Sodium–Glucose CotransporterInhibitors: Effects on Renal andIntestinal Glucose TransportFrom Bench to BedsideDiabetes Care 2015;38:2344–2353 | DOI: 10.2337/dc15-0642

Type 2 diabetes is a chronic disease with disabling micro- and macrovascularcomplications that lead to excessive morbidity and premature mortality. It affectshundreds of millions of people and imposes an undue economic burden onpopulations across the world. Although insulin resistance and insulin secretorydefects play a major role in the pathogenesis of hyperglycemia, several othermetabolic defects contribute to the initiation/worsening of the diabetic state.Prominent among these is increased renal glucose reabsorption, which ismaladaptive in patients with diabetes. Instead of an increase in renal glucoseexcretion, which could ameliorate hyperglycemia, there is an increase in renalglucose reabsorption, which helps sustain hyperglycemia in patients withdiabetes. The sodium–glucose cotransporter (SGLT) 2 inhibitors are novel antidia-betes agents that inhibit renal glucose reabsorption and promote glucosuria,thereby leading to reductions in plasma glucose concentrations. In this article,we review the long journey from the discovery of the glucosuric agent phlorizin inthe bark of the apple tree through the animal and human studies that led to thedevelopment of the current generation of SGLT2 inhibitors.

It took nearly 200 years from the isolation of phlorizin, a chemical found in appletree bark that inhibits sodium–glucose cotransporters (SGLTs) (1), to the approval ofthe first medications inhibiting SGLTs for treatment of type 2 diabetes (T2D). Duringthis time, several SGLTs were discovered and the roles of SGLT1 and SGLT2 inintestinal and renal glucose reabsorption have been elucidated in studies in genet-ically manipulated rodents, humans with SGLT gene mutations, healthy humans,and humans with diabetes (Fig. 1). This review provides an overview of the basic andclinical research that led to the translation of the initial findings of increased glu-cosuria with phlorizin to the development and approval of SGLT inhibitors and asummary of the clinical trial results obtained to date.

Identification, Distribution, and In Vitro Characterization of the SGLT InhibitorsIn the 1980s and 1990s, Wright and colleagues cloned SGLT1 (2) and SGLT2 (2,3) anddid much of the in vitro characterization, demonstrating that SGLT1 has a higheraffinity for glucose than SGLT2 (Km for glucose ;0.4 mmol/L and 2 mmol/L, re-spectively), whereas SGLT2 has a higher capacity (4). SGLT1 is expressed at highlevels in the intestine and is also expressed in the kidney, heart, and skeletal muscle,whereas SGLT2 is expressed almost exclusively in the kidney (4). Renal SGLT2 ex-pression is increased in hyperglycemic rodents (5,6) and in humans with T2D (7).Intestinal SGLT1 expression is regulated by diet and other factors (8) and is

1Veterans Affairs Medical Center, San Diego, CA2School of Medicine, University of California, SanDiego, San Diego, CA3Janssen Research & Development, LLC, SanDiego, CA4Regeneron Pharmaceuticals, Inc., Tarrytown, NY

Corresponding author: Sunder Mudaliar,smudaliar@vapop.ucsd.edu.

Received 3 April 2015 and accepted 4 September2015.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-0642/-/DC1.

© 2015 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

Sunder Mudaliar,1,2 David Polidori,3

Brian Zambrowicz,4 and Robert R. Henry1,2

2344 Diabetes Care Volume 38, December 2015

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increased in subjects with T2D (9). Fur-ther details on the structure and func-tion of the transporters can be found inref. 4.

Role of SGLT2 and SGLT1 in RenalGlucose ReabsorptionIn the 1930s, Shannon and Fisher eluci-dated the renal glucose reabsorption ki-netics in dogs (10). Their work showedthat 1) there is a maximum capacity forrenal tubular glucose transport (the tu-bular maximum glucose reabsorptionrate) (TmG), 2) nearly all filtered glucoseis reabsorbed when plasma glucose (PG)concentrations remain below a thresh-old value called the renal threshold forglucose (RTG), and 3) urinary glucose ex-cretion (UGE) increases nearly linearlywith PG when PG is above RTG.In the early 1970s, Vick, Diedrich, and

Baumann demonstrated that glucose re-absorption occurred in the proximal tu-bule (11), and Turner and Moran laterdemonstrated that this occurs throughtwo distinct sodium-dependent glucosetransport systems, one with relativelylow affinity and high capacity and onewith higher affinity and lower capacity

(12). Wright and colleagues later dem-onstrated that these two systems wereaccounted for by SGLT2 and SGLT1,respectively (4).

The effects of SGLT2 inhibitors on re-nal glucose kinetics were assessed usingcontrolled glucose infusion experimentsin rats (13) and humans (14,15). Theseexperiments showed that SGLT2 inhibi-tion leads to a reduction in TMG and RTGwhile maintaining a threshold-like rela-tionship between PG and the UGE rate(Fig. 2). Importantly, in subjects withT2D treated with SGLT2 inhibitors, theUGE rate is high when PG is high butdiminishes as PG approaches hypogly-cemic levels, suggesting a low risk oftreatment-induced hypoglycemia. TheSGLT2 inhibitor–induced increases inUGE are sustained at similar levels withlong-term treatment (16).

