Sotagliflozin As a Potential Treatment for Type 2 Diabetes Mellitus

Expert Opinion on Investigational Drugs

ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20

Sotagliflozin as a potential treatment for type 2 diabetes mellitus

Bertrand Cariou & Bernard Charbonnel

To cite this article: Bertrand Cariou & Bernard Charbonnel (2015) Sotagliflozin as a potential treatment for type 2 diabetes mellitus, Expert Opinion on Investigational Drugs, 24:12, 1647-1656, DOI: 10.1517/13543784.2015.1100361

To link to this article: http://dx.doi.org/10.1517/13543784.2015.1100361

Published online: 07 Nov 2015.

Submit your article to this journal

Article views: 192

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieid20

Download by: [University of Otago] Date: 15 December 2015, At: 07:53 Drug Evaluation Sotagliflozin as a potential treatment for type 2 diabetes mellitus

† Bertrand Cariou & Bernard Charbonnel † 1. Introduction Clinique d’Endocrinologie, l’institut du thorax, CHU de Nantes, Nantes F-44000, France 2. Physiology of SGLTs Introduction: SGLT1 is the primary transporter responsible for the absorption 3. Overview of the market of glucose and galactose in the intestine, while SGLT2 and SGLT1 are both 4. Introduction to the compound involved in the renal reabsorption of glucose. SGLT2 inhibitors are a new 5. Pharmacodynamics class of oral antidiabetic drugs, acting by increasing urinary glucose excretion 6. Pharmacokinetics (UGE). They offer the advantages of a reduced risk of hypoglycaemia, a decrease in body weight and blood pressure and an efficacy at all stages of 7. Clinical efficacy type 2 diabetes (T2DM). 8. Safety Areas covered: Herein, the authors focus specifically on sotagliflozin 9. Conclusion (LX4211), the first-in-class dual SGLT1/SGLT2 inhibitor. Original publications 10. Expert opinion in English were selected as the basis of this review. Clinical trials were identified using the Clinicaltrial.gov database. Expert opinion: By a potential additional mechanism of action on intestinal glucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from SGLT2 inhibitors by reducing postprandial glucose excursion and insulin secretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on UGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 inhibitors on HbA1C reduction, with a similar safety profile in short-term studies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 development as an adjuvant treatment in patients with T1DM after positive results from a pilot study.

Keywords: intestine, kidney, SGLT1, SGLT2, type 2 diabetes, type 1 diabetes

Expert Opin. Investig. Drugs (2015) 24(12):1647-1656

1. Introduction

Type 2 diabetes mellitus (T2DM) is a progressive disease under the combined control of environmental and genetic factors. Hyperglycemia in T2DM results

Downloaded by [University of Otago] at 07:53 15 December 2015 from a combination of insulin resistance in several insulin target tissues (including liver, skeletal muscle and adipose tissue) and β-cell dysfunction.[1,2]The relative contribution of these two defects to the pathogenesis of diabetes is still a matter of debate, even while the gradual decline of β-cell function appears to be critical in the course of the disease.[3] Current available therapies to combat T2DM are centered on controlling blood glucose levels by increasing insulin secretion, improving insulin sensitivity, reducing hepatic glucose production and intestinal glucose absorption. During the last decade, new contributors to the pathophysiology of T2DM have emerged.[4]Thisisnotablythecaseforthe kidney that controls glucose homeostasis by the action of sodium-dependent glucose transporter 2 (SGLT2) in the proximal tubule that reabsorbs ≈90% of the filtered glucose load. Thus, one alternative therapy to control blood glucose in T2DM is to inhibit SGLT2 in the kidney.[5] As discussed more in detail below, the rapid pharmacological development of SGLT2 inhibitors has been encouraged by (i) the long known hypoglycemic effect of phlorizin, a non- selective inhibitor of SGLTs; (ii) the cloning of SGLT2 in 1992,[6]enablingin vitro studies for screening molecules; (iii) the genetic proof-of-concept for safety

of SGLT2 inhibition, with the characterization of patients composed of 12 members, including sodium cotransporters with familial renal glucosuria (FRG).[7] Since the seminal for sugar, myoinositol (SMIT1), iodide (symporter NIS), report demonstrating the hypoglycemic efficacy of SGLT2 short-chain fatty acids and choline. There are actually six inhibitor by Oku et al. in 1999,[8] several SGLT2 inhibi- human SGLTs: SGLT1, SGLT2, SGLT4, SGLT5, SGLT6 tors have been developed and some of them are available on and SMIT1.[12] SGLT3 acts not as glucose transporter the market (for review, see [5], [9]). The description of but as a glucose sensor.[9] It is important to notice here efficacy and safety profiles of each SGLT2 inhibitor in the that SGLTs are widely expressed, highlighting their phy- differentclinicaltrialsisbeyondthescopeofthisreview. siological importance in organs other than the intestine Here, we will specifically focus on sotagliflozin (also known and kidney. The most well-known functions of SGLTs as LX4211), which is a dual SGLT1/SGLT2 inhibitor and a concern the intestinal and renal glucose absorption, potential new oral anti-diabetic drug. which mainly involved SGLT1 and SGLT2, respectively. SGLT1 is the primary transporter responsible for the absorption of glucose and galactose in the intestine. The initial dogma states that this process occurs across mature 2. Physiology of SGLTs enterocytes in two stages: (i) the first is the uptake of glucose and galactose at the apical side (i.e., in the brush border 2.1. Biology of human sodium-dependent glucose membrane); (ii) the second is the exit of glucose from the transporters cell into the blood through GLUT2 localized at the basolat- There are two classes of glucose transporters involved in eral membrane. However, the precise role of GLUT2 in glucose homeostasis: the facilitated transporters or unipor- intestinal glucose absorption remains unclear since both ters (GLUTs) and the active transporters or symporters mice deficient for GLUT2 and patients with Fanconi– (SGLTs) (for review, see [10]). The energy for active Bickel syndrome caused by mutations in GLUT-2 have a glucose transport by SGLTs is provided by the sodium normal response to glucose tolerance test.[13,14] gradient across the cell membrane. The sodium gradient Interestingly, expressions of both SGLT1 and GLUT2 are is maintained by the Na+/K+ pump, which requires increased in intestinal biopsies of diabetic compared to non- energy (Figure 1). The intestinal sodium/glucose transpor- diabetic control subjects.[15] The underlying molecular ter SGLT1 was the first member of the human family mechanism for the up-regulation of SGLT1 in diabetes called SLC5, which was cloned in 1987.[11]SLC5is remains unknown.

