Abstract: Blocking sodium-glucose cotransporters (SGLTs) to decrease the reabsorption of glucose -- and thus increase renal glucose excretion -- represents a novel therapeutic approach to diabetes that is independent of insulin secretion or action. Preclinical and clinical studies of SGLT2 inhibitors in subjects with type 2 diabetes (T2DM), as well as genetic mutations in kidney-specific SGLT2 that result in no adverse sequelae, appear to support this strategy. These investigations reveal that increasing renal glucose excretion by inhibiting SGLT2 can lower plasma glucose levels, as well as reduce body weight. Further data from larger trials are forthcoming regarding efficacy and safety, but the results reported thus far suggest that the positive impact of SGLT2 inhibitors may be attained without producing significant adverse effects. This class of agents, including dapagliflozin, may thus hold an advantage over many currently used medications for diabetes. This review outlines the role of SGLT2 in glucose homeostasis and the evidence currently available on the potential for clinical application of these agents in diabetes.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a paradigm shift: these are the first agents to exploit excreting glucose as a target of therapy. Employing suppression of renal glucose reabsorption as a therapeutic mechanism has shown promise in phase III clinical trials. Questions on issues such as safety and where these medications fit in the treatment arsenal of diabetes await clarification from further data in large clinical trials of agents, including dapagliflozin. The initial results to date have suggested that these agents are efficacious and safe.
Virtually all patients with type 2 diabetes must contend with varying degrees of both relative insulin deficiency and insulin resistance. The hyperglycemia that follows can facilitate beta-cell failure in the pancreas and worsen insulin resistance, thus triggering a cycle of glucose toxicity, which can contribute to increased apoptosis of beta-cells and lead to diminished beta-cell mass and thus reduced synthesis and secretion of insulin (Prentki and Nolan, 2006; Kaiser and Leibowitz, 2003).
Current T2DM therapies are often limited by their potential significant adverse effects. For instance, metformin can yield gastrointestinal effects, such as nausea and diarrhea; rarely, lactic acidosis may ensue (Inzucchi, 2002). Insulin and sulfonylureas can lead to weight gain and hypoglycemia (Inzucchi, 2002). Thiazolidinediones are also potential triggers of weight gain and edema (Inzucchi, 2002). Newer agents, such as the incretin mimetics, may cause nausea, vomiting, and diarrhea (Buse et al., 2004). Glycemic control may be difficult to reach. The search for new therapeutic agents devoid of these side effects thus continues.
The kidney plays a crucial role in controlling glucose levels. After its filtration in the blood, glucose is reabsorbed back into the plasma. What was an evolutionarily important adaptation that retains calories, has become a maladaptive response in individuals with diabetes. This process contributes to the sustained elevated serum glucose levels in patients with diabetes, as these individuals have an elevated capacity for renal glucose reabsorption (Farber et al., 1951).
Glucose Homeostasis and Imbalance in Patients with Diabetes
Cell membranes, which contain lipid, are impermeable to a polar compound such as glucose. Thus, carrier proteins aid in transporting glucose across the cell membrane. Once plasma glucose has been filtered by the renal glomeruli, it is reabsorbed by the SGLTs across the apical or luminal membranes of the epithelial cells of the proximal tubule, coupling the transport of sodium with that of glucose (Figure 1).
Both SGLT2 and SGLT1 actively transport glucose across the proximal convoluted tubule (PCT) cells of the kidney with varying capacities (Brown, 2000) (Table 1). SGLT2 is a high-capacity, low-affinity carrier found mainly in the S1 segment of the PCT, and handles approximately 90% of the reabsorbed glucose (Wright and Turk, 2004). The remaining 10% of filtered glucose that is reabsorbed is mediated by SGLT1, a low-capacity, high-affinity transporter that is located at the more distal S2/S3 segment of the PCT (Rahmoune et al., 2005; Wright, 2001). By coupling glucose transport with sodium across the luminal membrane, SGLT2 catalyzes the active transport of glucose against a concentration gradient (Wright, 2001; Lee and Han, 2007) (Figure 1). The inward sodium gradient across the luminal epithelium is maintained by active extrusion of sodium across the anti-luminal surface into the blood (Wright and Turk, 2004; Rahmoune et al., 2005). This process is driven by ATP.
