LX4211 paper sobre farmaco control de la glicemia para gente con diabetes mellitus tipo 2

Effects of LX4211, a Dual SGLT1/SGLT2 Inhibitor, PlusS veC

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Clinical Therapeutics/Volume 35, Number 3, 2013

Magliptin, or the combination. In both studies, bloods collected for the analysis of pharmacodynamicriables (GLP-1, PYY, GIP, glucose, and insulin). Inclinical study, urine was collected to assess urinarycose excretion.Results: Preclinical: 120 mice were treated and as-sed (5/time point/treatment group). With repeatily dosing, the combination was associated with ap-rently synergistic increases in active GLP-1 relativemonotherapywith either agent; this findingwas sup-rted by findings from an additional 14-day repeated-se experiment. Clinical: 18 patients were enrolled

rights reserved.

These data were presented, in part, in abstract format at the 2012Meeting of the American Diabetes Association, June 812, 2012, Phil-adelphia, Pennsylvania, and the European Association for the Study ofDiabetes, October 15, 2012, Berlin, Germany

Accepted for publication January 24. 2013.http://dx.doi.org/10.1016/j.clinthera.2013.01.0100149-2918/$ - see front matter

2013 Elsevier HS Journals, Inc. All rights reserved.itagliptin on Postprandial Actiontrol in Type 2 Diabetes

ian Zambrowicz, PhD1; Zhi-Ming Ding, MD,illip Banks, MS1; Anne Turnage, BA1; Joel Fr

ennis Ruff, MD2; Arthur Sands, MD, PhD1; a

exicon Pharmaceuticals, Inc., The Woodlands, Texaxas

STRACTBackground:Combination therapy is required to pro-e adequate glycemic control in many patients withe 2 diabetesmellitus (T2DM). Because sodium-depen-nt glucose transporter (SGLT)-1 inhibition results inincreased release of glucagon-like peptide (GLP)-1,d because dipeptidyl peptidase (DPP)-4 inhibitorsevent its inactivation, the 2 mechanisms togetherovide an intriguing potential combination therapy.Objectives: This combination was explored in pre-nical models and then tested in patients with T2DMcompare the effects of single-dose LX4211 400 mgd sitagliptin 100 mg, administered as monotherapyin combination, on GLP-1, peptide tyrosine tyrosineY), gastric inhibitory peptide (GIP), glucose, andulin.Methods: Preclinical: Obese male C57BL6J micere assigned to 1 of 4 treatment groups: LX4211 60/kg, sitagliptin 30 mg/kg, LX4211 sitagliptin, orctive vehicle. Clinical: This 3-treatment, 3-cross-er, randomized, open-label study was conducted at agle center. Patients on metformin monotherapyre washed out from metformin and were randomlyigned to receive sequences of single-dose LX4211,arch 2013GLP-1 and Glycemic

1; Ike Ogbaa, MD1; Kenny Frazier, BS1;n, MD1; Melinda Smith, BS1;avid Powell, MD1

d 2Icon Development Solutions, San Antonio,

d treated (mean age, 49 years; 56% male; 89%ite). The LX4211 sitagliptin combination wasociated with significantly increased active GLP-1,al GLP-1, and total PYY; with a significant reduc-n in total GIP; and with a significantly improvedod glucose level, with less insulin, compared withagliptin monotherapy. LX4211 was associated withignificant increase in total GLP-1 and PYY and auced total GIP, likely due to a reduction in SGLT1-diated intestinal glucose absorption, whereas sita-ptin was associated with suppression of all 3 pep-es relative to baseline. All treatments were wellerated, with no evidence of diarrhea with LX4211atment.Conclusions: The findings from the preclinical studiesggest that the LX4211 sitagliptin combination pro-ced synergistic increases in active GLP-1 after a mealallenge containing glucose. These initial clinical resultso suggest that a LX4211DPP-4 inhibitor combina-n may provide an option in patients with T2DM. Thetential long-term clinical benefits of such combinationatment need to be confirmed in large clinical trials.inicalTrials.gov identifier: NCT01441232. (Clin Ther.273

Key words: adult, diabetes, dipeptidyl peptidase-4,GIPYex

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Clinical Therapeutics

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TRODUCTIONpe 2 diabetes mellitus (T2DM) is a disease charac-ized by increased blood glucose levels that resultboth microvascular and macrovascular complica-ns.16 Microvascular complications include ne-ropathy, retinopathy, and neuropathy, whereas ma-vascular complications include heart disease,oke, and peripheral vascular disease. Diabetes is awing health concern in the United States andworld-de. In 2009, there were an estimated 24 million in-iduals with T2DM in the United States, and thatmber is forecast to roughly double by 2034.7 Therldwide incidence of T2DM is now estimated at 346llion.8 This surge in T2DM has been correlated withincrease in obesity.911 The economic burden ofbetes is enormous, with 2009 US spending on dia-tes and related costs estimated at$100 billion; thature is expected to triple by 2030.7

Treatments that help to control blood glucose haveen demonstrated to decrease the microvascular com-cations of diabetes.16 Metformin is standard first-e therapy; however, findings from studies suggestat only 50% of patients are well controlled bynotherapy at 3 years into treatment, and only% at 9 years.12 Thus, combination therapy is re-ired and becomes increasingly important as theease progresses.1316

LX4211 is a dual inhibitor of sodium dependentcose transporters (SGLT) 1 and 2. SGLT1 is thejor glucose/galactose transporter of the gastrointes-al (GI) tract, involved in the uptake of glucose fromdiet.17 Study findings suggest that inhibiting

LT1 results in reduced glucose absorption, whichmulates an increased release of beneficial peptidesch as glucagon-like peptide (GLP)-1 and peptide ty-sine tyrosine (PYY) from the GI tract, commencing 1ur after meals, with sustained effects throughout they.18 This GI response is likely the result of a trigger-of the natural homeostatic mechanism that sensesreased nutrient levels resulting from meals contain-excessive carbohydrates, fats, or other nutrients.19

ucose in the distal small intestine and short chainty acids (SCFAs)the bacterial fermentation prod-74gger their release of GLP-1, PYY, and other benefi-l peptides (ie, oxyntomodulin). This mechanism ofLT1 inhibition is supported by the report of a highlyective SGLT1 inhibitor that increased glucose levelsthe distal small intestine and cecum and increasedP-1 and PYY in rats.20 Similar GI responses areggered by roux-en-Y gastric bypass surgery2024 andingestion of dietary-resistant starch.2527 In addi-n to inhibiting SGLT1, LX4211 also inhibitsLT2, thereby reducing renal glucose reabsorptiond enhancing urinary glucose excretion (UGE). In aase 2 clinical trial, LX4211 was well tolerated andovided significant improvement in glycemic controler 4 weeks of dosing in patients with T2DM.18 Im-rtantly, LX4211 also lowered triglycerides and pro-ced trends in reductions of both body weight andod pressure.Sitagliptin inhibits dipeptidyl peptidase (DPP)-4, re-lting in incretin-mimetic effects.28,29 Active (a)P-1 and gastric inhibitory peptide (GIP) are releasedthe GI tract in response to meals but have shortlf-lives due to inactivation by the DPP-4 en-me.3032 Sitagliptin and other DPP-4 inhibitors thusrease levels of aGLP-1 and aGIP. aGLP-1 and aGIPhance glucose-dependent insulin release from pan-atic cells. GLP-1 has additional activities such aslaying gastric emptying, appetite suppression, andibition of glucagon release. In contrast, aGIP en-nces glucagon secretion and induces adiposity.3032

e net effect of sitagliptin treatment is enhanced gly-ic control, with no significant effect on bodyight.33