The roles of SGLT2 and SGLT1 in renalglucose reabsorption were further con-firmed through human and rodent ge-netic studies. In humans, familial renalglucosuria is a rare, benign conditionarising from SGLT2 mutations that reducerenal glucose reabsorption and lead toUGE ranging from 1 to 170 g/day, whereas

SGLT1mutations onlymildly increase UGE(17). Similarly, only minimal UGE is ob-served in SGLT1 knockout (KO) mice,whereas high UGE is seen in SGLT2 KOmice (17,18).

While it is often stated that SGLT2accounts for 90% of glucose reabsorp-tion, SGLT2 and SGLT1 appear sequen-tially in the proximal tubule, so it is anoversimplification to provide a singlevalue to describe their relative contribu-tion to glucose reabsorption. For exam-ple, under normoglycemic conditions,there is sufficient SGLT2 capacity to re-absorb virtually all filtered glucose, andonly minimal UGE is observed in humansor rodents lacking SGLT1. However,maximally effective SGLT2 inhibitordoses typically prevent ;50% of the fil-tered glucose from being reabsorbed,suggesting that SGLT1 has considerablygreater capacity for glucose reabsorp-tion than expected based on the com-monly quoted 90% value for SGLT2. Thisis supported by data from genetic mod-els, since SGLT2 KO mice exhibit onlyabout 30% of the UGE observed inSGLT1/SGLT2 double KO mice (17).These data, combined with human

Figure 1—Time line of some key developments in the understanding of SGLT-mediated glucose uptake and the development of SGLT inhibitors.

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data showing that phlorizin can blockvirtually all renal glucose reabsorption(19), suggest that dual SGLT1/2 renalinhibitors might achieve consider-ably greater UGE than selective SGLT2inhibitors.

Role of SGLT1 in Intestinal GlucoseAbsorptionSGLT1 is essential for intestinal glucose/galactose absorption and representsthe primary mechanism of glucose/galactose uptake from the lumen intoenterocytes (4). The essential nature ofSGLT1 is confirmed by the rare geneticdisease glucose-galactose malabsorp-tion (GGM), which arises from missensemutations in SGLT1 (19). This conditioncauses severe diarrhea if glucose or ga-lactose is consumed and can be fatal un-less glucose and galactose are removedfrom the diet. SGLT1 KO mice develop asimilar glucose-galactose malabsorp-tion syndrome when fed glucose butthrive normally when fed a glucose-and galactose-free diet (18).Studies in KO animals have further

elucidated the role of intestinal SGLT1.SGLT1 KO mice exhibited elevated glu-cose in the distal small intestine and co-lon and decreased cecal pH whenchallenged with a meal containing glu-cose (17,20). Reductions in serum totalglucagon-like peptide 1 (GLP-1) havebeen reported 5 min after a meal chal-lenge (17,20), but serum GLP-1 was in-creased from 30 min to 6 h after the

meal (20), indicating that SGLT1 maybe required for the early GLP-1 responseand that there is a second more pre-dominant phase of GLP-1 release thatdoes not require SGLT1 and is enhancedin the absence of SGLT1. The increasedGLP-1 seen in SGLT1 KO mice may bedue to increased glucose reaching thedistal small intestine and colon whereit, or its metabolites, can trigger GLP-1release (21,22). SGLT1 heterozygousmice thrived normally on a regular dietbut also exhibited elevated glucose inthe distal small intestine and cecumand elevated postmeal GLP-1 levels(17), indicating that partial SGLT1 inhi-bition might provide benefits without GIintolerability observed in the absence ofSGLT1 activity.

Development of Pharmaceutical SGLTInhibitors as Treatment for T2DAlthough phlorizin was known to in-crease UGE and was demonstrated tocompletely inhibit renal glucose reab-sorption in the 1930s (23), the potentialfor using increased UGE as a means toregulate PG was not demonstrated untilthe 1980s. Experiments by Rossetti andcolleagues in diabetic rats demon-strated that sustained phlorizin treat-ment normalized blood glucoseconcentrations resulting in reduced“glucotoxicity” and improvements inb-cell function and insulin sensitivity(24,25). However, phlorizin was not asuitable therapeutic agent due to poor

absorption, metabolism to phloretin,which inhibits GLUTs, and potential in-testinal malabsorption with SGLT1 inhi-bition. This led to the pursuit of selectiveSGLT2 inhibitors with improved proper-ties. The first publication demonstrat-ing the potential of a selective SGLT2inhibitor (T-1095) as a treatment for di-abetes in rodent models appeared in1999 (26). Since then, several SGLT2inhibitors have been developed andthree compounds are currently ap-proved for use in the U.S. and Europe(dapagliflozin, canagliflozin, and empa-gliflozin) (Table 1). Additionally, luseo-gliflozin, topogliflozin, and ipragliflozinhave been approved in Japan and othercompounds are in late-stage clinical tri-als. While these compounds have beenprimarily designed to be highly selec-tive for SGLT2 compared with SGLT1,there is variability in the selectivity,most notably for sotagliflozin, which isonly 20-fold selective for SGLT2 com-pared with SGLT1. A selective SGLT1 in-hibitor was tested in a phase 1 study in12 subjects and showed that SGLT1 in-hibitors block intestinal glucose ab-sorption, reduce GIP secretion, andenhance GLP-1 and peptide YY (PYY)secretion (27).

