Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, 3

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1 Originl Article Clinicl Cre/Eduction Dibetes Metb J 2015;39: pissn eissn DIABETES & METABOLISM JOURNAL Clinicl Chrcteristics nd Metbolic Predictors of Rpid Responders to Dipeptidyl Peptidse-4 Inhibitor s n Add-on Therpy to Sulfonylure nd Metformin Ye An Kim 1,2, Won Sng Yoo 3, Eun Shil Hong 1,4, Eu Jeong Ku 1,5, Kyeong Seon Prk 1,6, Soo Lim 1,6, Young Min Cho 1, Kyong Soo Prk 1, Hk Chul Jng 1,6, Sung Hee Choi 1,6 1 Deprtment of Internl Medicine, Seoul Ntionl University College of Medicine, Seoul, 2 Deprtment of Internl Medicine, Seoul Ntionl University Hospitl Helthcre System Gngnm Center, Seoul, 3 Deprtment of Internl Medicine, Dnkook University College of Medicine, Cheonn, 4 Deprtment of Internl Medicine, Konkuk University Chungju Hospitl, Konkuk University School of Medicine, Chungju, 5 Deprtment of Internl Medicine, Chungbuk Ntionl University Hospitl, Chungbuk Ntionl University College of Medicine, Cheongju, 6 Deprtment of Internl Medicine, Seoul Ntionl University Bundng Hospitl, Seoul Ntionl University College of Medicine, Seongnm, Kore Bckground: Dipeptidyl peptidse-4 (DPP-4) inhibitor dd-on therpy is new option for ptients with indequtely controlled type 2 dibetes who re tking combined metformin nd sulfonylure (SU). We evluted the efficcy nd sfety of this triple therpy nd the chrcteristics of rpid responders nd hypoglycemi-prone ptients. Methods: We included 807 ptients with type 2 dibetes who were prescribed newly dded DPP-4 inhibitor to ongoing metformin nd SU in 2009 to Glycemi nd other metbolic prmeters t bseline, 12, 24, nd 52 weeks, s well s episodes of hypoglycemi were nlyzed. Rpid responders were defined s ptients with 25% reduction in glycosylted hemoglobin (HbA1c) within 12 weeks. Results: At bseline, while on the submximl metformin nd SU combintion, the men HbA1c level ws 8.4%. Twelve weeks fter initition of DPP-4 inhibitor dd-on, 269 ptients (34.4%) chieved n HbA1c level 7%. Sixty-six ptients (8.2%, 47 men) were rpid responders. The durtion of dibetes ws shorter in rpid responders, nd their bseline fsting plsm glucose (FPG), HbA1c, C-peptide, nd homeostsis model ssessment of insulin resistnce were significntly higher. Ptients who experienced hypoglycemi fter tking DPP-4 inhibitor dd-on were more likely to be femle, to hve lower body weight nd lower triglyceride nd FPG levels, nd to hve higher homeostsis model ssessment of β-cells. Conclusion: An orl hypoglycemic triple gent combintion including DPP-4 inhibitor ws effective in ptients with uncontrolled dibetes. Proctive dose reduction of SU should be considered when DPP-4 inhibitor is dded for rpid responders nd hypoglycemi-prone ptients. Keywords: Combintion; Dibetes mellitus, type 2; Dipeptidyl-peptidse IV inhibitors; Hypoglycemi; Response; Sulfonylure compounds INTRODUCTION Dipeptidyl peptidse-4 (DPP-4) inhibitors hve emerged s new tretment option for ptients with type 2 dibetes. DPP-4 inhibition increses the level of ctive incretin hormones, such s glucgon-like peptide-1 (GLP-1) nd gstric inhibitory polypeptide. These hormones stimulte insulin secretion by direct ction on GLP-1 receptors in β-cells nd by indirect glucosedependent neuronl stimultion in the gut [1]. Type 2 dibetes mellitus is progressive disese chrcter- Corresponding uthor: Sung Hee Choi Deprtment of Internl Medicine, Seoul Ntionl University Bundng Hospitl, Seoul Ntionl University College of Medicine, 82 Gumi-ro 173beon-gil, Bundng-gu, Seongnm 13620, Kore E-mil: drshchoi@snu.c.kr Received: Jn. 14, 2015; Accepted: Apr. 22, 2015 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 2015 Koren Dibetes Assocition