Theoretically, LX4211 in combination with aP-4 inhibitor such as sitagliptin might provide en-nced benefit in patients with T2DMbecause they actough complementary mechanisms. LX4211 has 2ulin-independent mechanisms of action(1) SGLT2-pendent reductions in renal glucose reabsorption andSGLT1-mediated reduced intestinal glucose ab-

rptionwhereas sitagliptin enhances glucose-de-ndent insulin release. Additionally, LX4211 mighthance the incretin effects of sitagliptin because4211 increases GLP-1 release after meals and sita-ptin inhibits aGLP-1 inactivation.The present studies examined whether the LX4211agliptin combination results in increases in aGLP-1els, relative to either monotherapy, in mice, andether the combination enhances the GI peptide pro-Volume 35 Number 3

file and provides improved glycemic control over sita-gli

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Mptin monotherapy in patients with T2DM.

ATERIALS AND METHODSeclinical Pharmacology In Miceudy DesignGeneral methods for mouse care have been de-ibed.34 Both the single-dose and 14-day studies wererried out using obese maleC57BL6Jmice fed a high-diet containing 45% kcal from fat (D12451, Re-rch Diets Inc, New Brunswick, New Jersey) sinceaning and were at least 24 weeks of age at the timestudy. Randomization was based on body weight, toof 4 treatment groups: LX4211 60 mg/kg mono-rapy, sitagliptin 30 mg/kg monotherapy, the com-ation of LX4211 sitagliptin, or inactive vehicle.eatment was administered in the morning by oralvage. On the day ofmeal challenge, themice receivedmL/kg of low-fat diet (10% kcal as fat; D12450B,search Diets) suspended in dextrose water (9.2 g/kgcose, 2.5 g/kg protein, 0.6 g/kg fat) by oral gavageminutes after active or inactive drug administration.

sessmentsBloodwas collected from themice before and at 0.5,2, 3, and 6 hours after meal challenge to measureculating levels of aGLP-1 by ELISA (GLP-1 ActiveISA Kit, Millipore Corporation, St. Charles, Mis-uri). Blood collection and handling, and all aspectsthe assay protocol, were performed as recom-nded by Millipore. Because 500 L of blood is re-ired for a single aGLP-1 assessment, multiple mea-rements in the same mouse were not feasible;tead, independent groups of mice (n 5) were as-ned to each time point in each treatment arm.

atistical AnalysisAll preclinical pharmacology data are presented asan (SEM). The 06-hour time-course data forLP-1 levels in each treatment group were convertedAUC values by trapezoidal summation using Prismrsion 4.03 (GraphPad Software, Inc, San Diego, Cal-rnia). The effect of LX4211 and/or sitagliptin onLP-1 levelswas analyzedby2-wayANOVAalsousingism version 4.03. When a significant interaction wasmonstrated for the combinationof LX4211 sitaglip-, the effect of these compounds individually onLP-1 levels was assessed by ANOVA followed bynferroni testing; these analyses included data fromarch 2013mpounds.

inical Study In Patients With Type 2 Diabetesudy DesignThis clinical study was conducted in accordanceth the Declaration of Helsinki. The protocol wasproved by the institutional review board with juris-tion over the site (IntegReview Ethical Revieward, Austin, Texas), and all patients provided writ-informed consent before being enrolled into thedy. The 3-treatment, 3-crossover, randomized,en-label study was conducted at a single centerase I Center, ICONDevelopment Solutions plc, Santonio, Texas) between October 4, 2011, and No-mber 22, 2011, and included patients 28 to 65 yearsage diagnosed with T2DM at least 3 months beforeeening and currently taking metformin mono-rapy. At screening, all patients were required tove a hemoglobin A1c value of 6.5% to 10.5%, C-ptide1 ng/mL, and a body mass index45 kg/m2.tients were screened for adequate renal function andre excluded if they had an estimated glomerular fil-tion rate 60 mL/min/1.73 m2. Patients demo-phic characteristics are shown in Supplementalble I in the online version at http://dx.doi.org/.1016/j.clinthera.2013.01.010 http://www.blogger.m/blogger.g?blogID818251595177931289 - _ocom_1, and a complete list of inclusion and exclu-n criteria is included in Supplemental Appendix inonline version at http://dx.doi.org/10.1016/j.

nthera.2013.01.010.Metformin washout, which included daily glucom-r assessments and instructions on dietary guidelinesd restrictions, was performed over a 14-day periodrting on day15. Patients were instructed to returnthe clinic if their fasting plasma glucose (FPG) ex-ded 280 mg/dL on 2 consecutive days and were todiscontinued from the study if they had laboratorynfirmation of FPG280mg/dL. Patients completingtformin washout entered the inpatient facility be-ning 2 days prior to randomization (day 2) forrification of eligibility and diet stabilization. Baselinerameters, obtained on day 1, included glucose, in-lin, aGLP-1, total (t) GLP-1, tGIP, tPYY, ghrelin,d leptin.A randomization schedule was generated before thest dosing period by ICON Development Solutions,contract research organization that performed data275

management for the study. Eighteen patients were ran-doquoringstrLaeffbuwidedu2bglico

