The Kidney as a New Target for Antidiabetic Drugs SGLT2 Inhibitors

Review Article

The kidney as a new target for antidiabetic drugs: SGLT2 inhibitors

S. Cangoz PharmD, Y.-Y. Chang PharmD, S. J. Chempakaseril PharmD, R. C. Guduru PharmD, L. M. Huynh PharmD, J. S. John PharmD,S. T. John PharmD, M. E. Joseph PharmD, R. Judge PharmD, R. Kimmey PharmD, K. Kudratov PharmD, P. J. Lee PharmD, I. C. MadhaniPharmD, P. J. Shim PharmD, S. Singh PharmD, S. Singh PharmD, C. Ruchalski PharmD and R. B. Raffa PhDTemple University School of Pharmacy, Philadelphia, PA, USA

Received 12 February 2013, Accepted 20 May 2013

Keywords: diabetes, sodium/glucose transport, inhibitor, pharmacotherapy

SUMMARY

What is known and objective: A novel class of antidiabetic drugs SGLT2 (Na+/glucose cotransporter type 2) inhibitors targetrenal reabsorption of glucose and promote normal glucoselevels, independent of insulin production or its action atreceptors. We review this new mechanistic approach and thereported efcacy and safety of clinical testing of lead com-pounds.Methods: Information was obtained from various bibliographicsources, including PubMed and others, on the basic science andthe clinical trials of SGLT2 inhibitors. The information was thensummarized and evaluated from the perspective of contributionto a fuller understanding of the potential and current status ofthe lead clinical candidates.Results and discussion: Diabetes mellitus is a spectrum ofdisorders that involves inadequate insulin function resultingin adverse health sequelae due to acute and chronic hyperglyca-emia. Current antidiabetic pharmacotherapy primarily addresseseither insulin production at the pancreatic b-cells or insulinaction at insulin receptors. These drugs have less than fullclinical effectiveness and sometimes therapy-limiting adverseeffects. The third major component of glucose balance, namelyelimination, has not been a signicant therapeutic target to date.SGLT2 inhibitors are a novel approach.What is new and conclusion: A sufcient number of clinicaltrials have been conducted on sufciently chemically diverseSGLT2 inhibitors to reasonably conclude that they have efcacy(HbA1c reductions of 041%), and thus far, the majority ofadverse effects have been mild and transitory or treatable, withthe caveat of possible association with increased risk of breastcancer in women and bladder cancer in men.

WHAT IS KNOWN AND OBJECTIVE

Diabetes mellitus (DM) is a metabolic disorder of inadequateglycaemic control, dened by the American Diabetes Associationas a haemoglobin A1C (HgA1c) level 65%.1 According to theNational Health and Nutrition Examination Survey (NHANES),2

the prevalence of DM in the United States is projected to increasefrom nearly 26 million in 20103 to about 32 million by 2031. The

worldwide prevalence is estimated to reach nearly 370 million by2030.4

A recent study found that less than half of newly diagnosedtype 2 DM patients achieve an HbA1c

counteract the hyperglycaemia. This additional insulin contributesto hyperinsulinemia and down-regulation (decreased number) ofinsulin receptors located on target tissues. Although the exactmechanism of insulin resistance is not known, it is believed to berelated to decreased insulin receptor binding afnity or to defectsin insulin receptor signal transduction mechanisms (2nd messen-gers).19 Genetics, obesity and sedentary lifestyle also play a role indiabetes.2022

Currently, there are several pharmacotherapeutic classes ofantidiabetic agents approved for use in the United States (Table 1).These drugs target organs involved in glucose control such as thepancreas, liver, small intestine, skeletal muscle and adipose tissue.But the currently approved drugs decrease HbA1C level by onlyabout 12%, and further, some have various side effects thatinclude gastrointestinal intolerability, hypoglycaemia and weightgain among others.23 SGLT2 (Na+/glucose cotransporter type 2)inhibitors act at a novel target the renal reabsorption of glucose and by a novel mechanism: the inhibition of renal reabsorption ofglucose promotes normal glucose levels, independent of insulinproduction or its action at receptors. We review the mechanismand available clinical evidence related to the efcacy and safety ofSGLT2 inhibitors.

METHODS

Identication of studies

Computerized literature searches (MEDLINE, PubMed) of articlesin English or having abstracts in English were conducted usingkeywords related to mechanism of action, clinical trials andpotential deleterious properties of SGLT2 inhibitors (both ingeneral and for individual agents). Comprehensive reviews ofearly literature were obtained, as well as an extensive collection ofprimary literature.

Analysis

Each of the sources was reviewed for relevance to the mechanismof action or the clinical attributes of SGLT2 inhibition. In manycases, the information was obtained from studies that did not haveinvestigation of the mechanism as the primary outcome, but theresults were determined either to reect on the mechanism or tosuggest further avenues of investigation. Each item was evaluatedfor its relevance and strength of the evidence.

RESULTS AND DISCUSSION

Kidney as target of diabetes treatment

The kidney plays a major role in the regulation of glucosehomoeostasis.24 Contributing to this control are at least three of 12or more SGLTs (gene name SLC5A, 11 genes) Na+/glucosecotransporters: SGLT1, SGLT2 and SGLT3.2528 SGLT129 isexpressed in the distal proximal convoluted tubule (and in thegastrointestinal tract)30 and acts as a transporter for dietaryglucose and galactose.31 SGLT2 accounts for about 90% of therenally reabsorbed glucose; SGLT1 accounts for about 10%26,30,3234

(Table 2; Fig. 1).In healthy individuals, approximately 180 g of glucose is

reabsorbed daily via the sodium/glucose transport (SGLT) trans-porters.35 That is,

SGLT2 inhibitors

A major challenge of pharmaceutical innovation in diabetespharmacotherapy has been the development of medications thatare efcacious, but do not also produce the weight gain,hypoglycaemia or gastrointestinal side effects associated withmany of the current agents.55 Due to their novel mechanism ofaction, SGLT2 inhibitors represent a possible alternative. Thestrategy is to inhibit glucose reabsorption via selective blockade ofSGLT2 and lower serum glucose secondary to increased renalexcretion of glucose. SGLT2 selectivity is desirable, becausewhereas SGLT2 is primarily responsible for glucose regulation in

the kidney, SGLT1 plays only a minor role in the kidney. SGLT1 isabundant in the gastrointestinal tract, where inhibition might leadto undesirable adverse effects.56

