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SPECIAL FEATURE

Review

Sodium Glucose Cotransporter 2 Inhibitors as a New Treatment for Diabetes Mellitus

Sunil Nair and John P. H. Wilding

Diabetes and Endocrinology Research Unit, Clinical Sciences Centre, University Hospital Aintree, Liverpool L9 7AL, United Kingdom

Context: Sodium-glucose cotransporter 2 (SGLT2) expressed in the proximal renal tubules accounts for about 90% of the reabsorption of glucose from tubular fluid. Genetic defects of SGLT2 result in a benign familial renal glucosuria. Pharmacological agents that block SGLT2 are being tested as potential treatment for type 2 diabetes mellitus.

Evidence Acquisition: A Pubmed search was used to identify all relevant articles on the physiology of SGLTs as well as published preclinical and clinical experimental studies with SGLT2 inhibitors; a reference search of all retrieved articles was also undertaken.

Evidence Synthesis: SGLT2 is almost exclusively expressed in the proximal renal tubules. Preclinical studies with selective SLGT2 inhibitors show dose-dependent glucosuria and lowering of blood glucose in models of type 2 diabetes. Preliminary clinical studies of up to 3-month duration show dose-dependent lowering of glycosylated hemoglobin up to 0.9% along with modest weight loss. Side effects include an increase in genital fungal infection compared to placebo, increased urine volume (300 – 400 ml/24 h), and evidence of volume depletion consistent with mild diuretic effect.

Conclusion: SGLT2 inhibitors are showing promise as a useful addition to the current therapeutic options in type 2 diabetes mellitus. Results of ongoing phase III clinical trials are awaited and will determine whether the risk-benefit ratio will allow approval of this new class of drug for the management of type 2 diabetes mellitus. ( J Clin Endocrinol Metab 95: 34 – 42, 2010)

M anagement of type 2 diabetes mellitus (T2DM) re- mains complex and challenging. Although a wide

range of pharmacotherapy for T2DM is available, including metformin, insulin secretagogues (predominantly sulfonyl- ureas), thiazolidinediones, -glucosidase inhibitors, insulin, and more recently glucagon like peptide-1 agonists and dipeptidyl-peptidase-IV inhibitors, many patients do not achieve glycemic targets, partly due to limiting side effects of current therapies,includingweight gain, hypoglycemia, fluid retention, and gastrointestinal side effects. Hence, the search for new treatment strategiesis ongoing. Among the new ther- apies on the horizon, sodium-glucose cotransporter 2 (SGLT2) inhibitors seem promising, and there are a number of ongoing phase II and III clinical trialswith a variety of these compounds. SGLT2 is almost exclusively expressed in the renal proximal tubules and accounts for 90% of the renal

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2010 by The Endocrine Society doi: 10.1210/jc.2009-0473 Received March 4, 2009. Accepted October 14, 2009. First Published Online November 5, 2009

glucose reabsorption (1). SGLT2 inhibitors work indepen- dently of insulin and lead to negative energy balance by en- hanced urinary glucose excretion. This makes it mechanis- tically possible for this class of drugs to reduce glucose levels without causing hypoglycemia and weight gain. However, the side effect profile remains to be further elucidated in on- going phase III trials, and these compounds will need to be proven safe from a renal and cardiovascular perspective tomeet current regulatory requirements for new diabetes treatment.

Glucose Transport across Biological Membranes

Glucose transporters Glucose absorption at the enterocytes, reabsorption at the renal tubules, transport across the blood-brain barrier, and

Abbreviations: GLUT, Glucose transporter; HbA1c, glycosylated hemoglobin; MAD, mul- tiple ascending dose; SAD, single ascending dose; SGLT, sodium-glucose cotransporter; SLC, solute carrier family; T2DM, type 2 diabetes mellitus; UTI, urinary tract infection.

