Original Article Clinical Diabetes & Therapeutics INTRODUCTION DIABETES & METABOLISM JOURNAL

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1 Originl Article Clinicl Dibetes & Therpeutics Dibetes Metb J Published online Dec 2, pissn eissn DIABETES & METABOLISM JOURNAL Acrbose Add-on Therpy in Ptients with Type 2 Dibetes Mellitus with Metformin nd Sitgliptin Filure: A Multicenter, Rndomized, Double-Blind, Plcebo-Controlled Study He Kyung Yng 1, Seung-Hwn Lee 1,2, Juyoung Shin 1,2, Yoon-Hee Choi 1,2, Yu-Be Ahn 1,3, Byung-Wn Lee 4, Eun Jung Rhee 5, Kyung Wn Min 6, Kun-Ho Yoon 1,2 1 Deprtment of Internl Medicine, College of Medicine, The Ctholic University of Kore, Seoul, 2 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Seoul St. Mry s Hospitl, College of Medicine, The Ctholic University of Kore, Seoul, 3 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, St. Vincent s Hospitl, College of Medicine, The Ctholic University of Kore, Suwon, 4 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Severnce Hospitl, Yonsei University College of Medicine, Seoul, 5 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Kngbuk Smsung Hospitl, Sungkyunkwn University School of Medicine, Seoul, 6 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Eulji Generl Hospitl, Eulji University School of Medicine, Seoul, Kore Bckground: We evluted the efficcy nd sfety of crbose dd-on therpy in Koren ptients with type 2 dibetes mellitus (T2DM) who re indequtely controlled with metformin nd sitgliptin. Methods: A totl of 165 subjects were rndomized to metformin nd sitgliptin (, n=65), metformin, sitgliptin, nd crbose (, n=66) nd sitgliptin nd crbose (Sit+Acrb, explortory ssessment, n=34) therpy in five institutions in Kore. After 16 weeks of crbose dd-on or metformin-switch therpy, triple combintion therpy ws mintined from week 16 to 24. Results: The dd-on of crbose ( group) demonstrted.44%±.8% (P<.1 vs. bseline) decrese in glycosylted hemoglobin (HbA1c) t week 16, while chnges in HbA1c were insignificnt in the group (.9%±.1%, P=.113). After 8 weeks of triple combintion therpy, HbA1c levels were comprble between nd group (7.66%±.13% vs. 7.47%±.12%, P=.321). Acrbose dd-on therpy demonstrted suppressed glucgon secretion (re under the curve of glucgon, 4,726.17±415.8 ng min/l vs. 3,314.38± ng min/l, P=.4) in the bsence of excess insulin secretion during the mel tolernce tests t week 16 versus bseline. The incidence of dverse or serious dverse events ws similr between two groups. Conclusion: In conclusion, 16-week crbose dd-on therpy to metformin nd sitgliptin, effectively lowered HbA1c without significnt dverse events. Acrbose might be good choice s third-line therpy in ddition to metformin nd sitgliptin in Koren subjects with T2DM who hve predominnt postprndil hyperglycemi nd high crbohydrte intke. Keywords: Acrbose; Dibetes mellitus, type 2; Drug therpy, combintion; Metformin; Sitgliptin phosphte INTRODUCTION Dibetes mellitus is one of the most common metbolic disorders nd hs n incresing prevlence worldwide. Severl new clsses of gents, including glucgon-like peptide 1 (GLP-1) gonists, dipeptidyl peptidse-4 (DPP4) inhibitors, nd sodi- Corresponding uthor: Kun-Ho Yoon Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Seoul St. Mry s Hospitl, College of Medicine, The Ctholic University of Kore, 222 Bnpodero, Seocho-gu, Seoul 6591, Kore E-mil: yoonk@ctholic.c.kr Received: Mr. 3, 218; Accepted: Aug. 11, 218 This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. Copyright 218 Koren Dibetes Assocition pge 1 of 15

2 Yng HK, et l. um-glucose cotrnsporter 2 (SGLT-2) inhibitors, hve been introduced nd demonstrted drmtic increse in their use, wheres the older tretments continue to be replced or supplemented by newer therpies [1]. Among the vrious clsses of ntihyperglycemic gents, metformin remins the optiml gent s the initil mediction becuse of its low cost, proven sfety record, weight neutrlity nd possible benefits on crdiovsculr outcomes. Regrding second- nd third-line gents, the Americn Dibetes Assocition/Europen Assocition for the Study of Dibetes (ADA/ EASD) nd the Americn Assocition of Clinicl Endocrinologists/Americn College of Endocrinology (AACE/ACE) recommend n individulized pproch, considering the mediction efficcy, side effects, costs nd potentil weight chnge, rther thn one-size-fits-ll pproch [2,3]. α-glucosidse inhibitors hve been widely prescribed s monotherpy or s combintion with other orl ntihyperglycemic medictions in Asin countries [4,5], where postprndil hyperglycemi is known to be predominnt or eqully importnt contributor to excess hyperglycemi in type 2 dibetes mellitus (T2DM) [6]. Furthermore, DPP4 inhibitor nd α-glucosidse inhibitor combintion therpy represents n ttrctive tretment option by inhibiting the rpid elevtion of postprndil blood glucose levels without excessive insulin secretion, nd potentition of ctive GLP-1 secretion [7]. Previously, the synergistic effects of n α-glucosidse inhibitor nd DPP4 inhibitor on plsm insulin nd ctive GLP-1 levels were reported in mice [8,9]. In clinicl studies, DPP4-inhibitor dd-on therpy with the α-glucosidse inhibitor [1-13] or α-glucosidse inhibitor dd-on therpy with the DPP4 inhibitor [14-16] hve been shown to improve glycemic control nd stbilize glucose fluctution [14] in ptients with T2DM. However, the effect of crbose s third-line therpy in subjects who re poorly controlled with metformin nd DPP4- inhibitor hs less been evluted. In the present study, we evluted the efficcy nd sfety of dding crbose in Koren ptients with T2DM who showed n indequte response to metformin nd sitgliptin dul combintion therpy. METHODS Study popultion This study ws conducted s multicenter, 24-week, doubleblinded, rndomized, plcebo-controlled study in five institutions throughout Kore. The subjects were eligible for this study if they hd T2DM, were ged 2 to 8 yers, hd been tking stble doses of metformin ( 1, mg/dy) nd sitgliptin for t lest 12 weeks, nd hd glycosylted hemoglobin (HbA1c) 7.% to 1.%. The exclusion criteri were bnorml renl function (serum cretinine >133 μmol/l for men nd >124 μmol/l for women), bnorml liver function (sprtte trnsminse or lnine trnsminse 2.5 times the upper limit of norml) nd history of cute or chronic metbolic cidosis, congestive hert filure requiring tretment or showing New York Hert Assocition clss III/IV dyspne, inflmmtory bowel disese, intestinl ulcer, enterostenosis or chronic enteric disese. The prticipnts who hd history of myocrdil infrction, unstble ngin, coronry rtery bypss grft surgery within 6 months or mlignncy within 5 yers were lso excluded from the study. Study design The eligible prticipnts were rndomized nd ssigned t rtio of 2:2:1 to the following groups: the metformin, sitgliptin, nd crbose plcebo () group; metformin, sitgliptin nd crbose () group; or metformin plcebo, sitgliptin nd crbose (Sit+Acrb) group. In Sit+Acrb group, metformin ws switched to crbose; the verge dose of metformin ws 1,33 mg before week, nd the sme doses of metformin were dded-on t week 16 in ech individul. The subjects who received DPP4 inhibitors other thn sitgliptin (sxgliptin, n=44; vildgliptin, n=12; lingliptin, n=5; gemigliptin, n=1) were switched to sitgliptin 1 mg once dy. Acrbose or its plcebo ws prescribed n initil dose of 5 mg twice dy for the first 2 weeks, then 5 mg three times dy for the next 2 weeks nd subsequently 1 mg three times dy until the end of the study period. This initil tretment ws mintined for 16 weeks (crbose ddon or metformin-switch therpy), followed by n 8-week tretment with metformin, sitgliptin, nd crbose triple combintion (triple combintion therpy) in ll three groups (Fig. 1). Mel tolernce tests (MTTs) were performed in single institution t bseline nd week 16 in the nd Met+ Sit+Acrb group. The prticipnts ingested two cloric brs (268 kcl) (Soyjoy; Otsuk Phrmceuticl, Tokyo, Jpn) nd one cloric drink (2 kcl) (Newcre; Desng Welllife, Seoul, Kore), nd blood smples were obtined t, 3, 6, 9, nd 12 minutes during the MTT. The continuous glucose monitoring system (CGMS) ws pplied (MiniMed; Medtronic Inc., Northridge, CA, USA) to monitor glucose fluctutions t bse- pge 2 of 15