AB INTESTINE KIDNEY

Basolateral Basolateral membrane membrane GLUT2, ? GLUT2 SGLT1 SGLT1/2 + Na+ Na

Glucose Glucose ? Downloaded by [University of Otago] at 07:53 15 December 2015

Glucose/ Glucose Glucose/ Glucose Galactose Enterocyte Galactose Proximal tubule + Na+ Na

+ + Na K Na K + + K K + + + + Na+/K+ Na /K pump pump Gut Lateral intercellular Glomerulus Lateral intercellular Blood space lumen Tight space filtrate Tight Blood Junction Junction

Figure 1. A model for glucose transport across enterocytes (A) and proximal tubule (B). Glucose transport across the epithelium occurs in two steps. (1) Glucose and galactose are absorbed within the enterocyte from the intestinal lumen by SGLT1 in the brush-border membrane. Glucose is transported across the apical membrane of the proximal tubule by SGLT2 (S1 & S2 segments) and SGLT1 (S3 segment). The Na+ electrochemical gradient provides the energy source for glucose transport: the 2 Na+ ions that enter the cells with each glucose molecule are pumped out across the basolateral membrane by the Na+/K+ pump. Sugar that accumulates within the cell exits across the basolateral membrane by glucose transporter into the blood. GLUT2 is the major glucose transporter in the kidney.

1648 Expert Opin. Investig. Drugs (2015) 24(12) Sotagliflozin as a potential treatment for type 2 diabetes mellitus

SGLT2 and SGLT1 are both involved in the renal reab- with aging.[20] Importantly, patients with GGM do not sorption of glucose. Glucose is filtered across the renal glo- have significant defect in renal glucose reabsorption.[10] − − merulus amounting to ≈180 g/day/1.73 m2 in adults. In In addition, SGLT1-deficient (SGLT1 / ) mice maintained healthy individuals, virtually all the filtered glucose is reab- on a diet containing glucose and galactose exhibited diar- sorbed into the circulation and the urine is free from glucose. rhea with unformed and watery stools, reduced food intake However, when the plasma glucose concentration exceeds and decreased body weight.[21] However, mice heterozy- ≈14 mM in pathological conditions such as diabetes, glucose gous for SGLT1 (SGLT1±) had normal stools on glucose appears in the urine and above 20 mM the excretion diet, with an enhanced incretin response (i.e., increased increases in proportion to the filtered load. Microperfusion glucagon-like peptide-1 (GLP-1) concentrations following experiments in rabbit kidney demonstrate that ≈90% of meal challenges) linked to an increased delivery of glucose glucose is reabsorbed in the “early” convoluted proximal to the enteroendocrine cells in the distal small intestine. tubule (S1 & S2 segments) via SGLT2 with high-capacity [21] Altogether these data suggest that partial pharmaco- (80 pmol/min/mm) and low-affinity (Km 2 mM) properties. logical inhibition of SGLT1 might have some beneficial The remaining ≈10% of glucose reabsorption is mediated in glycemic effects while avoiding severe gastrointestinal S3 segment of proximal tubule by SGLT1 with low-capacity disorders. (10 pmol/min/mm) and high-affinity (Km 0.5 mM) properties. The cellular mechanism of renal glucose absorption is similar to those observed for intestinal glucose absorption 3. Overview of the market with a two-step process (Figure 1). In contrast to what Pharmacological management of T2DM is based on a observed in small intestine, basolateral GLUT2 plays a cri- patient-centered approach, allowing personalization taken tical role in the reabsorption of glucose in the kidney since into account for each patient profile the benefits of glycemic patients with Fanconi–Bicker syndrome exhibit massive renal control vs. its potential risk (mainly hypoglycemia).[22] glucosuria, up to 200 g/day.[10] Currently available antidiabetic drugs attempt to correct the underlying pathophysiological dysfunctions leading to 2.2. What does the genetics tell us about SGLTs inhibition? T2DM such as insulin resistance for the insulin sensitizers The characterization of subjects with mutations in either (metformin and thiazolidinediones) and impaired insulin SGLT1 or SGLT2 provided very useful information for secretion for the insulin secretagogues (sulfonylureas, glinides validating the therapeutic strategies based on SGLT and more recently incretin-mimetics).[23] In advanced stages inhibition. of the disease, insulin therapy should be required (often in combination with oral antidiabetic drugs) for managing 2.2.1. SGLT2 inhibition: familial renal glucosuria hyperglycemia. FRG is a rare autosomal recessive disorder linked to muta- More recently, SGLT2 inhibitors have emerged as new tions in SGLT2 gene (SLC5A2).[7,16] Urinary glucose excre- class of oral antidiabetic drugs (for review, see [24]). The tion (UGE) ranges from 1 to 162 g/1.73/m2/day1. place of SGLT2 inhibitors in the pharmacological manage- Importantly, there are no other associated renal abnormalities ment of T2DM has been clarified in a recent update of the (kidney insufficiency), even after 20 years of follow-up.[17] position statement of the American Diabetes Association Finally, FRG are not accompanied by alterations in intestinal (ADA) and the European Association for the Study of Downloaded by [University of Otago] at 07:53 15 December 2015 absorption, validating the specificity of SLGT1 in this pro- Diabetes (EASD).[22] It is underlined that their potential cess. These genetics data are reassuring for SGLT2 inhibition advantages are related to their specific mechanism of action, as a therapeutic strategy in T2DM. which is independent of insulin, allowing their use at any stages of T2DM. In addition, SGLT2 inhibitors’ use is 2.2.2. SGLT1 inhibition: glucose galactose associated with a low risk of hypoglycemic events (except malabsorption when they were used in combination with an insulin secre- Glucose galactose malabsorption (GGM) is a severe disease tagogue), a moderate weight loss and a decrease in systolic leading to abundant and fatal diarrhea in newborn chil- and diastolic blood pressure.[24] Adverse events are related to dren unless lactose, glucose and galactose are removed genital mycotic infections, volume depletion, diabetic ketoa- from the diet.[18] A homozygous mutation in SGLT1 cidosis (DKA), increased urinary calcium excretion and, was first described in two sisters with GGM in 1991.[19] potentially, bone fractures.[24,25] The mutations are mainly missense, but nonsense, frame Three SGLT2 inhibitors are currently available on the shift, splice-site and promoter region mutations have been market in EU and US: canagliflozin (Invokana®; developed also reported.[10] Patients with GGM display intolerance by Janssen); dapagliflozin (Farxiga® in US and Forxiga® in to glucose and galactose, but they can live normally on a EU; developed by Bristol Myers-Squibb in partnership with sugar-free diet. The tolerance to carbohydrate-containing AstraZeneca); empagliflozin (Jardiance®; Boehringer diet seems to improve, at variable inter-individual level, Ingelheim and Eli Lilly). Two additional SGLT2 inhibitors