Plasma glucose concentrations are normally maintained within a narrow range. Such tight regulation is critical for organs such as the brain, which utilizes glucose almost exclusively as its energy source. This homeostasis is orchestrated by an intricate interaction of various regulatory processes (Figure 2). Glucose uptake by the central nervous and peripheral tissues is matched by glucose production that is mainly mediated by the liver, and to a lesser extent, the kidney (Wright, 2001). By controlling glucose filtration and reabsorption, the kidney serves a unique role in glucose homeostasis. Under normal circumstances, approximately 180 grams (g) of glucose per day is freely filtered and essentially completely reabsorbed by the kidney, thus contributing to preserving this balance (Abdul-Ghani and DeFronzo, 2008) (Figure 3). The filtered load of glucose is the product of the plasma glucose concentration and the glomerular filtration rate. Thus, as the plasma glucose concentration rises, so does the filtered load of glucose in a linear fashion. When the plasma glucose concentration exceeds approximately 200 mg per 100 ml, all of the filtered glucose is reabsorbed, since the SGLTs have not yet reached their maximal capacity to reabsorb glucose (please refer to Figure 4 for a graphical depiction) (Abdul-Ghani and DeFronzo, 2008). When the cotransporters are approaching saturation, some of the filtered glucose is therefore not reabsorbed, but is excreted. Filtered glucose is reabsorbed in the PCT (Figure 4). When the filtered glucose load surpasses the tubular maximum (Tmax), the glucose excretion rate increases linearly and parallels the curve for filtered load. Thus, any amount of filtered glucose exceeding the Tmax is excreted and appears as glucose in the urine.
Development of SGLT2 Inhibitors
Phlorizin. Phlorizin has played a vital role in uncovering both the mechanism of renal glucose reabsorption and the role of hyperglycemia in diabetes. This agent was first isolated in 1835 from the root bark of the apple tree by French chemists, and was noted to be a potent but relatively nonselective inhibitor of both SGLT2 and SGLT1 (Ehrenkranz et al., 2005). Rossetti and his team compared the effects of phlorizin on blockade of renal glucose reabsorption in diabetic rats with controls. Diabetes had been induced by partial pancreatectomy. Phlorizin normalized insulin sensitivity in these diabetic rats, but did not influence insulin action in controls (Rossetti et al., 1987). Glycosuria ensued after phlorizin administration, which normalized both the fasting and fed plasma glucose levels and completely reversed insulin resistance. When phlorizin was discontinued, hyperglycemia and insulin resistance recurred. This study was the first demonstration that hyperglycemia alone can lead to the development of insulin resistance via glucose toxicity. Multiple subsequent investigations of phlorizin helped to establish that hyperglycemia contributes to the insulin resistance that characterizes T2DM (Freitas et al., 2008).
Although studies revealed that phlorizin administered orally to mice blunted the increase in blood glucose levels after ingesting a glucose solution, it was not further developed as an anti-diabetes medication due to poor intestinal absorption and resultant low bioavailability, as well as rapid in vivo degradation by β-glucosidase (Ehrenkranz et al., 2005). Another significant disadvantage is that phlorizin also acts on SGLT1, which is mainly expressed in the gastrointestinal tract. SGLT1 gene mutations lead to glucose and galactose malabsorption, dehydration, and diarrhea (Ehrenkranz et al., 2005). A third drawback is when phlorizin is hydrolyzed in the gut, phloretin is produced, which inhibits facilitative glucose transporters, such as GLUT1 (Ehrenkranz et al., 2005). Suppression of intestinal GLUT1 impairs intestinal transport of glucose and results in gastrointestinal side effects, such as diarrhea. This and other studies triggered the search for a phlorizin derivative that would minimize these shortcomings.
