its low bioavailability (~ 15%) and its action on SGLT-1, which can result in GI side effects, including diarrhea. Other SGLT-2 inhibitors, such as sergliflozin, did not reach advanced stages of clinical development for reasons related to their pharmacoki- netic profiles (i.e., their susceptibility to hydrolysis by GI tract enzymes resulted in relatively short half- lives and poor bioavailability).29–31 Canagliflozin has been approved in the United States, and dapagliflozin has been approved in Europe. Figure 3. Renal glucose handling before and following inhibition of SGLT-2. As Several other SGLT-2 inhibitors are the plasma glucose concentration increases, renal glucose reabsorption increases, in development (Table 1). following the line marked “Reabsorption” (in red). At plasma glucose concentra- tions greater than ~ 200 mg/dl, all the filtered glucose is reabsorbed, and there is Mechanism of Action and Potential no excretion. When glucose reaches a threshold, at ~ 200 mg/dl, the maximum Advantages capacity of the renal tubule to reabsorb glucose—or Tmax—is exceeded. Once past By lowering the renal threshold for this threshold, glucose begins to be excreted via the urine (dark blue line, labeled glucose excretion, SGLT-2 inhibitors “Excretion”). The actual thresholds for both reabsorption and excretion differ from suppress renal glucose reabsorp- the theoretical thresholds because of physiological variation among individual neph- tion and thereby increase UGE.19 rons (i.e., slight differences in their glucose-handling abilities). This is known as “splay” (green dashed lines). The dashed light blue lines depict renal glucose han- Hyperglycemia is thus ameliorated. dling after SGLT-2 inhibition. SGLT-2 inhibitors lower the renal glucose threshold, However, SGLT-2 inhibitors inhibit leading to urinary glucose excretion.16 Adapted from Ref. 16. reabsorption of only ~ 30–50% of the glucose filtered by the kidney.32 reason for this splay, or difference in Interest in the compound was dor- The reasons for this are unclear. thresholds, is physiological variation mant until the 1970s, with discovery One hypothesis is that SGLT-2 of the location of the transporters. among individual nephrons.