KARTUL

Sodium Glucose Cotransporter 2 Inhibitors as a NewTreatment 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 accountsfor about 90% of the reabsorption of glucose from tubular fluid. Genetic defects of SGLT2 resultin a benign familial renal glucosuria. Pharmacological agents that block SGLT2 are being tested aspotential treatment for type 2 diabetes mellitus.

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

Evidence Synthesis: SGLT2 is almost exclusively expressed in the proximal renal tubules. Preclinicalstudies with selective SLGT2 inhibitors show dose-dependent glucosuria and lowering of bloodglucose in models of type 2 diabetes. Preliminary clinical studies of up to 3-month duration showdose-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 urinevolume (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 therapeuticoptions in type 2 diabetes mellitus. Results of ongoing phase III clinical trials are awaited and willdetermine whether the risk-benefit ratio will allow approval of this new class of drug for themanagement of type 2 diabetes mellitus. (J Clin Endocrinol Metab 95: 34–42, 2010)

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

range of pharmacotherapy for T2DM is available, includingmetformin, insulin secretagogues (predominantly sulfonyl-ureas), thiazolidinediones, �-glucosidase inhibitors, insulin,and more recently glucagon like peptide-1 agonists anddipeptidyl-peptidase-IV inhibitors, many patients do notachieve glycemic targets, partly due to limiting side effects ofcurrent therapies, includingweightgain,hypoglycemia, fluidretention, and gastrointestinal side effects. Hence, the searchfornewtreatmentstrategies isongoing.Amongthenewther-apies on the horizon, sodium-glucose cotransporter 2(SGLT2) inhibitors seem promising, and there are a numberofongoingphaseIIandIIIclinical trialswithavarietyof thesecompounds. SGLT2 is almost exclusively expressed in therenal proximal tubules and accounts for 90% of the renal

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 levelswithout 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 beprovensafefromarenalandcardiovascularperspectivetomeetcurrent regulatory requirements for new diabetes treatment.

Glucose Transport across BiologicalMembranes

Glucose transportersGlucoseabsorptionat theenterocytes, reabsorptionat the

renal tubules, transport across the blood-brain barrier, and

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

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 twogroups of transporters: glucose transporters (GLUTs) andsodium-glucose cotransporters (SGLTs).

GLUTs are facilitative or passive transporters thatwork 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 usingthe sodium gradient produced by sodium/potassiumATPase pumps at the basolateral cell membranes. Theybelong to the SLC5 gene family, which has nine memberswith known functions. Of these, six are plasma membranesodium/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 inthe trachea, kidney, and heart, and its predominant sub-strates are glucose and galactose. SGLT2 is expressed inthe S1 and S2 segments of the proximal convoluted tubulesand is responsible for renal reabsorption of glucose (4).SGLT2 RNA is minimally expressed in the ileum, the levelof 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 isfound outside the kidney. There have been attempts toexamine expression of SGLT proteins, but availability ofantibodies that are specific enough seems to be the limitingfactor. Therefore, the functional significance of mRNAexpression 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 proteinexpression 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 infectiousdiarrheaworksviaSGLT1transportersintheenterocytes(8,9).

Much of the evidence for SGLT2 being a major path-way for renal glucose reabsorption comes from geneticstudies of individuals with familial renal glucosuria (10,11). Mutations in the SLC5A2 gene encoding SGLT2 leadto familial renal glucosuria, which is inherited as an au-tosomal recessive trait and is characterized by normalblood glucose levels, normal oral glucose tolerance testresults, and isolated persistent glucosuria (10, 12, 13). Astudy analyzing 23 families with index cases of renal glu-cosuria found that each family had a unique mutation intheSGLT2gene. Individualswhowere found tobecarriersof two mutated alleles showed severe glucosuria, definedby a urinary glucose of more than 10 g/1.73 m2 per 24 h(55 mmol/1.73 m2 per 24 h). The index patients who pre-sented with mild glucosuria and the family members of

cases of severe glucosuria were shown to be heterozygouscarriers of SGLT2 mutations (11, 14). Another studyfound 20 different SLC5A2 mutations within 17 pedi-grees. Glucosuria was mild in heterozygotes ranging from2.7 to 10 g/1.73 m2 per 24 h, whereas it was severe inhomozygotes ranging from 15.2 to 86.5 g/1.73 m2/24 h.Two patients in the homozygous group had plasma reninand serum aldosterone concentration raised to an averageof 4.6- and 3.1-fold, respectively, suggesting activation ofcompensatory mechanisms (15).