3 Acrbose s third-line dd-on therpy Type 2 dibetes mellitus with filure Rndomiztion Acrbose dd-on or metformin-switch therpy Week Week 16 Week 24 (control) (crbose dd-on) Sit+Acrb (metformin-switch to crbose) Triple combintion therpy A 185 Assessed for eligibility 2 Excluded 165 Rndomly ssigned 65 Metformin+Sitgliptin+Plcebo 66 Metformin+Sitgliptin+Acrbose 34 Plcebo+Sitgliptin+Acrbose 13 Discontinued intervention 2 Lost to follow-up 7 Withdrew informed consent 4 Hd other cuse 14 Discontinued intervention 1 Lost to follow-up 8 Withdrew informed consent 5 Hd other cuse 12 Discontinued intervention 3 Withdrew informed consent 1 Adverse events 8 Hd other cuse 52 Per-protocol popultion 65 Intention-to-tret popultion 52 Per-protocol popultion 66 Intention-to-tret popultion 22 Per-protocol popultion 34 Intention-to-tret popultion B Fig. 1. Study protocol (A) nd disposition of ptients (B)., group treted with metformin, sitgliptin, nd crbose plcebo;, group treted with metformin, sitgliptin, nd crbose; Sit+Acrb, group treted with metformin plcebo, sitgliptin nd crbose. line nd week 16 in the three groups from single institution. All of the prticipnts were instructed to check self-monitor their blood glucose (SMBG) levels seven times per dy (before ech mel, 2-hour fter ech mel nd t bedtime) t week 16 nd 24. Efficcy nd sfety ssessment The primry objective ws to compre the chnges in HbA1c between bseline nd week 16 in the nd + Acrb group. The secondry objectives were to compre the chnges in HbA1c between nd Sit+Acrb group, nd to evlute the chnges in body weight, wist circumference, systolic nd distolic blood pressures, fsting nd postprndil 2-hour glucose, totl cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol (LDL-C), nd C-rective protein (CRP) in three groups. The plsm glucose, insulin nd glucgon levels were mesured using smples obtined during the MTTs. The re under the curve (AUC) of glucose, insulin nd glucgon ws clculted using the trpezoid method. The homeostsis model ssessment of β-cell (HOMA-β) nd insulin resistnce (HOMA-IR) were clculted using the glucose nd insulin vlues obtined during MTT s following equtions, respectively: [2 fsting insulin (μu/ml)]/[fsting blood glucose (mmol/l) 3.5)]; [fsting blood glucose (mmol/l) fsting insulin (μu/ml)]/ The insulinogenic index ws clculted s follows: [3- minute insulin (μu/ml) fsting insulin]/[3-minute glucose (mg/dl) fsting glucose]. The CGMS prmeters were clculted from ech CGMS output, which ws extrcted using the CGMS 3. softwre pge 3 of 15