2 Kim YA, et l. ized by decresed insulin secretion nd incresed insulin resistnce [2]. When glycemic control is poor with dul orl hypoglycemic gents (OHAs), insulin injection or triple combintion therpy with other OHAs should be considered [3]. However, some ptients re reluctnt to strt insulin therpy becuse of psychologicl ntipthy such s misperceptions bout worsening of the disese, injection fer [4], or weight gin. DPP-4 inhibitors could be nother therpeutic option for substituting insulin therpy in ddition to ongoing submximl sulfonylure nd metformin combintion therpy for ptients with uncontrolled hyperglycemi [5-7]. There seems to be individul vribility in the response to DPP-4 inhibitors. In some ptients, DPP-4 inhibitors hve shown more prominent effects in lowering glycemi indictors such s the glycosylted hemoglobin (HbA1c) level. Previous studies hve nlyzed the predictors of clinicl response to DPP-4 inhibitors [8-13], but the predictors suggested by these studies were somewht inconsistent, nd these studies did not nlyze the effects of combintion therpy with sulfonylure nd DPP-4 inhibitors. The risk of hypoglycemi should be considered when DPP- 4 inhibitor is dded to sulfonylure-bsed regimen. The issue of sulfonylure dose reduction hs been rised when using DPP-4 inhibitors nd sulfonylure together [14,15]. In 2010, the Jpn Assocition for Dibetes Eduction nd Cre relesed guideline for reducing the dose of three mjor sulfonylures when dding DPP-4 inhibitor to prevent hypoglycemi [16]. However, it is uncler which ptients re true cndidtes for sulfonylure dose reduction when given DPP-4 inhibitor combintion therpy. In this study we evluted the efficcy of triple combintion therpy tht dded DPP-4 inhibitor to sulfonylure nd metformin combined therpy. We nlyzed the clinicl predictors of rpid response to DPP-4 inhibitor when newly dded to ongoing OHA combintion therpy. We lso nlyzed the chrcteristics of those ptients who experienced hypoglycemi, nd we identified the chrcteristics of ptients needing reduction in sulfonylure dose when given the DPP-4 inhibitor-oha combintion therpy. METHODS Study prticipnts In this retrospective observtionl study, we included those ptients with type 2 dibetes who were seen in the dibetes outptient clinic t Seoul Ntionl University Bundng Hospitl (SNUBH) from Mrch 2009 to October The eligible subjects were 918 ptients ged 21 to 89 yers who were prescribed DPP-4 inhibitor in ddition to the sulfonylure nd metformin combintion. Ptients were excluded if they hd history of type 1 dibetes, serious medicl illness, insulin use, or poor complince becuse of mentl illness. Ptients who chnged the mediction to different type of sulfonylure or DPP-4 inhibitor or who dded nother type of OHA were lso excluded. Among 894 ptients, 87 were lost to follow-up. Hypoglycemic episodes were reported in the medicl records with or without mesured glucose level. Ptients with severe hypoglycemi were identified from the records of emergency room visits or the necessity for medicl ssistnce. The lbortory dt, use of mediction, sulfonylure dose reduction, nd episodes of hypoglycemi were retrieved from the electronic medicl records. Finlly, 807 ptients who were prescribed sitgliptin (n=518) or vildgliptin (n=289) were included nd reviewed up to 52 weeks fter the ddition of the DPP-4 inhibitor. To evlute the response of the DPP-4 inhibitor dded to sulfonylure, we divided the ptients into two groups bsed on the chnge in HbA1c levels for the initil 3 months; those who showed 25% reduction in HbA1c within 12 weeks were defined s rpid responders, nd the others were defined s nonrpid responders. Previous clinicl trils [14,17] reported HbA1c reductions of 0.55% to 2.07%, which were greter with higher bseline HbA1c. Rpid declines in HbA1c were lso shown within the first 6 to 12 weeks in these studies. Hence, we clculted the chnge in HbA1c levels