The Effect of DPP-4 Inhibitors on Metabolic Parameters in Patients with Type 2 Diabetes

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1 Originl Article Clinicl Cre/Eduction Dibetes Metb J 214;38: pissn eissn DIABETES & METABOLISM JOURNAL The Effect of DPP-4 Inhibitors on Metbolic Prmeters in Ptients with Type 2 Dibetes Eun Yeong Choe 1, *, Yongin Cho 1, *, Younjeong Choi 1, Yujung Yun 1, Hye Jin Wng 2, Obin Kwon 1,3, Byung-Wn Lee 1, Chul Woo Ahn 1,4, Bong Soo Ch 1,2,4, Hyun Chul Lee 1,4, Eun Seok Kng 1,2,4 1 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, 2 Brin Kore 21 Plus Project for Medicl Science, 3 Deprtment of Phrmcology, 4 Institute of Endocrine Reserch, Yonsei University College of Medicine, Seoul, Kore Bckground: We evluted the effects of two dipeptidyl peptidse-4 (DPP-4) inhibitors, sitgliptin nd vildgliptin, on metbolic prmeters in ptients with type 2 dibetes mellitus. Methods: A totl of 17 type 2 dibetes ptients treted with sitgliptin or vildgliptin for more thn 24 weeks were selected. The ptients were seprted into two groups, sitgliptin (1 mg once dily, n=93) nd vildgliptin (5 mg twice dily, n=77). We compred the effect of ech DPP-4 inhibitor on metbolic prmeters, including the fsting plsm glucose (FPG), postprndil glucose (PPG), glycted hemoglobin (HbA1c), nd glycted lbumin (GA) levels, nd lipid prmeters t bseline nd fter 24 weeks of tretment. Results: The HbA1c, FPG, nd GA levels were similr between the two groups t bseline, but the sitgliptin group displyed higher PPG level (P=.3). After 24 weeks of tretment, ll of the glucose-relted prmeters were significntly decresed in both groups (P=.1). The levels of totl cholesterol nd triglycerides were only reduced in the vildgliptin group (P=.1), lthough the sitgliptin group received lrger quntity of sttins thn the vildgliptin group (P=.2).The men chnge in the glucose- nd lipid-relted prmeters fter 24 weeks of tretment were not significntly different between the two groups (P=not significnt). Neither sitgliptin nor vildgliptin tretment ws ssocited with reduction in the high sensitive C-rective protein level (P=.714). Conclusion: Vildgliptin nd sitgliptin exert similr effect on metbolic prmeters, but vildgliptin exerts more potent beneficil effect on lipid prmeters. Keywords: Dibetes mellitus; DPP-4 inhibitor; Glycted serum lbumin; Lipids INTRODUCTION The incresing prevlence of dibetes mellitus is incresing the economic burden of controlling blood glucose levels nd treting complictions [1,2]. Dibetes mellitus ptients lso exhibit more thn 3-fold greter risk of crdiovsculr disese (CVD) nd mortlity thn nondibetic subjects [3]. To prevent CVD, ptients with dibetes mellitus require comprehensive tretment tht includes the control of glucose, blood pressure nd cholesterol levels. The UK Prospective Dibetes Study demonstrted tht intensive glucose control of type 2 dibetes could prevent microvsculr complictions [4]. However, lrge follow-up clinicl studies reveled tht intensive tretment increses the risk of CVD nd mortlity due to hypoglycemi nd weight gin [5-7]. Therefore, vriety of potentil drugs hve been developed to control the glucose levels nd reduce severe hypoglycemi. Among these drugs, dipeptidyl peptidse-4 (DPP-4) inhibitors hve been proven effective Corresponding uthor: Eun Seok Kng Deprtment of Internl Medicine, Yonsei University College of Medicine, 5 Yonsei-ro, Seodemun-gu, Seoul , Kore E-mil: edgo@yuhs.c * Eun Yeong Choe nd Yongin Cho contributed eqully to this study s first uthors. Received: Jul. 6, 213; Accepted: Sep. 24, 213 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 214 Koren Dibetes Assocition