4 Yng HK, et l. pckge (Medtronic Minimed, MMT-731 version 3. C [3..128]). The men±stndrd devition (SD) nd coefficient of vrince (CV) of glucose were clculted using ll of the consecutive sensor redings mesured t 5-minute intervls over 3 dys. The men mplitude of glycemic excursion (MAGE) ws used to ssess the intrdy glucose vribility. MAGE ws clculted by mesuring the rithmetic men of the differences of the consecutive peks nd ndirs tht were lrger thn the SD [17]. Every dverse event (AE) ws monitored nd recorded regrdless of the intensity or cuse. All of the bnormlities identified in the clinicl lbortory tests, which included serum chemistry, hemtology, nd urine tests, were recorded. The durtions of the AEs nd the follow-up ctions were lso recorded. Sttisticl nlyses The smple size clcultion is bsed on the norml pproximtion of the test sttistic for compring two mens ssuming men difference of.6% [18], stndrd devition of 1.27%, power of 8%, two-sided significnce level of α of.5 nd drop-out rte of 15%. A totl of 165 subjects were required for group nd group. The Sit+Acrb group ws n explortory ssessment nd therefore smller number of prticipnts ws ssigned without forml sttisticl clcultion. All of the dt re expressed s the men±stndrd error vlues or s numbers with proportions. The differences in the bseline chrcteristics mong the three groups were determined using nlysis of vrince or the chi-squre test for the normlly distributed vribles nd the Kruskl-Wllis test or Fisher s exct test for the vribles with skewed devitions. The between-group differences in the HbA1c chnges from bseline to week 16 or from week 16 to 24 were ssessed by nlysis of covrince using bseline HbA1c s covrite. The pired t-test or Wilcoxon signed rnk test ws used to ssess the intr-group differences of the mesurements between the bseline nd week 16 or 24. For the sfety nlysis, ll of the rndomized ptients who received t lest one dose of the investigtionl product nd ttended visit fterwrd were included in the study. The lst observtion crried forwrd ws pplied for the ptients who withdrew in the middle of the study. All of the hypotheses were ssessed t the two-tiled 5% level of significnce. The subjects re ssigned to three groups t the rtio of 2:2:1 nd the block rndomiztion were pplied. The rndom lloction ws performed by sttisticin hving no stke in this study using SAS version softwre (SAS Institute Inc., Cry, NC, USA). The SAS version 9.2 softwre (SAS Institute Inc.) ws used to perform the sttisticl nlysis. All nlyses were performed in the intention-to-tret popultion. Ethics Every ptient who prticipted in this study provided his or her written informed consent. The study ws pproved by the independent Institutionl Review Bord of ech study center (XC11MINT18K). The study ws conducted in ccordnce with the ethicl principles of the Declrtion of Helsinki. RESULTS Bseline chrcteristics Among 185 subjects, 2 subjects were excluded nd 65, 66, nd 34 subjects were rndomly ssigned to the, Met+ Sit+Acrb, nd Sit+Acrb group, respectively (Fig. 1). The number of ptients who completed the entire study were 52, 52, nd 22 in the Met+Sti,, nd Sit+Acrb group, respectively. The men ge, mle proportion, body mss index (BMI), nd wist circumference differed mong the three groups (Tble 1). The men±stndrd error vlues of the bseline HbA1c were 8.%±.1%, 7.93%±.9%, nd 7.86%±.13% in the,, nd Sit+ Acrb group, respectively (P=.655). Other vribles, including the liver function test nd lipid prmeters did not show significnt differences mong the three groups. Primry objectives After 16 weeks of crbose dd-on therpy, the HbA1c levels reched 7.91%±.13% nd 7.49%±.11%, nd the HbA1c chnges compred to the bseline vlues were.9%±.1% (P=.113) nd.44%±.8% (P<.1) in the nd group, respectively (Fig. 2). After mintining metformin, sitgliptin, nd crbose triple combintion therpy from weeks 16 to 24, the HbA1c levels demonstrted 7.66%±.13% nd 7.47%±.12% in the nd Met+ Sit+Acrb group, respectively (P=.321, vs. Met+ Sit+Acrb group). The HbA1c chnges compred to week 16 were.25%±.5% (P<.1) nd.3%±.5% (P=.429) in the nd group, respectively. Anlyses of the per-protocol-popultion did not ttenuted these results (Supplementry Tble 1). pge 4 of 15

5 Acrbose s third-line dd-on therpy Tble 1. Bseline clinicl chrcteristics of the intention-to-tret popultion Chrcteristic Sit+Acrb P vlue Number Age, yr 56.55± ± ± Mle sex 35 (53.85) 23 (34.85) 2 (58.82).3 Body weight, kg 68.88± ± ± Height, cm ± ± ± Body mss index, kg/m ± ± ± Wist circumference, cm 88.57± ± ±1.2.8 Systolic blood pressure, mm Hg ± ± ± Distolic blood pressure, mm Hg 77.6± ± ± HbA1c, % 8.± ± ± Fsting plsm glucose, mmol/l 8.57± ± ± PP 2-hour plsm glucose, mmol/l 12.84± ± ± Blood ure nitrogen, mmol/l 5.43± ± ± Cretinine, μmol/l 72.27± ± ± AST, U/L 22.5± ± ± ALT, U/L 25.48± ± ± Totl cholesterol, mmol/l 3.99± ± ± Triglyceride, mmol/l 1.42± ± ± HDL-C, mmol/l 1.21± ±.3 1.2±.7.77 LDL-C, mmol/l 2.16± ±.6 2.8± CRP, mg/dl.35±.12.21±.5.38± Vlues re presented s men±stndrd error or number (%)., the group treted with metformin, sitgliptin, nd crbose plcebo;, the group treted with metformin, sitgliptin, nd crbose; Sit+Acrb, the group treted with metformin plcebo, sitgliptin nd crbose; HbA1c, glycosylted hemoglobin; PP, postprndil; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; CRP, C-rective protein. Secondry objectives After metformin-switch therpy in Sit+Acrb group, HbA1c level incresed by.84%±.21% (P<.1) nd reched 8.71%±.25% t week 16 (Fig. 1). After mintining metformin, sitgliptin, nd crbose triple combintion therpy from weeks 16 to 24, HbA1c decresed by.61%±.12% (P<.1) nd demonstrted 8.9%±.27% (P=.267, vs. Sit+Acrb group) in Sit+Acrb group. At week 16, the body weight of the enrolled subjects significntly decresed by 2.2±.85 kg (P<.1) nd 1.26±.87 kg (P=.19) in the nd Sit+Acrb group, respectively, but not in the group (P=.77) (Supplementry Tble 2). Compred to the bseline vlues, the fsting plsm glucose decresed by.57±.15 mmol/l (P<.1) in the group nd incresed by 1.8±.38 mmol/l (P<.1) in the Sit+Acrb group. The postprndil 2-hour glucose level decresed by 1.5±.42 mmol/l (P<.1) in the group nd incresed by 2.18±.72 mmol/l (P=.3) in the Sit+Acrb group t week 16 versus bseline. The intrgroup chnges in wist circumference, systolic nd distolic blood pressures, nd LDL-C level were insignificnt in the three groups t week 16 versus bseline. However, the triglyceride level incresed by.25±.8 mmol/l (P=.2) nd decresed by.21±.9 mmol/l (P=.14) in the Met+ Sit+Acrb nd Sit+Acrb group, respectively, t week 16 versus bseline. The MTTs were performed in 13 subjects from ech of the nd group (Fig. 3). Except for the insulin level t minute, the chnges in the glucose, insulin nd glucgon levels were insignificnt t ll of the time points pge 5 of 15