Expert Opin. Investig. Drugs (2015) 24(12) 1649 B. Cariou & B. Charbonnel

have been approved in Japan: ipragliflozin (Astellas Pharma) it should be underlined here that the IC50 for a competitive and tofogliflozin (Sanofi & Takeda). SGLT inhibitor is highly dependent on the glucose concen- Sotagliflozin (Lexicon) is a dual SGLT1/2 inhibitor, tration,[10] and that the selectivity of sotagliflozin for while KGA-2727 (Kissei) is a specific SGLT1 inhibi- SGLT2 over SGLT1 will increase with higher glucose con- tor.[26] centrations. Therefore, it will be critical to verify that this dual inhibition of SGLT1 and SGLT2 by sotagliflozin observed in vitro under controlled glucose concentrations 4. Introduction to the compound will translate in significant clinical differences compared to Sotagliflozin or LX4211 is an orally administered small SGLT2 inhibitors in diabetic patients. molecule (i.e., L-xyloside) developed by Lexicon Pharmaceuticals, Inc. (Princeton, NJ, USA), which acts as a 5.2. Pre-clinical studies dual SGLT1/SGLT2 inhibitor (see Drug summary box). Effects of sotagliflozin on glucose homeostasis have been [27,28] The molecular formula is C21H25ClO5S, with a assessed in mice.[30] As a prerequisite, it has been first molecular weight of 424.94. The chemical structures of demonstrated that sotagliflozin indeed acts as a dual sotagliflozin and SGLT2 inhibitors are shown in Figure 2. SGLT1/2 inhibitor in mouse with an IC50 of 62.0 nM Its development was based on the generation of several and 0.6 nM for SGLT1 and SGLT2, respectively. thousand strains of genetically modified mice. Indeed, it Sotagliflozin-treated mice showed a dose-dependent has been shown previously that mouse knockout phenotypes increase in plasma levels of total and active forms of the for selected target proteins correlate well with known drug incretin hormone GLP-1, as well as the satiety hormone efficacy.[29] As mentioned before, this approach allowed the peptide YY (PYY). This was accompanied by an increase of identification of partial inhibition of SGLT1 as a comple- gastrointestinal glucose levels in the distal small intestine mentary target of SGLT2 inhibition to lower blood glu- and caecum, suggesting that SGLT-1-mediated glucose cose.[21] absorption was inhibited by sotagliflozin. The reduced glucose absorption leads to a prolonged second phase of 5. Pharmacodynamics GLP-1 and PYY release by L-cells, which seems to be SGLT1-independent and could be mediated by short- 5.1. In vitro pharmacodynamics chain fatty acids produced by cecal fermentation of unab- In vitro studies in HEK293 cells overexpressing human sorbed glucose.[30] In parallel to these intestinal effects, SGLT2 and SGLT1 demonstrate that sotagliflozin inhibits sotagliflozin also significantly increased UGE, linked to SGLT2 with an IC50 of 1.8 nmol/l and SGLT1 with an IC50 SGLT2 inhibition. Altogether, these effects were associated of 36 nmol/l. Therefore, sotagliflozin is a dual inhibitor of with reduced postprandial glucose excursions after a meal SGLT1 and SGLT2 with ≈20-fold selectivity for SGLT2 test.[30] These findings are in accordance with previous over SGLT1, compared to 132 for canagliflozin and 144 study demonstrating an increased postprandial GLP-1 for dapagliflozin in the same conditions.[27,28] However, secretion in diabetic rats treated with another selective SGLT1 inhibitor: KGA-2727.[26] Sotagliflozin also improved glucose homeostasis in KKAy Drug summary mice, a rodent model of T2DM.[31] Sotagliflizin increased Downloaded by [University of Otago] at 07:53 15 December 2015 UGE dose-dependently, lowered HbA1C and glucose excur- Drug name: sotagliflozin (LX4211) sion after an oral glucose tolerance test, while increasing Phase: IIa/b plasma insulin levels at 30 min. The pancreatic insulin con- Indication: type 2 diabetes, type 1 diabetes tent was significantly increased in sotagliflozin-treated KKAy Pharmacology: Dual SGLT1/SGLT2 inhibitor mice. Sotagliflozin has a neutral effect on body weight since Route of administration: oral the energy lost linked to UGE is counterbalanced by a dose- Chemical structure: dependent increase in food intake.[31] Very recently, a study in NOD mice with established type 1 diabetes mellitus (T1DM) demonstrated that the combination of sotagliflozin with low insulin dose (0.05 UI/day) achieved comparable glycemic control to a high insulin dose (0.2 UI/day) alone, but with less hypoglycemic episodes.[32]

5.3. Phase 1 studies in healthy volunteers In healthy subjects, the maximum 24 h UGE was 44 g Pivotal trials: [37], [39], [41], [44] when sotagliflozin was administered as a single 300 mg

1650 Expert Opin. Investig. Drugs (2015) 24(12) Sotagliflozin as a potential treatment for type 2 diabetes mellitus

Figure 2. Chemical structures of non-selective SGLTs (phlorizin), selective SGLT2 (canagliflozin, dapagliflozin, empagliflozin, ipragliflozin) and dual SGLT1/SGLT2 inhibitor.

dose. Further increasing the dose did not provide additional with sotagliflozin. In contrast, sotagliflozin dose must be increase of UGE despite increased systemic exposure of taken before breakfast (i.e., the first meal of the day) rather sotagliflozin.[28,33] After multiple dosing of 300 mg/day, than before subsequent meals in order to maximize its the maximum UGE was 36 g,[28,33]whichislessthan effect on SGLT1 inhibition.[33] those observed with selective SGLT2 inhibitors: 62 g for dapagliflozin [34], 70 g for canagliflozin [35]and74gfor empagliflozin.[36] This reduction in 24 h-UGE could be 6. Pharmacokinetics either due to lesser inhibition of SGLT2 because sotagli-