2 Choe EY, et l. for glucose control without inducing hypoglycemi nd re widely used s the primry therpeutic option. Sitgliptin is the first DDP-4 inhibitor tht ws commercilly pproved for use. Mny clinicl trils demonstrted tht sitgliptin reduces the level of glycted hemoglobin (HbA1c) by.6% to 1.5% compred to plcebo in subjects of vrious ges nd ethnicities [8-1]. Vildgliptin, the second DPP-4 inhibitor developed, lso effectively reduces the plsm glucose levels [11,12]. Although both sitgliptin nd vildgliptin belong to the sme clss of DPP-4 inhibitors, these two drugs disply mny different properties, including structure, phrmcokinetics nd mechnism of ction to inhibit DPP-4 [13-15]. Sitgliptin is D compound tht contins pyrimidine structure nd displys 12.4-hour hlf-life. It is primrily metbolized by cytochrome p45 3A4 nd eliminted by renl excretion [13]. Alterntively, vildgliptin is 33 D compound tht contins cynopyridine structure nd displys 2-hour hlf-life. Becuse of its low protein binding ffinity (9%), vildgliptin is rpidly bsorbed, reching its pek plsm concentrtion within 1 hour, nd then rpidly eliminted [14]. However, despite its short hlf-life, vildgliptin exerts potent inhibitory effect for 24 hours by covlently binding to the DPP-4 receptor if dministered t dose of 5 mg twice dily [15,16]. Generlly, the effect of both drugs on the plsm glucose level nd the glucose indices is similr. Vildgliptin exerts more potent beneficil effect on the levels of oxidtive stress nd inflmmtion mrkers [17,18]. However, few ptients were exmined for only short durtion, so the long-term effects of both drugs on metbolic prmeters hve not been well studied. This study investigted the effects of two DPP-4 inhibitors, sitgliptin nd vildgliptin, on metbolic prmeters in ptients with type 2 dibetes mellitus. METHODS This retrospective study reviewed ptients who hd been dignosed with type 2 dibetes mellitus from Jnury 28 to December 212 t Severnce Hospitl Dibetes Center. Ptients who were receiving 1 mg of sitgliptin once dily or 5 mg of vildgliptin twice dily were selected nd the dosge of ech ptient s previous medictions ws mintined. The exclusion criteri were s follows: 1) ny chnge in prior medictions just before (the pst 12 weeks) or during the period of DPP-4 inhibitor tretment, including ny ltertion in dose, composition, or frequency; 2) chronic liver (Child-Pugh C) or kidney disese (stge IV); or 3) ny medictions tht could ffect the plsm glucose levels, such s steroid, thyroid hormone, or herbl drug. The enrolled ptients were seprted into the sitgliptin group or the vildgliptin group ccording the drug tht they were receiving. The metbolic prmeters, including the levels of fsting plsm glucose (FPG), postprndil 2-hour glucose (PPG), HbA1c, glycted lbumin (GA), totl cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), nd cretinine, were mesured t bseline nd every 12 weeks during the 24-week study. The high sensitivity C-rective protein (hscrp) ssy ws lso performed. The prevlence of hypertension, coronry rtery occlusive disese (CAOD), peripherl rtery occlusive disese (PAOD) nd stroke nd the medicl history of sttin dministrtion were recorded using the medicl