6 Yng HK, et l. Acrbose dd-on or metformin-switch therpy (bseline to week 16) HbA1c level (%) Sit+Acrb Bseline Week 16 Chnges in HbA1c level (%) from bseline to week , b, b Sit+Acrb A Metformin, sitgliptin nd crbose triple combintion therpy (week 16 to week 24) HbA1c level (%) Week 16 Week 24 Chnges in HbA1c level (%) from week 16 to week b, b Sit+Acrb B Fig. 2. Chnges in glycosylted hemoglobin (HbA1c) levels. Chnges in the HbA1c levels during crbose dd-on or metforminswitch therpy (A, bseline to week 16) nd metformin, sitgliptin, nd crbose triple combintion therpy (B, week 16 to 24). The men±stndrd error vlues of the HbA1c levels (%) re plotted in line grphs with demonstrting P<.5 compred to the HbA1c level in the group. The chnges in the HbA1c levels (%) from the bseline to week 16 nd from week 16 to 24 re plotted in the br grphs. The between-group differences in the chnges in the HbA1c from the bseline to week 16 nd from week 16 to 24 were ssessed by nlysis of covrince using bseline HbA1c s covrite., the group treted with metformin, sitgliptin, nd crbose plcebo;, the group treted with metformin, sitgliptin, nd crbose; Sit+Acrb, the group treted with metformin plcebo, sitgliptin nd crbose. P<.5 compred to bseline, b P<.5 compred to the HbA1c chnge in the group. in the group t week 16 versus bseline. In the Met+ Sit+Acrb group, the glucose level t minute ws significntly lower t week 16 compred to the bseline vlue (7.76±.26 mmol/l vs. 6.87±.31 mmol/l, P=.9). Although the insulin levels were similr t ll time points, the glucgon level t, 9, nd 12 minutes were significntly lower t week 16 compred to the bseline in the group. In the group, the AUC of glucgon significntly decresed t week 16 versus bseline (4,726.17± ng min/l vs. 3,314.38± ng min/l, P=.4), which ws not observed in the group (4,2.41± ng min/l vs. 3,941.19± ng min/l, P=.426). The HOMA-IR significntly incresed in the group (1.66±2.33, P=.24), but not in the group ( 1.2±2.8, P=.92) t week 16 versus bseline (Supplementry Tble 3). There were no significnt chnges in HOMA-β nd insulinogenic index between bseline nd week 16 in both groups. The CGMS mesurements were obtined in 11, 13, nd six subjects from the Met+Sti,, nd Sit+Acrb group, respectively (Tble 2). The SD of glucose during the 72- pge 6 of 15

7 Acrbose s third-line dd-on therpy Glucose (mmol/l) Bseline Week AUC of glucose (mmol min/l) 2, 1,5 1, 5 Bseline Week 16 A 3, Insulin (pmol/l) AUC of insulin (pmol min/l) 2, 1, B 6 8, Glucgon (ng/l) 4 2 AUC of glucgon (ng min/l) 6, 4, 2, C Fig. 3. Chnges in the glucose, insulin nd glucgon levels during the mel tolernce tests. The men±stndrd error vlues of the glucose (A), insulin (B), nd glucgon (C) levels t ech time point during the mel tolernce tests t bseline nd week 16 re plotted with line grphs, nd the men±stndrd devition of re under the curve (AUC) vlues re plotted in the br grphs., the group treted with metformin, sitgliptin, nd crbose plcebo;, the group treted with metformin, sitgliptin, nd crbose. P<.5 between bseline nd week 16. hour CGMS monitoring significntly decresed in the Met+ Sit+Acrb group t week 16 compred to the bseline vlue (P=.13). Among the three groups, the chnges in the men, SD nd CV vlues of the glucose level nd MAGE were similr. The SMBG levels were mesured t weeks 16 nd 24 in ll of the subjects from three groups. Compred to the mesure- pge 7 of 15

8 Yng HK, et l. Tble 2. Mesurements of glucose fluctution obtined from continuous glucose monitoring system Chrcteristic Sit+Acrb P vlue Number Men glucose, mg/dl.91± ± ± Stndrd devition of glucose, mg/dl.33±.3.65±.22.3± Coefficient of vrince of glucose, %.1±.15.22±.11.27± Men mplitude of glycemic excursion 8.79± ± ± Vlues re presented s men±stndrd error., the group treted with metformin, sitgliptin, nd crbose plcebo;, the group treted with metformin, sitgliptin, nd crbose; Sit+Acrb, the group treted with metformin plcebo, sitgliptin nd crbose. Chnges of P<.5 t week 16 compred to bseline. ments in the group, the group demonstrted lower vlues fter lunch (1.28±.37 mmol/l vs. 8.78±.29 mmol/l, P=.4) nd fter dinner (1.51±.44 mmol/l vs. 9.14±.33 mmol/l, P=.13) t week 16. However, t week 24, the SMBG levels were similr t ll time points in the subjects in the nd +Acrb group. Compred to the SMBG levels in the group, the Sit+Acrb group demonstrted higher vlues t ll time points t week 16. At week 24, the SMBG levels demonstrted similr levels between nd Sit+Acrb group before brekfst, before nd fter lunch. Bseline ge, sex, body weight, BMI, nd wist circumference significntly differed mong three groups. However, further djustment for ge, sex, nd BMI did not ttenuted the originl results, except for the chnges in triglyceride level t week 16 (P=.95) nd CRP level t week 24 (P=.711). Sfety profile Among the 165 subjects in the sfety nlysis popultion, 14 (21.54%), 19 (28.79%), nd 11 (32.35%) ptients reported one or more AEs in the,, nd Sit+Acrb group, respectively. Adverse drug rections (ADRs) were reported in nine (13.85%), 1 (15.15%), nd three (8.82%) subjects in the,, nd Sit+Acrb group, respectively. Serious dverse effects (SAEs) were reported in two (3.8%, chest pin nd lumbr spinl stenosis) nd one ptient (1.52%, spinl osteorthritis) in the nd Met+ Sit+Acrb group, respectively. There were no significnt differences in the prevlence of the AE, ADR, or SAE mong the three groups. None of the SAE ws relted to the investigtionl gents. DISCUSSION In this study, the 16-week crbose dd-on therpy in ptients with T2DM who were poorly controlled with metformin nd sitgliptin significntly improved the HbA1c level, reduced the SD of glucose during the 72-hour CGMS nd suppressed the glucgon secretion during the MTT. While switching metformin to crbose initilly worsened the blood glucose level, the metformin dd-on therpy to the Sit+Acrb group effectively lowered the HbA1c level by.61%±.12% in 8 weeks. The metformin, sitgliptin, nd crbose triple combintion therpy ws well tolerted nd ws not ssocited with tretmentrelted AEs. Despite the good initil efficcy of the orl ntihyperglycemic gents, ptients with T2DM often require multiple ntihyperglycemic gents to chieve glycemic control becuse of the progressive nture of dibetes mellitus [2,19]. Trditionlly, the most common combintion of orl ntihyperglycemic gents used for ptients with T2DM hs been metformin nd sulfonylure [2]. Previous studies on the efficcy of orl ntihyperglycemic gent triple combintion therpy hve been, for the most prt, conducted with dd-on therpy with metformin nd sulfonylure [21]. However, fter the introduction of DPP4 inhibitor, the proportion of metformin nd DPP4 inhibitor combintion therpy hs been incresing, reching 2% to 4% of the totl dul combintion therpy in the United Sttes [3]. In selecting third gent dded to metformin nd DPP4 inhibitor, the ADA/EASD guidelines recommend selecting one of the gents mong sulfonylure, thizolidinedione, SGLT-2 inhibitor or insulin, wheres other gents, including α-glucosidse inhibitor, re generlly not fvored becuse of their modest efficcy nd frequency of dministrtion [2]. However, considering the potentil synergistic effect of α-glucosidse inhibitor nd pge 8 of 15