Renal glucose transport in healthKidneys play a very important role in glucose ho-

meostasis. Blood glucose is freely filtered by the glomeruliand is essentially completely reabsorbed from the proxi-mal tubules via sodium-coupled transporters in the brushborder membrane. The glomeruli filter about 144 g ofglucose per 24 h, nearly 100% of which is reabsorbed inthe renal tubules. When blood glucose levels reach therenal threshold for reabsorption, which is about 8 to 10mmol/liter (180 mg/dl), glucosuria starts to develop (16).The proximal tubule has traditionally been divided intoS1, S2, and S3 segments based on the cell morphologies,although more recent ultra structural analyses of computer-assisted three-dimensional reconstruction of mouseproximal tubules revealed no obvious morphological seg-mentation of the proximal tubule (17). There is evidence,however, for heterogeneity of sodium-dependent glucosetransport 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 higheraffinity and low capacity for the same (18). SGLT2 is lo-cated in the S1 and S2 segments where the majority offiltered glucose is absorbed, and SGLT1 is located in S3segments 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 SGLT2mRNA in proximal tubule S1 segments (1) (Fig. 1).

Renal glucose transport in diabetesRenal tubular reabsorption is known to undergo ad-

aptations in uncontrolled diabetes; particularly relevant inthis context is the up-regulation of renal GLUTs. The in-crease in extracellular glucose concentration in diabeteslowers its outwardly directed gradient from the tubularcells into the interstitium. Hence, up-regulation of SGLT2is an important adaptation in diabetes to maintain renaltubular glucose reabsorption. SGLT2 mRNA expressionis up-regulated in diabetic rat kidneys and this up-regula-tion is reversed by lowering blood glucose levels (20). Hu-

J Clin Endocrinol Metab, January 2010, 95(1):34–42 jcem.endojournals.org 35


man exfoliated proximal tubular epithelial cells from freshurine of diabetic patients express significantly moreSGLT2 and GLUT2 than cells from healthy individuals(21). There is also evidence for up-regulation of GLUT2gene expression in renal proximal tubules in diabetic ratmodels (22–24). Uncontrolled diabetes leading to in-creased expression of SGLT2 has practical significance inthat the inhibitors are likely to produce greater degrees ofglucosuria in the presence of higher prevailing plasma glu-cose levels. This has been shown in preclinical studies withthe nonspecific SGLT inhibitor, T-1095 (25).

Interestingly, this up-regulation of SGLT2 receptors isalso seen in renovascular hypertensive rat models. Theauthors speculated that angiotensin II-induced SGLT2over expression probably contributes to increased absorp-tion of Na� and thereby development or maintenance ofhypertension. Rats treated with either ramipril or losartanshowed 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 InducingGlucosuria

Phlorizin is a glucoside consisting of a glucose moiety andtwo aromatic rings (aglycone moiety) joined by an alkylspacer. In the 19th century, French chemists isolated itfrom the bark of apple tree to be used in treatment of feverand infectious diseases, particularly malaria. Von Meringobserved in 1886 that phlorizin produces glucosuria. Ithas been used as a tool for physiological research for morethan 150 yr (27). In 1975, DeFronzo et al. (28) showedthat infusion of phlorizin in dogs increased fractional ex-cretion of glucose by 60%, whereas glomerular filtrationrate and renal plasma flow remained unchanged.