A avonoid isolated in 1835 from root bark of apple trees,57

phlorizin (1-[2,4-dihydroxy-6-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-phenyl]-3-(4-hydroxy-phenyl)propan-1-one),58 was observed to normalize insulin sensi-tivity in partial pancreatectomy-induced diabetic rats, whereasinsulin action in the control rats was not affected. The result wasglycosuria, which was observed to normalize glucose levels inboth fasting and fed states in rats. But additional study revealedonly poor absorption and low bioavailability of phlorizin. Inaddition, decreased glucose and galactose absorption, dehydrationand diarrhoea were observed (for a review of phlorizin, see Ref.58), so further studies were halted. Phlorizin was subsequentlyfound to be non-selective for SLGT2 vs. SLGT1 and to have poormetabolic stability because of a rapid in vivo degradation by b-glucosidase.58 Because it was evident that phlorizin would not beapplicable to human DM populations, compounds with greaterSGLT2 selectivity and metabolic stability have been sought.59

One such compound, sergliozin etabonate (2-(4-methoxyben-zyl)phenyl 6-O-(ethoxycarbonyl)-b-D-glucopyranoside),60 demon-strated greater SLGT-2 selectivity and decreased serum glucoseand HbA1c levels in rats.61 Additionally, it produced a dose-dependent reduction in weight compared with placebo and didnot show signicant inhibitory effects on glucose transporter 2(GLUT2, a transmembrane carrier protein that facilitates thepassive movement of glucose across cell membranes).60 Bothsingle-dose design (in healthy volunteers and patients with type 2DM) and multiple-dose design (in healthy overweight and healthyobese subjects) pharmacokinetics and pharmacodynamics clinicalstudies have been published.62,63 Remogliozin (5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O-(eth-oxycarbonyl)-b-D-glucopyranoside) also produced dose-relatedglycosuria and lower plasma glucose and HbA1c levels in rodentmodels61 and a reduction in serum glucose in patients with type 2DM.64 Although these agents demonstrated potential to controlglucose levels in rats, further investigation on them and othercompounds, such as AVE2268,65 T-1095,4553 TS-033 and YM-543,was discontinued.66,67 Although the exact reasons are unknown,the chemical structures of these compounds suggest that theymight be prone to hydrolytic degradation in the GI tract.

Current development continues to focus on increasing selectiv-ity for SGLT2 vs. SGLT1 (Fig. 2)56,65,66 and greater bioavailability.

Table 2. Selected characteristics of SGLT1 and SGLT225,30

SGLT1 SGLT2

Chromosome 22 q13.1 16 p11.2Gene SLC5A1 SLC5A2Organ expression Mostly small intestine (ileum), kidney

(proximal straight tubules), heartMainly renal proximal convoluted tubules;less in small intestine (ileum)

Afnity for glucose High (K = 04 mM) Low (K = 2 mM)Mechanism of glucose transport Active (against concentration gradient) Active (against concentration gradient)Cotransport Na+ (Na+/K+ ATPase-coupled) Na+ (Na+/K+ ATPase-coupled)Glucose transport to blood Glucose transporters (GLUT) Glucose transporters (GLUT)Capacity for glucose transport Low High% of renal glucose reabsorption ~10% ~90%

Glucose

SGLT2

SGLT1

~90%

~10%

PCT

GlDCT

LH

CD

Fig. 1. The roles of SGLT2 and SGLT1 in the renal reabsorption ofglucose. GL, glomerulus; PCT, proximal convoluted tubule; LH,loop of Henle; DCT, distal convoluted tubule; CD, collecting duct.

2013 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 350359352

SGLT2 inhibitors for type 2 DM S. Cangoz et al.

The most promising can be taken by mouth once daily. SeveralSGLT2 inhibitors are currently undergoing testing in clinical trials(Table 3; Fig. 3): Canagliozin ((2S,3R,4R,5S,6R)-2-{3-[5-[4-uoro-phenyl)-thiophen-

2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol)68 recently received FDA approval for type 2 DM. Inpreclinical studies, canagliozin decreased plasma glucose levels inmice on a hyperglycaemic diet. It has higher oral bioavailability andlonger half-life than T-109530 and is well tolerated, and the majorityof adverse effects appear to be mild.69 In premarketing studies, theaddition of canagliozin to metformin improved glycaemic controlwith signicant weight loss.70

Dapagliozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol)71 is currentlyin phase 3 clinical trials and is one of the most advanced SGLT2inhibitors in development.7281 The C-aryl glucoside bond in

dapagliozin deters enzyme degradation in the GI tract, allowingoral administration as a once-daily treatment. In addition to thisdesirable dosing prole, it is >1000-fold more selective for theSGLT2 transporter compared with SGLT1 (Fig. 2), and it apparentlydoes not cause hypoglycaemia.30 Dapagliozin has been approvedfor use in Europe.

Empagliozin (1-chloro-4-(b-D-glucopyranos-1-yl)-2-[4-((S)-tetrahy-drofuran-3-yl-oxy)-benzyl]-benzene; BI 10773) improved glycaemiccontrol in diabetic rats 82 and demonstrated greater efcacy andincrease in urinary glucose excretion compared with remogliozinin preclinical studies.30 In general, the C-glucoside SGLT inhibitorssuch as empagliozin, canagliozin, dapagliozin, ipragliozin andtofogliozin inhibit SGLT2 to a greater extent than do O-glucosidessuch as sergliozin, phlorizin and remogliozin. Empagliozinexhibited the highest selectivity for SGLT2 vs. SGLT156,65 (Fig. 2).

Ipragliozin (ASP-1941) is a novel benzothiophene derivative thatwas discovered during optimization of a series of C-glycosides forselective inhibitory activity against SGLT2 vs. SGLT1.83 It potently(nM range) inhibits mouse, rat and human SGLT2 and producesdose-dependent and sustained antihyperglycaemic effects in mousemodels of type 2 DM, but does not affect normoglycemia, intestinalglucose absorption or electrolyte balance.84 It was well tolerated inhealthy subjects during a 10-day study85 and was reported to begenerally safe, well tolerated and effective at blocking renal glucosereabsorption and decreasing plasma glucose levels in patients withtype 2 DM.86

LX4211 is a dual inhibitor of both SGLT2 and SGLT1. It has beenreported to dose-dependently increase the urinary excretion ofglucose and to improve fasting plasma glucose levels in patientswith type 2 DM.87

Tofogliozin ((1S,3R,4S,5S,6R)-6-[(4-ethylphenyl)methyl]-3,4,5,6-tet-rahydro-6-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2-[2H] pyran]-3,4,5-triol; CSG452; R7201; RG7201) is a potent and selective inhibitorof SGLT2 that has been reported to increase the renal clearance ofglucose and to lower blood glucose levels in Zucker diabetic fatty ratsand to improve glucose tolerance in db/dbmice without affecting bloodglucose in normoglycaemic rats.88