Effects of SGLT2 Inhibitors onGlycemiaSGLT2 inhibitors are effective in lower-ing PG when used as monotherapy or incombination with other oral agents/insulin. These effects have been demon-strated in large multicenter, multina-tional, placebo- and active-controlledstudies. Due to limited space, efficacystudies summarized are limited to thoseat least 24 weeks long with compoundsapproved for use in the European Union(EU) and U.S.

Monotherapy

Although metformin is the first choicepharmaceutical treatment for T2D, itcauses intolerable gastrointestinal (GI)side effects in occasional patients. Insuch patients, SGLT2 inhibitors can beused as monotherapy, and in clinical tri-als, compared with placebo/active com-parator, they lowered fasting PG (FPG)by 20–46 mg/dL and HbA1c by 0.54–1.45% in patients with baseline HbA1c7.9–9.1%. Those with higher baselineHbA1c had greater glycemic benefits,as did those on higher doses of SGLT2inhibitors (Supplementary Table 1).

Figure 2—Relationship between blood glucose concentrations and UGE rates in rodents andhumans treated with the SGLT2 inhibitor canagliflozin. Left panel: Results (mean 6 SE) from agraded glucose infusion study in Zucker diabetic fatty (ZDF) rats (13). Right panel: Results(mean 6 SD) from a stepwise hyperglycemic clamp study in human subjects with T2D (15). Inboth studies, canagliflozin treatment produces a left shift in the relationship between bloodglucose and UGE with no apparent change in the slope, leading to a reduction in RTG.

2346 Sodium–Glucose Cotransporter Inhibitors Diabetes Care Volume 38, December 2015

Dual Oral Combination Therapy

SGLT2 Inhibitor and Metformin Combination.

Over time, due in part to disease pro-gression, there is worsening glycemia inmetformin-treated patients. These pa-tients are often treated with the additionof sulfonylureas or dipeptidyl peptidase-4(DPP-4) inhibitors. In metformin-treatedpatients, adding an SGLT2 inhibitor resultsin additional glycemic benefit with low po-tential for hypoglycemia (unlike sulfonyl-ureas) and modest reductions in weightand blood pressure (not seen with DPP-4inhibitors or sulfonylureas). The addition ofSGLT2 inhibitors as add-on to metforminresults in FPG lowering by 15–40 mg/dLand HbA1c by 0.54–0.77% compared withplacebo in patients with mean baselineHbA1c between 7.9 and 8.2%. Comparedwith sulfonylureas, placebo-subtractedFPG is lowered by 20–27 mg/dL andHbA1c by 0.52–0.93% in patients withbaseline HbA1c 7.7–7.9%. Compared withDPP-4 inhibitors, placebo-subtracted FPGis lowered by 27–36 mg/dL and HbA1c by0.73–0.88% in patients with baselineHbA1c 7.9–8%. Of note, while dapagliflo-zin 10 mg, empagliflozin 25 mg, and can-agliflozin 100 mg were associated withequivalent glycemic control, canagliflo-zin 300 mg achieved superior glycemiccontrol compared with glimepiride andsitagliptin (Supplementary Table 2).SGLT2 Inhibitors and Nonmetformin Oral

Combination. In patients treated withnonmetformin oral agents (sulfonyl-ureas, DPP-4 inhibitors, or glitazones),the addition of SGLT2 inhibitors resultsin improved glycemia with placebo-sub-tracted FPG lowered by 10–40 mg/dLand HbA1c lowered by 0.4–0.9% in pa-tients with baseline HbA1c 8.0–8.4%.Higher doses of SGLT2 inhibitors re-sulted in greater HbA1c lowering, andcombining SGLT2 inhibitors with DPP-4

inhibitors/pioglitazone has a low poten-tial for hypoglycemia (SupplementaryTable 3).

Triple Oral Combination

The SGLT2 inhibitors are also effective inimproving glycemia in triple combina-tion with metformin and either sulfonyl-ureas, DPP-4 inhibitors, or glitazones,with placebo-subtracted FPG loweredby 20–38 mg/dL and HbA1c lowered by0.4–1.03% in patients with mean HbA1c7.8–8.1%. Of note, higher doses ofSGLT2 inhibitors resulted in greaterHbA1c lowering and canagliflozin300 mg had superior HbA1c loweringcompared with sitagliptin 100 mg inpatients on metformin and sulfonyl-urea combination (SupplementaryTable 4).

SGLT2 Inhibitor and Insulin Combination

Most patients with T2D eventually re-quire exogenous insulin therapy toachieve and maintain glycemic goals.The addition of insulin is associatedwith weight gain and increased hypogly-cemia risk. The addition of SGLT2 inhib-itors in patients inadequately controlledwith insulin andmean HbA1c 8.3–8.5% isassociated with improved glycemiccontrol with placebo-subtracted FPGlowered by 6–63 mg/dL and HbA1c low-ered by 0.39–1.27% in the settingof modest weight loss (1.31–3.5 kg)and lower insulin requirements (9–19units), without increasing major hy-poglycemic episodes (SupplementaryTable 5).

Effects of Dual SGLT1/2 Inhibitors onGlycemiaCombined renal SGLT2 and intestinalSGLT1 inhibition have the potential toincrease renal glucosuria and delay/reduce dietary glucose absorption,

albeit with a potential for diarrhea,bloating, and GI discomfort due to intes-tinal glucose/galactose malabsorption.Both sotagliflozin and canagliflozin havebeen associated with some intestinalSGLT1 inhibition, but neither is believedto have any meaningful renal SGLT1 in-hibition. Hence, it is not currently knownwhat the efficacy and safety profilewould be for a dual inhibitor that alsoprovides renal SGLT1 inhibition.