within 12 weeks in these studies nd set the criteri of 25% bove the rnge of 4.4% to 23.5% of the bseline HbA1c level. This study ws pproved by the Institutionl Review Bord of Seoul Ntionl University Bundng Hospitl, nd it conformed to the provisions of the Declrtion of Helsinki (s revised in Edinburgh 2000). Metbolic nd clinicl prmeters The ptients who chieved the trget HbA1c levels of 7% nd 6.5% were ssessed t bseline, 12, 24, nd 52 weeks. Plsm glucose levels were mesured using Hitchi 747 chemistry nlyzer (Hitchi, Tokyo, Jpn). HbA1c levels were mesured using Bio-Rd vrint II Turbo HPLC nlyzer (Bio-Rd, Hercules, CA, USA) t Seoul Ntionl University Bundng Hospitl, Ntionl Glycohemoglobin Stndrdiztion Progrm level II-certified lbortory. The fsting plsm concen- 490 Dibetes Metb J 2015;39:

3 Rpid responders to DPP4 inhibitor dd-on trtions of totl cholesterol, triglycerides, high density lipoprotein cholesterol, nd low density lipoprotein cholesterol were mesured using the Hitchi 747 chemistry nlyzer. Plsm C- peptide nd insulin concentrtions were mesured by rdioimmunossy (Linco, St. Louis, MO, USA). The homeostsis model ssessment (HOMA) ws used to ssess β-cell function (HOMA-β) nd insulin resistnce (HOMA-IR) [18]. HOMA- IR ws clculted using the formul: fsting insulin (μu/ml) [fsting glucose (mg/dl)/405]. HOMA-β ws clculted using the formul: 20 fsting insulin (μu/ml)/[fsting glucose (mg/dl) 63]. Clinicl prmeters including ge, sex, height, weight, durtion of dibetes, nd doses of medictions were collected from electronic records. Body mss index (BMI) ws clculted using the formul: body weight in kg divided by height in meters squred. Sttisticl nlyses Sttisticl nlyses were performed using SPSS version 18.0 (SPSS Inc., Chicgo, IL, USA). We used the Kolmogorov-Smirnov test to verify whether the dt were normlly distributed. Dt re shown s the men±stndrd devition or s number nd percentge. Anlysis of vrince with repeted mesurements nd pired t-tests were used to nlyze the chnges in glycemi prmeters. Student t-test for continuous dt nd the chi-squre test for ctegoricl dt were used to compre rpid responders nd non-rpid responders. Student t-test nd chi-squre test were lso used to compre between groups with or without episodes of hypoglycemi. We lso performed logistic regression nlysis using bseline HbA1c levels, mle sex, nd durtion of dibetes to predict the rpid responders for DPP-4 inhibitor dd-on therpy to the sulfonylure nd metformin combintion. P vlues 0.05 were considered significnt. RESULTS Demogrphics nd bseline chrcteristics Ptient chrcteristics re shown in Tble 1. The men ge ws 61.1 yers, the men durtion of dibetes ws 11.5 yers, nd 58.6% were men nd 41.4% women. The men bseline HbA1c level ws 8.4%, nd the bseline fsting plsm glucose (FPG) nd 2-hour plsm glucose (2hPG) concentrtions were nd mg/dl, respectively. The most frequent sulfonylure given ws glimepiride (88.8% of ptients) with men dose of 4.1±2.1 mg/dy, nd the dose of metformin ws 1,241.9±483.8 mg/dy. Among 807 ptients, dose reduction of sulfonylure Tble 1. Bseline chrcteristics of the ptients (n=807) Chrcteristic Vlue Age, yr 61.1±11.5 Sex, mle:femle 473:334 Durtion of dibetes, yr 11.5±6.9 Type of sulfonylure, M:C:B 717:82:8 Dose of sulfonylure, mg, M:C:B 4.1±2.1:84.9±62.3:8.4±3.0 Type of DPP-4 inhibitor, S:V b 518:289 Dose of DPP-4 inhibitor, mg, S:V b 97.9±10.1 Dose of metformin, mg 1,241.9±483.8 Body mss index, kg/m ±3.4 Triglycerides, mg/dl 153.4±101.4 HDL-C, mg/dl 46.3±12.3 LDL-C, mg/dl 84.3±26.2 AST, U/L 24.4±11.5 ALT, U/L 28.0±17.3 Cretinine, mg/dl 1.0±0.3 Glycosylted hemoglobin, % 8.4±1.2 Fsting plsm glucose, mg/dl 153.4± Hour plsm glucose, mg/dl 261.1±76.8 C-peptide, ng/ml 2.2±1.3 Fsting insulin, μu/ml 15.2±10.0 HOMA-β 61.1±41.0 HOMA-IR 2.1±1.2 Vlues re presented s men±stndrd