TS-071((1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methyl-phenyl]-1-thio-D-glucitol) was selected from a series of derivatives ofthe novel scaffold C-phenyl 1-thio-D-glucitol as a potent inhibitor ofSGLT2 (nM range) with 1650-fold selectivity over SGLT1.66 Itincreased the urinary excretion of glucose in Zucker fatty rats andin beagle dogs, improved glucose tolerance without stimulatinginsulin secretion in Zucker fatty rats and reduced hyperglycaemia instreptozotocin (STZ)-induced diabetic rats and db/db mice.67

SGLT2 inhibition in combination with other therapy has beenstudied. For example, canagliozin has been studied andapproved for use in combination with sitagliptin and metforminin patients with DM who are not adequately controlled; dapagli-ozin has been examined in combination with metformin andinsulin therapy in patients with DM who were not adequatelycontrolled on their drug regimens; and ipragliozin has beentested in various combinations.67,89,90

Representative clinical trial data

We identied 41 clinical studies of canagliozin registered atClinicalTrials.gov.91 In current phase 3 trials, canagliozin is beingcompared with placebo in patients who have type 2 DM for 1 year(NCT01106625) or 4 years (NCT01032629). It is also being com-pared with sitagliptin (a dipeptidyl peptidase-4 inhibitor) in twophase 3 trials (NCT01106677 and NCT01081834). In an exploratoryphase 2 study, 29 subjects with type 2 DM not optimally controlledon insulin and up to one oral agent were randomized tocanagliozin 100 mg daily or 300 mg twice daily or placebo.After 28 days, a decrease in A1c and body weight was noted inpatients administered canagliozin (A1c: 019%, 073%, 092%;

Table 3. Clinical development of SGLT2 inhibitors in the UnitedStates for the treatment of diabetes

Drug Development company Phase of development

Canagliozin JNJ/Mitsubishi Tanabe ApprovedDapagliozin Bristol-Myers Squibb/AstraZeneca Phase IIIASP-1941 Astellas/Kotobuki Phase III (Japan)BI 10773 Boehringer Ingelheim Phase IIBI 44847 Boehringer Ingelheim/Ajinomoto Phase IIR-7201 Roche/Chugai Phase IITS-071 Taisho Phase IILX4211 Lexicon Phase IIRemogliozin GlaxoSmithKline DiscontinuedYM-543 Astellas/Kotobuki DiscontinuedTS-033 Taisho DiscontinuedAVE2268 Sano-Aventis DiscontinuedSergliozin GlaxoSmithKline/Kissei DiscontinuedT-1095 Tanabe Discontinued

Dapagliflozin

TS-071

Tofogliflozin

Empagliflozin

Remogliflozin

Ipragliflozin

AVE2268

Phlorizin

T-1095

Canagliflozin

Sergliflozin

0 500 1000 1500 2000 2500 3000

Selectivity (SGLT2 vs SGLT1)

Fig. 2. Selectivity of sodium/glucose transport inhibitors,expressed as the ratio of in vitro IC50 (nM) values.

56,65,66



body weight: +003 kg, 073 kg, 119 kg for placebo, 100 mgonce daily and 300 mg twice daily groups, respectively) (Devineni,2012). In another randomized phase 2 trial (NCT00642278), 451patients with type 2 DM were randomized to canagliozin 50, 100,200 or 300 mg once daily, or 300 mg twice daily, or sitagliptin100 mg once daily, or placebo twice daily. A greater reduction inHbA1c was noted in treatment groups that received 300 mg ofcanagliozin once or twice daily compared with sitagliptin at12 weeks (071%, 073% vs. 056%, respectively). In thisstudy, the patients receiving sitagliptin gained weight, in contrastto the signicant weight loss in the patients treated with canagli-ozin (13% to 23% for canagliozin compared with +04% for

sitagliptin). The rate of symptomatic genital infections was morecommon (38% vs. 2%), and urinary tract infections were morecommon (39% vs. 2%) for canagliozin than for sitagliptin. TheFDA is requiring post-marketing trials to investigate cardiovascu-lar outcomes and pharmacovigilance studies for suspected adverseeffects. One such study underway is CANVAS (CanagliozinCardiovascular Outcomes Assessment) for major cardiovascularadverse effects.

We found 53 studies for dapagliozin registered at ClinicalTri-als.gov,92 including 21 phase 1, 8 phase 2, and 24 phase 3 trials. Inone phase 2 study, 389 type 2 DM treatment-nave patients wererandomized to receive 25, 5, 10, 20 or 50 mg of dapagliozin,

R1 R2

Phlorizin

T-1095

Canagliflozin

Sergliflozin

Remogliflozin

Dapagliflozin

TS-071

Fig. 3. Chemical structures of representative SGLT2 inhibitors.



placebo or metformin XR 750/1500 mg as active comparator. After12 weeks of therapy, the dapagliozin group had a signicantdecrease in fasting blood glucose levels and HbA1C (adjustedmean reductions of 055 to 090%, 018% and 073% in thedapagliozin group, placebo group and metformin group, respec-tively, and decrease in adjusted mean fasting plasma glucose levelsof 16 to 31 mg/dL, 6 mg/dL and 18 mg/dL in thedapagliozin, placebo and metformin groups, respectively).80 Ina phase 3 trial (NCT00680745), dapagliozin was studied asadjunctive to sulfonylurea therapy (specically glimepiride) atdoses 25, 5 and 10 mg daily compared with glimepiride alone. Atthe completion of the study (24 week), the adjusted mean HbA1Cwas signicantly decreased in all dapagliozin treatment armsmore than with monotherapy or placebo (013%, 058%,063%, 082% in placebo and dapagliozin 25-, 5- and 10-mggroups, respectively). Secondary outcome measures, such as bodyweight and fasting plasma glucose values, were also reduced frombaseline in all treatment groups (072 kg, 118 kg, 156 kg,226 kg and 011 mM, 093 mM, 118 mM and 158 mM inthe placebo and dapagliozin 25-, 5- and 10-mg groups, respec-tively) (note: mM 9 18 mg/dL).73 Regarding adverse events,effects on renal hemodynamics were noted in clinical trials. Inparticular, increased diuresis and blood pressure lowering effectswere noted in patients receiving dapagliozin.80 Signicant weightloss also was noted (which is a possible new indication(NCT00297180)). Dapagliozin is metabolized in the liver to aninactive glucuronidated metabolite that is subsequently eliminatedrenally.93 The pharmacokinetic parameters were within US FDA(Federal Drug Administration) limits in mild and moderate hepaticimpairment, but in patients with severe hepatic impairment, theneed for long-term studies has been suggested, with carefulassessment of riskbenet ratio.94 As expected from the com-pounds mechanism of action,76 the excreted glucose per day wasdecreased substantially in patients with reduced renal function.95