In clinical studies, sotagliflozin hasbeen shown to improve glycemia with-out any clinically significant increase inGI side effects. As monotherapy in T2D,sotagliflozin 150/300 mg once daily for28 days lowered placebo-subtractedFPG by 39 and 55 mg/dL and HbA1c by0.66 and 0.76%, respectively, in patientswith baseline HbA1c 8.1% (31). Of note,in another study, sotagliflozin 400 mgQD in combination with metforminresulted in greater reductions in FPGand HbA1c compared with sotagliflozin200 mg QD despite similar amounts ofUGE (32). This suggests that part of theefficacy with 400 QD is through SGLT1inhibition in the GI tract.

The 300-mg dose of canagliflozin alsohas transient intestinal SGLT1 inhibitionand reduces postprandial PG excur-sions in the meal after dosing in bothhealthy subjects and subjects withT2D (14,33,34) through a non-UGE-associated mechanism. This additionaleffect on postprandial glucose is postu-lated to be due to transient proximalintestinal SGLT1 inhibition.

Effects of SGLT2 Inhibitors in Type 1DiabetesCurrently, SGLT2 inhibitors are not ap-proved in type 1 diabetes (T1D). How-ever, given their insulin-independentmechanism of action, there is potential

Table 1—Summary of the most advanced SGLT2 inhibitor compounds (refs. 28–31)

CompoundSGLT2 IC50(nmol/L)

SGLT1 IC50(nmol/L)

SGLT2/SGLT1selectivity

Highest approveddose (mg)a Status

Canagliflozin 4.2 663 160 300 Approved in U.S., EU, Japan, other countries

Dapagliflozin 1.2 1,400 1,200 10 Approved in U.S., EU, Japan, other countries

Empagliflozin 3.1 8,300 2,700 25 Approved in U.S., EU

Ipragliflozin 5.3 3,000 570 50 Approved in Japan

Luseogliflozin 2.3 3,990 1,770 5 Approved in Japan

Tofogliflozin 6.4 12,000 1,875 20 Approved in Japan

Ertugliflozin 0.9 1,960 2,200 25 Phase 3

LX-4211 (sotagliflozin) 1.8 36 20 400 Completed phase 2

aHighest approved dose or the highest dose still in development for compounds that have not yet been approved.

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to use these agents in T1D. In small pilotstudies, use of SGLT inhibitors in addi-tion to insulin increased UGE and mod-estly improved glycemia and bodyweight with lower insulin doses, less glu-cose variability, and no increase in hypo-glycemia (35–37). Longer-term studiesare in progress to characterize the effi-cacy and importantly the safety of theseagents, especially regarding potential de-velopment of diabetic ketoacidosis (DKA).

Metabolic, Renal, Cardiovascular, andGI Effects of SGLT InhibitorsIn addition to lowering PG by increasingUGE, SGLT2 inhibitor treatment is asso-ciated with additional metabolic, reno-vascular, GI, and cardiovascular effects.

Insulin Secretion

Consistent with the improvements inb-cell function observed in rats treatedwith phlorizin, improvements in mea-sures of b-cell function have been ob-served in patients with T2D treatedwith SGLT2 inhibitors. Improvementsin model-based measures of b-cell glu-cose function obtained from mixed-meal tolerance tests were observed insubjects treated with empagliflozin(38) and canagliflozin (39). These im-provements were observed within thefirst day of treatment (38) and withtreatment of 6–12 months (39). Withuse of the frequently sampled intrave-nous glucose tolerance test method, nu-merical improvements were observed inthe acute insulin response to glucose insubjects treated with dapagliflozin for3months, although the increase relativeto placebo did not reach statistical sig-nificance (P = 0.06). Longer studies areneeded to assess whether SGLT2 inhib-itors slow the progressive decline inb-cell function that occurs in diabetes.

Peripheral Insulin Sensitivity

Improvements in peripheral insulin sen-sitivity have also been observed in pa-tients treated with SGLT2 inhibitors. Intwo hyperinsulinemic-euglycemic clampstudies ranging from2weeks to 3monthsafter treatment with dapagliflozin, in-creases in glucose disposal rate of;15–20% occurred relative to placebo(40,41). With use of mixed-meal toler-ance test–based measurements of insu-lin sensitivity in patients treated withempagliflozin and canagliflozin, numeri-cal increases in insulin sensitivity mea-sures were observed in multiple studies(38,39), although the changes did not

always reach statistical significance.Potential mechanism(s) leading to im-proved insulin sensitivity include amelio-ration of glucotoxicity and body weightreduction.