devition. DPP-4, dipeptidyl peptidse-4; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; HOMA-β, homeostsis model ssessment of β-cell function; HOMA-IR, homeostsis model ssessment of insulin resistnce. M:C:B, glimepirde:gliclzide:glibenclmide, b S:V, sitglitpin: vildgliptin. ws performed in 160 ptients, while the others mintined or incresed the sulfonylure dose during the 1-yer follow-up fter DPP-4 inhibitor dd-on. In this study, the dose of sulfonylure ws reduced when ptient showed rpid improvement in HbA1c levels or reported minor or mjor hypoglycemic symptoms fter ddition of the DPP-4 inhibitor. Ptients with sulfonylure reduction were more frequently prescribed glimepiride (95.0% vs. 87.3%, P=0.021) or sitgliptin (74.4% vs. 61.7%, P=0.003) nd hd lower BMI (25.0±3.5 kg/m 2 vs. 25.6±3.4 kg/m 2, P=0.045) thn the ptients without sulfonylure reduction (dt re not shown). The types of DPP-4 inhibitors used were sitgliptin for 64.2% Dibetes Metb J 2015;39:

4 Kim YA, et l. Percent of ptients (%) HbA1c 7% HbA1c 6.5% Bseline 12 Weeks 24 Weeks 52 Weeks A HbA1c (%) Week Sitgliptin group Vildgliptin group B Fig. 1. (A) Percentge of ptients who chieved the trget glycosylted hemoglobin (HbA1c) levels of 7% nd 6.5% ssessed t bseline, 12, 24, nd 52 weeks. (B) HbA1c levels (±SE) t bseline, 12, 24, nd 52 weeks in ptients with dditionl sitgliptin (open circles) or vildgliptin (blck squres). Significnt chnge in HbA1c level t week 52. of ptients nd vildgliptin for 35.8% of ptients. The dose of the DPP-4 inhibitor ws 100 mg/dy in 95.7% of ptients. Twenty-two ptients were prescribed sitgliptin, nd 12 ptients (4.2%) were prescribed vildgliptin t dose of 50 mg/ dy. One ptient ws prescribed sitgliptin t dose of 75 mg/ dy. The men BMI ws 25.5 kg/m 2, indicting tendency towrd ptients being overweight. Efficcy of triple combintion therpy The percentges of ptients who chieved the trget HbA1c 7% nd 6.5% levels were 33.3% (n=269) nd 14.0% (n=113) t 12 weeks of DPP-4 inhibitor dd-on, respectively (Fig. 1A). These percentges incresed slightly t 24 weeks to 35.2% (n= 284, HbA1c 7%) nd 14.5% (n=117, HbA1c 6.5%), respectively, nd were mintined t 52 weeks (32.3% nd 13.4%, respectively). The men chnge in HbA1c level from the bseline of 8.4% t 12 weeks ws 0.8%±1.2% (P<0.001). The chnges in FPG nd 2hPG t 12 weeks fter the ddition of DPP-4 inhibitor were 18.0±49.9 nd 38.3±87.2 mg/dl, respectively (P<0.001 for ech). These reductions in HbA1c, FPG, nd 2hPG levels t 12 weeks were mintined t 52 weeks. At 52 weeks, the chnges in HbA1c, FPG, nd 2hPG from the bseline were 1.0%±1.9%, 13.5±52.1, nd 23.1±86.8 mg/dl, respectively. The chnges in glycemi prmeters were similr in the sitgliptin-treted group nd the vildgliptin-treted group t 12 nd 24 weeks (Fig. 1B). The chnges in HbA1c nd 2hPG levels from bseline to 52 weeks were slightly greter in the sitgliptin group thn in the vildgliptin group: 1.2%±2.2% vs. 0.8%±1.4% for HbA1c (P=0.016) nd 33.7±91.1 mg/dl vs. 8.7±79.0 mg/dl for 2hPG (P=0.029). The bseline insulin concentrtion ws 15.2 μu/ml, nd the C-peptide concentrtion ws 2.2 ng/ml. HOMA-β nd HOMA-IR were 61.1± 41.0 nd 2.1±1.2, respectively. Insulin nd C-peptide concentrtions incresed grdully from bseline to 52 weeks fter tretment (dt not shown). The chnges in insulin nd C- peptide concentrtions from bseline to 52 weeks were 1.1± 7.8 μu/ml (P=0.241) nd 0.2±0.8 ng/ml (P=0.252). Predictors of clinicl responses to DPP-4 inhibitors dded to sulfonylure-bsed regimens Ptients with reduction in HbA1c of 25% within 12 weeks were defined s rpid responders (n=66, 8.2% of enrolled ptients). For these ptients, the HbA1c levels were 10.1% t bseline nd 6.9% t 12 weeks fter the ddition of DPP-4 inhibitors (P<0.001). Excluding 26 ptients with no vilble HbA1c vlues t 3 months, the others were defined s non-rpid