Dapagliozin had no clinically signicant effect on QT prolonga-tion in healthy volunteers.96

A summary of clinical measures outcomes is presented inTable 4 for canagliozin,97 dapagliozin,75 empagliozin 98 andipragliozin.99

WHAT IS NEW AND CONCLUSION

Current and future clinical trials will continue to delineate thetherapeutic efcacy of the concept of SGLT2 inhibition in generaland specic inhibitors in particular. Likewise, the clinical efcacyof combinations of SGLT2 inhibitors together with current ordevelopmental DM agents and insulin is being, or will be, assessedin clinical trials.

The more pressing issue, as with any new therapeutic approach,is the question of the adverse effect prole of such an approach or of specic agents if all or some of the adverse effects are notclass effects. As summarized in the recent review by Ferranniniand Solini,100 the adverse effect concerns noted thus far were asfollows: An increased incidence of genitourinary infections (possibly as a

consequence of the higher glucose levels that result from SGLT2inhibition providing a more favourable environment for bacterial orfungal growth). This adverse effect seems to occur more often infemale patient (particularly post-menopausal) and in more suscep-tible patients (e.g. patients with a history of such infections). Theextent, seriousness and possible adaptation with continued treat-ment still need to be better dened. But the infections thus farappear to be treatable and, albeit inconvenient, outweighed by thebenets of better glycaemic control.

An increased incidence of genital infections (vulvovaginitis, balani-tis, prostatitis). These appear to be responsive to standard treatment,have led to considerable dropout rates in the clinical trials and,similar to genitourinary infections, likely outweighed by the benetsof better glycaemic control.

Possible small (

of breast cancer. It is not feasible to establish the relative risk withany degree of certainty at this time given the small number ofevents (nine cases in the dapagliozin treatment groups and zeroin the comparator groups) and a wide condence interval for theincidence rate ratio that includes 10 and innity. Therefore, it isuncertain whether dapagliozin treatment is associated with anincreased risk of breast cancer. Continued follow-up of allparticipants in the dapagliozin trials for breast cancer and furtheranalysis with a direct comparison between the dapagliozintreatment arms and the comparator arms should be conducted toevaluate the relative risk of breast cancer associated with dapa-gliozin treatment. And further from the same source: In theclinical trials of dapagliozin, no cases of bladder cancer wereobserved in female patients. Nine cases occurred during a totalfollow-up of 22371 subject-years in males in the dapagliozinarms, amounting to a rate of 402 (95% CI, 184764) per 100 000subject-years. This compared to one case during 9898 subject-years in male controls, or 101 (95% CI, 13562) new cases per100 000 subject-years the clinical trials were not powered tostatistically distinguish between nine cases of bladder cancer in theactive treatment arms compared to one case in the control arms.However, event rates for males observed in the active treatmentarms signicantly exceeded the rates expected in an age-matchedreference diabetic population.

As of this writing, it is unclear whether there is an increased riskof breast or bladder cancer and if so, whether it is unique to aparticular agent or agents or whether it is inherent in the SGLT2mechanism of action. In an effort to gain some insight into thisquestion, we searched the literature for possible connectionbetween SGLT and cancer. The rst study to measure the levelsof SGLT1 and SGLT2 gene expression in cancer cells102 found nosignicant differences in the level of either gene expressionbetween the primary lung cancers and normal lung tissues. Theexpression of SGLT1 was the same in primary lung cancers andtheir metastatic lesions, but the expression of SGLT2 was signif-icantly higher in the metastatic lesions than in the primary lungcancers. Based on this, the authors posit that SGLT inhibitorsmight be useful for the treatment of cancers. Other ndings includethe following: Epidermal growth factor (EGFR) and SGLT1 coexpression may

contribute to the growth and survival of oral squamous cellcarcinoma.103

High SGLT1 expression in pancreatic adenocarcinomas is signi-cantly correlated with disease-free survival, and a trend was foundfor overall survival, especially in younger patients.104

SGLT1-mediated increase in glucose uptake is important for therepair of plasma membrane injury.105

SGLT1, but not SGLT2, expression was observed in short-termcultures of squamous cell carcinomas of the head and neck.106

Overexpression of SGLT1 protein levels correlates with poorprognosis of patients with ovarian carcinoma.107

Phlorizin inhibits the cytoprotection of SGLT1-mediated increase inanti-apoptotic proteins and protection of enterocytes from lipopoly-saccharide-induced apoptosis and barrier defects.108

EGFR prevented autophagic cell death in a human metastaticprostate cancer cell line by maintaining intracellular glucose levelthrough interaction with and stabilization of SGLT1.109

SGLT1 expression was found to be higher in colorectal cancer tissuesthan in normal tissues, related to clinical stage but not to otherclinical characteristics, objective response rate, disease control rate oroverall survival.110

It is clear from the above that there is an absence of muchinformation about SGLT2 and cancer. What little there is suggeststhat there might be a possible protective benet from a selectiveand exclusive inhibition of SGLT2, but the information is toosparse and such projections are too speculative. A relationshipbetween SGLT1 and cancer is even more ambiguous, but a casecould be made that SGLT1 promotes cancer growth in some way.It is also possible that it is not the absolute level of SGLT1 orSGLT2 that is important, but rather the ratio of the two or even theup- or down-regulation of one secondary to the under- oroverexpression of the other.

Summary and conclusion

Currently available drugs provide less than fully adequate therapyfor the majority of patients with DM. As a result, they have greatermorbidity and mortality compared with age-matched non-diabet-ics. The current drugs have individual shortcomings in efcacyand/or limiting adverse effects, but they are also limited in theirphysiological approaches (targets), mainly the inhibited insulinsecretion or insulin receptor resistance characteristic of thedisorder. An important factor in the control of glucose homoeo-stasis has largely been overlooked, namely elimination in theurine. Canagliozin, which is now FDA-approved, and otherSGLT2 inhibitors currently in clinical trials or other stages ofdevelopment target this important site.