Downloaded by [University of Otago] at 07:53 15 December 2015 flozin has lower systemic exposure compared to the other Pharmacokinetics of sotaglifozin has been assessed in phase 1 gliflozins, or due to reduced plasma glucose levels through- trial conducted in healthy subjects. The maximum plasma out the day due to the additional SGLT1 inhibition with concentration of sotagliflozin at day 7 after multiple-dose less glucose available to be filtered and spilled into the administration was 165 ng/ml and the pharmacokinetic urine. half-life (t1/2) of the product was 29 h, supporting once- Because systemic exposure with sotagliflozin is insuffi- daily dosing.[28] Sotagliflozin is rapidly absorbed with cient to inhibit SGLT1, intra-luminal inhibition of intest- detectable plasma concentration ≈15 min after drug intake, inal SGLT1 is assessed empirically by measuring the with approximately 70% of the drug that was absorbed. release of GLP-1 and PYY following a standardized meal. Plasma levels decline in a biphasic pattern, with a rapid [33] Treatment with sotagliflozin resulted in significant distribution phase and a slower terminal elimination phase. increase of total and active GLP-1, and PYY concentra- Sotagliflozin is mainly eliminated in the urine in a glucur- tions, while decreasing postprandial glucose excursion onide form, with additional elimination in the feces as compared to placebo.[33] Different dosing schedules (var- unchanged component. In patients with T2DM, orally ious times before breakfast and lunch) were tested and it given sotagliflozin was quickly detected in the plasma (i.e., was established that dose timing is not critical for max- within 15 min), with a maximum plasma drug concentration imizing the pharmacodynamic effect of SGLT2 inhibition at 0.5–2.0 h after dosing (230–307 ng/ml) in the 300 mg

Expert Opin. Investig. Drugs (2015) 24(12) 1651 B. Cariou & B. Charbonnel

group.[37] The steady state was achieved between day 7 and HbA1C reduction for sotagliflozin. Indeed, there was a ≈ day 14, and the t1/2 was 13.5 ± 5.3 h in the 300 mg group. plateau of UGE reached at the 200 mg qd dose ( 60 g/ For more details, please see [37]. day), despite a dose-proportional increase in systemic exposure to sotagliflozin with the higher dosages. In contrast, the dose relationship to HbA1C reduction was quite different 7. Clinical efficacy with an increased efficacy between 200 mg qd and 400 mg qd dosages (−0.52% vs. −0.91%). These results The efficacy and safety of sotagliflozin have been assessed in suggest that SGLT2-mediated hypoglycemic effect peaked phase 1 and phase 2 trials in different populations of at 200 mg qd, while SGLT1-mediated effects increased with patients. higher dosages. However, dose relationship to GLP-1 secretion was not assessed in this study to confirm this 7.1. Sotagliflozin in patients with T2DM hypothesis. Besides its hypoglycemic efficacy, sotagliflozin significantly The first clinical trial reported in the literature is a 28-day ≈ randomized, placebo-controlled trial with sotagliflozin 150 or reduced body weight with mean loss of 2 kg and systolic 300 mg once daily in patients with T2DM, either drug naive blood pressure (SBP) by 6 mmHg in the 400-mg dose or under metformin therapy.[37] Sotagliflozin decreased pla- group.[39] In the 12-week study, there were no significant cebo-subtracted fasting plasma glucose (FPG) values by 39 differences in HDL, LDL or triglycerides in sotagliflozin and 55 mg/dl in the 150- and 300-mg dose arms, respec- group,[39] while a significant reduction of TG was pre- tively. Glucose tolerance assessed by the area under the curve viously observed in the 28-day study.[37] of a 4-h 75-g oral glucose tolerance test was significantly reduced by 38% and 39% with sotagliflozin 150 and 7.2. Sotagliflozin in patients with T2DM and renal 300 mg, respectively. This translated into a significant pla- impairment cebo-subtracted HbA1C reduction of 0.66% and 0.76% in It is well known that SGLT2 inhibitors display reduced 150- and 300-mg dose groups, respectively. Mechanistically, efficacy in patients with T2DM and chronic kidney disease sotagliflozin induced a quick and dose-dependent increase in (CKD), due to reduced kidney filtration of glucose.[40] UGE with a peak on day 1 (44 and 65 g/day in 150- and Since sotagliflozin doesn’t exclusively target the kidney, it 300-mg dose groups) and a slow decline at day 28 (37 and could be hypothesized that a significant hypoglycemic effi- 48 g/day), probably because of improved glycemic control in cacy linked to SGLT1 inhibition might be observed in this sotagliflozin-treated patients with less quantity of glucose population. A short-term (7 days) proof-of-concept study was filtered in urine. The effect of sotagliflozin on SGLT1 was conducted with sotagliflozin (400 mg) in T2DM patients assessed by measuring GLP-1 secretion following meal tests with CKD.[41] In 15 patients with an estimated glomerular in a sub-study conducted in 12 patients with T2DM.[37] filtration rate (eGFR) <45 mL/min/1.73 m2 at baseline, the Sotagliflozin, 300 mg, resulted in significant elevations of reduction of UGE with sotagliflozin was attenuated, as total and active GLP-1 as well as PYY between 0 and 13 h expected (20 g/24 h). However, sotagliflozin significantly (which encompassed the three scheduled meals). In parallel, reduced post-prandial glucose increment following a standar- plasma glucose and insulin were significantly reduced in dized mixed meal compared to placebo (p = 0.001; primary sotagliflozin group, whereas plasma glucagon did not vary. end point), potentially linked to the concomitant increase in Downloaded by [University of Otago] at 07:53 15 December 2015 The stimulation of GLP-1 secretion suggests that the combi- total and active GLP-1. Sotagliflozin also decreased placebo- nation of sotagliflozin with DPP4 inhibitors could be syner- subtracted FPG by 27.3 mg/dl (p < 0.001). An additional gistic on glucose control. A single-dose, cross-over study was significant reduction of SBP of 10.2 mmHg was seen in conducted in 18 patients with T2DM with either sotagliflo- sotagliflozin group. Altogether, these results indicate that zin (400 mg), sitagliptin (100 mg) or a combination of both. SGLT1 inhibition achieved by sotagliflozin is clinically rele- [38] Combination treatment was associated with a significant vant in this population. increase in active GLP-1 over that resulting from either monotherapy. A 12-week dose ranging study of sotagliflozin (75 mg qd, 7.3. Sotagliflozin in patients with type 1 diabetes 200 mg qd, 200 mg bid, 400 mg qd) in patients with The potential interest of SGLT2 inhibitors in T1DM is T2DM under metformin therapy (mean HbA1C at base- currently tested in several pilot studies.[42,43]Sincepost- line: 8.1%) has been recently published.[39] Sotagliflozin prandial insulin levels were found to be reduced by sota- decreased HbA1C in dose-dependent manner with a max- gliflozin in healthy volunteers,[33] a 29-day randomized, imum reduction of −0.83% (placebo-subtracted) in the double-blind, placebo-controlled pilot study has been con- 400 mg qd group. FPG was also reduced by 29 mg/dl at ducted with sotagliflozin 400 mg qd in 33 patients with the 400 mg qd dose. Interestingly, this study clearly demon- T1DM.[44] The primary end point was the change of strated a dissociation in the dose relationships to UGE and total daily bolus insulin dose from day 0 to day 29. The