responders. The 12-week vlues were less thn the trget HbA1c of 7.0% (Fig. 2). This rpid improvement in HbA1c ws mintined t 7.0% t 24 weeks nd t 6.7% t 52 weeks. The other group of ptients (non-rpid responders) lso showed n improvement in HbA1c levels from 8.2% t bseline to 7.4% t 52 weeks (P<0.001). The durtion of dibetes ws shorter (8.8 yers vs yers, P=0.002) in the rpid responders thn in the non-rpid responders, nd higher percentge of rpid responders were men (71.2% vs. 56.9%, P=0.027) (Tble 2). Bseline HbA1c nd FPG levels were higher in rpid responders thn in non-rpid responders: 10.1% vs. 8.2% for HbA1c 492 Dibetes Metb J 2015;39:

5 Rpid responders to DPP4 inhibitor dd-on HbA1c (%) Weeks Rpid responder Non-rpid responder Fig. 2. Glycosylted hemoglobin (HbA1c) levels (±SE) t bseline, 12, 24, nd 52 weeks in rpid responders (open circles) nd non-rpid responders (blck squres). (P<0.001) nd mg/dl vs mg/dl for FPG (P= 0.007), respectively. Bseline C-peptide concentrtions nd HOMA-IR levels were lso higher in rpid responders: 3.0 ng/ ml vs. 2.1 ng/ml for C-peptide (P=0.030) nd 2.5 vs. 2.1 for HOMA-IR (P=0.044). Fsting insulin concentrtions nd HOMA-β levels were non-significntly higher in the rpid responders. There were no differences in ge, BMI, cretinine concentrtion, nd other prmeters between rpid nd nonrpid responders. In the logistic regression, higher bseline HbA1c levels nd shorter durtions of dibetes were independent predictors for the rpid responders with the DPP4 inhibitor dd-on, while mle sex showed mrginl significnce (P= 0.054) (Tble 3). Chrcteristics of ptients who experienced hypoglycemi In the rpid responder group, there were more ptients with symptoms of hypoglycemi thn in the non-rpid responder group (24.2% vs. 13.4%, P=0.026). The dose of sulfonylure ws reduced more frequently in the rpid responder group thn in the non-rpid responder group (33.3% vs. 18.2%, P= 0.005). Among the 918 ptients given DPP-4 inhibitor in ddition to sulfonylure, 117 ptients experienced hypoglycemi. Severe hypoglycemi ws reported in 17 ptients. Among the 17 ptients with severe hypoglycemi, 16 were older thn 70 yers nd one ws 63 yers old with renl impirment. Three of these 17 ptients hd renl impirment (cretinine >1.4 mg/ dl), three hd poor orl intke, nd three were prescribed n incresed dose of sulfonylure. Tble 2. Chrcteristics of rpid responders, ptients with (HbA1cB HbA1c12wk)/HbA1cB 25%, nd non-rpid responders, ptients with (HbA1cB HbA1c12wk)/HbA1cB <25% Chrcteristic Rpid responders (n=66) Non-rpid responders (n=715) P vlue Age, yr 58.1± ± Sex, mle:femle 47:19 407: Dibetes durtion, yr 8.8± ± Sulfonylure type, M:C:B 60:6:0 635:73:7 - Sulfonylure dose, M:C:B 3.7:60.0:0 4.1:87.4:8.9 - DPP-4 inhibitor type, S:V b 41:25 455: DPP-4 inhibitor dose, 100.0: : mg, S:V b Metformin dose, mg 1,293.0± ,233.5± Body mss index, kg/m ± ± Triglyceride, mg/dl 152.3± ± HDL-C, mg/dl 47.7± ± LDL-C, mg/dl 88.2± ± AST, U/L 25.1± ± ALT, U/L 31.0± ± Cretinine, mg/dl 0.9± ± HbA1c, % 10.1± ±1.1 <0.001 Fsting plsm glucose, mg/dl 2-Hour plsm glucose, mg/dl 174.3± ± ± ± C-peptide, ng/ml 3.0± ± Fsting insulin, μu/ml 17.3± ± HOMA-β 71.2± ± HOMA-IR 2.5± ± Hypoglycemic symptoms c 16 (24.2) 96 (13.4) Sulfonylure reduction 44 (66.7) 130 (18.2) Vlues re presented s men±stndrd devition or number (%). HbA1c, glycosylted hemoglobin; DPP-4, dipeptidyl peptidse-4; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; HOMA-β, homeostsis model ssessment of β-cell function; HOMA-IR, homeostsis model ssessment of insulin resistnce. M:C:B, glimepirde:gliclzide:glibenclmide, b S:V, sitglitpin: vildgliptin, c Hypoglycemic symptoms: subjective symptoms or mesured hypoglycemi. Except for HbA1c, severl other fctors might be relted to hypoglycemi (Fig. 3). The ptients with hypoglycemic symptoms hd higher percentge of women (53.0% vs. 39.4%, Dibetes Metb J 2015;39:

6 Kim YA, et l. Tble 3. Logistic regression nlysis for prmeters tht predict rpid responders to dipeptidyl peptidse-4 inhibitor dd-on therpy to sulfonylure nd metformin combintion Prmeter β Coefficient SE Odds rtio (95% CI) P vlue Mle sex ( ) Bseline HbA1c ( ) Durtion of dibetes ( ) <0.001 SE, stndrd error; CI, confidence intervl; HbA1c, glycosylted hemoglobin. Sex (%, femle) Hypo Hypo Non-hypo Non-hypo Weight (kg) A Hypo Non-hypo B Hypo Non-hypo C Triglyceride (mg/dl) Fsting plsm glucose (mg/dl) Hypo Non-hypo HOMA-β D Hypo Non-hypo E Fig. 3. (A) More women were mong the ptients with hypoglycemi symptoms (P=0.008). (B) Ptients with hypoglycemi symptoms weighed less (P=0.003), (C) hd lower concentrtions of triglycerides (P=0.031), (D) lower fsting plsm glucose (P<0.001), nd (E) hd higher homeostsis model ssessment of β-cell function (HOMA-β) levels (P=0.001). Hypo, ptients who experienced hypoglycemi; Non-hypo, ptients who did not experience hypoglycemi. P<0.05. P=0.008), lower body weight (65.2±10.7 kg vs. 68.9±12.3 kg, P=0.003), lower triglyceride levels (134.4±74.1 mg/dl vs ±105.0 mg/dl, P=0.031), lower FPG levels (138.0±38.7 mg/dl vs ±48.7 mg/dl, P<0.001), nd higher HOMA-β levels (83.3±51.2 vs. 57.5±38.1, P=0.001) thn the ptients without hypoglycemic symptoms. DISCUSSION In this study, we found tht the ddition of DPP-4 inhibitor to n ongoing submximl dose of sulfonylure nd metformin combintion in Koren ptients with type 2 dibetes ws effective in improving glycemi prmeters for up to 52 weeks. Bsed on the previous studies [14,17], we identified the chrcteristics of rpid responders to this triple combintion therpy s those showing decrese in HbA1c levels of 25% in the initil 12 weeks of the dd-on. Rpid responders were more likely to be men nd hd shorter durtion of dibetes nd higher bseline levels of FPG, HbA1c, C-peptide, nd HOMA-IR. More ptients in the rpid responder group reported hypoglycemi or required further reduction in sulfonylure dose compred with the non-rpid responder group. The ptients with hypoglycemi in this study were more likely to be femle, with lower body weight nd triglyceride nd FPG concentrtions nd higher HOMA-β level. In clinicl prctice, some ptients showed n exceptionl response to DPP-4 inhibitors. We wnted to chrcterize these ptients, especilly in the context of the DPP-4 inhibitor ddon to the combintion of submximl doses of sulfonylure nd metformin. We were lso interested in identifying impor- 494 Dibetes Metb J 2015;39:

7 Rpid responders to DPP4 inhibitor dd-on tnt clinicl prmeters tht could help predict rpid response to DPP-4 inhibitors. Our clinicl predictors of rpid response to the DPP-4 inhibitor dded to the sulfonylure-bsed regimen were consistent with prmeters reported by some studies but differed from those reported by other studies [8-13]. The inconsistency might be due to different study design. We included lrge numbers of ptients of the sme ethnicity (n=807) who were prescribed n ongoing sulfonylure nd metformin combintion t one dibetes center. In contrst with other studies, BMI nd ge were not significntly ssocited with rpid response to the ddition of DPP-4 inhibitor [8,9]. The rpid chnges in FPG nd HbA1c levels nd shorter durtion of dibetes were more frequent in rpid responders, nd this finding is consistent with previous studies [10,19]. The mechnism of glycemic improvement mplified by the combintion of DPP-4 inhibitor nd sulfonylure is thought to reflect intensified insulin secretion by the pncretic β-cells, the common trget of these drugs [20]. Exchnge protein ctivted by camp 2 (Epc2) is ctivted by sulfonylure nd incretin hormone [21,22], which increses insulin secretion nd synergistic improvement in hyperglycemi nd β-cell cpcity [23]. Those who