Endogenous Glucose Production

Treatment with SGLT2 inhibitors in-creases endogenous glucose production(EGP). EGP increased after a single doseof canagliflozin in healthy subjects (14)and increased by ;17–25% after singleand multiple doses of empagliflozin anddapagliflozin in patients with T2D(38,41). Despite this increase in EGP,SGLT2 inhibitors still lower fasting andpostprandial glucose and improveglycemia in T2D patients. Although anincrease in EGP appears paradoxical, itis possible that this is a physiological re-sponse to counter the acute glucosuriceffect of SGLT2 inhibition. Notably, in theabove studies, increases in plasma gluca-gon and decreases in plasma insulinwere observed, leading to an increasedglucagon-to-insulin ratio that may be re-sponsible for the observed EGP increase.Recent work documenting expression ofSGLT1/2 in humanpancreatica-cells sug-gests that SGLT2 inhibitors may act di-rectly on these cells to increase glucagonsecretion (42). Preliminary studies indi-cate that combining an SGLT2 inhibitorwith a DPP-4 inhibitor blunts the gluca-gon increase seen with SGLT2 inhibitormonotherapy and further improves gly-cemic control (43). However, it is notknown whether the combination ofSGLT2 inhibitors with GLP-1 receptoragonists blunts the increase in EGP.

Body Weight/Body Composition

Increased UGE with SGLT2 inhibition re-sults in caloric loss and osmotic diuresisleading to transient fluid loss that appearslargely attenuated with sustained treat-ment (44). Both processes can lead toweight loss, particularly during the earlytreatment period. In patients treatedwith SGLT2 inhibitors, a progressive reduc-tion in body weight is typically observedover the first 12–26 weeks, followed bymaintenance of the reduced body weightwith minimal further reduction after 26weeks. In the phase 3 clinical studies,SGLT2 inhibition typically provided meanplacebo-subtracted weight loss of;2–5%(;1.5–6 kg) (45–47).

While fluid loss may contribute tothe initial weight loss with SGLT2 in-hibitor treatment, the majority of the

steady-state weight loss appears tobe due to fat loss. In studies with DEXAmeasurement of body composition,;70% of weight loss was attributed tofat and numerically greater reductionsoccurred in visceral compared with sub-cutaneous adipose tissue (48,49). In-terestingly, treatment with empagliflozinor dapagliflozin also shifted substrateutilization from carbohydrate to lipidmetabolism (38,39).

Renovascular Effects of SGLTInhibitorsIn addition to increasing UGE, inhibitingSGLT2-mediated renal glucose and so-dium reabsorption leads to changes influid balance, blood pressure, and renalfunction.

Urine Volume

Although the magnitude of UGE is gen-erally sustained with continued treat-ment, the increases in urine volumeappear to be largely attenuated aftermultiple dosing. No significant changesin urine volume were noted after 2 or12weeks of treatmentwith canagliflozin(44) or after 4 weeks of treatment withempagliflozin (50) in phase 1 studies,and only modest increases in mean dailyurine volume (;100–500 mL/day) werereported with SGLT2 inhibitors in phase3 studies (45–47).

Plasma Volume

Given the mechanism of action of SGLT2inhibitors to produce osmotic diuresis,it is expected that therewould be changesin plasma volume. In a 12-week studywith dapagliflozin, plasma volume wasmeasured in a subset of subjects using125I-labeled human serum albumin. After12 weeks’ treatment, median plasma vol-ume decreased by;7% with dapagliflozincompared with an increase of 5% withplacebo. However, these results werebased on a small sample size of 8–10subjects/group (51). In a 12-week studywith canagliflozin in patients with T2D,plasma volume measured using indocyaninegreen dilution decreased ;10% com-pared with placebo after 1 week oftreatment, and this effect was largelyattenuated with sustained treatment(44). In phase 3 clinical studies, volume-related adverse events were generallyhigher in the SGLT2 inhibitor groups, par-ticularly in elderly subjects, those withlow estimated glomerular filtration rate(eGFR), or those on diuretics (especiallyloop diuretics).

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Glomerular Filtration Rate

Since SGLT2 inhibitors cause osmotic di-uresis and small reductions in plasmavolume and blood pressure, it is im-portant to document their effects onrenal function (Table 2). In the studywith dapagliflozin in patients with mod-erate renal impairment (52), meaneGFR and creatinine clearance fell by;3–5 mL/min/1.73 m2 after 1 week oftreatment but stabilized thereafterthrough 104 weeks of therapy, whereasthese parameters slowly declined in theplacebo group. Similar changes havebeen seen with canagliflozin where thereductions in eGFR were largest at week3 (the first postbaseline measurement)and trended back toward baseline overthe 26-week treatment period (53). Sim-ilarly, with empagliflozin treatment inpatients with stage 2, 3, or 4 chronickidney disease (CKD), initial small de-creases in eGFR returned to baselineby the end of the 3-week follow-up aftertreatment completion at 52 weeks (54).The initial eGFR reduction with SGLT2inhibition may be related not only toantihypertensive and diuretic effectsbut also to increased tubulo-glomerularfeedback (55).

Effects on Glycemia in Patients With CKD

With decreasing eGFR, there is lowerglycemic efficacy of SGLT2 inhibitorsdue to a lesser filtered load of glucose.In studies in patients with T2D andmod-erate renal impairment, SGLT2 inhibi-tion was associated with approximately a0.3–0.45% fall in HbA1c compared withbaseline (52–54). Thoughmodestcomparedwith placebo, these reductions reachedstatistical significance for canagliflozinandempagliflozinbutnot fordapagliflozin(where the placebo group experienced

an HbA1c decrease of 0.32%). Of note, inthe empagliflozin study, significant low-ering was only seen in patients withCKD2 and CKD3 but not in those withCKD4. Current clinical guidelines forSGLT2 inhibitor use in renal impairmentare listed in Table 3.