1652 Expert Opin. Investig. Drugs (2015) 24(12) Sotagliflozin as a potential treatment for type 2 diabetes mellitus

mean HbA1C at baseline was ≈8.0% with 0.6 UI/kg total 9. Conclusion insulin dose. Bolus insulin dose was reduced by 32.1% from baseline in sotagliflozin group (p = 0.007), compared Sotagliflozin is the first-in-class drug acting as a dual SGLT1/ to 6.4% in placebo group. This was accompanied by a 2 inhibitor. The interest of partial inhibition of SGLT1 has lower mean daily glucose assessed by continuous glucose been suggested by preclinical data obtained in vivo in +/− monitoring (148.8 md/dl vs. 170.3 mg/dl; p = 0.01) and a SGLT1 mice. Results from phase 1 and phase 2 clinical significant reduction in HbA1C (−0.55% vs. −0.06%; trials have demonstrated that dual inhibition of SGLT1 and p = 0.002) in sotagliflozin, compared to placebo group. SGLT2 with sotagliflozin leads to postprandial glucose CGM analyses indicated that the percentage of time in reduction, stimulated GLP-1 and PYY secretion and target glucose range 70–180 mg/dl was significantly higher increased UGE. Altogether, these effects lead to significant with sotagliflozin compared to placebo (68.2% vs. 54.0%; reductions of HbA1C in patients with T2DM in combina- p = 0.003). There was also a numeric decrease in percent tion with metformin, as well as in patients with T2DM and time below 70 mg/dl in both the sotagliflozin and placebo CKD. Finally, pilot study suggests that sotagliflozin might groups. Body weight decreased (1.7 kg) with sotagliflozin improve glycemic control and reduce bolus insulin doses in compared with a 0.5 kg gain (p = 0.005) in the placebo subjects with T1DM. group. 10. Expert opinion 8. Safety The development and the commercialization of SGLT2 inhi- To date, it is difficult to have a clear idea about the safety of bitors have opened new perspectives for the pharmacological sotagliflozin since the duration of published clinical trials is management of T2DM. As underlined in the ADA/EASD short, with a maximum of 12 weeks. Thus, additional long- position statement paper, this class offers the advantages of a term studies are needed to state about the benefit-risk ratio of reduced risk of hypoglycemia, a decrease in body weight and this SGLT1/SGLT2 dual inhibitor. Based on phlorizin experi- blood pressure and an efficacy at all stages of T2DM.[22] ence, the major safety concern is gastrointestinal disorders Major side effects of SLGT2 inhibitors include genital myco- related to SGLT1 inhibition. In the recent study performed tic infection and volume depletion. In the absence of head- in patients with T2DM on metformin therapy, the proportion to-head trials, the efficacy and safety profiles of the three of patients with any gastrointestinal adverse events was 22% commercially available SGLT2 inhibitors (i.e., dapagliflozin, and 20% in sotagliflozin and placebo groups, respectively.[39] canagliflozin and empagliflozin) can be considered identical. It is also reassuring to observe that even at the dosage of One known limitation of these drugs is their decreased 400 mg qd daily, the proportion of diarrhea was similar to efficacy in subjects with CKD (eGFR < 45 ml/min), due to those observed in placebo group (8.5% vs. 6.7%; n = 5 vs. 4 their kidney-targeted action.[40] While SGLT2 use is often episodes).[39] Occurrence of nausea seemed to be higher in associated with a reversible increase in serum creatinine, sotagliflozin 400 mg qd compared to placebo in the dose recent data suggest that SGLT2 inhibition could be benefi- ranging study (10.2% vs. 5.0%; n = 6 vs. 3 episodes), poten- cial for diabetic nephropathy progression.[40,46] There are tially linked to the increase of GLP-1.[39] also some potential safety signals with SGLT2 inhibitors that Since SGLT2 inhibition with sotagliflozin is weaker than require additional information. This is the case from the Downloaded by [University of Otago] at 07:53 15 December 2015 those with selective SGLT2 inhibitors, it might be expected effects on lipid metabolism, with an undesirable modest that adverse events related to genitourinary infections occur at a (≈5–10%) increase in plasma LDL-C, which occurs by a lower frequency. There were indeed very few episodes of vulvo- still unknown mechanism. Importantly, the cardiovascular vaginal infection (<2%) and the frequency of urinary tract outcome trial (CVOT) EMPA-REG has just been demon- infection occurred at a similar rate than in placebo group.[39] strated that the use of empagliflozin in addition to standard Finally, they were no cases of hypoglycemia in T2DM care in patients with T2DM, and high cardiovascular risk patients under a combination of sotagliflozin and metformin. significantly decreases both cardiovascular and overall mor- In patients with T1DM, sotagliflozin use was associated talities by 38% and 32%, respectively.[47] The other CVOT with increased frequency of nausea compared to placebo with either dapagliflozin (DECLARE) or canagliflozin (n = 3 vs. 1), without any difference for hypoglycemic events (CANVAS) are ongoing.[48] As mentioned before, there is and genito-urinary infections.[44] Of note, two cases of also an ongoing follow-up of upper-limb fractures of patients DKA, a rising concern for SGLT2 inhibitors,[45] have on canagliflozin, due to an imbalance in reported case in been reported in patients with T1DM using continuous clinical trials.[22,25] Finally, the FDA has warned in May glucose infusion with pump.[44] 2015 that SGLT2 inhibitors may increase the risk of Clearly, trials of longer duration are required to have a DKA.[49] Of note, such DKA was not always accompanied precise picture regarding the safety of sotagliflozin compared by hyperglycemia, causing a delay in diagnosis.[45] However, to the commercially available SGLT2 inhibitors. a recent report from the canagliflozin type 2 diabetes clinical