9 Acrbose s third-line dd-on therpy DPP4 inhibitor, this combintion might be n idel choice in T2DM. Especilly, elderly subjects with high risk of hypoglycemi nd high crbohydrte intke or postprndil hyperglycemi would be one of the optiml cndidtes for metformin, DPP4 inhibitor nd α-glucosidse inhibitor triple combintion. Acrbose is known to reduce HbA1c by.7% to.8% in monotherpy [22] nd by.6% when dded to metformin monotherpy [23]. When used in combintion, the mjority of the ntihyperglycemic gents reduced HbA1c to lesser extent compred to monotherpy [23]. In our study, the crbose ddon therpy to metformin nd sitgliptin reduced HbA1c by.44%±.8%. Unfortuntely, no direct comprison of crbose with other ntihyperglycemic gents in combintion with metformin nd DPP4 inhibitor is vilble, nd the efficcy of crbose s third-line therpy wrrnts dditionl clinicl trils. α-glucosidse inhibitors block the decomposition of discchrides by inhibiting α-glucosidse in the brush border of smll intestinl mucosl epithelil cells [24]. As result, sugrs tht re primrily bsorbed in the upper smll intestine re bsorbed more slowly through the entire smll intestine, which in turn, cuses the reltive suppression of glucose-dependent insulinotropic polypeptide (GIP) secretion from the K-cells in the upper smll intestine, nd enhnces GLP-1 secretion from the L-cells in the lower smll intestine [25]. In murine model of dibetes, tretment with DPP4-inhibitor nd α-glucosidse inhibitor elicited 2.5- to 4.9-fold synergistic increse in ctive GLP-1 compred to the control [8]. In the subjects without T2DM, the AUC of the plsm ctive GLP-1 level increment ws potentited when miglitol nd sitgliptin were used in combintion (153% increse compred to the plcebo) thn when they were used s monotherpy (38% nd 78% increse fter miglitol nd sitgliptin monotherpy, respectively) [26]. In subjects with T2DM, the combintion of miglitol nd sitgliptin demonstrted dditive effect on glycemic control nd ctive GLP-1 level compred to miglitol monotherpy or sitgliptin monotherpy [27]. Furthermore, enhncement of ctive GIP by sitgliptin ws bolished by combintion therpy with miglitol. Unfortuntely, we were unble to mesure the ctive GLP-1 or GIP level, which might hve provided more informtion on the likely synergistic effects of sitgliptin nd crbose. A single dministrtion or 2-week tretment of crbose filed to demonstrte significnt chnges in the plsm glucgon level during MTT in the subjects with T2DM [28,29]. In report by Kishimoto nd Nod [3], the short-term co-dministrtion of α-glucosidse inhibitor (miglitol) nd DPP4-inhibitor (ngliptin) showed tendency for suppressed glucgon secretion in four ptients. Theoreticlly, GLP-1 reduces glucose levels through its potent insulinotropic ction s well s by suppressing glucgon secretion [31]. It remins uncler whether GLP-1 suppresses glucgon secretion directly [32] or indirectly by other prcrine fctors [31] or vi the centrl nd peripherl nervous systems [33]. Also, suppressed glucgon secretion in the group might be due to the modultion of bile cid metbolism in the smll intestine. Recent report by Gu et l. [34] demonstrted tht crbose modulted the composition of gut thereby chnging gut bile cid composition, resulting improvement in metbolic prmeters. Also, metformin hs been proposed to increse GLP-1 secretion vi modultion of bile cids [35]; inhibitory effect of metformin on bile cid rebsorption increses the luminl concentrtion of bile cids nd stimultes Tked G-protein receptor 5 (TGR5) on enteroendocrine L-cells, leding to incresed GLP-1 secretion. Previous studies with smll number of prticipnts hve demonstrted insignificnt chnges in glucgon secretion fter short-term tretment of α-glucosidse inhibitors [28-3,36]. However, in our study, the glucgon levels were suppressed fter crbose dd-on therpy in the Met+ Sit+Acrb group. Whether this effect is ssocited with chnges in GLP-1 or GIP levels wrrnts dditionl evlution. While α-glucosidse inhibitors re known to hve neutrl effect on body weight, there were moderte body weight reductions in nd Sit+Acrb group in our study. This finding is in line with those of previous other studies [4,27,37,38]. Reduced nutrient bsorption, improved gut microbiot nd prolonged stimultion of enteroinsulinr xis with decresed hyperinsulinemic response hve been suggested s explntions for weight reduction effect of crbose [4,37]. In study with overweight (BMI 25 kg/m 2 ) Jpnese ptient with T2DM [27], only those with miglitol nd sitgliptin combintion therpy, but not with miglitol or sitgliptin monotherpy, demonstrted reduced viscerl ft mss nd incresed serum diponectin level. This fvorble effect on body ft composition ws explined by potentited increse in GLP- 1 level nd decresed or neutrl effect on GIP level with the combintion therpy. The limittions of this study include single ethnic group, nd smll number of prticipnts who performed MTT nd pge 9 of 15