A sufcient number of clinical trials have been conducted on asufcient number of relatively chemically diverse SGLT2 inhib-itors to reasonably conclude that they have efcacy in type 2 DM,that is, they improve glycaemic control to a therapeutically usefulextent, lower HbA1c levels about 051% do not cause hypo-glycaemia, and thus far, the majority of adverse effects have beenmild and transitory or treatable. The morbidity and mortality ofDM plus the absence of fully adequate therapy have led some tosuggest that these agents are worth considering. As a cautionarynote, however, more serious adverse effects might have goneundetected in the clinical trials to date due to the relatively smallnumber of trial participants compared with the exposure popu-lation (the total population of patients with DM). The sites ofthese adverse effects might be related to tissues in which SGLT2(or SGLT1) is expressed (e.g. heart, blood-brain barrier, etc.).Another, as yet unresolved, area of concern is the apparent excesscases of breast and bladder cancer that have been at leastspeculated to be associated with one SGLT2 inhibitor. We foundno obvious connection between cancer and inhibition of SGLT2 orinhibition of SGLT1 by non-specic inhibitors, but up-regulationof SGLT1 in response to inhibition of SGLT2 is a theoreticalpossibility. Only careful evaluation will elucidate whether thiseffect is real and, if so, is limited to a single agent or chemicalfamily, or is an inherent unavoidable adverse effect of inhibitionof SGLT2.

REFERENCES

1. ADA. American Diabetes AssociationStandards of Medical Care in Diabetes 2012. Diabetes Care, 2012;35:S11S63.

2. CDC. Diagnosed and Undiagnosed Diabetesin the United States, All Ages, 2010. 2011.Available at: http://www.cdc.gov/

diabetes/pubs/estimates11.htm (accessed30 April 2013).



3. CDCP. Centers for Disease Control andPrevention. National Diabetes Fact Sheet:National Estimates and General Informationon Diabetes and Prediabetes in the UnitedStates, 2011. Atlanta, GA: U.S. Departmentof Health and Human Services, Centers forDisease Control and Prevention, 2011.Available at: http://www.cdc.gov/diabe-tes/pubs/pdf/ndfs_2011.pdf (accessed 30April 2013).

4. Wild S, Roglic G, Green A, Sicree R, KingH. Global prevalence of diabetes: estimatesfor the year 2000 and projections for 2030.Diabetes Care, 2004;27:10471053.

5. Nichols GA, Kimes TM, Harp JB, Kou TD,Brodovicz KG. Glycemic response andattainment of A1C goals following newlyinitiated insulin therapy for type 2 diabe-tes. Diabetes Care, 2012;35:495497.

6. TODAY-Study-Group. A clinical trial tomaintain glycemic control in youth withtype 2 diabetes. N Engl J Med,2012;366:22472256.

7. Nicholson G, Hall GM. Diabetes mellitus:new drugs for a new epidemic. Br JAnaesth, 2011;107:6573.

8. Holman RR, Paul SK, Bethel MA, Mat-thews DR, Neil HA. 10-year follow-up ofintensive glucose control in type 2 diabe-tes. N Engl J Med, 2008;359:15771589.

9. Turner R, Cull C, Holman R. UnitedKingdom Prospective Diabetes Study 17:a 9-year update of a randomized, con-trolled trial on the effect of improvedmetabolic control on complications innon-insulin-dependent diabetes mellitus.Ann Intern Med, 1996;124:136145.

10. TaplinCE,BarkerJM.Autoantibodiesintype1diabetes.Autoimmunity, 2008;41:1118.

11. Bottazzo GF, Florin-Christensen A, Doni-ach D. Islet-cell antibodies in diabetesmellitus with autoimmune polyendocrinedeciencies. Lancet, 1974;2:12791283.

12. Schatz D, Krischer J, Horne G et al. Isletcell antibodies predict insulin-dependentdiabetes in United States school age chil-dren as powerfully as in unaffected rela-tives. J Clin Invest, 1994;93:24032407.

13. Bolli G, de Feo P, Compagnucci P et al.Abnormal glucose counterregulation ininsulin-dependent diabetes mellitus. Inter-action of anti-insulin antibodies andimpaired glucagon and epinephrine secre-tion. Diabetes, 1983;32:134141.

14. Moloney PJ, Coval M. Antigenicity ofinsulin: diabetes induced by specic anti-bodies. Biochem J, 1955;59:179185.

15. Quinn L. Type 2 diabetes: epidemiology,pathophysiology, and diagnosis. Nurs ClinNorth Am, 2001;36:175192, v.

16. Defronzo RA. Banting Lecture. From thetriumvirate to the ominous octet: a new

paradigm for the treatment of type 2diabetes mellitus. Diabetes, 2009;58:773795.

17. Meier JJ, Ueberberg S, Korbas S, SchneiderS. Diminished glucagon suppression afterbeta-cell reduction is due to impairedalpha-cell function rather than an expan-sion of alpha-cell mass. Am J PhysiolEndocrinol Metab, 2011;300:E717E723.

18. Ferrannini E. The stunned beta cell: a briefhistory. Cell Metab, 2010;11:349352.

19. Choi K, Kim YB. Molecular mechanism ofinsulin resistance in obesity and type 2diabetes. Korean J Intern Med, 2010;25:119129.

20. Polychronakos C, Li Q. Understandingtype 1 diabetes through genetics: advancesand prospects. Nat Rev Genet, 2011;12:781792.

21. Slomko H, Heo HJ, Einstein FH. Minire-view: epigenetics of obesity and diabetes inhumans. Endocrinology, 2012;153:10251030.

22. Sattereld DW, Volansky M, Caspersen CJet al. Community-based lifestyle interven-tions to prevent type 2 diabetes. DiabetesCare, 2003;26:26432652.

23. Inzucchi SE. Oral antihyperglycemic ther-apy for type 2 diabetes: scientic review.JAMA, 2002;287:360372.

24. Neumiller JJ, White JR Jr, Campbell RK.Sodium-glucose co-transport inhibitors:progress and therapeutic potential in type2 diabetes mellitus. Drugs, 2010;70:377385.

25. Lee YJ, Lee YJ, Han HJ. Regulatory mech-anisms of Na(+)/glucose cotransporters inrenal proximal tubule cells. Kidney IntSuppl, 2007;106:2735.

26. Wright EM. Renal Na(+)-glucose cotrans-porters. Am J Physiol Renal Physiol,2001;280:F10F18.

27. Uldry M, Thorens B. The SLC2 family offacilitated hexose and polyol transporters.Pugers Arch, 2004;447:480489.

28. Wright EM, Turk E. The sodium/glucosecotransport family SLC5. Pugers Arch,2004;447:510518.

29. Hediger MA, Coady MJ, Ikeda TS, WrightEM. Expression cloning and cDNAsequencing of the Na+/glucose co-trans-porter. Nature, 1987;330:379381.