Expert Opin. Investig. Drugs (2015) 24(12) 1653 B. Cariou & B. Charbonnel

program indicates that the incidence of such DKA is very the rate of genito-urinary infection is lower compared to low: 0.763 patient-years for canagliflozin 300 mg.[50] SGLT2 inhibitors. In the same way, it seems that sotagli- As the first claimed dual SGLT1/SGLT2 inhibitor, sota- flozin does not increase glucagon secretion [37] nor LDL-C gliflozin opens new perspectives compared to selective [37,39], potentially because of weaker SGLT2 inhibition. It SGLT2 inhibitors. By its mechanism of action on intestinal has been recently demonstrated that SGLT2 inhibitors glucose absorption, sotagliflozin might differentiate from directly act on α-cells to stimulate glucagon secretion,[54] SGLT2 inhibitors by reducing postprandial glucose excursion leading to an increase in hepatic glucose production.[55] and insulin secretion, as well as by increasing GLP-1 secre- This neutral effect of sotagliflozin on glucagon signaling tion (Figure 3). The first target population from sotagliflozin should be confirmed in clamp studies and could be linked is patients with T2DM. Despite a weaker effect on UGE either to partial SGLT2 inhibition or to SGLT1-mediated than selective SGLT2 inhibitors, sotagliflozin seems to be at increase in GLP-1. On the other hand, additional safety least as effective than canagliflozin, dapagliflozin or empagli- concerns may rise due to SGLT1 inhibition. Indeed, flozin with a 3-month placebo-subtracted HbA1C reduction SGLT1 is widely expressed and its function in some tissues of 0.83%, 0.72%, 0.67% and 0.70%, respectively,[39,51– (heart, muscle, pancreas, etc.) remains largely unknown.[10] 53] although this needed to be confirmed in further head to Of note, systemic exposure with sotagliflozin at the doses head trials. Based on the synergistic action of SGLT1 and studied in diabetes seems to be insufficient to inhibit sys- DPP-4 inhibition on GLP-1 activity,[38] the combination of temic SGLT1.[37] However, deciphering these new func- sotagliflozin with DPP-4 inhibitors appears an interesting tions of SGLTs is important not only for improving our option. One clinical situation in which sotagliflozin could knowledge in the pathophysiology of glucose homeostasis be superior to selective SGLT2 inhibitors is CKD since but also to monitor the safety of SGLTs inhibitors. SGLT1 inhibition seems to compensate the reduced efficacy Finally, pilot studies suggest that SGLT2 inhibitors could be of SGLT2 inhibition.[41] This needs to be proven in longer used as adjuvant treatment in patients with T1DM in addition trials, with a concomitant assessment of the effect of sotagli- to insulin therapy. One limitation for their use in this popula- flozin on eGFR and albuminuria. tion is certainly the risk of euglycemic DKA. Potential under- The specific pharmacodynamic properties of sotagliflozin lying mechanisms could be an increase of glucagon secretion could impact its safety profile compared to those of SGLT2 leading to increased ketogenesis and/or a decrease of renal inhibitors. Since UGE increases in a weaker extent with clearance of ketone bodies, as previously described with phlor- sotagliflozin, it would be interesting to determine whether izin.[56] Although sotagliflozin appears more potent than selective SGLT2 inhibitors in T1DM, it is critical to carefully assess the risk of DKA in the ongoing phase 3 trials. Sotagliflozin is a promising new drug for the management of both T2DM and T1DM, which at this time is only being developed for management of T1DM. However, the clinical data are currently limited to short-term studies and there are some safety issues that need to be clarified with this new class. In addition, the effects on both microvascular and macrovascular complications need to be assessed in dedicated studies. Downloaded by [University of Otago] at 07:53 15 December 2015 Declaration of interest

B Cariou has taken part in the advisory panels for and has received research support from Novo Nordisk A/S, Sanofi Aventis. He has also attended advisory boards for Amgen Inc., AstraZeneca, Genfit, Janssen Pharmaceuticals, Eli Lilly and Company, Novo Nordisk A/S and Sanofi Aventis. His co-author B Charbonnel has received fees for consultancy, Figure 3. Hypoglycemic action of SGLT1/SGLT2 inhibitor speaking, travel and accommodation from AstraZeneca, sotagliflozin. Sotagliflozin decreases intestinal glucose Janssen Pharmaceuticals, Eli Lilly and Company, Merck absorption via inhibition of SGLT1, leading to a stimulation of both GLP-1 and PYY by enteroendocrine L-cells in distal Sharp and Dohme, Novartis, Novo Nordisk A/S, Roche, small intestine and a reduction of post-prandial glucose Sanofi Aventis and Takeda. The authors have no other (PPG) levels. In parallel, SGLT2 inhibition (and in a lesser relevant affiliations or financial involvement with any orga- extent SGLT1 inhibition) by sotagliflozin in kidney increases nization or entity with a financial interest in or financial urinary glucose excretion (UGE). This dual effect ultimately conflict with the subject matter or materials discussed in results in HbA1C reduction. the manuscript apart from those disclosed.

1654 Expert Opin. Investig. Drugs (2015) 24(12) Sotagliflozin as a potential treatment for type 2 diabetes mellitus

References 1. Kahn CR. Insulin action, diabetogenes, the endoplasmic reticulum. Proc Natl Acad the Study of Diabetes (EASD). and the cause of type II diabetes (Banting Sci USA. 2001;98:11330–11335. Diabetologia. 2015;58:429–442. – Lecture). Diabetes. 1994;43:1066 1084. 14. Santer R, Groth S, Kinner M, et al. The 23. Charbonnel B, Cariou B. Pharmacological 2. Saltiel AR, Kahn CR. Insulin signalling mutation spectrum of the facilitative glu- management of type 2 diabetes: the and the regulation of glucose and lipid cose transporter gene SLC2A2 (GLUT2) potential of incretin-based therapies. metabolism. Nature. 2001;414:799–806. in patients with Fanconi-Bickel syndrome. Diabetes Obes Metab. 2011;13:99–117. – 3. UK Prospective Diabetes Study Group. Hum Genet. 2002;110:21 29. 24. Tahrani AA, Barnett AH, Bailey CJ. SGLT UK prospective diabetes study 16. 15. Dyer J, Wood IS, Palejwala A, et al. inhibitors in management of diabetes. Lancet Overview of 6 years’ therapy of type II Expression of monosaccharide transporters Diabetes Endocrinol. 2013;1:140–151. diabetes: a progressive disease. Diabetes. in intestine of diabetic humans. Am J 25. Taylor SI, Blau JE, Rother KI. Possible – 1995;44:1249 1258. Physiol Gastrointest Liver Physiol. adverse effects of SGLT2 inhibitors on – 4. Defronzo RA. Banting lecture. From the 2002;282:G241 248. bone. Lancet Diabetes Endocrinol. triumvirate to the ominous octet: a new 16. Calado J, Sznajer Y, Metzger D, et al. 2015;3:8–10. paradigm for the treatment of type 2 dia- Twenty-one additional cases of familial 26. Shibazaki T, Tomae M, Ishikawa- – betes mellitus. Diabetes. 2009;58:773 795. renal glucosuria: absence of gentic hetero- Takemura Y, et al. KGA-2727, a novel 5. Hasan FM, Alsahli M, Gerich JE. SGLT2 geneity, high prevalence of private muta- selective inhibitor of a high-affinity sodium inhibitors in the treatment of type 2 diabetes. tions and further evidence of volume glucose cotransporter (SGLT1), exhibits Diabetes Res Clin Pract. 2014;104:297–322. depletion. Nephrol Dial Transplant. antidiabetic efficacy in rodent models. J 2008;23:3874–3879. – 6. Wells RG, Pajor AM, Kanai Y, et al. Pharmacol Exp Ther. 2012;342:288 296. Cloning of human kidney cDNA with 17. Scholl-Burgi S, Santer R, Ehrich JH. Long- 27. Goodwin NC, Mabon R, Harrison BA, similarity to the sodium-glucose cotran- term outcome of renal glucosuria type 0: et al. Novel L-xylose derivatives as selec- sporter. Am J Physiol Renal Fluid the original patient and his natural history. tive sodium-dependent glucose cotran- – Electrolyte Physiol. 1992;263:F459–F465. Nephrol Dial Transplant. 2004;19:2394 sporter 2 (SGLT2) inhibitors for the 2396. 7. Santer R, Kinner M, Lassen CL, et al. treatment of type 2 diabetes. J Med Chem. – Molecular analysis of the SGLT2 gene in 18. Lindquist B, Meeuwisse GW. Chronic 2009;52:6201 6204. patients with renal glucosuria. J Am Soc diarrhoea caused by monosaccharide 28. Lapuerta P, Zambrowicz B, Strumph P, et al. Nephrol. 2003;14:2873–2882. malabsorption. Acta Paediatr. Development of sotagliflozin, a dual sodium- 1962;51:674–685. 8. Oku A, Ueta K, Arakawa K, et al. T-1095, dependent glucose transporter 1/2 inhibitor. – an inhibitor of renal Na+-glucose cotran- 19. Turk E, Zabel B, Mundlos S, et al. Diab Vasc Dis Res. 2015;12:101 110. sporters, may provide a novel approach to Glucose/galactose malabsorption caused 29. Zambrowicz BP, Turner CA, Sands AT. + treating diabetes. Diabetes. 1999;48:1794– by a defect in the NA /glucose cotran- Predicting drug efficacy: knockouts model – 1800. sporter. Nature. 1991;350:354 356. pipeline drugs of the pharmaceutical • 9. Ferrannini E, Solini A. SGLT2 inhibition The first human mutation in SGLT1 industry. Curr Opin Pharmacol. – in diabetes mellitus: rationale and clinical associated to glucose-galactose 2003;3:563 570. prospects. Nat Rev Endocrinol. malabsorption. 30. Powell DR, Smith M, Greer J, et al. 2012;8:495–502. 20. Xin B, Wang H. Multiple sequence varia- LX4211 increases serum glucagon-like

Downloaded by [University of Otago] at 07:53 15 December 2015 10. Wright EM, Loo DD, Hirayama BA. tions in SLC5A1 gene are associated with peptide 1 and peptide YY levels by redu- Biology of human sodium transporters. glucose-galactose malabsorption in a large cing sodium/glucose cotransporter 1 Physiol Rev. 2011;91:733–794. cohort of old order Amish. Clin Genet. (SGLT1)-mediated absorption of intestinal 2011;79:86–91. glucose. J Pharmacol Exp Ther. •• An excellent and comprehensive review – 21. Powell DR, DaCosta CM, Gay J, et al. 2013;345:250 259. on the physiology of SGLTs. Improved glycemic control in mice lack- • A mechanistic study in mice deciphering 11. Hediger MA, Coady M, Ikeda T, et al. ing Sglt1 and Sglt2. Am J Physiol the effect of SGLT1 inhibition and Expression cloning and cDNA sequencing Endocrinol Metab. 2013;304:E117–E130. sotagliflozin on GLP-1 secretion. of the Na+/glucose co-transporter. Nature. •• The genetic proof in mice that partial 31. Powell DR, DaCosta C, Smith M, et al. 1987;330:379–381. inhibition of SGLT1 improves glucose Effect of LX4211 on glucose homeostasis 12. Wright EM, Hirayama BA, Loo DD. homeostasis without gastrointestinal and body composition in preclinical Active sugar transport in health and dis- side effects. models. J Pharmacol Exp Ther. ease. J Intern Med. 2007;1:32–43. – 22. Inzucchi SE, Bergenstal RM, Buse JB, 2014;350:232 242. 13. Stumpel F, Burcelin R, Jungermann K, et al. Management of hyperglycaemia in 32. Powell DR, Doree D, Jeter-Jones S, et al. et al. Normal kinetics of intestinal glucose type 2 diabetes, 2015: a patient-centered Sotagliflozin improves glycemic control in absorption in the absence of GLUT2: evi- approach. Update to a position statement nonobese diabetes-prone mice with type 1 dence for a transport pathway requiring of the American Diabetes Association diabetes. Diabetes Metab Syndr Obes. glucose phosphorylation and transfer into (ADA) and the European Association for 2015;8:121–127.

Expert Opin. Investig. Drugs (2015) 24(12) 1655 B. Cariou & B. Charbonnel

33. Zambrowicz B, Ogbaa I, Frazier K, et al. 41. Zambrowicz B, Lapuerta P, Strumph P, announcement [Internet]. 2015 [cited Effects of LX4211, a dual sodium-depen- et al. LX4211 therapy reduces postpran- 2015 May 15]. http://www.fda.gov/Drugs/ dent glucose cotransporters 1 and 2 inhi- dial glucose levels in patients with type 2 DrugSafety/ucm446845.htm bitor, on postprandial glucose, insulin, diabetes mellitus and renal impairment 50. Erondu N, Desai M, Ways K, et al. glucagon-like peptide 1, and peptide tyro- despite low urinary glucose excretion. Clin Diabetic ketoacidosis and related events in – sine tyrosine in a dose-timing study in Ther. 2015;37:71 82. the canagliflozin type 2 diabetes clinical healthy subjects. Clin Ther. 42. Henry RR, Rosentstock J, Edelman S, program. Diabetes Care. 2015 Jul 22. pii: – 2013;35:1162 1173. et al. Exploring the potential of the dc151251. [Epub ahead of print] • The first proof in human that sotagliflo- SGLT2 inhibitor dapagliflozin in type 1 51. Rosenstock J, Aggarwal N, Polidori zin improves post-prandial glycemia and diabetes: a randomized, double-blind, pla- D, et al. Canagliflozin DIA 2001 study increases GLP-1 secretion in humans. cebo-controlled pilot study. Diabetes Care. group/ Dose-ranging effects of – 34. Komoroski B, Vacchharajani N, Boulton 2015;38:412 419. canagliflozin, a sodium glucose cotran- D, et al. Dapagliflozin, a novel SGLT2 43. Pieber TR, Famulla S, Eilbracht J, et al. sporter 2 inhibitor, as add-on to inhibitor, induces dose-dependent gluco- Empagliflozin as adjunct to insulin in metformininsubjectswithtype2dia- suria in healthy subjects. Clin Pharmacol patients with type 1 diabetes: a 4-week, betes. Diabetes Care. 2012;35:1232– Ther. 2009;85:520–526. randomized, placebo-controlled trial 1238. 35. Sha S, Divineni D, Ghosh A, et al. (EASE-1). Diabetes Obes Metab. 2015. 52. List JF, Woo V, Morales E, et al. Sodium- Canagliflozin, a novel inhibitor of sodium DOI:10.1111/dom.12494. [Epub ahead of glucose cotransport inhibition with dapa- glucose co-transporter 2, dose dependently print] gliflozin in type 2 diabetes. Diabetes Care. reduces calculated renal threshold for glu- 44. Sands AT, Zambrowicz BP, Rosenstock J, 2009;32:650–657. cose excretion and increases urinary glu- et al. Sotagliflozin, a dual SGLT1 and 53. Ferraninni E, Seman L, Seewaldt-Becker cose excretion in healthy subjects. Diabetes SGLT2 inhibitor, as adjunct therapy to E,etal.PhaseIIb,randomized,placebo- – Obes Metab. 2011;13:669 672. insulin in type 1 diabetes. Diabetes Care. controlled study of the SGLT2 inhibitor – 36. Sarashina A, Koiwai K, Seman LJ, et al. 2015;38:1181 1188. empagliflozin in patients with type 2 Safety, tolerability, pharmacokinetics and • A pilot study highlighting the potential diabetes. Diabetes Obes Metab. pharmacodynamics of empagliflozin, a interest of sotagliflozin in type 1 2013;15:721–728. sodium glucose cotransporter 2 (SGLT2) diabetes. 54. Bonner C, Kerr-Conte J, Gmyr V, et al. inhibitor, in healthy Japanese subjects. 45. Taylor SI, Blau JE, Rother KI. Perspective: Inhibition of the glucose transporter Drug Metab Pharmacokinet. SGLT2 inhibitors may predispose to ketoa- SGLT2 with dapagliflozin in pancreatic – 2013;28:213 219. cidosis. J Clin Endocrinol Metab. 2015 Jun alpha cells triggers glucagon secretion. 37. Zambrowicz B, Freiman J, Brown PM, 18:jc20151884. [Epub ahead of print] Nat Med. 2015;21:512–517. et al. LX2411, a dual SGLT1/SGLT2 46. Thomas MC, Jandeleit-Dahm K, Bonnet 55. Merovci A, Solis-Herrera C, Daniele G, inhibitor, improved glycemic control in F. Beyond glycosuria: exploring the intra- et al. Dapagliflozin improves muscle insu- patients with type 2 diabetes in a rando- renal effects of SGLT−2 inhibition in dia- lin sensitivity but enhances endogenous mized, placebo-controlled trial. Clin betes. Diabetes Metab. 2014;40:S17–22. glucose production. J Clin Invest. Pharmacol Ther. 2012;92:158–169. – 47. Zinman B, Wanner C, Lachin JM, et al. 2014;124:509 514. 38. Zambrowicz B, Ding ZM, Ogbaa I, et al. Empagliflozin, cardiovascular outcomes, 56. Cohen JJ, Berglund F, Lotspeich WD. Effects of LX4211, a dual SGLT1/SGLT2 and mortality in type 2 diabetes. New Engl Renal tubular absorption of acetoacetate, inhibitor, plus sitagliptin on postprandial J Med. 2015. DOI:10.1056/ inorganic sulfate and inorganic phos-

Downloaded by [University of Otago] at 07:53 15 December 2015 active GLP-1 and glycemic control in type NEJMoa1504720. [Epub ahead of print] phate in the dog as affected by glucose 2 diabetes. Clin Ther. 2013;35:273–285. • A positive cardiovascular outcome study and phlorizin. Am J Physiol. – 39. Rosenstock J, Cefalu WT, Lapuerta B, demonstrating that empagliflozine 1956;184:91 96. et al. Greater dose-ranging effects on A1C reduces cardiovascular and overall mor- levels than on glucosuria with LX4211, a tality in high CV risk patients with Affiliation dual inhibitor of SGLT1 and SGLT2, in † T2DM. Bertrand Cariou 1,2,3 & Bernard Charbonnel3 patients with type 2 diabetes on metformin † 48. Neal B, Perkovic V, de Zeeuw D, et al. Author for correspondence monotherapy. Diabetes Care. Rationale, design, and baseline character- 1Clinique d’Endocrinologie, l’institut du thorax, 2015;38:431–438. istics of the Canagliflozin Cardiovascular CHU de Nantes, Nantes F-44000, France • A 12-week dose-ranging study with Assessment Study (CANVAS)-a rando- Tel: 00 33 2 53 48 27 07; sotagliflozin in patients with T2DM mized placebo controlled trial. Am Heart J. Fax: 00 33 2 53 48 27 08; under metformin therapy. 2013;166:217–223. E-mail: [email protected] 2 ’ 40. Yale JF, Bakris G, Cariou B, et al. Efficacy 49. FDA Drug Safety Communication: FDA l institut du thorax, Inserm, UMR1087, Nantes and safety of canagliflozin in subjects with warns that SGLT2 inhibitors for diabetes F-44000, France 3 type 2 diabetes and chronic kidney disease. may result in a serious condition of too Faculté de Médecine, Université de Nantes, – Diabetes Obes Metab. 2014;16:1016 much acid in the blood. FDA safety Nantes F-44000, France 1027.

1656 Expert Opin. Investig. Drugs (2015) 24(12) 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP 图书馆。图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具