Early SGLT2 Inhibitors. As phlorizin lacked specificity for SGLT2 and was associated with substantial side effects, investigators sought to develop new compounds to inhibit SGLT2 with high potency and selectivity. Other aims included optimizing bioavailability through enhanced stability, and improving safety profiles. The first orally available phlorizin derivative reported was T-1095. Preclinical studies on this agent confirmed the initial evidence that inhibition of renal SGLTs could be a viable target for therapy in diabetes. Although this compound was more metabolically stable than phlorizin, it too was nonselective (Oku et al., 1999). T-1095 was not developed further, so no clinical data are available for this agent. Subsequently, sergliflozin and remogliflozin, which possessed greater SGLT2 selectivity, were tested and sergliflozin progressed to clinical trials.
For reasons not entirely known, but most probably related at least in part to their pharmacokinetic profiles, and possibly also due to an unfavorable efficacy and side-effect profile, these agents did not undergo further development. Both sergliflozin and remogliflozin contain O-glucoside linkages that render them susceptible to hydrolysis by β-glucosidase enzymes in the gastrointestinal tract.
Agents Currently Under Development
Several SGLT2 inhibitors now in various stages of clinical development, but published data are limited. Several clinical studies of dapagliflozin have been reported. Preliminary trial data for canagliflozin have been published only in abstract form, and will not be discussed.
Dapagliflozin. Dapagliflozin (developed by Bristol-Myers Squibb and AstraZeneca), the SGLT2 inhibitor that has progressed the furthest in development, is undergoing phase III trials as a once-daily, oral treatment for T2DM. A C-aryl glucoside linkage found in dapagliflozin confers resistance to degradation in the gastrointestinal tract by β-glucosidase enzymes (Meng et al., 2008). Consequently, dapagliflozin can be administered orally without modification, therefore carrying a more favorable pharmacokinetic profile than earlier agents. Dapagliflozin is approximately 1,200-times more selective for SGLT2 over SGLT1. An in vitro study revealed that dapagliflozin exhibited around 30-times greater potency against SGLT2 in humans than phlorizin, and approximately 4-fold less potency versus phlorizin against human SGLT1 (Han et al., 2008).
In the rat, dapagliflozin administration resulted in an acute increase in glycosuria, unaccompanied by hypoglycemia (Meng et al., 2008; Han et al., 2008). In Zucker diabetic fatty (ZDF) rats, urine glucose levels doubled with all doses of dapagliflozin compared with vehicle (Han et al., 2008). Fasting and postprandial glucose levels decreased, concomitant with the glycosuria. Similarly, fasting glucose was reduced in streptozocin-induced diabetic rats following administration of a single dose of dapagliflozin (Han et al., 2008). Such declines in fasting glucose levels were sustained in ZDF rats after 15 days of repeated dosing of dapagliflozin. Taken together, this and other preclinical trials suggested a potential novel strategy of treating hyperglycemia which did not target insulin secretion or its actions. These observations of efficacy in animal models led to further clinical investigations in humans.
Komoroski and colleagues conducted the first clinical studies that assessed the safety and pharmacokinetic and pharmacodynamic parameters of single and multiple doses of dapagliflozin in healthy individuals (Komoroski et al., 2009). In the single-ascending dose study, a single dose of 2.5 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 250 mg, or 500 mg of dapagliflozin, or placebo was randomly assigned. Subjects were then enrolled at the next higher dose if results from the first trial indicated that dapagliflozin was safe and well tolerated in at least six subjects. The multiple-ascending dose study was similarly designed, with the administration of five sequential doses of 2.5 mg, 10 mg, 20 mg, 50 mg, or 100 mg of dapagliflozin, or placebo. Doses of 20-50 mg per day of dapagliflozin produced near-maximal SGLT2 blockade (a glucose excretion of up to ~3 g per hour and ~60 g per day) for at least 24 hours. The glycosuria observed was sustained, dose-dependent, and did not cause hypoglycemia in these subjects. Renal glucose reabsorption was inhibited by approximately 20-30% on day 1 and approximately 16-50% on day 14.