Hemoglobin and Hematocrit

Small increases in hemoglobin and he-matocrit are consistently seen in phase3 studies with SGLT2 inhibitors. Whilethese increases are consistent withsmall reductions in fluid volume, smallincreases in reticulocytes, erythropoie-tin, and red cell mass were reported in a12-week study with dapagliflozin (51),suggesting that changes in hematopoie-sis may contribute to changes in hemo-globin and hematocrit.

Electrolytes/Uric Acid

In clinical studies, changes in mean se-rum electrolytes were infrequent. Withdapagliflozin, there were no changesfrom baseline levels of mean serum so-dium, potassium, bicarbonate, calcium,or chloride at week 24 and up to102 weeks. There were small increasesin mean serum inorganic phosphorus lev-els from baseline (46). SGLT2 inhibitor useis associated with decreases in serum uricacid (56). Hyperuricemia is known to beassociated with an increased risk of gout,kidney stones, and cardiovascular disease.Whether lowering uric acid has beneficialeffects on renal or cardiovascular compli-cations will require evaluation in longer-term studies.

Renal Hyperfiltration and Diabetic

Nephropathy

Glomerular hyperfiltration is an early re-nal hemodynamic abnormality reflect-ing increased intraglomerular pressure.

Studies suggest that in hypertensive sub-jects with T2D with normo- or microal-buminuria, persistent hyperfiltration isan independent risk factor for accelera-ted renal function loss and develop-ment or progression of nephropathy,whereas amelioration of hyperfiltrationis renoprotective (56). In a recent studyin patients with T1D and no macroalbu-minuria, treatment with empagliflozinfor 8 weeks improved HbA1c by 0.5%with lower insulin requirements andwas associated with a significant atten-uation of renal hyperfiltration (55). Theauthors concluded that although sev-eral factors may have contributed tothe decrease in glomerular filtrationrate to near-normal levels, they postu-lated that activationof tubulo-glomerularfeedback by empagliflozin made a sub-stantial contribution. They speculatedthat long-term SGLT2 inhibitor use couldbe renoprotective by reducing intraglo-merular pressure, thereby reducing therisk of developing overt diabetic ne-phropathy. Existing data from phase 3studies in patients with T2D and CKDshowmodest improvements in albumin-uria progression with SGLT2 inhibitortreatment compared with placebo(52–54). Long-term studies are beingconducted to determine whether theSGLT2 inhibitors retard/prevent the de-velopment and progression of diabeticnephropathy.

Cardiovascular Effects of SGLTInhibitors

Blood Pressure

SGLT2 inhibitor treatment is associatedwith reductions in blood pressure that arelikely attributable to both an osmoticdiuretic effect and weight loss. In a

Table 2—Changes in renal function with SGLT2 inhibitors (refs. 45–47)

Placebo

Canagliflozin (mg)

Placebo

Dapagliflozin (mg)

Placebo

Empagliflozin (mg)

100 300 5 10 10 25

n 90 90 89 84 83 85 87 90 89

eGFR (mL/min/1.73 m2)

Baseline 40.0 39.8 38.8 45.6 44.2 43.9 CKD2 71.8 CKD2 70.8 CKD2 72.3CKD3 44.3 NA CKD3 45.4CKD4 22.0 NA CKD4 24.4

Change from baseline to 6 months 21.4 23.6 23.9 20.25 22.38 24.80 NA NA NA

Change from baseline to 1 year NA NA NA 22.58 22.08 24.46 CKD2 20.71 CKD2 22.04 CKD2 22.47CKD3 20.3 CKD3 22.8CKD4 21.1 CKD4 21.4

Change from baseline to 2 years NA NA NA 22.38 21.71 23.50 NA NA NA

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prespecified pooled analysis of 12 placebo-controlled studies (46), treatment with da-pagliflozin 10mg for 24weeks resulted in asystolic blood pressure (SBP)/diastolicblood pressure change from baseline of24.4/22.1 mmHg vs. 20.9/20.5 mmHgwith placebo. Similar placebo-correctedchanges from baseline in SBP have beenseen with canagliflozin 100/300 mgof 23.7/25.4 mmHg and empagliflozin10/25 mg of 23.35/23.93 (45,47). In arecent meta-analysis of .50 studies,compared with other glucose-loweringagents, SGLT2 inhibitors reduced meanSBP by24.45 mmHg (57). Although thesechanges in blood pressure are favorable,longer-term studies are needed to deter-minewhether these changes are sustainedand, importantly, lead to lower cardiovas-cular morbidity and mortality.

Lipids

LDL cholesterol (LDL-C) is a major car-diovascular disease risk factor, andreduction of LDL-C is a primary compo-nent of cardiovascular disease risk re-duction strategies. SGLT2 inhibitortreatment is associated with small in-creases in LDL-C and HDL cholesterol.In long-term data over 2 years, the pla-cebo-subtracted increases in LDL-C withdapagliflozin, canagliflozin, and empa-gliflozin were ;5, 3, and 6 mg/dL in pa-tients with a baseline LDL-C of;103, 92,and 93 mg/dL, respectively. For HDLcholesterol, the placebo-subtracted in-crease from a baseline of ;47 mg/dLwas ;1, 0.6, and 3.5 mg/dL with dapa-gliflozin, canagliflozin, and empagliflo-zin, respectively (45–47).Data from the first cardiovascular out-

come study with an SGLT2 inhibitor wererecently reported and demonstratedthat empagliflozin treatment reduced a

composite measure of cardiovasculardeath, nonfatal myocardial infarction,and nonfatal stroke by 16% comparedwith placebo, with much of the benefitdriven by a 38% reduction in cardiovascu-lar death (58). Notably, reductions in therisks of death from cardiovascular causesand from any cause occurred early in thetrial, and these benefits continuedthroughout the study. Further researchis needed to understand the mecha-nisms responsible for the reduction incardiovascular events. Cardiovascularoutcome studies with canagliflozinand dapagliflozin are still ongoing(59,60) and will provide further infor-mation on the effects of SGLT2 inhibi-tors on cardiovascular outcomes.