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 andgalactose from the small intestines and of glucose from therenal tubules. Phlorizin caused heavy glucosuria andmarked inhibition of glucose uptake in the small intestineduring enteric perfusion in normal rats. It also signifi-cantly reduces blood glucose on oral glucose tolerance testin mice and lowers blood glucose in streptozotocin-in-duced diabetic rats (30). It improves counter-regulatoryresponses reducing the risk of hypoglycemia in animalmodels (31). In 1986, Unger’s group (32) reported that ivglucose failed to suppress the marked hyperglucagonemiafound 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 completelynormalized insulin sensitivity but had no effect on insulinaction in controls (33, 34), suggesting that the effect on in-sulin sensitivity was by reversal of glucotoxicity, rather thanby a direct effect on insulin sensitivity. Animal studies withphlorizin have shown that its effect of changing the ambientglucose independent of insulin levels can up-regulate the glu-cose transport response to insulin inadiposecells,whichmaybe as a result of changes in GLUT functional activity (35).

These findings provided important proof of conceptdata, although phlorizin itself is unsuitable for develop-ment as a drug for the treatment of diabetes because of itsnonselectivity and low oral bioavailability (25, 36).

T-1095 is a synthetic phlorizin derivative, which unlikephlorizin is absorbed into the circulation on oral admin-istration and is metabolized to its active form T-1095A. Itsuppresses the activity of SGLT1 and -2 in the kidney andincreases urinary glucose excretion in diabetic animals,thereby decreasing blood glucose levels. With long-termT-1095 treatment, both blood glucose and glycosylatedhemoglobin (HbA1c) levels were reduced in streptozoto-cin-induced diabetic rats and the obese insulin resistantyellow KK rat models (25). Chronic administration ofT-1095 lowered blood glucose and HbA1c levels, partiallyimproved glucose intolerance and insulin resistance, andprevented the development of diabetic neuropathy in thediabetic insulin-resistant GK rat models. There were noadverse 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 SGLT2Inhibitors

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

FIG. 1. Diagram of proximal renal tubular cell showing secondaryactive transport of glucose by SGLT2. The sodium gradient, producedby the Na/K ATPase pump at the basolateral cell membrane, is used forsodium and glucose cotransport. Glucose is transported passively byGLUT2 into the interstitium.

36 Nair and Wilding SGLT2 Inhibitors for Diabetes J Clin Endocrinol Metab, January 2010, 95(1):34–42


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

bonate, which are orally administered, are the ethyl car-bonate prodrug esters of sergliflozin A and remogliflozin,respectively. Creating a carbon-carbon bond between theglucose 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 thatis currently in phase III trials. Several such structural al-terations and new SGLT2 inhibitors have been reported(39–42) (Table 1).

Antisense oligonucleotide therapyPreliminary findings of a novel method of SGLT2 in-

hibition have been presented in abstract form. ISIS388626, an antisense oligonucleotide, reduces the expres-sion of SGLT2 gene in the proximal renal tubules ofrodents and dogs. Once-weekly administration of ISIS388626 reduced renal SGLT2 mRNA expression by up to80%. It did not affect the expression of SGLT1 or GLUTgenes. Consistent with this, ISIS 388626 increased glucos-uria and improved plasma glucose and HbA1c in Zuckerdiabetic fatty rats. There was no accumulation in liver,intestine, or cardiac tissues after 6 months of dosing inZucker diabetic fatty rats, whereas kidney antisense oli-gonucleotide concentration was high, confirming its tissuespecificity (43). A study examining the long-term effect ofISIS 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

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

TABLE 1. SGLT2 inhibitors with published preclinical studies

Drug Chemical structure Preclinical studiesT-1095 O-Glucoside T-1095, an inhibitor of renal SGLTs, may provide a novel approach

to treating diabetes (25)Long-term treatment with the SGLT inhibitor T-1095 causes

sustained improvement in hyperglycemia and prevents diabeticneuropathy in Goto-Kakizaki rats (37)

AVE2268 Substituted glycopyranoside Effects of AVE2268, a substituted glycopyranoside, on urinaryglucose excretion and blood glucose in mice and rats (59)

Remogliflozin etabonate O-glucoside Remogliflozin etabonate, in a novel category of selective low-affinitySGLT2 inhibitors, exhibits antidiabetic efficacy in rodent models (41)

Sergliflozin O-glucoside Sergliflozin, a novel selective inhibitor of low-affinity SGLT2,validates the critical role of SGLT2 in renal glucose reabsorptionand modulates plasma glucose level (36)