showed rpid response to DPP-4 inhibitor in this study hd higher C-peptide level nd shorter durtion of dibetes t bseline. We propose tht their improved β-cell cpcity might be relted to the synergistic potentition for insulin secretion with the sulfonylure nd DPP-4 inhibitor combintion. In this study popultion, 35% of the ptients with poor glycemic control under ner-mximum dose of metformin nd sulfonylure reched trget HbA1c level of 7.0% in 12 weeks fter the dd-on DPP-4 inhibitor s triple therpy, nd this effect ws mintined for up to 52 weeks. A previous rndomized, prllel-group study hs shown the efficcy nd sfety of sitgliptin in 229 ptients tking metformin nd sulfonylure [14] in which there ws 0.89% reduction in the HbA1c level to 8.3% from the bseline to 24 weeks [14]. Our group hs reported previously tht dding DPP-4 inhibitor to n insulinbsed regimen ws more effective thn 25% increse in insulin dose [24]. In clinicl prctice, some ptients re resistnt to strting insulin therpy. Our results suggested tht dding DPP-4 inhibitor to ongoing submximl doses of sulfonylure nd metformin s triple combintion therpy my be preferble to switching to insulin therpy, even for ptients with high HbA1c level with long durtion of dibetes. Hypoglycemi is the most importnt obstcle in treting ptients with dibetes. Therefore, we lso wnted to identify the clinicl chrcteristics of ptients prone to hypoglycemi when given DPP-4 inhibitor s prt of triple therpy. Being femle, hving lower BMI, lower triglyceride nd FPG concentrtions, nd higher HOMA-β level were significntly ssocited with hypoglycemi in ptients receiving the triple therpy. In ptients with preserved β-cell function, the potentited insulin relese stimulted by the ddition of DPP-4 inhibitor incresed the percentge of ptients reporting hypoglycemi. Lower FPG nd triglyceride levels re relted to lower heptic glucose production in the fsting stte nd increse the risk of hypoglycemi. Consistent with two previous Koren studies [10,12], we found no reltionship between BMI nd the response to DPP-4 inhibitor; however, in our study, lower body weight ws relted to more frequent hypoglycemi. A reduction in the dose of sulfonylure should be considered in elderly ptients, especilly those with decresed renl function nd poor orl intke, when DPP-4 inhibitor is dded. This study hd limittions. This ws retrospective study, lthough it included lrge number of ptients. Minor hypoglycemi ws self-reported by ptients, nd not ll incidents were ccompnied by documented glucose level. The enrolled subjects were ll Korens with long durtion of dibetes nd uncontrolled glycemic sttus. In ddition, the ptient profiles in this study differed from those of previous studies. The men durtion of dibetes ws 11.5 yers in our ptients, nd they hd uncontrolled hyperglycemi while under tretment with high doses of sulfonylure nd metformin. Thus, the dt from this study my not be generlizble to ll ethnic groups or types of ptients. Our dt suggested tht reducing the dose of sulfonylure did not reduce the efficcy of triple therpy in providing glycemic control even in ptients with longer durtion of dibetes nd uncontrolled hyperglycemi. Dose reduction could be considered in ptients with low FPG concentrtions, preserved β-cell function, nd fvorble lipid profile. In conclusion, this study hs provided evidence of the efficcy of DPP-4 inhibitor dd-on therpy for ptients tking sulfonylure nd metformin combintion t ner-mximum dose. The triple combintion therpy my be preferble for some ptients, even for those using the mximum dose of sulfonylure nd metformin combintion, insted of switching to n insulin-bsed regimen. A reduction in sulfonylure dose could be recommended when strting the DPP-4 inhibitor Dibetes Metb J 2015;39:

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