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2mly assigned among 3 blocks of 6 treatment se-ences to receive LX4211 400mg, sitagliptin 100mg,the combination, at 8 AM, 1 hour before the morn-meal. The treatment block and treatment sequenceuctures were generated in accordance with a 3 3tin square design balanced for first-order carryoverects. No formal sample size calculation was made,t the number of required patients was consistentth those in other trials with similar objectives andsign. The LX4211 dose was selected because it pro-ced maximal hemoglobin A1c reduction in a Phasedose-ranging study.35 The maximum dose of sita-ptin was chosen to determine whether the LX4211mbination produces any additional benefit.Each patient received a single dose of LX4211, agle dose of sitagliptin, and the combination doseer the course of the study, in 3 successive treatmentriods (doses on days 1, 8, and 15) separated by 7-dayshout, during which patients were fed a lowglyce-c index diet of 2200 kcal/d, with caloric intake ony given day consisting of 38% to 51% carbohydrate,% to 22% protein, and 35% to 41% fat. Threentical meals were provided at baseline (day 1),d on each of the 3 dosing days (days 1, 8, and 15),th breakfast 1 hour after dosing, lunch at 4 hourser dosing, dinner at 8 hours after dosing, and aack at 12 hours after dosing. All meals were 0.5 hourduration, with instructions on completing the mealovided. Meal compositions were 493 total kcal foreakfast (52% carbohydrate, 14% protein, and 34%), 772 total kcal for lunch (47% carbohydrate, 23%otein, and 30% fat), 833 total kcal for dinner (44%rbohydrate, 21% protein, and 35% fat), and a 135-al snack that was given after all pharmacodynamicasurement samples were obtained for the day. Theatient active-treatment period included a final fol--up and discharge 2 days after the final dosing day.

ethods used to generate and implement the randomocation sequence are described in the online versionhttp://dx.doi.org/10.1016/j.clinthera.2013.01.010.e study schema is illustrated in Supplemental Figuren the online version.The primary objective was to evaluate the effectssingle-dose LX4211 and sitagliptin, administeredmonotherapy or in combination, on tGLP-1 andLP-1 in patients with T2DM. The secondary objec-e was to measure the pharmacodynamic effects ofgle-dose LX4211 and sitagliptin, administered as76cose (PPG), UGE, insulin, and tPYY, as well as toaluate the tolerability of LX4211 and sitagliptin, intients with T2DM. Exploratory variables includedIP, leptin, and ghrelin. The timing of all pharmaco-namic measures relative to dosing is shown in Sup-mental Table II in the online version at http://.doi.org/10.1016/j.clinthera.2013.01.010.

sessmentsThe end points were measured at baseline (day 1)d on each of the 3 days of dosing. Plasma glucose,ulin, GLP-1, and PYY measures were obtained atltiple time points throughout the day (Supplementalble II in the online version at http://dx.doi.org/.1016/j.clinthera.2013.01.010) to capture the ef-ts on these parameters after each meal. Plasma GIP,tin, and ghrelin measures were taken at time pointsexamine breakfast responses to minimize bloodaws. Total and active GLP-1, tPYY, tGIP, ghrelin,d leptin were measured by Pacific Biomarkers (Seat-, Washington). Comparisons of active and totalP-1, tPYY, glucose, and insulin were based on totalCs 0 to 13 hours after dosing. Comparisons of tGIP,tin, and ghrelin were based on total AUC 0 to 4urs.Tolerability assessments included physical exami-tion (including weight and vital signs), ECG, clinicaloratory assessment, and adverse-events (AE) assess-nts; AEs were coded and listed by organ system andeferred terms based on the Medical Dictionary forgulatory Activities (MedDRA) version 12.0.

atistical AnalysisContinuous variables were summarized by the num-r of patients with nonmissing data, mean (SD), ordian (range). Categorical variables were summa-ed as number (%). All tests of treatment effects wereided at the 0.05 level of significance, with no adjust-nts made for multiple comparisons. SAS version.3 (SAS Institute Inc., Cary, North Carolina) wased to make all statistical comparisons and to sum-rize the data descriptively.Imputation or any other data-assignment rule wast used to substitute values for missing observations.l data analyses and summaries were based on ob-ved cases. The lone exception was for the pharma-dynamic variables, whereby values reported belowlower limit of quantification were assigned a valueVolume 35 Number 3

of LLOQ/2. For all calculations of changes from base-linoth

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Me, baseline was defined as day 1 unless notederwise.Analysis of a few pharmacodynamic measures wassed on single data point values taken on days1, 1,and 15. These measures included UGE and FPG.her measures required a more complex modeling ofily values, and to fully capture the effect of treat-nts on the extent of changes in these variables, dif-ent derivations of AUCwere calculated. AUC valuesre calculated for GLP-1 (total and active), PPG, in-lin, PYY, and GIP. The AUC measures were deriveding all time points collected within a study day (days, 1, 8, and 15) but varied as to how they were cal-lated. The total AUC (ie, AUC0last) reflects the sum-tion of subareas from time 0 (predose value) to thet value measured on a day. Thus, the total area wasAUC measured down to a metabolic level of

ero. The net incremental AUCs were estimated bybtracting the area below the predose level from thea above the predose level. The linear trapezoidalorithm was used to derive all AUC estimates.A Latin square design balanced for first-order car-ver effects was implemented to allow the effects ofatment and period (time-related effects) to be eval-ted independently and efficiently. A generalized lin-r mixed model (GLMM) was parameterized to re-ct these design restrictions and permitted unbiasedtistical testing/estimation of the desired treatmentmparisons.Analysis of the tGLP-1 data using AUC0last wasbjected to a period effect (P 0.001). However,ing net incremental AUC data, the statistical modelowed no significant period (P 0.79) or interaction 0.40) effects. This was due, in part, to the sub-ction of the period effect from these measures byjusting for time 0 on each study day.Interpretation of the tPYY and tGIP AUC0last datas influenced by the presence of a treatment-by-pe-d interaction effect (P 0.10); tPYY results wereo affected by a significant period effect (P 0.001).such, analysis of tPYY and tGIP AUC0last data wassed on a GLMM with an added term for first-orderrryover effects. Use of this adjusted GLMM for theY data allowed for a more clear-cut interpretationbetween-treatment effects using the AUC0last val-s across all periods. Analysis of the tGIP AUC0lastta using the first-order carryover effectadjustedarch 20134) as well as a remedy for the interaction effect.

SULTSeclinical Pharmacology In MiceIn initial studies, mice dosed with either LX4211 oragliptin monotherapy exhibited increased aGLP-1els relative to vehicle at 1 hour after meal challenge,d the combination of LX4211 sitagliptin was as-ciated with a further additive, but not synergistic,rease in aGLP-1. However, at 2 hours after mealallenge, LX4211 sitagliptin was associated with aar synergistic increase in aGLP-1 (Supplementalure 2 in the online version at http://dx.doi.org/.1016/j.clinthera.2013.01.010). In a confirmatorydy, single-dose LX4211 or sitagliptin monotherapys associated with a significantly increased AUC forLP-1 levels measured between 0 and 6 hours afteral challenge, and the LX4211 sitagliptin combi-tion was associated with a further, significant, ap-rently synergistic increase in aGLP-1AUC (Figure 1A).On multidose testing (14 days of once-daily dosing)LX4211 or sitagliptin monotherapy, aGLP-1 levelsasured between 0 and 6 hours after meal challengere increased relative to those with vehicle (Figure), and the LX4211 sitagliptin combination wasociated with a significant, apparently synergistic in-ase in aGLP-1 compared with that with either agentne. With repeated daily dosing, the combinationpeared to produce greater increases in aGLP-1 thanre found in the single-dose studies, an effect that waspported by findings from an additional 14-day re-ated-dosing experiment (Supplemental Figure 3 in

online version at http://dx.doi.org/10.1016/j.nthera.2013.01.010). These findings suggest that the4211 sitagliptin combination produces synergis-increases in aGLP-1 after a meal challenge contain-glucose.

inical Studies In Patients With Type 2 DiabetesIn the 18 T2DM patients enrolled (Supplementalure 4 in the online version at http://dx.doi.org/10.16/j.clinthera.2013.01.010), LX4211 monotherapys associated with significantly increased 24-hourE, as expected based on its inhibition of SGLT2 inkidney (Figure 2 and Table I), and the LX4211

agliptin combination was associated with a similarrease. As anticipated based on its mechanism of ac-277

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2n, sitagliptin monotherapy was not associated withreased UGE.On assessment of GI peptides, glucose, insulin, ghre-, and leptin, combination treatment was associatedth a significant increase in aGLP-1 over that resultingm either monotherapy (Figure 3A and Table I). Thisrease in aGLP-1 appeared to have occurred in a syner-tic manner with the combination as was also observedmice. tGLP-1 and tPYY, with combination treatment,re significantly increased relative to those resultingm sitagliptin monotherapy and were significantly re-ced relative to those resulting from LX4211 mono-

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Figure 2. Mean (SD) 24-hour urinary glucose ex-cretion (UGE) with LX4211, sitagliptin,and their combination in patients withtype 2 diabetes mellitus. *P 0.001 ver-sus LX4211 sitagliptin.78rapy (Figure 3B and 3C andTable I). tGIP was signif-ntly reduced with the combination treatment relativeeither monotherapy (Figure 3D and Table I). Therere no significant differences in ghrelin or leptin levelsth combination therapy relative to eithermonotherapyta not shown). Taken together, LX4211 sitagliptinatment was associated with increased aGLP-1,LP-1, and tPYY and decreased tGIP compared withagliptin monotherapy.There was evidence of a period effect in this study;wever, the presence of a period effect did not influ-ce the interpretation of between-treatment differ-ces. The period effect may have impacted the inter-etation of within-treatment effects, and to this point,ther statistical analyses were performed to compareresults versus baseline (Figure 3). Analytic findings

rived using the net incremental AUC data on tGLP-1presented in Supplemental Table III in the online

rsion at http://dx.doi.org/10.1016/j.clinthera.2013..010. These data suggest that LX4211 increased theLP-1 level from baseline (change in least squaresan [LSM], 24.63 pmol h/L; P 0.001), whereasagliptin had an opposing effect, with a reductionm baseline of nearly the same magnitude as the in-ase seen with LX4211 (change in LSM, 23.78ol h/L; P 0.001). The comparison of the combi-tion treatment to sitagliptin monotherapy furtherderscored the apparent effect of LX4211, wherebydifference in LSMs demonstrated an increase of

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MThe tPYY and tGIP data resulting from the adjustedMM are presented in Supplemental Tables IV andrespectively, in the online version at http://dx.doi.g/10.1016/j.clinthera.2013.01.010. LX4211 was as-ciated with an increase from baseline in LSM tPYYC0last of 61.67 pmol h/L (P 0.001). In con-st, sitagliptin was associated with a reduced tPYYC0-last over time, by 134.72 pmol h/L (P 0.001).mparison of the combination treatment to sitaglip-showed a difference in AUC0last LSMs of 43.61ol h/L (P 0.014). This difference suggests a pos-e effect of LX4211 (ie, increasing tPYY levels) whened in the combination treatment. On analysis ofy-1 data only (period 1), which was absent of anyriod effect, tPYY was increased with combinationatment compared with sitagliptin monotherapy, asected by a difference in LSMs of 55.20 pmol h/L.l treatments were associated with significant reduc-ns from baseline over time in tGIP AUC0last (P 01). Use of both drugs in combination appeared tove been additive in effect. The net contribution of4211 in the combination was a reduction of 32.24ol h/L (P 0.001).Importantly, glycemic control was improved through-t the day with the combination therapy relative toher monotherapy (FPG, 2366.7, 2412.8, and 2209.6 h/L with LX4211, sitagliptin, and the combina-

n, respectively) and was achieved with significantlys insulin than that required with sitagliptin mono-

Table I. Pharmacodynamic properties of LX4211 and stion in patients with type 2 diabetes (N 18).

Parameter

LX4211

Monotherapy vs Combination*

UGE, g/24 h 92.2 8.2 (24.8 to 8.4)Insulin, M h/mL 479.2 68.1 (2.3 to 133.9)PPG, mg h/L, 013 h 2366.7 157.0 (312.9 to 1.PYY, pmol h/L 403.3 152.8 (187.1 to 11tGLP-1, pmol h/L 161.9 26.1 (38.8 to 13.aGLP-1, pmol h/L 69.2 98.2 (80.9 to 115.4)GIP total, pmol h/L 117.4 45.3 (62.7 to 29.

GIP gastric inhibitory peptide; GLP glucagon-like peptide; PPGglucose excretion.*Estimated difference (95% CI) between combination and single-doseP 0.001 versus combination.P 0.05 versus combination.arch 2013rapy (479.2, 623.4, 547.3M h/mL) (Table I andure 4).LX4211waswell tolerated, and all 18 patients com-ted the study with no reports of serious AEs or with-awals due to AEs. Overall, 4 patients (22.2%) expe-nced at least 1 treatment-emergent AE (TEAE), withotal of 10 TEAEs distributed among the treatmentups as follows: 1 with LX4211, 4 with sitagliptin,d 5 with LX4211 sitagliptin. Seven events wereessed as mild and 3 were moderate; 2 were assessedpossibly related to the study treatment (genital can-iasis during LX4211 treatment and headache dur-sitagliptin treatment), and 8 were considered unre-ed. The only GI TEAE reportedwas constipation1se with sitagliptin treatment and 2 with LX4211 agliptin treatment (Table II).