Dapagliflozin C-aryl glucosides Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for thetreatment of T2DM (46)

Dapagliflozin, a selective SGLT2 inhibitor, improves glucosehomeostasis in normal and diabetic rats (60)

Dapagliflozin, a selective SGLT2 inhibitor, improves glucosehomeostasis in normal and diabetic rats (61)

JNJ-28431754/TA-7284 JNJ-28431754/TA-7284, an SGLT inhibitor, lowers blood glucoseand reduces body weight in obese and T2DM animal models (62)

BI 10773 In vitro properties and in vivo effect on urinary glucose excretion ofBI 10773, a novel selective SGLT2 inhibitor (63)



more than 1000-fold increase in glucosuria without anyassociated hypoglycemia, and the glucosuria persisted forseveral 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 isabout to commence using a 12-nucleotide antisense oli-gonucleotide, ISIS-SGLT2RX although very careful safetyevaluation will need to be undertaken given the novelty ofthis approach.

SGLT2 inhibitors in clinical development

DapagliflozinDapagliflozin is a potent and highly selective SGLT2

inhibitor. The elimination half-life after intraarterialadministration was 4.6, 7.4, and 3.0 h in rats, dogs, andmonkeys, respectively (45). Single and multiple ascend-ing dose (SAD and MAD) studies with dapagliflozinconfirmed that it has a pharmacokinetic profile consis-tent with once-daily dosing and produces a dose-depen-dent increase in glucosuria in humans. Dapagliflozinwas rapidly absorbed after oral administration, andmaximum plasma concentrations (Cmax) were observedwithin 2 h of administration. The mean half-life afterthe last dose in the MAD study ranged from 11.2 to16.6 h, and the data were similar for the SAD study withhigh dose. In the MAD study, a dose of 100 mg producedurine glucose of 58.3 g per 24 h and 55.4 g per 24 h ond 14. Dapagliflozin had no effect on urine and serumelectrolytes, serum albumin, osmolality, or renal tubu-lar markers such as N-acetyl-b-D-glucosaminidase and�2-microglobulin. Two events of mild asymptomatichypoglycemia were reported in the SAD study. No treat-ment-related serious adverse events were reported ineither study (46).

In a phase IIa study, 47 patientswith T2DM were randomized to re-ceive 5, 25, or 100 mg of dapagliflozinor placebo for 14 d. Those receiving25 and 100 mg dapagliflozin had ap-proximately 40% inhibition of renalglucose reabsorption as comparedwith baseline resulting in glucose ex-cretion of up to 70 g per 24 h. Two ofthe 24 women who received dapagli-flozin were diagnosed with mild vul-vovaginal mycotic infections that re-solved in 4 d with treatment. The mostfrequently 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 50mg), metformin extended release, or placebo for 12 wkhas recently been reported. Dapagliflozin improved hy-perglycemia and caused weight loss by inducing con-trolled glucosuria with urinary loss of approximately200 –300 kcal/d. There was a weight loss of 2.5 to 3.4kg in the dapagliflozin-treated patients, compared with1.2 kg with placebo and 1.7 kg with metformin. Dapa-gliflozin treatment was not associated with clinicallysignificant osmolarity, volume, or renal status changes.There was also no compensatory increase in hunger asassessed by visual analog scales. The rates of bacterialurinary tract infections (UTIs) were similar in the treat-ment and placebo arms, but there was higher incidenceof 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, 10and 20 mg dapagliflozin, plus oral antidiabetic agents and50% 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 frombaseline vs. placebo. Mean changes from fasting plasmaglucose were �17.8, �2.4, and �9.6 mg/dl, and meanchanges 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 groupswere 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 dapagliflozin20-mg group than placebo. Also total hypoglycemicevents were more frequently reported with dapagliflo-

FIG. 3. A, Mean change in HbA1c over time. B, Mean change from baseline in total bodyweight over time. Error bars represent 95% confidence intervals. DAPA, Dapagliflozin; INS,insulin; PLA, placebo. [Reproduced with permission from Wilding et al.: Diabetes Care32:1656–1662, 2009 (49).]