Wilding and colleagues reported a study investigating the effect of dapagliflozin on hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), postprandial glucose, and weight in patients with T2DM, who were experiencing suboptimal control on oral agents and high insulin doses (Wilding et al., 2009). A total of 71 individuals with T2DM were randomized in 26 centers in the United States and in Canada. Patients were on stable-dose insulin-sensitizing agents — metformin ≥1,000 mg and/or pioglitazone ≥30 mg, or rosiglitazone 4 mg — for ≥6 weeks and half of their usual insulin dose (at least 50 units daily) for at least 12 weeks before enrollment, with no change in dose for at least 6 weeks. Twenty-three patients were randomized to placebo, 24 to the dapagliflozin 10 mg group, and 24 received 20 mg of dapagliflozin. The primary end point — the change in HbA1c from baseline at week 12 (last observation carried forward, LOCF) — was reported to decrease 0.7% (10 mg) and 0.78% (20 mg) in the dapagliflozin groups versus placebo. Indeed, 65.2% of patients in both dapagliflozin groups exhibited a ≥0.5% decline from baseline HbA1c compared with 15.8% of the placebo cohort. The mean changes in fasting plasma glucose levels from baseline at week 12 were +17.8 mg per 100 ml (placebo), +2.4 mg per 100 ml (10 mg dapagliflozin), and -9.6 mg per 100 ml (20 mg dapagliflozin). The mean changes in total body weight were -1.9 kg (placebo), -4.5 kg (10 mg dapagliflozin), and -4.3 kg (20 mg dapagliflozin). Mean changes in postprandial glucose at 120 minutes at week 12 (LOCF) were +18.7 mg per 100 ml with placebo and insulin, -34.3 mg per 100 ml for 10 mg dapagliflozin and insulin, and -41.9 mg per 100 ml for 20 mg dapagliflozin and insulin. The urinary glucose excretion at week 12 for those receiving placebo was -1.5 g per 24 hours, compared with 83.5 g per 24 hours in the 10 mg dapagliflozin group, and 85.2 g per 24 hours for those given 20 mg dapagliflozin. Mean decreases in standing systolic and diastolic blood pressures were detected in both dapagliflozin cohorts. The modification of diet in renal disease-estimated glomerular filtration rates at the end of the study were normal compared with baseline.
A phase III randomized, double-blind, placebo-controlled trial of dapagliflozin as an add-on agent examined 546 poorly controlled T2DM patients on maximum doses of metformin (≥1500 mg/day). These subjects were randomized to receive dapagliflozin 2.5 mg qday, 5 mg qday, or 10 mg qday, or placebo (Bailey et al., 2010). Baseline HgbA1c (glycohemoglobin A1c) values were 7.9%, 8.2%, 7.9%, and 8.1% for the 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. After 24 weeks, reductions in mean HbA1c were significantly higher in the dapagliflozin groups compared with placebo group (2.5 mg: -0.67%, 5 mg: -0.70%, and 10 mg: -0.84 versus -0.3% in the placebo group; p ≤ 0.0002 for all comparisons). FPG levels were significantly lower in all patients on dapagliflozin compared with placebo (2.5 mg: -0.99 mmol/l, 5 mg: -1.19 mmol/l, and 10 mg: -1.3 mmol/l versus -0.33 mmol/l in the placebo group; p ≤ 0.0019 for all the comparisons). More subjects in the dapagliflozin groups reached an HgbA1c <7% compared with placebo (2.5 mg: 33%, 5 mg: 37.5%, and 10 mg: 40.6 versus 25.9% in the placebo group; p = 0.0275 and 0.0062 for the dapagliflozin 5 and 10 mg groups, respectively). Urinary glucose excretion increased in all patients on dapagliflozin, while the placebo group experienced reductions. Mean body weight and waist circumference declined in subjects in the dapagliflozin groups (2.5 mg: -2.2 kg, 5 mg: -3 kg, and 10 mg: -2.9 kg versus -0.9 kg in the placebo group; p < 0.0001 for all comparisons) (2.5 mg: -1.7 cm, 5 mg: -2.7 cm and 10 mg: -2.5 cm versus -1.3 cm in the placebo group; p not provided).
Without an increase in hypotensive episodes, dapagliflozin-treated patients also showed larger reductions in mean seated systolic blood pressure (2.5 mg: -2.1 mmHg, 5 mg: -4.3 mmHg, and 10 mg: -5.1 mmHg versus -0.2 mmHg in the placebo group) and diastolic blood pressure (2.5 mg: -1.8 mmHg, 5 mg: -2.5 mmHg, and 10 mg: -1.8 mmHg versus -0.1 mmHg in the placebo group; p not provided) compared with the placebo group (Bailey et al., 2010). Compared with the placebo group, a greater percentage of hypertensive patients on dapagliflozin with uncontrolled baseline blood pressure achieved blood pressures of 130/80 mmHg [8.8% of patients in the placebo group. Differences versus placebo were: 2.5 mg: 20.7% (95%CI: 6.7 - 34.8), 5 mg: 21.7% (95% CI: 7.3 - 36.1), and 10 mg: 28.7% (95%CI: 12.7 - 44.3); p not provided].
Ferrannini and colleagues conducted a 24-week, phase III double-blind, placebo-controlled clinical study of 485 treatment-naïve T2DM patients randomized to dapagliflozin (2.5, 5, or 10 mg qday) or placebo with baseline HbA1c of 7-10%. Mean decreases in HgbA1c, FPG, and body weight were similar whether dapagliflozin was administered in the morning or evening (Ferrannini et al., 2010). More patients achieved an HbA1c <7% in the dapagliflozin groups compared with placebo (2.5 mg: 41%, 5 mg: 44%, and 10 mg: 51 versus 32% in placebo group; p value was not provided). Mean FPG also declined to a greater extent in patients on dapagliflozin versus placebo (2.5 mg: -15.2 mg/dl, 5 mg: -24.1 mg/dl, and 10 mg: -28.8 mg/dl versus -4.1 mg/dl in the placebo group; p < 0.001 for 5 mg and p < 0.0001 for the 10 mg group versus placebo). For body weight, there was a non-significant trend for greater reduction with dapagliflozin, as compared with placebo (2.5 mg: -3.3 kg, 5 mg: -2.8 kg, and 10 mg: -3.2 versus -2.2 kg in the placebo group). Urinary glucose excretion increased with subjects on dapagliflozin, compared with those in the placebo group.
A high HgbA1c cohort (baseline HbA1c 10.1-12%) of 74 T2DM patients were randomized to receive a morning dose of dapagliflozin at either 5 or 10 mg. Changes in mean HbA1c were greater in comparison with the other two cohorts (5 mg: -2.88%; 10 mg: -2.66%; p not provided); this also held for changes in FPG (5 mg: -77.1 mg/dl; 10 mg: -84.3 mg/dl; p not provided).
Safety of SGLT2 Inhibition
Hypoglycemia is one of the major concerns of many diabetes agents. Given that SGLT2 inhibitors act independently of glucose-dependent insulin secretion, and that they incompletely inhibit glucose reabsorption, this adverse effect would not be expected to occur. Virtually no instances of major hypoglycemic events have been reported to date (Komoroski et al., 2009; List et al., 2009; Wilding et al., 2009; Bailey et al., 2010; Ferrannini et al., 2010). Further results are pending from larger trials of longer duration. Although the risk of hypoglycemia is low, if SGLT2 inhibitors are concurrently administered with other anti-diabetic agents such as metformin or the insulin secretagogues, it is important to investigate its potential development.
The mechanism of action of SGLT2 inhibitors raises other safety issues, including the development of urinary tract infections and fungal genitourinary infections, as well as deterioration of renal function. Clinical studies to date on dapagliflozin have found that the rates of urinary tract infections were comparable in treatment and placebo groups — in the Bailey study, rates of urinary tract infection were equal in all groups (2.5 mg: 4%, 5 mg: 7%, and 10 mg: 8 versus 8% in the placebo group) (Bailey et al., 2010). Elevated urine volume of 400-600 ml per day was detected in the studies of dapagliflozin, and was associated with a dose-related elevation in hematocrit (range 1.5-2.9%) (List et al., 2009), and increased urea. The diuresis may be due more to an osmotic effect than to sodium loss. Two recent clinical studies noted an increased incidence in fungal genitourinary infections, most occurring in the higher dosage groups (List et al., 2009; Wilding et al., 2009; Bailey et al., 2010). The Bailey study, for instance, noted genitourinary infections in 8% of those on 2.5 mg, 13% in the 5 mg group, and 9% in the 10 mg group, compared with 5% in the placebo group.
In addition, in all of the larger trials of dapagliflozin, no deaths have occurred (Komoroski et al., 2009; List et al., 2009; Wilding et al., 2009; Bailey et al., 2010; Ferrannini et al., 2010) and no serious adverse events related to dapagliflozin were observed in these studies. Although two subjects experienced a serious adverse event in the study by Wilding and colleagues, one was on placebo, while the other received the higher dose (20 mg) of dapagliflozin. No clinically significant changes in renal function or serum electrolytes were noted (Bailey et al., 2010; Ferrannini et al., 2010).
Perhaps the most compelling evidence for the long-term safety of this class of agents that affect glucose reabsorption is found from studying individuals with familial renal glycosuria — an autosomal genetic disorder resulting from mutations in the gene encoding SGLT2; its mode of transmission is thought to be co-dominant with incomplete penetrance (Calado et al., 2004; van den Heuvel et al., 2002). Familial renal glycosuria is characterized by persistent isolated glycosuria of approximately 10-120 g per day, in the face of normal fasting serum glucose, normal glucose tolerance tests, the absence of any signs of general renal tubular dysfunction or other pathological changes, and normal life expectancies (Calado et al., 2004; van den Heuvel et al., 2002). Individuals with familial renal glycosuria usually report no complaints, and only rarely have hypoglycemia or hypovolemia.
Of the SGLTs, SGLT2 offers the most promise as a therapeutic target, because it is responsible for most of the renal glucose reabsorption and it is expressed exclusively in the kidney. Inhibition of SGLT2 represents a particularly appealing strategy to treating diabetes, as, in contrast to many other current diabetes therapies, SGLT2 inhibitors do not directly influence insulin secretion, thereby utilizing a novel mechanism of action. Thus, there is a low risk of hypoglycemia (Wright et al., 2001). Although clinical trials of many of the SGLT2 inhibitors are in the early stages, data from investigations so far are encouraging. Currently, all published clinical studies of SGLT2 inhibitors have been performed in individuals with T2DM. Acute administration of SGLT2 inhibitors reduces both preprandial and postprandial blood glucose, and chronic administration may decrease glucotoxicity (Bakris et al., 2009). The energy deficit due to excretion of calories in the urine can reduce weight, or exert a weight-neutral effect. As the target tissue is limited to the kidney, the potential for off-target adverse effects is also minimized, and the data compiled thus far indicate that this class of agents has been generally safe and well tolerated.
Their novel mechanism of action suggests that SGLT2 inhibitors might have the potential to be used in combination with oral anti-diabetic agents as well as insulin to exert additive or synergistic effects on lowering glucose levels in T2DM. In addition, the potential for an increase in side effects, such as hypoglycemia, following such combination therapy is unknown.
Another area of uncertainty involves the contributions of diuresis versus reduction in adiposity to total weight loss. One study postulated that the larger reduction in weight during week 1 of dapagliflozin administration, coupled with a partial, rapid resurgence in weight after discontinuation of higher doses, might represent the effect of diuresis, whereas more sustained weight loss is due to decreased adipose tissue (List et al., 2009). The safety of this class of agents in women of child-bearing age also is unknown, as is the impact of these inhibitors on bone metabolism.
In summary, increasing urinary glucose excretion by inhibiting renal glucose reabsorption represents a potential new strategy for treating hyperglycemia. SGLT2 inhibitors may have indications both in the treatment and prevention of T2DM, and perhaps T1DM. Further studies in large numbers of human subjects are necessary to further assess efficacy, safety, and how to most effectively employ these agents in the treatment of diabetes.
The author would like to express his appreciation to Dr. Daniel Porte, and to Dr. Robert Henry, for their discussions and support.
The author reports no existing or potential conflicts of interest.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(58):255-263, March 2011.]