records. The FPG levels were determined vi the stndrd glucose oxidse method using 747 utomtic nlyzer (Hitchi, Tokyo, Jpn). The HbA1c levels were mesured vi high performnce liquid chromtogrphy. The serum GA level ws determined vi n enzymtic method using n lbumin-specific proteinse, ketomine oxidse, nd lbumin ssy regent (LUCICA GA-L; Ashi Ksei Phrm Co., Tokyo, Jpn), s well s Hitchi 7699 Pmodule utonlyzer (Hitchi Instruments Service, Tokyo, Jpn). The fsting nd postprndil 2-hour insulin nd C-peptide levels were mesured vi rdioimmunossy method t bseline. To nlyze insulin resistnce nd insulin secretion, homeosttic model ssessment-insulin resistnce (HOMA-IR) nd the chnge in the C-peptide level were clculted s follows: HOMA-IR= fsting insulin (μu/ml) FPG (mmol/l)/22.5, nd C-peptide= postprndil 2-hour C-peptide fsting C-peptide. The body mss index (BMI) ws lso clculted ccording to the following eqution: BMI=weight (kg)/height 2 (m 2 ). The men chnge ( ) in ech metbolic prmeter ws clculted using following formul: level fter 24 weeks of tretment level t bseline. Sttisticl nlysis All descriptive dt were expressed s the mens±stndrd devition. Continuous vribles of the sitgliptin group nd the vildgliptin group were compred nd nlyzed using t- tests. Nominl vribles were compred using the chi-squre test. Anlyses of more thn three mesured prmeters were performed using repeted mesures nlysis of vrince. P vlues of less thn.5 were considered to be sttisticlly significnt. Person correltion coefficient (r) ws used to ssess the 212 Dibetes Metb J 214;38:

3 Effect of DPP-4 inhibitors strength of the reltionships between the clinicl nd lbortory vribles. Vribles displying P<.5 bsed on univrite nlysis were subjected to multivrite nlysis. SPSS version 17. (SPSS Inc., Chicgo, IL, USA) ws used for the nlyses. RESULTS Bseline chrcteristics A totl of 17 ptients suffering from type 2 dibetes mellitus who hd received sitgliptin or vildgliptin for more thn 24 weeks were selected. Ninety-three ptients were tking sitgliptin, nd 77 ptients were tking vildgliptin. The bseline chrcteristics of both groups re presented in Tble 1. The men ge of the subjects ws 61.3±12.9 yers in the sitgliptin group nd 58.7±12.2 yers in the vildgliptin group (P=.186). The dibetes mellitus durtion ws over 6 yers in both groups (P=.642). There ws no difference in the metbolic prmeters of the FPG, HbA1c, GA, cretinine, estimted glomerulr filtrtion rte, TG or totl, nd LDL-C or HDL-C level t bseline. However, the PPG level ws significntly higher in the sitgliptin group thn in the vildgliptin group (P=.3). Although HOMA-IR ws not different between the groups (P=.48), the postprndil 2-hour C-peptide level nd the chnge in the C-peptide level were significntly higher in the subjects tking vildgliptin thn in those tking sitgliptin (P=.3). There ws no significnt difference in the prevlence of hypertension, CAOD, PAOD, or stroke (P=not significnt) between the groups. Sttins were more frequently dministered in the sitgliptin group thn in the vildgliptin group (P=.2). Chnge in the metbolic prmeters fter 24 weeks of tretment After 24 weeks of DPP-4 inhibitor tretment, ll of the glucose prmeters were significntly decresed compred to bseline in both groups (Tble 2). The HbA1c nd GA levels were significntly decresed compred to the premediction levels (Fig. 1A nd B). The rtio of GA to HbA1c ws significntly reduced from 2.5 to 2.3 (P=.1). There were