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uptake and release by all cells in the body are effected by two groups of transporters: glucose transporters (GLUTs) and sodium-glucose cotransporters (SGLTs). GLUTs are facilitative or passive transporters that work along the glucose gradient. They belong to the SLC2 (solute carrier family 2) gene family, which has 13 mem- bers: GLUT 1-12 and the H -myoinositol cotransporters. They are expressed in every cell of the body (2, 3). SGLTs cotransport sodium and glucose into cells using the sodium gradient produced by sodium/potassium ATPase pumps at the basolateral cell membranes. They belong to the SLC5 gene family, which has nine members with known functions. Of these, six are plasma membrane sodium/substrate cotransporters for solutes such as glu- cose, myoinositol, and iodide (SGLT 1-6). SGLT1 is pri- marily expressed in the small intestine but is also found in the trachea, kidney, and heart, and its predominant sub- strates are glucose and galactose. SGLT2 is expressed in the S1 and S2 segments of the proximal convoluted tubules and is responsible for renal reabsorption of glucose (4). SGLT2 RNA is minimally expressed in the ileum, the level of which was insignificant by Northern blot analysis (5). Although one study using real-time PCR suggests wide- spread SGLT2 RNA expression in a variety of tissues (6), there is no published data to show that SGLT2 protein is found outside the kidney. There have been attempts to examine expression of SGLT proteins, but availability of antibodies that are specific enough seems to be the limiting factor. Therefore, the functional significance of mRNA expression in nonrenal tissues has not been established. However, there is some evidence for SGLT2 mRNA ex- pression by real-time PCR as well as for SGLT2 protein expression in the placenta by Western blot analysis (7). SGLT1 gene mutations lead to glucose-galactose malab- sorption, which causes potentially fatal diarrhea. The oral re- hydration therapy that saves millions of lives from infectious diarrheaworksviaSGLT1 transportersin theenterocytes (8,9). Much of the evidence for SGLT2 being a major path- way for renal glucose reabsorption comes from genetic studies of individuals with familial renal glucosuria (10, 11). Mutations in the SLC5A2 gene encoding SGLT2 lead to familial renal glucosuria, which is inherited as an au- tosomal recessive trait and is characterized by normal blood glucose levels, normal oral glucose tolerance test results, and isolated persistent glucosuria (10, 12, 13). A study analyzing 23 families with index cases of renal glu- cosuria found that each family had a unique mutation in the SGLT2 gene. Individuals who were found to be carriers of two mutated alleles showed severe glucosuria, defined by a urinary glucose of more than 10 g/1.73 m 2 per 24 h (55 mmol/1.73 m 2 per 24 h). The index patients who pre- sented with mild glucosuria and the family members of

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cases of severe glucosuria were shown to be heterozygous carriers of SGLT2 mutations (11, 14). Another study found 20 different SLC5A2 mutations within 17 pedi- grees. Glucosuria was mild in heterozygotes ranging from 2.7 to 10 g/1.73 m 2 per 24 h, whereas it was severe in homozygotes ranging from 15.2 to 86.5 g/1.73 m 2 /24 h. Two patients in the homozygous group had plasma renin and serum aldosterone concentration raised to an average of 4.6- and 3.1-fold, respectively, suggesting activation of compensatory mechanisms (15).

Renal glucose transport in health Kidneys play a very important role in glucose ho- meostasis. Blood glucose is freely filtered by the glomeruli and is essentially completely reabsorbed from the proxi- mal tubules via sodium-coupled transporters in the brush border membrane. The glomeruli filter about 144 g of glucose per 24 h, nearly 100% of which is reabsorbed in the renal tubules. When blood glucose levels reach the renal threshold for reabsorption, which is about 8 to 10 mmol/liter (180 mg/dl), glucosuria starts to develop (16). The proximal tubule has traditionally been divided into S1, S2, and S3 segments based on the cell morphologies, although more recent ultra structural analyses of computer- assisted three-dimensional reconstruction of mouse proximal tubules revealed no obvious morphological seg- mentation of the proximal tubule (17). There is evidence, however, for heterogeneity of sodium-dependent glucose transport along the proximal tubule. The S1 and S2 seg- ments of the proximal convoluted tubules show low af- finity and high capacity for sodium-dependent glucose ab- sorption, whereas the more distal parts show higher affinity and low capacity for the same (18). SGLT2 is lo- cated in the S1 and S2 segments where the majority of filtered glucose is absorbed, and SGLT1 is located in S3 segments responsible for reabsorbing the remaining glu- cose (4, 19). Combined in situ hybridization and immu- nocytochemistry with tubule segment-specific marker an- tibodies demonstrated an extremely high level of SGLT2 mRNA in proximal tubule S1 segments (1) (Fig. 1).

Renal glucose transport in diabetes Renal tubular reabsorption is known to undergo ad- aptations in uncontrolled diabetes; particularly relevant in this context is the up-regulation of renal GLUTs. The in- crease in extracellular glucose concentration in diabetes lowers its outwardly directed gradient from the tubular cells into the interstitium. Hence, up-regulation of SGLT2 is an important adaptation in diabetes to maintain renal tubular glucose reabsorption. SGLT2 mRNA expression is up-regulated in diabetic rat kidneys and this up-regula- tion is reversed by lowering blood glucose levels (20). Hu-

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36 Nair and Wilding

SGLT2 Inhibitors for Diabetes

36 Nair and Wilding SGLT2 Inhibitors for Diabetes FIG. 1. Diagram of proximal renal tubular cell

FIG. 1. Diagram of proximal renal tubular cell showing secondary active transport of glucose by SGLT2. The sodium gradient, produced by the Na/K ATPase pump at the basolateral cell membrane, is used for sodium and glucose cotransport. Glucose is transported passively by GLUT2 into the interstitium.

man exfoliated proximal tubular epithelial cells from fresh urine of diabetic patients express significantly more SGLT2 and GLUT2 than cells from healthy individuals (21). There is also evidence for up-regulation of GLUT2 gene expression in renal proximal tubules in diabetic rat models (22–24). Uncontrolled diabetes leading to in- creased expression of SGLT2 has practical significance in that the inhibitors are likely to produce greater degrees of glucosuria in the presence of higher prevailing plasma glu- cose levels. This has been shown in preclinical studies with the nonspecific SGLT inhibitor, T-1095 (25). Interestingly, this up-regulation of SGLT2 receptors is also seen in renovascular hypertensive rat models. The authors speculated that angiotensin II-induced SGLT2 over expression probably contributes to increased absorp- tion of Na and thereby development or maintenance of hypertension. Rats treated with either ramipril or losartan showed significant reduction in the intensity of immuno- staining and levels of SGLT2 protein and mRNA (26). This may have relevance in diabetes, given the high prev- alence of hypertension in diabetes.

Therapeutic Potential of Inducing Glucosuria

Phlorizin is a glucoside consisting of a glucose moiety and two aromatic rings (aglycone moiety) joined by an alkyl spacer. In the 19th century, French chemists isolated it from the bark of apple tree to be used in treatment of fever and infectious diseases, particularly malaria. Von Mering observed in 1886 that phlorizin produces glucosuria. It has been used as a tool for physiological research for more than 150 yr (27). In 1975, DeFronzo et al. (28) showed that infusion of phlorizin in dogs increased fractional ex- cretion of glucose by 60%, whereas glomerular filtration rate and renal plasma flow remained unchanged.