30. Chao EC, Henry RR. SGLT2 inhibitionanovel strategy for diabetes treatment. NatRev Drug Discov, 2010;9:551559.

31. Hediger MA, Rhoads DB. Molecular phys-iology of sodium-glucose cotransporters.Physiol Rev, 1994;74:9931026.

32. Rahmoune H, Thompson PW, Ward JM,Smith CD, Hong G, Brown J. Glucosetransporters in human renal proximaltubular cells isolated from the urine of

patients with non-insulin-dependent dia-betes. Diabetes, 2005;54:34273434.

33. Wells RG, Pajor AM, Kanai Y, Turk E,Wright EM, Hediger MA. Cloning of ahuman kidney cDNA with similarity to thesodium-glucose cotransporter. Am J Phys-iol, 1992;263:F459F465.

34. Kanai Y, Lee WS, You G, Brown D,Hediger MA. The human kidney lowafnity Na+/glucose cotransporter SGLT2.Delineation of the major renal reabsorptivemechanism for D-glucose. J Clin Invest,1994;93:397404.

35. Abdul-Ghani MA, DeFronzo RA. Inhibi-tion of renal glucose reabsorption: a novelstrategy for achieving glucose control intype 2 diabetes mellitus. Endocr Pract,2008;14:782790.

36. Moe OW, Berry CA, Rector FCJ. Renaltransport of glucose. In: Brenner BM, ed.Brenner and Rectors the kidney, 5th edn.Philadelphia: WB Saunders, 375415, 1996.

37. Deetjen P, von Baeyer H, Drexel H. Renalglucose transport. In: Seldin DW, GiebischG, eds. Seldin and Giebischs the kidney, 2ndedn.NewYork:RavenPress, 28732888, 1992.

38. Kinne RK, Castaneda F. SGLT inhibitors asnew therapeutic tools in the treatment ofdiabetes. Handb Exp Pharmacol,2011:203;105126.

39. Isaji M. Sodium-glucose cotransporterinhibitors for diabetes. Curr Opin InvestigDrugs, 2007;8:285292.

40. Jabbour SA, Goldstein BJ. Sodium glucoseco-transporter 2 inhibitors: blocking renaltubular reabsorption of glucose to improveglycaemic control in patients with diabe-tes. Int J Clin Pract, 2008;62:12791284.

41. Bakris GL, Fonseca VA, Sharma K, WrightEM. Renal sodium-glucose transport: rolein diabetes mellitus and potential clinicalimplications. Kidney Int, 2009;75:12721277.

42. Vallon V, Sharma K. Sodium-glucosetransport: role in diabetes mellitus andpotential clinical implications. Curr OpinNephrol Hypertens, 2010;19:425431.

43. Nomura S. Renal sodium-dependent glu-cose cotransporter 2 (SGLT2) inhibitors fornew anti-diabetic agent. Curr Top MedChem, 2010;10:411418.

44. Asano T, Ogihara T, Katagiri H et al.Glucose transporter and Na+/glucose co-transporter as molecular targets of anti-diabetic drugs. Curr Med Chem,2004;11:27172724.

45. Ueta K, Ishihara T, Matsumoto Y et al.Long-term treatment with the Na+-glucosecotransporter inhibitor T-1095 causes sus-tained improvement in hyperglycemia andprevents diabetic neuropathy in Goto-Ka-kizaki Rats. Life Sci, 2005;76:26552668.



46. Nunoi K, Yasuda K, Adachi T et al. Bene-cial effect of T-1095, a selective inhibitorof renal Na+-glucose cotransporters, onmetabolic index and insulin secretion inspontaneously diabetic GK rats. Clin ExpPharmacol Physiol, 2002;29:386390.

47. Yasuda K, Okamoto Y, Nunoi K et al.Normalization of cytoplasmic calciumresponse in pancreatic beta-cells of spon-taneously diabetic GK rat by the treatmentwith T-1095, a specic inhibitor of renalNa+-glucose co-transporters. Horm MetabRes, 2002;34:217221.

48. Arakawa K, Ishihara T, Oku A et al.Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administrationof the Na(+)-glucose cotransporter inhib-itor T-1095. Br J Pharmacol, 2001;132:578586.

49. Oku A, Ueta K, Arakawa K et al. Correc-tion of hyperglycemia and insulin sensi-tivity by T-1095, an inhibitor of renal Na+-glucose cotransporters, in streptozotocin-induced diabetic rats. Jpn J Pharmacol,2000;84:351354.

50. Oku A, Ueta K, Arakawa K et al. Antihy-perglycemic effect of T-1095 via inhibitionof renal Na+-glucose cotransporters instreptozotocin-induced diabetic rats. BiolPharm Bull, 2000;23:14341437.

51. Adachi T, Yasuda K, Okamoto Y et al. T-1095, a renal Na+-glucose transporterinhibitor, improves hyperglycemia instreptozotocin-induced diabetic rats.Metabolism, 2000;49:990995.

52. Oku A, Ueta K, Nawano M et al. Antidi-abetic effect of T-1095, an inhibitor of Na(+)-glucose cotransporter, in neonatallystreptozotocin-treated rats. Eur J Pharmacol,2000;391:183192.

53. Oku A, Ueta K, Arakawa K et al. T-1095,an inhibitor of renal Na+-glucose cotrans-porters, may provide a novel approach totreating diabetes. Diabetes, 1999;48:17941800.

54. Marsenic O. Glucose control by the kidney:an emerging target in diabetes. Am J KidneyDis, 2009;53:875883.

55. Nathan DM, Buse JB, Davidson MB et al.Management of hyperglycemia in type 2diabetes: a consensus algorithm for theinitiation and adjustment of therapy: aconsensus statement from the AmericanDiabetes Association and the EuropeanAssociation for the Study of Diabetes.Diabetes Care, 2006;29:19631972.

56. Grempler R, Thomas L, Eckhardt M et al.Empagliozin, a novel selective sodiumglucose cotransporter-2 (SGLT-2) inhibitor:characterisation and comparison withother SGLT-2 inhibitors. Diabetes ObesMetab, 2012;14:8390.

57. Gosch C, Halbwirth H, Stich K. Phloridzin:biosynthesis, distribution and physiologi-cal relevance in plants. Phytochemistry,2010;71:838843.