chnges in both the FPG nd PPG levels (Fig. 1C nd D). However, there ws no significnt difference between the groups in the mgnitude of the chnge in the glucose prmeters (Tble 2). The totl cholesterol nd TG levels were significntly decresed in the vildgliptin group (P=.1) (Fig. 1E nd F) regrdless of sttin use (Supplementry Tble 1). The LDL-C level ws lso Tble 1. Bseline chrcteristics of the ptients Chrcteristic Sitgliptin (n=93) Vildgliptin (n=77) P vlue Age, yr 61.3± ± Sex, mle/femle 33/6 31/ BMI, kg/m ± ± Wist-hip rtio.92±.5.92± Dibetes durtion, yr 6.6± ± FPG, mg/dl 144.6± ± PPG, mg/dl 24.2± ±6.5.3 HbA1c, % 7.8±1. 7.6± GA, % 19.8± ± GA:HbA1c rtio 2.5±.4 2.5±.5.77 Cretinine, mg/dl 1.±.4 1.±.4.75 egfr, ml/min/1.73 m ± ± Cholesterol, mg/dl 166.6± ± Triglyceride, mg/dl 27.± ± Insulin, μu/ml 11.4± ± HOMA-IR 4.±.3 4.5±.6.48 C-peptide, ng/ml Fsting 2.8± ± Postprndil 2-hour 6.1± ± C-peptide 3.3± ±2.6.3 HTN 59 (63.4) 46 (59.7).368 CAOD 27 (29.) 16 (2.8).146 PAOD 3 (3.2) 4 (5.2).396 Stroke 14 (15.1) 11 (14.3).532 Sttin 63 (67.6) 34 (44.2).2 Vlues re presented s men±stndrd devition or number(%). Student t-test ws performed. BMI, body mss index; FPG, fsting plsm glucose; PPG, postprndil glucose; HbA1c, glycted hemoglobin; GA, glycted lbumin; egfr, estimted glomerulr filtrtion rte; HOMA-IR, homeosttic model ssessment-insulin resistnce; HTN, hypertension; CAOD, coronry rtery occlusive disese; PAOD, peripherl rtery occlusive disese. P<.5. reduced, lthough this result ws not sttisticlly significnt (P=.77). There ws no significnt chnge in the lipid prmeters in the sitgliptin group (Tble 2). Although the men chnges in the lipid prmeters were not significntly different between the two groups, vildgliptin displyed trend to reduce the totl cholesterol levels further thn sitgliptin (P=.71). The hscrp level ws 1.9±1.2 mg/l in the sitgliptin Dibetes Metb J 214;38:

4 Choe EY, et l. Tble 2. Drug effects on metbolic prmeters fter 24 weeks of tretment Prmeter Sitgliptin (n=93) Vildgliptin (n=77) Bseline 24 weeks P vlue Bseline 24 weeks P vlue FPG, mg/dl 144.6± ± ± ± FPG 28.9± ± PPG, mg/dl 24.2± ± ± ± PPG 45.3± ± HbA1c, % 7.8±1. 6.8± ± ±.9.1 HbA1c 1.±.9.9± GA, % 19.8± ± ± ±3.4.1 GA 4.1± ± GA:HbA1c rtio 2.5±.4 2.3± ±.5 2.3±.4.1 GA:HbA1c rtio.2±.3.2±.3.45 Cholesterol, mg/dl Totl 166.6± ± ± ± Totl 5.4± ± HDL 42.1± ± ± ± HDL.3± ± LDL 81.6± ± ± ± LDL.1± ± Triglyceride, mg/dl 27.± ± ± ± Triglyceride 33.1± ± hscrp, mg/dl 1.9± ± ± ± hscrp.3±1.4.1± Vlues re presented s men±stndrd devition. Student pired t-test or t-test ws performed. FPG, fsting plsm glucose;, level t 24 weeks to level t bseline for the given prmeter; PPG, postprndil glucose; HbA1c, glycted hemoglobin; GA, glycted lbumin; HDL, high density lipoprotein; LDL, low density lipoprotein; hscrp, high sensitive C-rective protein. P<.5. group nd 1.5±1.4 mg/l in the vildgliptin group t bseline. There ws no sttisticl significnce difference in the hscrp level fter DPP-4 inhibitor tretment. Proportion of subjects tht reched the tretment trget gol A decrese in the HbA1c level of over 1% from bseline ws chieved in 39.8% of the ptients dministered sitgliptin nd 36.4% of the ptients dministered vildgliptin (P=.746) (Fig. 2A). The proportion of ptients exhibiting n HbA1c level of less thn 7% ws 73% in the sitgliptin group nd 79.5% in the vildgliptin group (P=.362) (Fig. 2B). There ws no significnt difference between the two groups in terms of glucose