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.

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

healthy volunteers and a phase IIa study where the samedose range was given to eight subjects with T2DM showeda dose-dependent increase in urinary glucose excretionthat plateaued at higher doses. It did not cause hypogly-cemia in nondiabetic subjects, and there was a 1.5-kgweight 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 ofremogliflozin.

Remogliflozin etabonateRemogliflozin 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 thanthat of phlorizin, but for SGLT1 it was only 1/20 that ofphlorizin in in vitro studies. Animal studies have showngood linearity between urinary glucose excretion andthe 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 T2DMwith minimal risk of hypoglycemia. There was no druginteraction affecting the pharmacokinetics of eitherdrug (52). In another study, remogliflozin etabonateadministered to 10 healthy subjects (doses ranging from20 to 1000 mg) and six subjects with T2DM (dosesranging from 50 to 500 mg) was rapidly absorbed andconverted to remogliflozin, which had a plasma half-lifeof 120 min across doses and groups. It caused a dose-dependent increase in urinary glucose excretion in allsubjects. There were no effects on plasma electrolytesand no serious adverse events (53).

AVE2268A 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 glycemiccontrol and to assess safety and tolerability. The results ofthis study are awaited.

Adverse effectsIncreased urine volume (up to 400 ml) was observed

in clinical studies with dapagliflozin, associated withincreased hematocrit and urea, suggesting slight volumedepletion. Electrolyte imbalance is also a considerationbecause physiological studies have shown increased so-dium loss with phlorizin. A phase II trial reported onecase 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 whohave neuropathy, hyporeninemic hypoaldosteronism,and nephropathy could be rendered more vulnerable tosodium wasting and hypovolemia will need to be as-sessed further. A statistically significant increase inmagnesium (0.18 � 0.16 mEq/liter; P � 0.001) anddecrease 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 0.8pg/ml increase for placebo. There was no change in se-rum 1,25-dihydroxyvitamin D and 25-hydroxyvitaminD values from baseline, and the mean changes in the24-h urinary calcium-to-creatinine ratio were similar tothose with placebo (48). The long-term effects on bonehealth will also need to be clarified by ongoing phaseIII trials.

The apparent presence of SGLT2 in the placenta doesraise concern about its safety in women of child-bearingage.

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 ofbacteriuria among diabetic patients with glucosuriacompared with patients without glucosuria. Defects inthe local urinary cytokine secretions and an increasedadherence of the microorganisms to the uroepithelialcells have been proposed to increase the incidence ofUTI in patients with diabetes (54, 55). This suggests thatrisk of UTI may not be increased in patients takingSGLT2 inhibitors, and this has been borne out by theavailable clinical data.

Symptomatic vulvovaginal candidiasis is more preva-lent in patients with diabetes compared with the normalpopulation (56, 57), and this increased prevalence is as-sociated with poor glycemic control (58), but it is un-known whether circulating glucose concentrations or thepresence of glucosuria is the critical factor. Both reportedphase II studies with dapagliflozin suggest an increase in



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

Future Potential

SGLT2 inhibitors have a unique mechanism of actionand have the potential to become a new treatment forT2DM. Several phase III trials with these compoundsare ongoing and if their efficacy and safety profile areproven to be adequate, these agents may gain a place inthe management of T2DM, particularly where weightgain is a concern. The potential for use as an insulin-sparing agent in patients on insulin has been highlightedin a recent trial (49) and a future role in the managementof type 1 diabetes mellitus cannot be ruled out, althoughSGLT2 inhibitors have not yet been tested for thisindication.

Acknowledgments

Address all correspondence and requests for reprints to: JohnP. H. Wilding, Diabetes and Endocrinology Research Unit, Clin-ical Sciences Centre, University Hospital Aintree, LongmooreLane, Liverpool L9 7AL, United Kingdom. E-mail: [email protected].

Disclosure Summary: J.P.H.W. is a consultant to Bristol MyersSquibb/AstraZeneca (BMS/AZ),GlaxoSmithKline,andJohnson&Johnson in relation to SGLT2 inhibitors for diabetes treatment andis 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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