SCUSSIONmbination therapies play an important role in main-ning glycemic control in patients with T2DM. Combi-tions that act on different mechanisms and pathwaysy produce complementary benefits that might be ad-ive with respect to clinical benefit, and combinationst act through different mechanisms of action witherlapping effects on common pathways have the po-tial for not only additive but also synergistic benefits.e example is metformin sitagliptin.3640 This com-ation provides complementary mechanisms of en-nced insulin sensitivity and decreased hepatic glucoseoduction (metformin) and improved glucose-depen-

tin administered as monotherapy and in combina-

SitagliptinLX4211 SitagliptinMonotherapy vs Combination*

7.5 76.4 (59.8 to 93.0) 83.9623.4 76.1 (141.9 to 10.3) 547.3

2412.8 203.2 (359.0 to 47.3) 2209.6206.9 43.6 (9.3 to 77.9) 250.5105.9 29.9 (17.2 to 42.6) 135.8128.8 38.6 (21.3 to 55.9) 167.4109.2 32.2 (49.1 to 15.4) 78.4

randial glucose; PYY peptide tyrosine tyrosine; UGE urinary

djusted means.casit

DICotainamaditthaovtenOnbinhapr279

detinenrelitinabhaanofob

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1

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1

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tGLP

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B

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2nt insulin release and reduction in glucagon (sitaglip-), mediated in part through the common pathway ofhanced GLP-1 activity, with metformin enhancing theease of GLP-1 from the GI tract and sitagliptin inhib-g its inactivation.41 Future combinationsmay be valu-le for diabetes treatment, especially if they provide en-nced glycemic control in addition to cardiovasculard metabolic benefits such as weight loss. Weight loss isparticular importance given the correlation betweenesity and diabetes.4245

LX4211 sitagliptin could theoretically provideth complementary and synergistic benefits. Thechanism of action of LX4211 includes 2 insulin-ependent benefits, enhanced UGE, and reduced glu-se absorption by the intestine, which could augmentinsulin-dependentmechanism of enhanced glucose-

35

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Time (h)

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-1 (

pmol

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*

*

A

C

Figure 3. Mean (SD) plasma concentrations of active g(B), peptide tyrosine tyrosine (PYY) (C), and g2 diabetes mellitus after single-dose adminisStatistical comparisons are based on total AUh for tGIP. *P 0.001 versus combination; 80pendent insulin release produced by DPP-4 inhibi-n. In addition, the mechanisms of both LX4211 andagliptin converge to act on GI peptide mechanisms,ich might provide an additive benefit. LX4211 en-nces postprandial release of aGLP-1 as sitagliptinevents its inactivation, and LX4211 also enhancessecretion of tPYY.The authors have previously reported that LX4211ggers increased GLP-1 and PYY release from the GIct after meals.18 This finding appears to have beenresult of reduced glucose absorption, which allowscose to reach the distal end of the small intestine andlon.20 Glucose in the distal end of the small intestinesensed by L cells and triggers their release of GLP-1,Y, and other beneficial peptides.19 Once the glucoseches the colon, it is fermented by bacteria into SC-

LX4211

LX4211 + Sitagliptin

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on-like peptide (aGLP)-1 (A), and total (t) GLP-1c inhibitory peptide (GIP) (D) in patients with typen of LX4211, sitagliptin, or LX4211 sitagliptin.h for aGLP-1, tGLP-1, and tPYY, and total AUC04.05 versus combination.detiositwhhaprthe

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Ms, which can also be sensed by L cells, thus stim-ting additional secretion of GLP-1, PYY, andher peptides. SCFAs (eg, acetate, propionate, bu-ate) are rapidly absorbed by the colon and haveen shown to decrease ghrelin release and increasetin release.4648 In the present study, it is likelyat LX4211 sitagliptin produced enhanced ef-ts with respect to GI peptides relative to sitaglip-monotherapy, through mechanisms similar to

ose observed with LX4211 monotherapy.LX4211 sitagliptin was associated with increasedLP-1, tGLP-1, and tPYY relative to sitagliptinnotherapy. GLP-1 and PYY might provide multiplenefits30,49 because both are appetite suppressants,d GLP-1 has additional effects, including suppres-n of glucagon release, suppression of hepatic gluco-ogenesis, and stimulation of metabolic rate. The ac-ity of the combination on GLP-1 and PYY mayntribute to enhanced glycemic control as well as

200

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cose

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Figure 4. Mean (SD) plasma concentrations of glucosmellitus after single-dose administration of Lcomparisons are based on total AUCs. *P

Table II. Treatment-emergent adverse events (TEAEs)and sitagliptin administered as monotherapy a18). Data are number (%) of patients.

Parameter LX4211 Sit

Patients with 1 TEAE 1 (5.6) 2Gastrointestinal disorder 0 1Constipation 0 1arch 2013er metabolic benefits for patients. In mice, repeatedsing with LX4211 sitagliptin was associated withreases in aGLP-1 greater than those achieved withgle dosing. Based on these multiple-dose pharma-logy results in mice, single-dose studies in patientsy underestimate the full effect of long-term combi-tion therapy on aGLP-1.The pharmacodynamic properties of SGLT1 inhibi-n, with respect to GLP-1 release at varying times rela-e to glucose exposure/meals, have emerged from pre-nical studies conducted elsewhere inmice and in recentnical trials of LX4211 conducted by the authors.18 Thedings from 2 separate preclinical studies suggest thatLT1activity is required forGI release ofGLP-1 shortlyer exposure to glucose. In 1 study, coadministrationinjection into the upper small intestine) of glucose andloridzin, an inhibitor of SGLT1, was associated withppression of glucose-dependentGLP-1 release from theper small intestine at 5 minutes postinjection.50 In a

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and insulin (B) in patients with type 2 diabetes1, sitagliptin, or LX4211 sitagliptin. Statistical

versus combination.

e gastrointestinal system organ class with LX4211combination in patients with type 2 diabetes (N

in LX4211 Sitagliptin Overall

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2cedGLP-1 response relative to that inwild-typemice atinutes after an oral glucose challenge.51 These near-

m measures are in contrast to longer-term increasedP-1 responses observed in humans treated with421118 and have also been observed in rats with aective SGLT1 inhibitor.20 The authors have also ob-ved a transient inhibition of aGLP-1 release after4211 treatment in mice (data not shown), which waslowed by a sustained increase of GLP-1 levels overe. Together, these data suggest that SGLT1 activityy be required for the transient early aGLP-1 releasethin minutes after a meal but not the more sustainedP-1 release over time.Findings from previous studies suggest that whileagliptin increases postprandial aGLP-1 and aGIP, itppresses tGLP-1, tGIP, and tPYY levels, a reflectionall GLP-1, GIP, and PYY released from the GIct.41,52 This decrease in GI peptide release has beenpothesized to be due to a negative-feedback loopssibly fueled by a pharmacologically induced in-ase in aGLP-1, the result of DPP-4 inhibition. Sup-ession of both GLP-1 and PYY release may explainweight neutrality with sitagliptin treatment.52 Post-

andial GLP-1 and PYY increases with the LX4211agliptin combination relative to sitagliptin mono-rapy, in the context of an overall reduction in ca-ic load associated with LX4211-mediated UGE anduced intestinal glucose absorption, may produceight loss and its associated benefitsa testable hy-thesis in a longer-term trial.Although the focus is often placed on the absoluteod concentrations of GLP-1 and PYY, it should bephasized that the release of these peptides from theirrmal site may be important for obtaining optimal ben-ts.5359 The GI tract is innervated by afferent vagalrves that express both GLP-1 and PYY receptors. Thegus nerve signals directly from theGI tract to the brain,d it has been demonstrated in animals that the fullnefits of GLP-1 and PYY are lost when the vagus nerveut in the abdomen. Similarly, it has been reported thatfull effects of GLP-1 on postprandial glucose, gastricptying, and appetite are lost in vagotomized humanbjects.60 Thus, the release of these peptides from theGIct may provide enhanced benefits at lower blood con-trations than when GLP-1 analogues are deliveredrenterally.In this current clinical study, tGIP, leptin, and ghre-were measured after LX4211 treatment. Combina-82n in tGIP relative to that resulting from eithernotherapy. K cells secrete GIP, are found primarilythe upper small intestine, and respond to glucose ands in the diet.30 In particular, the transport of glucosems important for GIP release.50,51,61 This hypothe-is supported by findings from preclinical studies,ich have suggested that pharmacologic inhibition ofdium-dependent glucose transport in the GI tract re-ces postprandial GIP release. This finding may ex-in the reduction in GIP release after breakfast withLT1 inhibition. The apparent enhanced effect of4211 sitagliptin on GIP reduction is consistentth a feedback-inhibition effect on tGIP observedth sitagliptin treatment.41 In the context of diabetes,P has beneficial effects, such as enhancing glucose-pendent insulin release, as well as potential negativeects (eg, increasing glucagon, increasing peripheraliposity).3032 GIP-receptor knockout mice are resis-t to diet-induced obesity and have reduced adi-cyte mass and obese/obese (ob/ob); GIP-receptor//ob double-knockouts exhibit less weight gain andiposity and improved glucose tolerance and insulinsitivity relative to ob/ob knockout mice.62 The netect of GIP reduction after pharmacologic inhibitionSGLT1 remains to be determined.Ghrelin and leptin concentrations were not signifi-ntly changed after breakfast with combination treat-nt relative to either monotherapy. It may be thatLT1 inhibition does not increase systemic SCFAs suf-iently to trigger effects on these peptides. Alternatively,effects of SCFAsmight not yet be present at breakfast,longer-term treatment may be required. Potential lep-and ghrelin effects warrant further exploration in ad-ional clinical trials of LX4211.Perhaps the most important result of the presentdy was the net effect of the LX4211 sitagliptinmbination treatment on glucose and insulin. Thembination was associated with significant reduc-ns in blood glucose levels throughout the day rela-e to that resulting from either monotherapy. Insulinel was significantly reduced relative to that resultingm sitagliptin monotherapy and significantly in-ased relative to that resulting from LX4211 mono-rapy. The net effect of the combination treatmentglycemic control was apparently enhanced, with aer insulin concentration relative to that resultingm sitagliptin monotherapy. This reduction in insu-requirements with combination dosing was likelyVolume 35 Number 3

the result of the insulin-independent activity ofLXblytiopoovrhindhibsuwijec

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M4211 on a reduction in overall glucose load. Nota-, LX4211 and the LX4211 sitagliptin combina-n were well tolerated, with no notable GI AEs re-rted in this study. Although theoretical concernser the potential for SGLT1 inhibition to cause diar-ea have led most drug-development efforts in theustry to have been focused on selective SGLT2 in-itors,17,63,64 the present study provides additionalpport for the favorable GI safety profile observedth LX4211 in multiple studies in both healthy sub-ts and patients with T2DM.

NCLUSIONS4211, a first-in-class dual SGLT1/SGLT2 inhibitor, pro-es a potential option for T2DM. The delayed intestinalcose absorption and increased postprandial GLP-1 andY release may provide differentiation from, and the po-tial for producing enhanced benefits over, selectiveLT2 inhibitors. The findings from this study further thisferentiation by suggesting that combinations of LX4211th DPP-4 inhibitors provide additive or synergistic incre-benefits that would not be expected with a selectiveLT2 inhibitor. This study also provides an importantnchmark for the assessment of the novel mechanism ofionofLX4211comparedwith,and incombinationwith,established agent andmechanism used extensively in theatment of T2DM. These initial results suggest that a4211 DPP-4 inhibitor combination has the potentialt only to enhance glycemic control but also to provideditional improvements in metabolic and cardiovascularrameters observed to date with LX4211 but not withP-4 inhibitors.Thepotential long-termclinicalbenefitsofh combination treatment need to be confirmed in largeical trials.

KNOWLEDGMENTSe authors thank Kristi A. Boehm for her writing anditing assistance, Johanna Bronner for ensuring theegrity of the database, Gui-lan Ye for monitoringety, and Kevin Rando for study monitoring.Dr. Zambrowicz, Dr. Ogbaa, Mr. Frazier, Mr.nks, Ms. Turnage, Dr. Freiman, Dr. Ruff, and Dr.nds contributed to the clinical study design; Dr.ng, Ms. Smith, and Dr. Powell contributed to theeclinical study design. All of the authors contributedthe writing and final approval of the manuscript.arch 2013xicon Pharmaceuticals, Inc. provided the fundingthese studies.At the time this work was conducted, all of the au-rs, with the exception of D. Ruff, were employees of,d owned stock options in, Lexicon Pharmaceuticals.e authors have indicated that they have no other con-ts of interest with regard to the content of this article.

PPLEMENTAL MATERIALpplemental files accompanying this article can bend in the online version at http://dx.doi.org/10.16/j.clinthera.2013.01.010.

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. Washburn WN. Evolution of so-dium glucose co-transporter 2 in-hibitors as anti-diabetic agents. Ex-pertOpinTherPat.2009;9:14851499.

owicz, Lexicon Pharmaceuticals,Woodlands, TX 77381. E-mail:285

Supplemental Appendix

INIn

to

1.

2.

3.

4.

5.

Ex

to

1

2. Current use of any blood glucose lowering agent

3

4

5

6

7

8

9

10

11

12

13

14

15


2CLUSION AND EXCLUSION CRITERIAclusion CriteriaSubjects must have met all of the following criteriabe considered eligible to participate in the study:

Adults 18 to 65 years of age at the time ofScreening:a. Females must have been of non-childbearing po-

tential, surgically sterile (documented hysterec-tomy, tubal ligation, or bilateral salpingo-oo-phorectomy) or postmenopausal (defined as 12months of spontaneous amenorrhea). If neces-sary, follicular-stimulating hormone results35IU/L at Screening were confirmatory in the ab-sence of a clear postmenopausal history.

b. Males must have agreed to use an adequatemethod of contraception during the study andfor 30 days after the Discharge visit. Adequatemethods of contraception for subjects or partnerincluded the following: condom with spermici-dal gel, diaphragm with spermicidal gel, coil (in-trauterine device), surgical sterilization, vasec-tomy, oral contraceptive pill, depo-progesteroneinjections, progesterone implant, NuvaRing,Ortho Evra, and abstinence. If a subject wasnot sexually active but became active, he or hispartner was to have used medically acceptedforms of contraception.

History of T2DM for at least 3 months prior toScreening with the following laboratory values:a. HbA1c value of 6.5% to 10.5%b. C-peptide 1.0 ng/mLBody mass index (BMI) 45 kg/m2 at Screeningand planned Day 2Willing and able to perform self-monitoring ofblood glucoseWilling and able to provide written informedconsent

clusion Criteria:Subject who met any of the following criteria werebe excluded from participating in the study:

. History of any of the following: type 1 diabetesmellitus, diabetic ketoacidosis, hyperosmolar non-ketotic syndrome, or diabetes resulting from pan-creatic disorder or secondary diabetes (eg, fromacromegaly, Cushings disease, etc)85.e1other than metformin. Exposure to metformin within 14 days prior toplanned Day 1

. History of renal disease, or clinically significantabnormal kidney function tests at Screening orplanned Day -2, including glomerular filtrationrate 60 mL/min as calculated using the Cock-croft-Gault equation

. Presence of active hepatic disease or clinically sig-nificant abnormal liver function tests at Screeningor planned Day -2 (aspartate transaminase [AST]or alanine transaminase [ALT]2.5 times the up-per limit of normal)

. History of myocardial infarction, severe/unstableangina, or coronary revascularization procedurewithin 6 months prior to planned Day -2

. History of clinically significant cardiac arrhyth-mias (eg, supraventricular tachycardia, ventriculartachycardia, or atrial fibrillation) within 1 yearprior to planned Day -2

. Congestive heart failure and/or New York HeartAssociation Class III or IV symptoms of heart fail-ure

. Subjects with uncontrolled Stage III hypertension(defined as systolic BP 180 mm Hg or diastolicBP 110 mm Hg)

. History of 2 or more emergency room visits, doc-tors visits, or hospitalizations due to hypoglyce-mia within the 6 months prior to planned Day -2,or has a current diagnosis of hypoglycemia un-awareness

. History of alcohol or drug abuse (using Diagnosticand Statistical Manual of Mental Disorders, 4thEdition criteria) within 12 months prior to Screen-ing

. History of bowel resection 20 cm, any malab-sorptive disorder, severe gastroparesis, any GIprocedure for the purpose of weight loss (includ-ing LAPBAND), which would slow gastric emp-tying

. History of human immunodeficiency virus or hep-atitis C virus antibody

. History of major surgery within 3 months prior toplanned Day -2 or was planning any surgery dur-ing the course of the study

. History of any active infection within 2 weeksprior to planned Day -2Volume 35 Number 3

16. History of pancreatitis, including hemorrhagic ornecrotizing pancreatitis

17. History of any malignancy within the last 5 years(except benign skin cancer, including basal andsquamous cell carcinoma of skin and carcinoma insitu of uterine cervix), which could have affectedthe diagnosis of T2DM or assessment of LX4211or sitagliptin

18. History of any serious adverse reaction or hyper-sensitivity to an SGLT inhibitor or any inactivecomponent of LX4211, (ie, microcrystalline cellu-lose, croscarmellose sodium [disintegrant], talc,silicone dioxide, andmagnesium stearate [non-bo-vine]), unless reaction was deemed irrelevant tothe study by the Investigator and Lexicon

19. History of any serious adverse reaction or hyper-sensitivity to sitagliptin or any inactive componentof sitagliptin, (ie, microcrystalline cellulose, anhy-drous dibasic calcium phosphate, croscarmellose

20

21

22. Positive urine pregnancy test at Screening or serumpregnancy at planned Day -2 (females only)

23. Positive urine screen for drugs of abuse at Screen-ing or planned Day -2

24. Positive breath test for alcohol at Screening orplanned Day -2

25. Donation or loss of 400 mL of blood or bloodproduct within 8 weeks prior to planned Day -2

26. Receipt of any protein or antibody-based thera-peutic agents (eg, growth hormones or monoclo-nal antibodies) within 3 months prior to plannedDay-2. Note: Influenza vaccine was allowed if ad-ministered 14 days prior to Day -2

27. Unwillingness to discontinue use of cigarettes orany tobacco product for the duration of study par-ticipation, beginning on Day -2

28. Use of corticosteroids (eg, prednisone) within 2weeks prior to planned Day 1 (day of 1st dose ofstudy medication). Note: Ocular, topical, or in-

29

30

31

3233


Msodium, magnesium stearate, sodium stearyl fu-marate, polyvinyl alcohol, polyethylene glycol,talc, titanium dioxide, red iron oxide, and yellowiron oxide), unless reaction was deemed irrelevantto the study by the Investigator and Lexicon

. The presence of clinically significant physical, lab-oratory, or ECG findings or any concurrent con-dition at Screening that, in the opinion of the In-vestigator and/or Lexicon might have interferedwith any aspect of safety, study conduct, or inter-pretation of results

. Triglycerides1000 mg/dL at Screening or plannedDay -2arch 2013haled steroid preparations were permitted. Use of digoxin or warfarin within 2 weeks prior toScreening

. Need for dietary restrictions, unless the restric-tions were approved by the Investigator and Lex-icon

. Use of any other investigational agent or treatmentwithin 30 days prior to planned Day -2

. Inability or difficulty swallowing whole tablets

. Unwilling or unable to communicate or cooperatewith the Investigator for any reason285.e2

Supplemental Table I. Baseline demographic andclinical characteristics ofthe population in this studyof LX4211, sitagliptin, orboth in patients with type 2diabetes mellitus (N 18).

Characteristic Value

DemographicAge, median (range), y 49.0 (2865)Sex, no. (%)

Male 10 (55.6)Female 8 (44.4)

Race, no. (%)Black or African American 2 (11.1)White 16 (88.9)


2Hispanic ethnicity, no. (%) 14 (77.8)

Clinical, mean (SD)Height, cm 169.05 (9.3)Weight, kg 90.26 (12.3)BMI, kg/m2 31.69 (4.5)C-Peptide, ng/mL 2.965 (1.088)FPG, mg/dL 182.9 (55.42)HbA1c, % 8.028 (1.120)Insulin, U/mL 51.46 (26.96)Triglycerides, mg/dL 162.89 (59.28)24-hr UGE, g/d 24.07 (35.27)GIP, pmol/L 46.32 (16.46)

BMI body mass index; FPG fasting plasma glucose;GIP gastric inhibitory peptide; Hb hemoglobin;UGE urinary glucose excretion.85.e3 Volume 35 Number 3

Treatment B: 100 mg sitagliptin (one [1] - 100 mg tablet)

Treatment C: 400 mg LX4211 + 100 mg sitagliptin, concurrently

D

Supplemental Figure 1. Study schema.


MSupplemental Table II. Timing of all pharmacodynamic measures relative to administration times of LX4211,sitagliptin, or both on study days 1 (baseline), 1, 8, and 15 in patients with type 2diabetes mellitus (N 18).*

Time Point/ Parameter Predose

Hours After Study Drug Administration

0 0.5 11.5 1.5 2 3 4 55.5 5.5 6 7 8 9 99.5 9.5 10 11 12 13 13

Meal B L D SGLP-1, glucose, insulin,PYY, GIP, and leptin(18.5 mL P800 tube)

X X X X X X

Ghrelin (12 mL EDTAtube)

X X X X X X

GLP-1, glucose, insulin,and PYY (2 mL P800tube)

X X X X X X X X X X

B breakfast; D dinner; GIP gastric inhibitory peptide; GLP glucagon-like peptide; L lunch; PYY peptide tyrosine tyrosine; S snack.*All dosing and sampling times are based on meal times (sample times are 3 minutes).With the exception of day 1, study drugs (LX4211, sitagliptin, or both) were administered at 0 hour on each dosing day.Patients were given 30 minutes to complete each meal.46 to 15 14

D/Cmetformin

Washout(metformin) Washout Washout

SCREENING

Ck-in(Sequester)

Number of Subjectsper Sequence

Treatment A: 400 mg LX4211 (two [2] - 200 mg tablets)

Period 1Treatment

Period 2Treatment

Period 3Treatment

BL Dose1

ay 2 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Dose2

Dose3

D/C

3 A B C

3 B C A

3 C A B

3 C B A

3 A C B

3 B A Carch 2013 285.e4

160

*

140

120

aGLP

-1 (

pM)

100

80

60

40

20

0Vehicle LX4211 Sitagliptin LX4211 +

A 250 LX4211 60 mg/kg

LX4211 + sitagliptinVehicle

Sitagliptin 30 mg/kg200

150

100

50

00 0.5

Time (h)

aGLP

-1 (

pM)

*

*

1 3 6

Supplemental Figure 3. Active glucagon-like pep-tide (aGLP)-1 concentra-tions after meal challengein mice administered multi-ple-dose (14-day) LX4211,sitagliptin, LX4211 sita-gliptin, or inactive vehicle(n 5 per group). *P 0.0001; P 0.011; P 0.0003 (2-way ANOVA).


2

aGLP

-1 (

pM)

60

50

40

30

20

10

0

60 mg/kg 30 mg/kg Sitagliptin

Vehicle LX421160 mg/kg

Sitagliptin30 mg/kg

LX4211 +Sitagliptin

B

Supplemental Figure 2. Increases from baseline inactive glucagon-like pep-tide (aGLP)-1 concentra-tions at (A) 1 hour and (B)2 hours after meal chal-lenge in mice administeredsingle-dose LX4211, sita-gliptin, LX4211 sita-gliptin, or inactive vehicle(n 5 per group). *P 0.0208; P 0.0017;P 0.116; P 0.0006(2-way ANOVA).85.e5 Volume 35 Number 3

Allocated to intervention for dosing sequences ABC, BCA, CAB, CBA, ACB, and BAC (n = 18; 3 per dosing sequence)

Allocation

Follow-Up


MIncluded in the final analysis (n =18)

Excluded from analysis (n= 0)

Lost to follow-up (n = 0) Discontinued intervention (n = 0)

Analysis

Supplemental Figure 4. Study flow.

Supplemental Table III. Changes from baseline in total glucagon-like peptide 1 with LX4211, sitagliptin, or bothin patients with type 2 diabetes mellitus (adjusted generalized linear mixed model) (N18). Values are least squares mean (95% CI) (pmol h/L).

Parameter

LX4211 Sitagliptin LX4211 Sitagliptin

Value P Value P Value P

Change vsbaseline

24.63 (12.20 to 37.06) 0.001 23.78 (36.20 to 11.35) 0.001 0.56 (12.99 to 11.87) 0.93

Difference vscombination

25.19 (40.70 to 9.69) 0.002 23.21 (7.71 to 38.71) 0.005 Assessed for eligibility (n = 38)

Excluded (n = 20) Did not meet inclusion criteria (n = 15) Declined to participate (n = 3) Enrollment filled (n = 2)

Randomized (n= 18)

Enrollmentarch 2013 285.e6

Supplemental Table V. Changes from baseline in total gastric inhibitory peptide with LX4211, sitagliptin, or both


2in patients with type 2 diabetes mellitus (adjusted generalized linear mixed model) (N18). Values are least squares mean (95% CI) (pmol h/L).

Parameter



Change vsbaseline

55.16 (66.68 to 43.65) 0.001 68.78 (80.29 to 57.26) 0.001 101.02 (112.53 to 89.50) 0.001


45.85 (62.71 to 29.00) 0.001 32.24 (49.10 to 15.38) 0.001 Supplemental Table IV. Changes from baseline in total peptide tyrosine tyrosine with LX4211, sitagliptin, orboth in patients with type 2 diabetes mellitus (adjusted generalized linear mixed model)(N 18). Values are least squares mean (95% CI) (pmol h/L).

Parameter



Change vsbaseline

61.67 (38.24 to 85.10) 0.001 134.72 (158.14 to 111.29) 0.001 91.11 (114.53 to 67.68) 0.001


152.78 (187.07 to 118.49) 0.001 43.61 (9.32 to 77.90) 0.014 85.e7 Volume 35 Number 3

Effects of LX4211, a Dual SGLT1/SGLT2 Inhibitor, Plus Sitagliptin on Postprandial Active GLP-1 a ...IntroductionMaterials and MethodsPreclinical Pharmacology In MiceStudy DesignAssessmentsStatistical Analysis

Clinical Study In Patients With Type 2 DiabetesStudy DesignAssessmentsStatistical Analysis

ResultsPreclinical Pharmacology In MiceClinical Studies In Patients With Type 2 Diabetes

DiscussionConclusionsConflicts of InterestSupplemental MaterialAcknowledgmentsReferencesSupplemental AppendixINCLUSION AND EXCLUSION CRITERIAInclusion CriteriaExclusion Criteria

Documents

LX4211 paper sobre farmaco control de la glicemia para gente con diabetes mellitus tipo 2