GI Effects of Dual SGLT1/2 Inhibitors

Intestinal Glucose Absorption and Incretin/

PYY Secretion

Gut hormones (GLP-1, GIP) play an impor-tant role in glucose homeostasis. Growingevidence suggests that SGLT1 transportplays a role in entero-endocrine hormonerelease. In human studies, treatmentwith sotagliflozin increased GLP-1 andPYY levels after meals and reduced bloodGIP levels after breakfast in patients withT2D (31) and increased GLP-1 and PYY inhealthy subjects (61). Similar gut hormonechanges have been seen in healthysubjects after single 300-mg doses ofcanagliflozin (14). Transient effects onintestinal glucose absorption withcanagliflozin are believed to be due tolocally high intestinal drug concentra-tions occurring shortly after dosing.However, virtually all of the ingestedglucose is absorbed over a 6-h period.

There is a potential opportunity to com-bine dual SGLT1/2 inhibitors with DPP-4inhibitors based on their complementary

mechanisms of action. In a small pilotstudy, combination sotagliflozin and sita-gliptin treatment elevated active GLP-1levels after meals above levels achievedwith sitagliptin alone (62). Whether thiscombination results in greater glycemicbenefit remains to be determined.

Long-term Efficacy of SGLT2InhibitorsAt 208 weeks, in metformin-treated pa-tients, dapagliflozin compared with gli-pizide produced sustained reductions inHbA1c (20.30%), body weight (24.38 kg),and SBP (23.67) with lower hypoglycemiarates (5.4 vs. 51.5%). Of note, glycemiccontrol gradually deteriorated over timein both study arms but was slower withdapagliflozin. At 52 weeks, mean HbA1creduction was 0.5% and similar in botharms (baseline mean 7.7%). At 208 weeks,the HbA1c decrease from baseline was0.10 with dapagliflozin versus a 0.20% in-crease with glipizide (16).

Side Effects and Safety Profile

Urinary Tract and Genital Infections

SGLT2 inhibitor use is associated withincreased incidence of both urinarytract infections (UTIs) and genital tractinfections (GTIs) (45–47). UTIs occurredmore frequently in female patients, andmost diagnosed infections were mild/moderate and responded to standard an-timicrobial treatment. There was no in-crease in serious or upper UTIs. In thephase 3 studies, the incidence of UTIswas 4.0, 5.9, and 4.3% with placebo, can-agliflozin 100 mg, and canagliflozin 300 mg,respectively; 3.7, 5.7, and 4.3% with pla-cebo, dapagliflozin 5 mg, and dapagliflo-zin 10 mg, respectively; and 7.6, 9.3, and7.7% with placebo, empagliflozin 10 mg,and empagliflozin 25 mg, respectively.

Table 3—Dose adjustment with renal function when using SGLT2 inhibitors (refs. 45–47)

Drug

eGFR (mL/min/1.73 m2)

,30 30–45 45–60 .60

Dapagliflozin - Do not start drug - Do not start - Do not start drug - Start at 5 mg QD- D/C if on drug - D/C if on drug - D/C if on drug and eGFR

persistently ,60- Increase to 10 mg QD as neededto decrease glucose

Canagliflozin - Do not start drug - Do not start drug - Start at 100 mg QD - Start at 100 mg QD- D/C if on drug - D/C if on drug and eGFR persistently

,45- Do not increase dose - Increase to 300 mg QD as needed

to decrease glucose- If on 300 mg, decrease doseto 100 mg

Empagliflozin - Do not start drug - Do not start - Start at 10 mg and increase to25 mg QD as needed todecrease glucose

- Start at 10 mg and increase to25 mg QD as needed todecrease glucose

- D/C if on drug - D/C if on drug and eGFR ,45persistently

D/C, discontinued.

2350 Sodium–Glucose Cotransporter Inhibitors Diabetes Care Volume 38, December 2015

Most GTIs in the clinical studies weremild tomoderate and resolved spontane-ously or responded to standard antifungaltherapy. Infections rarely led to treat-ment discontinuation. A small minorityof patients experience recurrent events.In some studies, male genital mycotic in-fections occurred more commonly in un-circumcised males and those with a priorhistory of balanitis/balanoposthitis.These patients were more likely to expe-rience recurrent infections. In the phase 3studies, the incidence of female GTIs was3.2, 10.4, and 11.4% with placebo, cana-gliflozin 100mg, and canagliflozin 300mg,respectively; 0.9, 5.7, and 4.8% with pla-cebo, dapagliflozin 5 mg, and dapagliflo-zin 10 mg, respectively; and 1.5, 5.4, and6.4% with placebo, empagliflozin 10 mg,and empagliflozin 25 mg, respectively.The incidence of male GTIs was 0.6,

4.2, and 3.7%with placebo, canagliflozin100mg, and canagliflozin 300mg, respec-tively; 0.3, 2.8, and 2.7% with placebo,dapagliflozin 5 mg, and dapagliflozin10 mg, respectively; and 0.4, 3.1, and1.0% with placebo, empagliflozin 10 mg,and empagliflozin 25 mg, respectively.