10 Yng HK, et l. CGMS. Only 13 prticipnts in ech group were ble to perform MTT. Among the totl subjects in the group (n=66), fsting plsm glucose nd postprndil 2-hour plsm glucose significntly decresed fter 16 weeks of tretment. However, mong subjects who performed MTT, the glucose level t ech time point or AUC of glucose ws similr between bseline nd week 16 in the group (n=13), except for the fsting glucose level. This discrepncy might be the consequence of reltively lower bseline HbA1c (7.93%±.9% vs. 7.78%±.13%) nd fsting plsm glucose (8.21±.21 mmol/l vs. 7.76±.26 mmol/l) s well s the smll number of enrolled prticipnts who performed MTT compred to the totl popultion. Bloomgrden et l. [39] demonstrted tht irrespective of the mediction clss, the bseline glycemic sttus strongly influenced the efficcy of the ntihyperglycemic gents. Therefore, further studies re required to confirm our study results. Yng et l. [4] reported tht considerble crbohydrte intke ws ssocited with trend towrd greter HbA1c decrese in Chinese subjects treted with crbose. Although the Koren diet is moving towrds Western dietry pttern, Korens re still typiclly reported to consume n excessive mount of crbohydrte nd less protein nd ft [4]. Detiled informtion regrding the crbohydrte intke might be useful for understnding the efficcy of crbose. Finlly, one subject with pst history of totl gstrectomy ws included in group. In subjects with gstrectomy, insulin nd GLP-1 secretion or glucose vribility my be ltered. However, MTT nd CGMS were not performed in this subject, nd therefore we were unble to obtin these informtion. In conclusion, 16-week crbose dd-on therpy in subjects who were poorly controlled with metformin nd sitgliptin effectively lowered the HbA1c levels by.44%±.8% nd ws ccompnied by suppressed glucgon secretion in the bsence of excessive insulin secretion during the MTT. Although the substitution of crbose for metformin worsened the blood glucose level, the dd-on of metformin nd the mintennce of triple combintion effectively reduced the HbA1c levels by.61%±.7% s erly s 8 weeks. Additionlly, the metformin, sitgliptin, nd crbose triple combintion therpy ws generlly well tolerted without AEs. CONFLICTS OF INTEREST This study ws supported by grnt from Byer Kore, Co. Ltd. (Grnt number: 15938). REFERENCES 1. Hmpp C, Borders-Hemphill V, Moeny DG, Wysowski DK. Use of ntidibetic drugs in the U.S., Dibetes Cre 214;37: Inzucchi SE, Bergenstl RM, Buse JB, Dimnt M, Ferrnnini E, Nuck M, Peters AL, Tsps A, Wender R, Mtthews DR. Mngement of hyperglycemi in type 2 dibetes, 215: ptient-centered pproch: updte to position sttement of the Americn Dibetes Assocition nd the Europen Assocition for the Study of Dibetes. Dibetes Cre 215;38: Grber AJ, Abrhmson MJ, Brzily JI, Blonde L, Bloomgrden ZT, Bush MA, Dgogo-Jck S, Dvidson MB, Einhorn D, Grber JR, Grvey WT, Grunberger G, Hndelsmn Y, Hirsch IB, Jellinger PS, McGill JB, Mechnick JI, Rosenblit PD, Umpierrez G, Dvidson MH. AACE/ACE comprehensive dibetes mngement lgorithm 215. Endocr Prct 215;21: Yng W, Liu J, Shn Z, Tin H, Zhou Z, Ji Q, Weng J, Ji W, Lu J, Liu J, Xu Y, Yng Z, Chen W. Acrbose compred with metformin s initil therpy in ptients with newly dignosed type 2 dibetes: n open-lbel, non-inferiority rndomized tril. Lncet Dibetes Endocrinol 214;2: Sheu WH, Rosmn A, Mithl A, Chung N, Lim YT, Deerochnwong C, Soewondo P, Lee MK, Yoon KH, Schnell O. Addressing the burden of type 2 dibetes nd crdiovsculr disese through the mngement of postprndil hyperglycemi: n Asin-Pcific perspective nd expert recommendtions. Dibetes Res Clin Prct 211;92: Wng JS, Tu ST, Lee IT, Lin SD, Lin SY, Su SL, Lee WJ, Sheu WH. Contribution of postprndil glucose to excess hyperglycemi in Asin type 2 dibetic ptients using continuous glucose monitoring. Dibetes Metb Res Rev 211;27: Nrit T, Ktsuur Y, Sto T, Hosob M, Fujit H, Morii T, Ymd Y. Miglitol induces prolonged nd enhnced glucgonlike peptide-1 nd reduced gstric inhibitory polypeptide responses fter ingestion of mixed mel in Jpnese type 2 dibetic ptients. Dibet Med 29;26: Horikw Y, Eny M, Iizuk K, Chen GY, Kwchi S, Suw T, Tked J. Synergistic effect of α-glucosidse inhibitors nd dipeptidyl peptidse 4 inhibitor tretment. J Dibetes Investig 211;2: Moritoh Y, Tkeuchi K, Hzm M. Combintion tretment with logliptin nd voglibose increses ctive GLP-1 circul- pge 1 of 15

11 Acrbose s third-line dd-on therpy tion, prevents the development of dibetes nd preserves pncretic bet-cells in predibetic db/db mice. Dibetes Obes Metb 21;12: Tjim N, Kdowki T, Okmoto T, Sto A, Okuym K, Minmide T, Arjon Ferreir JC. Sitgliptin dded to voglibose monotherpy improves glycemic control in ptients with type 2 dibetes. J Dibetes Investig 213;4: Msud K, Aoki K, Kmiko K, Tkiht M, Ito Y, Ngkur M, Kwski S, Akem N, Hsegw M, Nkjim S, Shinod K, Toumur S, Tsunod S, Enomoto H, Shimotomi H, Teruchi Y. Glycemic control fter ddition of the dipeptidyl peptidse-4 inhibitor logliptin in ptients with type 2 dibetes showing indequte response to thrice--dy tretment with α-glucosidse inhibitors. Expert Opin Phrmcother 213;14: Seino Y, Fujit T, Hiroi S, Hirym M, Kku K. Alogliptin plus voglibose in Jpnese ptients with type 2 dibetes: rndomized, double-blind, plcebo-controlled tril with n open-lbel, long-term extension. Curr Med Res Opin 211;27 Suppl 3: Min SH, Yoon JH, Hhn S, Cho YM. Efficcy nd sfety of combintion therpy with n α-glucosidse inhibitor nd dipeptidyl peptidse-4 inhibitor in ptients with type 2 dibetes mellitus: A systemtic review with met-nlysis. J Dibetes Investig 218;9: Kurozumi A, Okd Y, Mori H, Aro T, Tnk Y. Efficcy of α-glucosidse inhibitors combined with dipeptidyl-peptidse-4 inhibitor (logliptin) for glucose fluctution in ptients with type 2 dibetes mellitus by continuous glucose monitoring. J Dibetes Investig 213;4: Aoki K, Kmiym H, Yoshimur K, Shibuy M, Msud K, Teruchi Y. Miglitol dministered before brekfst incresed plsm ctive glucgon-like peptide-1 (GLP-1) levels fter lunch in ptients with type 2 dibetes treted with sitgliptin. Act Dibetol 212;49: Kusunoki Y, Ktsuno T, Myojin M, Miykoshi K, Ikw T, Mtsuo T, Ochi F, Tokud M, Muri K, Miuchi M, Hmguchi T, Miygw J, Nmb M. Effect of dditionl dministrtion of crbose on blood glucose fluctutions nd postprndil hyperglycemi in ptients with type 2 dibetes mellitus under tretment with logliptin. Endocr J 213;6: Service FJ, Molnr GD, Rosever JW, Ackermn E, Gtewood LC, Tylor WF. Men mplitude of glycemic excursions, mesure of dibetic instbility. Dibetes 197;19: Lm KS, Tiu SC, Tsng MW, Ip TP, Tm SC. Acrbose in NID- DM ptients with poor control on conventionl orl gents. A 24-week plcebo-controlled study. Dibetes Cre 1998;21: Turner RC, Cull CA, Frighi V, Holmn RR. Glycemic control with diet, sulfonylure, metformin, or insulin in ptients with type 2 dibetes mellitus: progressive requirement for multiple therpies (UKPDS 49). UK Prospective Dibetes Study (UKP- DS) Group. JAMA 1999;281: Lee YK, Song SO, Kim KJ, Cho Y, Choi Y, Yun Y, Lee BW, Kng ES, Ch BS, Lee HC. Glycemic effectiveness of metforminbsed dul-combintion therpies with sulphonylure, pioglitzone, or DPP4-inhibitor in drug-nïve Koren type 2 dibetic ptients. Dibetes Metb J 213;37: Merns ES, Sulsberry WJ, White CM, Kohn CG, Lemieux S, Sihbout A, Slmuch I, Colemn CI. Efficcy nd sfety of ntihyperglycemic drug regimens dded to metformin nd sulphonylure therpy in type 2 dibetes: network metnlysis. Dibet Med 215;32: vn de Lr FA, Lucssen PL, Akkermns RP, vn de Lisdonk EH, Rutten GE, vn Weel C. Alph-glucosidse inhibitors for ptients with type 2 dibetes: results from Cochrne systemtic review nd met-nlysis. Dibetes Cre 25;28: Monmi M, Lmnn C, Mrchionni N, Mnnucci E. Comprison of different drugs s dd-on tretments to metformin in type 2 dibetes: met-nlysis. Dibetes Res Clin Prct 28;79: Bischoff H. The mechnism of lph-glucosidse inhibition in the mngement of dibetes. Clin Invest Med 1995;18: Lee A, Ptrick P, Wishrt J, Horowitz M, Morley JE. The effects of miglitol on glucgon-like peptide-1 secretion nd ppetite senstions in obese type 2 dibetics. Dibetes Obes Metb 22;4: Aoki K, Msud K, Miyzki T, Togshi Y, Teruchi Y. Effects of miglitol, sitgliptin or their combintion on plsm glucose, insulin nd incretin levels in non-dibetic men. Endocr J 21; 57: Mikd A, Nrit T, Yokoym H, Ymshit R, Horikw Y, Tsukiym K, Ymd Y. Effects of miglitol, sitgliptin, nd initil combintion therpy with both on plsm incretin responses to mixed mel nd viscerl ft in over-weight Jpnese ptients with type 2 dibetes. the MASTER rndomized, controlled tril. Dibetes Res Clin Prct 214;16: Hucking K, Kostic Z, Pox C, Ritzel R, Holst JJ, Schmiegel W, Nuck MA. Alph-glucosidse inhibition (crbose) fils to enhnce secretion of glucgon-like peptide 1 (7-36 mide) nd to dely gstric emptying in type 2 dibetic ptients. Dibet pge 11 of 15

12 Yng HK, et l. Med 25;22: Ueno H, Tsuchimochi W, Wng HW, Ymshit E, Tsubouchi C, Ngmine K, Skod H, Nkzto M. Effects of miglitol, crbose, nd sitgliptin on plsm insulin nd gut peptides in type 2 dibetes mellitus: crossover study. Dibetes Ther 215; 6: Kishimoto M, Nod M. Additive effects of miglitol nd ngliptin on insulin-treted type 2 dibetes mellitus: cse study. Clin Drug Investig 215;35: de Heer J, Rsmussen C, Coy DH, Holst JJ. Glucgon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucgon secretion vi somtosttin (receptor subtype 2) in the perfused rt pncres. Dibetologi 28;51: De Mrinis YZ, Slehi A, Wrd CE, Zhng Q, Abdulkder F, Bengtsson M, Brh O, Brun M, Rmrchey R, Amisten S, Hbib AM, Moritoh Y, Zhng E, Reimnn F, Rosengren A, Shibski T, Gribble F, Renstrom E, Seino S, Elisson L, Rorsmn P. GLP-1 inhibits nd drenline stimultes glucgon relese by differentil modultion of N- nd L-type C2+ chnnel-dependent exocytosis. Cell Metb 21;11: Gotoh K, Mski T, Chib S, Ando H, Fujiwr K, Shimski T, Mitsutomi K, Ktsurgi I, Kkum T, Skt T, Yoshimtsu H. Hypothlmic brin-derived neurotrophic fctor regultes glucgon secretion medited by pncretic efferent nerves. J Neuroendocrinol 213;25: Gu Y, Wng X, Li J, Zhng Y, Zhong H, Liu R, Zhng D, Feng Q, Xie X, Hong J, Ren H, Liu W, M J, Su Q, Zhng H, Yng J, Wng X, Zho X, Gu W, Bi Y, Peng Y, Xu X, Xi H, Li F, Xu X, Yng H, Xu G, Mdsen L, Kristinsen K, Ning G, Wng W. Anlyses of gut microbiot nd plsm bile cids enble strtifiction of ptients for ntidibetic tretment. Nt Commun 217;8: Bhne E, Hnsen M, Bronden A, Sonne DP, Vilsboll T, Knop FK. Involvement of glucgon-like peptide-1 in the glucoselowering effect of metformin. Dibetes Obes Metb 216;18: Ymguchi M, Sji T, Mit S, Kulmtycki K, He YL, Furiht K, Sekiguchi K. Phrmcokinetic nd phrmcodynmic interction of vildgliptin nd voglibose in Jpnese ptients with type 2 dibetes. Int J Clin Phrmcol Ther 213;51: Pn C, Yng W, Bron JP, Wng Y, Niggli M, Mohideen P, Wng Y, Foley JE. Comprison of vildgliptin nd crbose monotherpy in ptients with type 2 dibetes: 24-week, double-blind, rndomized tril. Dibet Med 28;25: Holmn RR, Cull CA, Turner RC. A rndomized double-blind tril of crbose in type 2 dibetes shows improved glycemic control over 3 yers (U.K. Prospective Dibetes Study 44). Dibetes Cre 1999;22: Bloomgrden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower bseline glycemi reduces pprent orl gent glucose-lowering efficcy: met-regression nlysis. Dibetes Cre 26;29: Lee M, Che SW, Ch YS, Cho MS, Oh HY, Kim MK. Development of Koren Diet Score (KDS) nd its ppliction ssessing dherence to Koren helthy diet bsed on the Koren Food Guide Wheels. Nutr Res Prct 213;7: pge 12 of 15

13 Acrbose s third-line dd-on therpy Supplementry Tble 1. Chnges in HbA1c in intention-to-tret popultion nd per-protocol popultion Vrible Sit+Acrb P vlue P vlue b Intention-to-tret popultion Number Week HbA1c level 8.± ± ± Week 16 HbA1c level 7.91± ± ± Difference vs. bseline.9±.1.44±.8.84±.21.7 <.1 P vlue.113 <.1 <.1 Week 24 HbA1c level 7.66± ± ± Difference vs. week 16.25±.5.3±.5.61± P vlue < <.1 Per-protocol popultion Number Week HbA1c level 8.1± ± ± Week 16 HbA1c level 7.86± ± ± Difference vs. bseline.15±.12.55±.1.74± P vlue.49 <.1.2 Week 24 HbA1c level 7.55± ± ± Difference vs. week 16.31±.6.3±.6.93± <.1 P vlue < <.1 Vlues re presented s men±stndrd error. HbA1c, glycosylted hemoglobin;, the group treted with metformin, sitgliptin, nd crbose plcebo;, the group treted with metformin, sitgliptin, nd crbose; Sit+Acrb, the group treted with metformin plcebo, sitgliptin nd crbose. vs., b vs. Sit+Acrb. pge 13 of 15

14 Yng HK, et l. Supplementry Tble 2. Chnges in the clinicl chrcteristics t weeks 16 nd 24 in the intention-to-tret popultion Chrcteristic Sit+Acrb P vlue At week 16 (chnge=week 16 bseline) Number Body weight, kg.4± ± ±.87.9 Wist circumference, cm.37± ±.74.9± Systolic blood pressure, mm Hg.8± ± ± Distolic blood pressure, mm Hg.49±.96.6± ± Fsting plsm glucose, mmol/l.19±.18.57± ±.38 <.1 Postprndil 2-hour plsm glucose, mmol/l.71± ± ±.72 <.1 Blood ure nitrogen, mmol/l.39±.16.37±.18.3± Cretinine, μmol/l 1.98± ±.88.57± AST, U/L 3.59± ± ± ALT, U/L 4.3± ± ± Totl cholesterol, mmol/l.7±.7.13±.7.1±.1.6 Triglyceride, mmol/l.2±.8.25±.8.21±.9.41 HDL-C, mmol/l.3±.2.3±.1.1±.4.18 LDL-C, mmol/l.9±.6.1±.5.9± CRP, mg/dl.7±.11.6±.5.18± At week 24 (chnge=week 24 bseline) Body weight, kg.25± ± ±.9.94 Wist circumference, cm.18± ±.75.3± Systolic blood pressure, mm Hg 2.77± ± ± Distolic blood pressure, mm Hg.68±.99.2±.97.12± Fsting plsm glucose, mmol/l.55±.2.55±.21.11± Postprndil 2-hour plsm glucose, mmol/l 1.73± ±.43.6± Blood ure nitrogen, mmol/l.49±.16.16±.17.59± Cretinine, μmol/l.1±.82.55±.75.62± AST, U/L 3.5± ± ± ALT, U/L 5.94± ± ± Totl cholesterol, mmol/l.7±.9.12±.7.7± Triglyceride, mmol/l.7±.1.25±.8.15± HDL-C, mmol/l.2±.2.1±.2.1± LDL-C, mmol/l.8±.5.3±.6.1±.7.58 CRP, mg/dl.9±.11.7±.5.22± Vlues re presented s men±stndrd error., the group treted with metformin, sitgliptin, nd crbose plcebo;, the group treted with metformin, sitgliptin, nd crbose; Sit+Acrb, the group treted with metformin plcebo, sitgliptin nd crbose; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; CRP, C-rective protein. Chnges of P<.5 t weeks 16 or 24 compred to bseline. pge 14 of 15

15 Acrbose s third-line dd-on therpy Supplementry Tble 3. Indices on insulin resistnce nd secretion t bseline nd week 16 Index P vlue HOMA-IR Bseline 3.49± ± Week ± ± HOMA-β Bseline 37.67± ± Week ± ± Insulinogenic index Bseline 3.17± ± Week ± ± Vlues re presented s men±stndrd error., the group treted with metformin, sitgliptin, nd crbose plcebo;, the group treted with metformin, sitgliptin, nd crbose; HOMA-IR, homeostsis model ssessment of insulin resistnce; HOMA-β, homeostsis model ssessment of β-cell function. Chnges of P<.5 t week 16 compred to bseline. pge 15 of 15