J Clin Endocrinol Metab, January 2010, 95(1):34 – 42

Phlorizin is a high-affinity competitive inhibitor of Na- dependent glucose transport in renal and intestinal epi- thelia (29). Hence, it causes malabsorption of glucose and galactose from the small intestines and of glucose from the renal tubules. Phlorizin caused heavy glucosuria and marked inhibition of glucose uptake in the small intestine during enteric perfusion in normal rats. It also signifi- cantly reduces blood glucose on oral glucose tolerance test in mice and lowers blood glucose in streptozotocin-in- duced diabetic rats (30). It improves counter-regulatory responses reducing the risk of hypoglycemia in animal models (31). In 1986, Unger’s group (32) reported that iv glucose failed to suppress the marked hyperglucagonemia found in insulin-deprived alloxan-induced diabetic dogs; however, when hyperglycemia was corrected by phlorizin, the hyperglucagonemia became readily suppressible. Phlori- zin treatment of partially pancreatectomized rats completely normalized insulin sensitivity but had no effect on insulin action in controls (33, 34), suggesting that the effect on in- sulin sensitivity was by reversal of glucotoxicity, rather than by a direct effect on insulin sensitivity. Animal studies with phlorizin have shown that its effect of changing the ambient glucose independent of insulin levels can up-regulate the glu- cose transport response toinsulinin adipose cells,whichmay be as a result of changes in GLUT functional activity (35). These findings provided important proof of concept data, although phlorizin itself is unsuitable for develop- ment as a drug for the treatment of diabetes because of its nonselectivity and low oral bioavailability (25, 36). T-1095 is a synthetic phlorizin derivative, which unlike phlorizin is absorbed into the circulation on oral admin- istration and is metabolized to its active form T-1095A. It suppresses the activity of SGLT1 and -2 in the kidney and increases urinary glucose excretion in diabetic animals, thereby decreasing blood glucose levels. With long-term T-1095 treatment, both blood glucose and glycosylated hemoglobin (HbA1c) levels were reduced in streptozoto- cin-induced diabetic rats and the obese insulin resistant yellow KK rat models (25). Chronic administration of T-1095 lowered blood glucose and HbA1c levels, partially improved glucose intolerance and insulin resistance, and prevented the development of diabetic neuropathy in the diabetic insulin-resistant GK rat models. There were no adverse side effects reported at the end of the study (37). This drug, however, did not proceed to clinical develop- ment, presumably because it also inhibits SGLT1 (Fig. 2).

Development of Selective SGLT2 Inhibitors

Several specific and potent SGLT2 inhibitors have under- gone preclinical testing. Most SGLT2 inhibitors are glu-

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J Clin Endocrinol Metab, January 2010, 95(1):34 – 42

J Clin Endocrinol Metab, January 2010, 95(1):34 – 42 FIG. 2. Schematic representation of normal renal

FIG. 2. Schematic representation of normal renal glucose reabsorption and the effect of SGLT2 inhibition. The amount of glucose filtered increases linearly with increasing plasma glucose concentration ( gray dotted line). The threshold at which glucose appears in the urine is a plasma glucose concentration of around 8.3 mmol/liter, but some variability in reabsorption by individual nephrons is thought to account for the “splay” shown in the figure. Above the saturation threshold (13.3 mmol/liter), glucosuria increases in a linear fashion with plasma glucose. In diabetes due to up-regulation of SGLT2, the reabsorption curve is shifted to the right . SGLT2 inhibitors lower both the saturation threshold and the transport maximum (Tmax) for glucose. This results in increased glucosuria for a given plasma glucose level, represented here as a left shift of the glucosuria curve.

cosides, structurally related to phlorizin, which is an o- glucoside. The o-glucosides have to be administered as their prodrug esters to avoid degradation by -glucosidase in the small intestine. Sergliflozin and remogliflozin eta-

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bonate, which are orally administered, are the ethyl car- bonate prodrug esters of sergliflozin A and remogliflozin, respectively. Creating a carbon-carbon bond between the glucose and aglycone moiety converts o-glucosides to c- glucosides, which have a different pharmacokinetic pro- file, making them unsusceptible to -glucosidase (38). Dapagliflozin is the first c-glucoside to be discovered that is currently in phase III trials. Several such structural al- terations and new SGLT2 inhibitors have been reported (39 – 42) (Table 1).

Antisense oligonucleotide therapy Preliminary findings of a novel method of SGLT2 in- hibition have been presented in abstract form. ISIS 388626, an antisense oligonucleotide, reduces the ex pres- sion of SGLT2 gene in the proximal renal tubules of rodents and dogs. Once-weekly administration of ISIS 388626 reduced renal SGLT2 mRNA expression by up to 80%. It did not affect the expression of SGLT1 or GLUT genes. Consistent with this, ISIS 388626 increased glucos- uria and improved plasma glucose and HbA1c in Zucker diabetic fatty rats. There was no accumulation in liver, intestine, or cardiac tissues after 6 months of dosing in Zucker diabetic fatty rats, whereas kidney antisense oli- gonucleotide concentration was high, confirming its tissue specificity (43). A study examining the long-term effect of ISIS 388626 in nonhuman primates showed dose-depen- dent reduction in SGLT2 expression, with more than 75% reduction at the highest dose. This was accompanied by a