control. The proportion of ptients who chieved reduction in the GA level of over 3% from bseline ws 63.6% in the sitgliptin group nd 5.8% in the vildgliptin group (P=.136) (Fig. 2C). The proportion of ptients displying GA level of less thn 14% ws 37% in the sitgliptin group nd 35% in the vildgliptin group (P=.46) (Fig. 2D). DISCUSSION This study compred the effects of sitgliptin nd vildgliptin on metbolic prmeters. The efficcy of sitgliptin nd vildgliptin were directly compred bsed on vrious glucose nd lipid prmeters over the course of 24 weeks of tretment. We found tht vildgliptin exerts similr effect on glucose control to tht of sitgliptin, but vildgliptin exerts more potent beneficil effect on the lipid profiles. The metbolic prmeters could be esily nd consistently mesured in most outp- 214 Dibetes Metb J 214;38:

5 Effect of DPP-4 inhibitors GA (%) 2 1 HbA1c (%) A 3 6 B 2 3 FPG (mg/dl) Totl cholesterol (mg/dl) C E PPG (mg/dl) Triglyceride (mg/dl) D F Fig. 1. (A-F) Chnge in the metbolic prmeters during dipeptidyl peptidse-4 (DPP-4) inhibitor tretment. Vlues re presented s men±stndrd error., sitgliptin;, vildgliptin; GA, glycted lbumin; HbA1c, glycted hemoglobin; FPG, fsting plsm glucose; PPG, postprndil glucose. P<.5, compred to bseline. tient clinics. There were no significnt differences in the chnges in the glucose prmeters. Additionlly, similr proportion of the enrolled ptients ttined the trget glucose rnge fter tretment with the DPP-4 inhibitor in both mediction groups. Significnt chnges in the lipid prmeters following sitgliptin tretment were not detected. However, with vildgliptin tretment, the totl cholesterol nd TG levels were significntly decresed compred to bseline, lthough the vildgliptin group received lower mount of sttin drug compred to the sitgliptin group. There re mny studies tht investigted the clinicl efficcy of DPP-4 inhibitors [19-24]. Mny studies reported n improvement in the glucose sttus compred to plcebo when dministered s supplement to the existing tretment or s combintion therpy with vrious drugs, including metformin, sulfonylure, thizolidinedione, or insulin, in ptients suffering from type 2 dibetes mellitus with impired glucose control. In ddition, the clinicl prmeters tht could ffect glycemic control were evluted [1,25,26]. In this study, the GA level ws used to evlute the chnge in glucose metbolism over the course of 2 to 3 weeks s n of index short-durtion glucose control [27]. The GA level is currently widely Dibetes Metb J 214;38:

6 Choe EY, et l. ΔHbA1c 1% P=.746 HbA1c <7% P=.362 A B 1 8 P= P=.46 ΔGA 3% 6 4 GA <14% C D Fig. 2. (A-D) Proportion of subjects tht reched the trget glucose rnge. Student t-test ws performed., sitgliptin; VIL- DA, vildgliptin; HbA1c, glycted hemoglobin; HbA1c 1, greter thn 1% decrese in the HbA1c level from bseline; GA, glycted lbumin; GA 3, greter thn 3% decrese in the GA level from bseline. used s n index of glycemic control during intensive dibetes tretment s more rpid glyction index thn HbA1c for glucose control nd excursion [27-29]. In mny studies, both drugs exerted similr effect on glucose reduction compred to plcebo, but some studies reported tht vildgliptin my exert more potent effect to reduce of oxidtive stress nd glucose fluctutions, which my ply role in its protection ginst vsculr dmge [17,3,31]. Recently, prospective rndomized control tril reported tht sitgliptin nd vildgliptin tretment