58. Ehrenkranz JR, Lewis NG, Kahn CR, RothJ. Phlorizin: a review. Diabetes Metab ResRev, 2005;21:3138.

59. Hardman TC, Rutherford P, Dubrey SW,Wierzbicki AS. Sodium-glucose co-trans-porter 2 inhibitors: from apple tree toSweet Pee. Curr Pharm Des,2010;16:38303838.

60. Katsuno K, Fujimori Y, Takemura Y et al.Sergliozin, a novel selective inhibitor oflow-afnity sodium glucose cotransporter(SGLT2), validates the critical role ofSGLT2 in renal glucose reabsorption andmodulates plasma glucose level. J Pharma-col Exp Ther, 2007;320:323330.

61. Fujimori Y, Katsuno K, Nakashima I,Ishikawa-Takemura Y, Fujikura H, IsajiM. Remogliozin etabonate, in a novelcategory of selective low-afnity sodiumglucose cotransporter (SGLT2) inhibitors,exhibits antidiabetic efcacy in rodentmodels. J Pharmacol Exp Ther,2008;327:268276.

62. Hussey EK, Clark RV, Amin DM et al.Single-dose pharmacokinetics and phar-macodynamics of sergliozin etabonate, anovel inhibitor of glucose reabsorption, inhealthy volunteers and patients with type2 diabetes mellitus. J Clin Pharmacol,2010;50:623635.

63. Hussey EK, Dobbins RL, Stoltz RR et al.Multiple-dose pharmacokinetics and phar-macodynamics of sergliozin etabonate, anovel inhibitor of glucose reabsorption, inhealthy overweight and obese subjects: arandomized double-blind study. J ClinPharmacol, 2010;50:636646.

64. Dobbins RL, OConnor-Semmes R, KapurA et al. Remogliozin etabonate, a selec-tive inhibitor of the sodium-dependenttransporter 2 reduces serum glucose intype 2 diabetes mellitus patients. DiabetesObes Metab, 2012;14:1522.

65. Bickel M, Brummerhop H, Frick W et al.Effects of AVE2268, a substituted glyco-pyranoside, on urinary glucose excretionand blood glucose in mice and rats. Arz-neimittelforschung, 2008;58:574580.

66. Kakinuma H, Oi T, Hashimoto-Tsuchiya Yet al. (1S)-1,5-anhydro-1-[5-(4-ethoxyben-zyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucito l (TS-071) is a potent, selectivesodium-dependent glucose cotransporter 2(SGLT2) inhibitor for type 2 diabetestreatment. J Med Chem, 2010;53:32473261.

67. Yamamoto K, Uchida S, Kitano K et al. TS-071 is a novel, potent and selective renalsodium-glucose cotransporter 2 (SGLT2)

inhibitor with anti-hyperglycaemic activ-ity. Br J Pharmacol, 2011;164:181191.

68. Nomura S, Sakamaki S, Hongu M et al.Discovery of canagliozin, a novel C-glucoside with thiophene ring, assodium-dependent glucose cotransporter2 inhibitor for the treatment of type 2diabetes mellitus. J Med Chem,2010;53:63556360.

69. Sha S, Devineni D, Ghosh A et al. Cana-gliozin, a novel inhibitor of sodium glu-cose co-transporter 2, dose dependentlyreduces calculated renal threshold for glu-cose excretion and increases urinary glu-cose excretion in healthy subjects. DiabetesObes Metab, 2011;13:669672.

70. Rosenstock J, Aggarwal N, Polidori D et al.Dose-ranging effects of canagliozin, asodium-glucose cotransporter 2 inhibitor,as add-on to metformin in subjects withtype 2 diabetes. Diabetes Care,2012;35:12321238.

71. Meng W, Ellsworth BA, Nirschl AA et al.Discovery of dapagliozin: a potent, selec-tive renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor for thetreatment of type 2 diabetes. J Med Chem,2008;51:11451149.

72. Chao EC. Dapagliozinredening treat-ment of T2DM? Nat Rev Endocrinol,2011;7:696697.

73. Strojek K, Yoon KH, Hruba V, Elze M,Langkilde AM, Parikh S. Effect of dapagli-ozin in patients with type 2 diabetes whohave inadequate glycaemic control withglimepiride: a randomized, 24-week, dou-ble-blind, placebo-controlled trial. DiabetesObes Metab, 2011;13:928938.

74. Katsiki N, Papanas N, Mikhailidis DP.Dapagliozin: more than just another oralglucose-lowering agent? Expert Opin Inves-tig Drugs, 2010;19:15811589.

75. Ferrannini E, Ramos SJ, Salsali A, Tang W,List JF. Dapagliozin monotherapy in type2 diabetic patients with inadequate glyce-mic control by diet and exercise: a ran-domized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care,2010;33:22172224.

76. Hanefeld M, Forst T. Dapagliozin, anSGLT2 inhibitor, for diabetes. Lancet,2010;375:21962198.

77. Calado J. Dapagliozin, an oral sodiumglucose cotransporter type 2 inhibitor forthe treatment of type 2 diabetes mellitus.IDrugs, 2009;12:785798.

78. Woo VC. Dapagliozin: where does it t inthe treatment of type 2 diabetes? ExpertOpin Pharmacother, 2009;10:25272535.

79. Brooks AM, Thacker SM. Dapagliozin forthe treatment of type 2 diabetes. AnnPharmacother, 2009;43:12861293.



80. List JF, Woo V, Morales E, Tang W,Fiedorek FT. Sodium-glucose cotransportinhibition with dapagliozin in type 2diabetes. Diabetes Care, 2009;32:650657.

81. Kipnes M. Dapagliozin: an emergingtreatment option in type 2 diabetes. ExpertOpin Investig Drugs, 2009;18:327334.

82. Thomas L, Grempler R, Eckhardt M et al.Long-term treatment with empagliozin, anovel, potent and selective SGLT-2 inhib-itor, improves glycaemic control and fea-tures of metabolic syndrome in diabeticrats. Diabetes Obes Metab, 2012;14:9496.

83. Imamura M, Nakanishi K, Suzuki T et al.Discovery of Ipragliozin (ASP1941): anovel C-glucoside with benzothiophenestructure as a potent and selective sodiumglucose co-transporter 2 (SGLT2) inhibitorfor the treatment of type 2 diabetes mell-itus. Bioorg Med Chem, 2012;20:32633279.

84. Tahara A, Kurosaki E, Yokono M et al.Pharmacological prole of ipragliozin(ASP1941), a novel selective SGLT2 inhib-itor, in vitro and in vivo. Naunyn Schmiede-bergs Arch Pharmacol, 2012;385:423436.

85. Veltkamp SA, Kadokura T, KrauwinkelWJ, Smulders RA. Effect of Ipragliozin(ASP1941), a novel selective sodium-dependent glucose co-transporter 2 inhib-itor, on urinary glucose excretion inhealthy subjects. Clin Drug Investig,2011;31:839851.

86. Schwartz SL, Akinlade B, Klasen S, Ko-walski D, Zhang W, Wilpshaar W. Safety,pharmacokinetic, and pharmacodynamicproles of ipragliozin (ASP1941), a noveland selective inhibitor of sodium-depen-dent glucose co-transporter 2, in patientswith type 2 diabetes mellitus. DiabetesTechnol Ther, 2011;13:12191227.

87. Croasdell G. American Diabetes Associa-tion70th scientic sessionsresearch onnovel therapeutics: part 1. IDrugs,2010;13:595597.

88. Suzuki M, Honda K, Fukazawa M et al.Tofogliozin, a potent and highly specicsodium/glucose cotransporter 2 inhibitor,improves glycemic control in diabetic ratsand mice. J Pharmacol Exp Ther,2012;341:692701.

89. Lee YJ, Heo JS, Suh HN, Lee MY, Han HJ.Interleukin-6 stimulates alpha-MG uptakein renal proximal tubule cells: involvementof STAT3, PI3K/Akt, MAPKs, and NF-kappaB. Am J Physiol Renal Physiol,2007;293:F1036F1046.

90. Lee YJ, Han HJ. Troglitazone ameliorateshigh glucose-induced EMT and dysfunc-tion of SGLTs through PI3K/Akt, GSK-3{beta}, Snail1, and {beta}-catenin in renalproximal tubule cells. Am J Physiol RenalPhysiol, 2009;298:F1263F1275.

91. Available at: http://clinicaltrials.gov/ct2/results/details?term=canagliozin (acces-sed 30 April 2013).

92. Available at: http://clinicaltrials.gov/ct2/results/details?term=Dapagliozin (acces-sed 30 April 2013).

93. Obermeier M, Yao M, Khanna A et al. Invitro characterization and pharmacokinet-ics of dapagliozin (BMS-512148), a potentsodium-glucose cotransporter type IIinhibitor, in animals and humans. DrugMetab Dispos, 2010;38:405414.

94. Kasichayanula S, Liu X, Zhang W, PsterM, LaCreta FP, Boulton DW. Inuence ofhepatic impairment on the pharmacokinet-ics and safety prole of dapagliozin: anopen-label, parallel-group, single-dosestudy. Clin Ther, 2011;33:17981808.

95. Komoroski B, Vachharajani N, Feng Y, LiL, Kornhauser D, Pster M. Dapagliozin,a novel, selective SGLT2 inhibitor,improved glycemic control over 2 weeksin patients with type 2 diabetes mellitus.Clin Pharmacol Ther, 2009;85:513519.

96. Carlson GF, Tou CK, Parikh S, Birming-ham BK, Butler K. Evaluation of the effectof dapagliozin on cardiac repolarization:a thorough QT/QTc study. Diabetes Ther,2011;2:123132.

97. Stenlof K, Cefalu WT, Kim KA et al.Efcacy and safety of canagliozin mono-therapy in subjects with type 2 diabetesmellitus inadequately controlled with dietand exercise. Diabetes Obes Metab,2013;15:372382.

98. Ferrannini E, Seman L, Seewaldt-Becker E,Hantel S, Pinnetti S, Woerle HJ. A PhaseIIb, randomized, placebo-controlled studyof the SGLT2 inhibitor empagliozin inpatients with type 2 diabetes. Diabetes ObesMetab, 2013; in press [doi:10.1111/dom.12081].

99. Fonseca VA, Ferrannini E, Wilding JP et al.Active- and placebo-controlled dose-nd-ing study to assess the efcacy, safety, andtolerability of multiple doses of ipraglio-zin in patients with type 2 diabetes mell-itus. J Diabetes Complications, 2013;27:268273.

100. Ferrannini E, Solini A. SGLT2 inhibition indiabetes mellitus: rationale and clinicalprospects. Nat Rev Endocrinol, 2012;8:495502.

101. FDA. FDA Brieng Document. NDA 202293.Dapagliozin Tablets, 5 and 10 mg. Sponsor:Bristol-Myers Squibb. Advisory CommitteeMeeting, July 19, 2011. Available at:http://www.fda.gov/downloads/Advi-soryCommittees/CommitteesMeetingMa-terials/Drugs/Endocrinologicand Meta-bolicDrugsAdvisoryCommittee/UCM262994.pdf (accessed 30 April 2013).

102. Ishikawa N, Oguri T, Isobe T, FujitakaK, Kohno N. SGLT gene expression inprimary lung cancers and their meta-static lesions. Jpn J Cancer Res,2001;92:874879.

103. Hanabata Y. Expression analysis of EGFRand SGLT1 in oral squamous cell carci-noma. Kokubyo Gakkai Zasshi, 2011;78:1218.

104. Casneuf VF, Fonteyne P, Van Damme Net al. Expression of SGLT1, Bcl-2 and p53 inprimary pancreatic cancer related to sur-vival. Cancer Invest, 2008;26:852859.

105. Ikari A. Regulatory mechanisms of intra-cellular distribution of Na+-dependentglucose transporter and the role in recov-ery from cellular injury. Yakugaku Zasshi,2004;124:959964.

106. Helmke BM, Reisser C, Idzko M, DyckhoffG, Herold-Mende C. Expression of SGLT-1in preneoplastic and neoplastic lesions ofthe head and neck. Oral Oncol, 2004;40:2835.

107. Lai B, Xiao Y, Pu H, Cao Q, Jing H, Liu X.Overexpression of SGLT1 is correlatedwith tumor development and poor prog-nosis of ovarian carcinoma. Arch GynecolObstet, 2012;285:14551461.

108. Yu LC, Flynn AN, Turner JR, Buret AG.SGLT-1-mediated glucose uptake protectsintestinal epithelial cells against LPS-induced apoptosis and barrier defects: anovel cellular rescue mechanism? FASEB J,2005;19:18221835.

109. Weihua Z, Tsan R, Huang WC et al.Survival of cancer cells is maintained byEGFR independent of its kinase activity.Cancer Cell, 2008;13:385393.

110. Guo C, Liao Y, Li Y et al. Genotypinganalysis of Helicobacter pylori using multi-ple-locus variable-number tandem-repeatsanalysis in ve regions of China and Japan.BMC Microbiol, 2011;11:197.



The Kidney as a New Target for Antidiabetic Drugs SGLT2 Inhibitors

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