TABLE 1. SGLT2 inhibitors with published preclinical studies

Drug

Chemical structure

Preclinical studies

T-1095

O-Glucoside

T-1095, an inhibitor of renal SGLTs, may provide a novel approach

AVE2268

Substituted glycopyranoside

to treating diabetes (25) Long-term treatment with the SGLT inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki rats (37) Effects of AVE2268, a substituted glycopyranoside, on urinary glucose excretion and blood glucose in mice and rats (59)

Remogliflozin etabonate

O-glucoside

Remogliflozin etabonate, in a novel category of selective low-affinity

Sergliflozin

O-glucoside

SGLT2 inhibitors, exhibits antidiabetic efficacy in rodent models (41) Sergliflozin, a novel selective inhibitor of low-affinity SGLT2,

Dapagliflozin

C-aryl glucosides

validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level (36) Discovery of dapagliflozin: a potent, selective renal sodium-

JNJ-28431754/TA-7284

dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of T2DM (46) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats (60) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats (61) JNJ-28431754/TA-7284, an SGLT inhibitor, lowers blood glucose

BI 10773

and reduces body weight in obese and T2DM animal models (62) In vitro properties and in vivo effect on urinary glucose excretion of BI 10773, a novel selective SGLT2 inhibitor (63)

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38 Nair and Wilding

SGLT2 Inhibitors for Diabetes

J Clin Endocrinol Metab, January 2010, 95(1):34 – 42

J Clin Endocrinol Metab, January 2010, 95(1):34 – 42 FIG. 3. A, Mean change in HbA1c

FIG. 3. A, Mean change in HbA1c over time. B, Mean change from baseline in total body

weight over time. Error bars represent 95% confidence intervals. DAPA, Dapagliflozin; INS, insulin; PLA, placebo. [Reproduced with permission from Wilding et al. : Diabetes Care

32:1656 –1662, 2009 (49).]

more than 1000-fold increase in glucosuria without any associated hypoglycemia, and the glucosuria persisted for several weeks after treatment cessation (44). This novel approach is of potentially great interest, and ISIS Pharmaceuticals (San Diego, CA) recently an- nounced that translation into human phase I studies is about to commence using a 12-nucleotide antisense oli- gonucleotide, ISIS-SGLT2 RX although very careful safety evaluation will need to be undertaken given the novelty of this approach.

SGLT2 inhibitors in clinical development

Dapagliflozin Dapagliflozin is a potent and highly selective SGLT2 inhibitor. The elimination half-life after intraarterial administration was 4.6, 7.4, and 3.0 h in rats, dogs, and monkeys, respectively (45). Single and multiple ascend- ing dose (SAD and MAD) studies with dapagliflozin confirmed that it has a pharmacokinetic profile consis- tent with once-daily dosing and produces a dose-depen- dent increase in glucosuria in humans. Dapagliflozin was rapidly absorbed after oral administration, and maximum plasma concentrations ( C max ) were observed withi n 2 h of adm inistration. The mean half-life after the last dose in the MAD study ranged from 11.2 to 16.6 h, and the data were similar for the SAD study with high dose. In theMAD study, a dose of 100 mg produced urine glucose of 58.3 g per 24 h and 55.4 g per 24 h on d 14. Dapagliflozin had no effect on urine and serum electrolytes, serum albumin, osmolality, or renal tubu- lar markers such as N-acetyl-b- D -glucosaminidase and 2-microglobulin. Two events of mild asymptomatic hypoglycemia were reported in the SAD study. No treat- ment-related serious adverse events were reported in either study (46).

In a phase IIa study, 47 patients with T2DM were randomized to re- ceive 5, 25, or 100 mg of dapagliflozin or placebo for 14 d. Those receiving 25 and 100 mg dapagliflozin had ap- proximately 40% inhibition of renal glucose reabsorption as compared with baseline resulting in glucose ex- cretion of up to 70 g per 24 h. Two of the 24 women who received dapagli- flozin were diagnosed with mild vul- vovaginal mycotic infections that re- solved i n 4 d with treatment. The most frequently reported treatment emer-

gent adverse events were gastrointes- tinal, including constipation, nausea, and diarrhea. There were no drug dis- continuations due to adverse events (47). A phase IIb multiple-dose study to evaluate safety and efficacy of dapagliflozin-randomized T2DM pa- tients to five dapagliflozin doses (2.5, 5, 10, 20, or 50 mg), metformin extended release, or placebo for 12 wk has recently been reported. Dapagliflozin improved hy- perglycemia and caused weight loss by inducing con- trolled glucosuria with urinary loss of approximately 200 –300 kcal/d. There was a weight loss of 2.5 to 3.4 kg in the dapagliflozin-treated patients, compared with 1.2 kg with placebo and 1.7 kg with metformin. Dapa- gliflozin treatment was not associated with clinically significant osmolarity, volume, or renal status changes. There was also no compensatory increase in hunger as assessed by visual analog scales. The rates of bacterial urinary tract infections (UTIs) were similar in the treat- ment and placebo arms, but there was higher incidence of genital infections in the dapagliflozin vs. placebo, especially at higher doses (48). A double-blind, three-arm parallel group, placebo-con- trolled study randomized 71 patients 1:1:1 to placebo, 10 and 20 mg dapagliflozin, plus oral antidiabetic agents and 50% of their prestudy daily insulin dose. At wk 12, dapa- gliflozin 10- and 20-mg groups demonstrated 0.70% and 0.78% mean differences in HbA1C change from baseline vs. placebo. Mean changes from fasting plasma glucose were 17.8, 2.4, and 9.6 mg/dl, and mean changes in total body weight were 1.9, 4.5, and 4.3 kg (placebo, 10-, and 20-mg dapagliflozin groups, respectively). The baseline HbA1c in the three groups were 8.4 0.9, 8.4 0.7, and 8.5 0.9, respectively. Overall, adverse events were balanced across all groups, but more genital infections occurred in the dapagliflozin 20-mg group than placebo. Also total hypoglycemic events were more frequently reported with dapagliflo-

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J Clin Endocrinol Metab, January 2010, 95(1):34 – 42

zin than placebo, although none of them was major (49) (Fig. 3).

A number of phase III clinical trials with dapagliflozin,

mostly as add-on therapies to existing antidiabetic drugs, are now under way.

Sergliflozin

A phase I study with 50 –500 mg of sergliflozin in 14

healthy volunteers and a phase IIa study where the same dose range was given to eight subjects with T2DM showed a dose-dependent increase in urinary glucose excretion that plateaued at higher doses. It did not cause hypogly- cemia in nondiabetic subjects, and there was a 1.5-kg weight loss from baseline to d 15 compared with placebo. There were no clinically significant effects on serum elec- trolytes or calculated creatinine clearance (50, 51). Devel- opment of sergliflozin has been discontinued in favor of remogliflozin.

Remogliflozin etabonate Remogliflozin etabonate is metabolized to its active form remogliflozin, which is a benzylpyrazole glu- coside. Its skeleton differs from that of phlorizin, T-1095, or sergliflozin, and hence is from a new cate- gory of SGLT2 inhibitors. Its inhibitory effect for hu- man SGLT2 is approximately three times greater than that of phlorizin, but for SGLT1 it was only 1/20 that of phlorizin in in vitro studies. Animal studies have shown good linearity between urinary glucose excretion and the dose of remogliflozin etabonate. It did not signifi-

cantly alter the plasma glucose level in 16-h fasted nor- mal rats (41).

A study with 13 T2DM patients supported its coad-

ministration with metformin in patients with T2DM with minimal risk of hypoglycemia. There was no drug interaction affecting the pharmacokinetics of either drug (52). In another study, remogliflozin etabonate administered to 10 healthy subjects (doses ranging from 20 to 1000 mg) and six subjects with T2DM (doses ranging from 50 to 500 mg) was rapidly absorbed and converted to remogliflozin, which had a plasma half-life of 120 min across doses and groups. It caused a dose- dependent increase in urinary glucose excretion in all subjects. There were no effects on plasma electrolytes and no serious adverse events (53).