resulted in reduction in the crotid rtery intr medi thickness (IMT) by decresing the oxidtive stress nd inflmmtion mrker levels [18]. In tht study, there ws no significnt chnge in the lipid prmeters nd no difference between the two groups in the reduction in the glucose prmeters over the course of 12 weeks of tretment. However, vildgliptin induced stronger reduction in the IMT thn sitgliptin. Predictors of the IMT chnge were only found for glucose fluctutions, mesured s the men mplitude of glucose excursion nd the LDL levels. In our study, there ws no difference in the chnge in the glucose prmeters, including the GA level nd the GA to HbA1c rtio. However, there ws significnt reduction in the lipid prmeters in the vildgliptin group. Some studies reported this effect of DPP-4 inhibitor tretment on the lipid prmeters [17,26,32,33] nd found n ssocition between DPP-4 inhibitor tretment nd reduced totl cholesterol levels. We investigted the chnge in lipid prmeters during 24-week DPP-4 inhibitor tretment period nd compred the efficcy of the two drugs. Although there ws no significnt difference in the mgnitude of the men chnge between the two groups, vildgliptin tretment resulted in significntly reduced levels of totl cholesterol nd TG. This study hs some limittions. Becuse it ws not rndomized clinicl tril, there were biochemicl differences between the two groups t bseline. We could not exclude the possibility of differences in drug complince between the two medictions. The number of enrolled ptients ws reltively smll becuse there were few subjects who hd not chnged other orl hypoglycemic medictions. Although we continuously followed up for up to 24 weeks, we did not detect direct effect of either drug on the development of CVD. Therefore, long-term follow-up studies of dibetes using DPP-4 inhibitors re needed to obtin dditionl evidence of their benefits. In conclusion, vildgliptin exerts similr effect on metbolic profiles to tht of sitgliptin, but vildgliptin exerts more potent beneficil effect on lipid profiles. 216 Dibetes Metb J 214;38:

7 Effect of DPP-4 inhibitors CONFLICTS OF INTEREST No potentil conflict of interest relevnt to this rticle ws reported. ACKNOWLEDGMENTS This study ws finncilly supported by the Kiturmi Fculty Reserch Assistnce Progrm of Yonsei University College of Medicine ( ). REFERENCES 1. Chen L, Mglino DJ, Zimmet PZ. The worldwide epidemiology of type 2 dibetes mellitus: present nd future perspectives. Nt Rev Endocrinol 212;8: Ginter E, Simko V. Dibetes type 2 pndemic in 21st century. Brtisl Lek Listy 21;111: Fox CS, Cody S, Sorlie PD, D Agostino RB Sr, Pencin MJ, Vsn RS, Meigs JB, Levy D, Svge PJ. Incresing crdiovsculr disese burden due to dibetes mellitus: the Frminghm Hert Study. Circultion 27;115: UK Prospective Dibetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylures or insulin compred with conventionl tretment nd risk of complictions in ptients with type 2 dibetes (UKPDS 33). Lncet 1998;352: Zoungs S, Ptel A, Chlmers J, de Gln BE, Li Q, Billot L, Woodwrd M, Ninomiy T, Nel B, McMhon S, Grobbee DE, Kengne AP, Mrre M, Heller S; ADVANCE Collbortive Group. Severe hypoglycemi nd risks of vsculr events nd deth. N Engl J Med 21;363: ADVANCE Collbortive Group, Ptel A, McMhon S, Chlmers J, Nel B, Billot L, Woodwrd M, Mrre M, Cooper M, Glsziou P, Grobbee D, Hmet P, Hrrp S, Heller S, Liu L, Mnci G, Mogensen CE, Pn C, Poulter N, Rodgers A, Willims