DKA

Some cases of DKA have recently beenreported with SGLT2 inhibitor use in clini-cal practice (63–65). Many of these oc-curred in patients with T1D in whom thedrug was used off-label, although somecases have occurred in patients with T2D.In most cases, there were other contribut-ing factors including acute illness, infec-tions, reduced carbohydrate intake,missed insulin doses/pump failures, recentsurgery, and alcohol use. In several pa-tients the blood glucose level was lowerthan commonly seen in DKA and in rarecases in the euglycemic range. All patientsrecovered with intravenous fluids alongwith insulin and glucose infusions and dis-continuationof the SGLT2 inhibitor. Poten-tial mechanisms that may make patientstaking SGLT2 inhibitors more susceptibleto developing DKA include an increase inthe glucagon-to-insulin ratio, increasedfree fatty acids, a shift in substrate oxida-tion from carbohydrate to fat, and possiblyreductions in ketone body clearance (66).

Skeletal Effects

The SGLT2 inhibitors may potentiallyaffect calcium and phosphorus homeo-stasis leading to adverse skeletal ef-fects (67). In clinical studies, there have

been minimal changes in serum cal-cium, phosphorus, magnesium, 25-OH-vitamin D, and parathyroid hormonethat appear to be clinically insignificant.In a randomized, double-blind, placebo-controlled study, dapagliflozin treat-ment over 2 years did not affect markersof bone turnover or bone mineral den-sity in patients with T2D inadequatelycontrolled on metformin (48). In studieswith canagliflozin, there have been smallchanges in bone markers and bone min-eral density that appear to be clinicallyinsignificant (49). Of note, there is a nu-merical excess of bone fractures insome studies with canagliflozin anddapagliflozin (45,46). A more definitiveanswer to the deleterious effects ofSGLT2 inhibitors on bone should becomeavailable from the results of the largecardiovascular outcome trials currentlyin progress (58–60).

Hypoglycemia

Due to the insulin-independent mecha-nism of action of the SGLT2 inhibitors,hypoglycemia incidence rates are lowwith SGLT2 inhibitor use, except whenthey are used in combination with sul-fonylureas and insulin, the doses ofwhich may need to be lowered to avoidhypoglycemia (45–47).

Malignancies

In the preapproval clinical studies, therewas an excess of bladder cancers withdapagliflozin treatment. However, therewere too few cases to determine rela-tionship to the drug. Hence, until addi-tional data become available dapagliflozinshould not be used in patients with knownbladder cancer (46).

ConclusionsT2D is a chronic disease with significantmorbidity and mortality. The introduc-tion of SGLT2 inhibitors has provided aparadigm shift in diabetesmanagement.Glucosuria, once considered a manifes-tation of poor glycemic control, is nowbeing used to lower blood glucose lev-els. Increased glucosuria with SGLT2 in-hibition improves glycemia and leads tocaloric loss and modest weight reduc-tion, small decreases in blood pressure(mainly SBP), and a low incidence of hy-poglycemia. These properties have ledto the increasing use of these agents inclinical practice in combination withmetformin and other agents includ-ing insulin. The insulin-independent

mechanism of action of these agentsmeans that these drugs could also beof glycemic benefit in T1D. However, re-cent reports of DKA with SGLT2 inhibi-tors in T2D and in T1D with off-labeluse mandate further detailed study, es-pecially in T1D. Other side effects includean increase in the incidence of GTIs andin some studies a numerical excess ofUTIs and bone fractures. Dual SGLT1/2inhibition is also emerging as a viabletherapeutic option without an increasein GI symptoms associated with moreextensive SGLT1 inhibition. The potentialfor benefit due to the effects of SGLT1 ongut hormones remains to be deter-mined. The long-term implications ofincreased glucosuria in patients withdiabetes are not known. Early datasuggest that SGLT2 inhibition leads toincreased glucosuria and increased de-livery of sodium to the distal tubule,which may modulate tubulo-glomerularfeedback and reduce glomerularhyperfiltration. The benefits of such ef-fects require long-term studies that arein progress to evaluate the consequencesof SGLT2 inhibitors on cardiovasculardisease, a major contributor to diseaseburden in patients with diabetes.

Funding. This work was supported by a grantfrom theMedical Research Service, Departmentof Veterans Affairs, to R.R.H.Dualityof Interest. S.M. is on theadvisoryboardand speaker’s bureau and serves as a consultantfor AstraZeneca and has also received researchsupport paid to the Veterans Medical ResearchFoundation from Janssen Pharmaceuticals. D.P.is an employee of Janssen Research & Develop-ment, LLC, and B.Z. is an employee of RegeneronPharmaceuticals, Inc. R.R.H. is on the advisoryboard for AstraZeneca and is on the advisoryboard and serves as a consultant for BoehringerIngelheim and Janssen Pharmaceuticals.Author Contributions. S.M. and D.P. re-searched data and wrote the manuscript. B.Z.and R.R.H. researched data, contributed todiscussion, and reviewed and edited the man-uscript. All authors contributed to the compo-sition of the present version of the article andapproved the final version.

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