AVE2268

A phase II study with AVE2268 recruited 300 patients

with T2DM not adequately controlled by metformin to as- sess the effects of several doses of AVE2268 on glycemic control and to assess safety and tolerability. The results of this study are awaited.

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Adverse effects

Increased urine volume (up to 400 ml) was observed

in clinical studies with dapagliflozin, associated with

increased hematocrit and urea, suggesting slight volume depletion. Electrolyte imbalance is also a consideration because physiological studies have shown increased so- dium loss with phlorizin. A phase II trial reported one case of dehydration and prerenal azotemia, which re- solved with oral rehydration and withholding angio- tensin-converting enzyme inhibitor and diuretic ther- apy (49). Whether patients with diabetes mellitus who have neuropathy, hyporeninemic hypoaldosteronism, and nephropathy could be rendered more vulnerable to sodium wasting and hypovolemia will need to be as- sessed further. A statistically significant increase in magnesium (0.18 0.16 mEq/liter; P 0.001) and

decrease in uric acid levels ( 1.14 1.15 mg/dl; P

0.001) were reported in a phase II trial with dapagli- flozin compared with placebo. In terms of bone metab- olism, an increase in parathormone concentration (range, 0.6 –7.0 pg/ml above baseline of 31.1–35.0 pg/ ml) has been noted, which was greater than the 0.8 pg/ml increase for placebo. There was no change in se- rum 1,25-dihydroxyvitamin D and 25-hydroxyvitamin

D values from baseline, and the mean changes in the

24-h urinary calcium-to-creatinine ratio were similar to those with placebo (48). The long-term effects on bone health will also need to be clarified by ongoing phase

III trials.

The apparent presence of SGLT2 in the placenta does raise concern about its safety in women of child-bearing age. Another important question is whether increased glucos- uria would predispose to UTIs or genital fungal infections. In vivo studies have not shown a higher prevalence of bacteriuria among diabetic patients with glucosuria compared with patients without glucosuria. Defects in the local urinary cytokine secretions and an increased adherence of the microorganisms to the uroepithelial cells have been proposed to increase the incidence of UTI in patients with diabetes (54, 55). This suggests that risk of UTI may not be increased in patients taking SGLT2 inhibitors, and this has been borne out by the available clinical data. Symptomatic vulvovaginal candidiasis is more preva- lent in patients with diabetes compared with the normal population (56, 57), and this increased prevalence is as- sociated with poor glycemic control (58), but it is un- known whether circulating glucose concentrations or the presence of glucosuria is the critical factor. Both reported phase II studies with dapagliflozin suggest an increase in

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40 Nair and Wilding

SGLT2 Inhibitors for Diabetes

genital fungal infection, so this will need close observation in the future.

Future Potential

SGLT2 inhibitors have a unique mechanism of action and have the potential to become a new treatment for T2DM. Several phase III trials with these compounds are ongoing and if their efficacy and safety profile are proven to be adequate, these agents may gain a place in the management of T2DM, particularly where weight gain is a concern. The potential for use as an insulin- sparing agent in patients on insulin has been highlighted in a recent trial (49) and a future role in the management of type 1 diabetes mellitus cannot be ruled out, although SGLT2 inhibitors have not yet been tested for this indication.

Acknowledgments

Address all correspondence and requests for reprints to: John P. H. Wilding, Diabetes and Endocrinology Research Unit, Clin- ical Sciences Centre, University Hospital Aintree, Longmoore Lane, Liverpool L9 7AL, United Kingdom. E-mail: j.p.h.wilding@ liv.ac.uk. Disclosure Summary: J.P.H.W. is a consultant to Bristol Myers Squibb/AstraZeneca (BMS/AZ),GlaxoSmithKline, and Johnson& Johnson in relation to SGLT2 inhibitors for diabetes treatment and is an investigator for ongoing trials with dapagliflozin (BMS/AZ). S.N. is a coinvestigator in an ongoing clinical trial of dapagliflozin (BMS/AZ).

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