B, Bompoint S, de Gln BE, Joshi R, Trvert F. Intensive blood glucose control nd vsculr outcomes in ptients with type 2 dibetes. N Engl J Med 28;358: ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismil-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushmn WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewld WT. Long-term effects of intensive glucose lowering on crdiovsculr outcomes. N Engl J Med 211;364: Brzili N, Guo H, Mhoney EM, Cporossi S, Golm GT, Lngdon RB, Willims-Hermn D, Kufmn KD, Amtrud JM, Goldstein BJ, Steinberg H. Efficcy nd tolerbility of sitgliptin monotherpy in elderly ptients with type 2 dibetes: rndomized, double-blind, plcebo-controlled tril. Curr Med Res Opin 211;27: Iwmoto Y, Tniguchi T, Nonk K, Okmoto T, Okuym K, Arjon Ferreir JC, Amtrud J. Dose-rnging efficcy of sitgliptin, dipeptidyl peptidse-4 inhibitor, in Jpnese ptients with type 2 dibetes mellitus. Endocr J 21;57: Kim SA, Shim WH, Lee EH, Lee YM, Beom SH, Kim ES, Yoo JS, Nm JS, Cho MH, Prk JS, Ahn CW, Kim KR. Predictive clinicl prmeters for the therpeutic efficcy of sitgliptin in koren type 2 dibetes mellitus. Dibetes Metb J 211;35: Keting GM. Vildgliptin: review of its use in type 2 dibetes mellitus. Drugs 21;7: Grber AJ, Foley JE, Bnerji MA, Ebeling P, Gudbjornsdottir S, Cmissc RP, Couturier A, Bron MA. Effects of vildgliptin on glucose control in ptients with type 2 dibetes indequtely controlled with sulphonylure. Dibetes Obes Metb 28;1: Hermn GA, Stevens C, Vn Dyck K, Bergmn A, Yi B, De Smet M, Snyder K, Hillird D, Tnen M, Tnk W, Wng AQ, Zeng W, Musson D, Winchell G, Dvies MJ, Rmel S, Gottesdiener KM, Wgner JA. Phrmcokinetics nd phrmcodynmics of sitgliptin, n inhibitor of dipeptidyl peptidse IV, in helthy subjects: results from two rndomized, double-blind, plcebo-controlled studies with single orl doses. Clin Phrmcol Ther 25;78: Golightly LK, Dryn CC, McDermott MT. Comprtive clinicl phrmcokinetics of dipeptidyl peptidse-4 inhibitors. Clin Phrmcokinet 212;51: He YL. Clinicl phrmcokinetics nd phrmcodynmics of vildgliptin. Clin Phrmcokinet 212;51: He YL, Serr D, Wng Y, Cmpestrini J, Riviere GJ, Decon CF, Holst JJ, Schwrtz S, Nielsen JC, Ligueros-Syln M. Phrmcokinetics nd phrmcodynmics of vildgliptin in ptients with type 2 dibetes mellitus. Clin Phrmcokinet 27; 46: Rizzo MR, Brbieri M, Mrfell R, Polisso G. Reduction of oxidtive stress nd inflmmtion by blunting dily cute glucose fluctutions in ptients with type 2 dibetes: role of dipeptidyl peptidse-iv inhibition. Dibetes Cre 212;35: Brbieri M, Rizzo MR, Mrfell R, Boccrdi V, Esposito A, Pn- Dibetes Metb J 214;38:

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9 Effect of DPP-4 inhibitors Supplementry Tble 1. Lipid profile chnges ccording to sttin tretment Sttin Sitgliptin (n=93) Vildgliptin (n=77) Bseline 24 weeks P vlue Bseline 24 weeks P vlue Totl, mg/dl 182.4± ± ± ± Totl.33± ± HDL, mg/dl 41.6± ± ± ± HDL.9± ± LDL, mg/dl 9.4± ± ± ± LDL 9.6±28..9± Triglyceride, mg/dl 213.8± ± ± ± Triglyceride.65± ± Sttin+ Totl, mg/dl 162.2± ± ± ± Totl 7.7± ± HDL, mg/dl 42.± ± ± ± HDL.8± ± LDL, mg/dl 79.8± ± ± ± LDL 4.2± ± Triglyceride, mg/dl 199.9± ± ± ± Triglyceride 11.5± ± Vlues re presented s men±stndrd devition. Student pired t-test or t-test ws performed., level t 24 weeks to level t bseline for the given prmeter; HDL, high density lipoprotein; LDL, low density lipoprotein. P<.5, compred to bseline. Dibetes Metb J 214;38: