http://dx.doi.org/10.4093/jkd.2013.14.3.111 DPP-4 억제제의비교 고려대학교의과대학내분비내과김남훈, 김신곤 Comparison of DPP-4 Inhibitors Nam Hoon Kim, Sin Gon Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Abstract During past several years, a novel class of antihyperglycemic agents, dipeptidyl peptidase-4 (DPP-4) inhibitors, has become one of the most important options in the management of type 2 diabetes. These agents have unique insulinotropic actions as well as other advantages such as lower hypoglycemia and a weight-neutral effect compared to traditional insulin secretagogues. To date, 6 different DPP-4 inhibitors have been introduced: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin and gemiglitin. This review provides a summary of the clinical data for each DPP-4 inhibitor, and discusses the similarities and differences between them. (J Korean Diabetes 2013;14:111-119) Keywords: Dipeptidyl-peptidase IV inhibitors, Incretins, Diabetes mellitus 111 인크레틴효과 (incretin effect) 란당분을경구로투여했을때동량의당분을정맥주사했을때보다더강력한인슐린분비자극이일어나는것을말하며, 이러한개념은이미 1960 년대에선구적인연구자들에의해제시되었다 [1]. 뒤이은연구는인크레틴효과가혈당의존적인방식으로일어나며 [2], 건강한사람에비해당뇨병환자에서이러한효과가감소되어있음을보여주었다 [3]. 인크레틴호르몬인 GIP (glucosedependent insulinotropic peptide), GLP-1 (glucagon like peptide-1) 및이에대한생리적분해효소인 DPP-4 (dipeptidyl peptidase-4) 의발견은당뇨병의새로운치료약제인 GLP-1 agonist 와 DPP-4 억제제의개발을가능케하였다. GLP-1 agonist 가먼저시장에등장했음에도불구하고상대적으로비싼가격과투여경로 ( 피하주사 ) 의단점으로인해처방과사용에제한적이었던반면, DPP-4 억제제의경우 GLP-1 agonist 의여러장점을공유하면서도상대적으로싼가격과경구투여라는장점덕분에임상의사들이손쉽게선택하는약제가되었다. 최근발표된당뇨병치료의 주요가이드라인에서 DPP-4 억제제를 2 차약제, 혹은특정한환자군에서는 1 차약제로까지권고하고있다 [4,5]. 현재까지세계시장에출시된 DPP4 억제제는총 6 종으로 sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin 이그것이다. 이약제들은모두유사한방식으로인체에작용하지만효능과안전성의측면에서차이가있고, 각각의약제들의특수한장점들과의학적근거들도조금씩다르다. 이번종설에서는 DPP-4 억제제간의차이와특수성을중심으로살펴보고자하였고, 더불어안전성에관한최근의이슈들을정리하였다. 구조와작용기전, 약동학 정상적인인체내환경에서혈장 GLP-1 은 DPP-4 에의해급속히분해되어반감기가약 2 분에지나지않는다 [6]. 모든 DPP-4 억제제는 DPP-4 에가역적이고경쟁적으로부착하여 DPP-4 억제효과를나타내고 교신저자 : 김신곤, 서울시성북구인촌로 73 고려대학교안암병원내분비내과, E-mail: k50367@korea.ac.kr
112 GLP-1 의급속한분해를지연시킨다. 이들의 IC50 ( 효소를 50% 억제할수있는약물농도 ) 는약제마다약간씩의차이가있으나모두아주낮은 nanomole 에지나지않아 DPP-4 에대한높은친화력과강력한억제작용을보여준다 (Table 1). 구조적인측면에서보았을때각각의 DPP-4 억제제는서로상이한모습을보이지만, 결합방식의측면에서는크게두가지계열로나눌수있다. Sitagliptin, linagliptin, alogliptin, gemigliptin 은 DPP-4 의촉매영역과비공유결합 (non-covalent bonds) 을형성하지만, vildagliptin 과 saxagliptin 은공유결합을통한효소 - 억제제복합체를형성하여결합과해리모두가지연되는결과를보여준다. 이러한특성은 vildagliptin 과 saxaglpitin 이짧은반감기에도불구하고오래작용할수있는이유가된다. DPP family 에는 DPP-4 뿐만아니라구조적으로유사한 DPP-2, DPP-8, DPP-9, 그리고 FAP (fibroblast activation protein) 등이포함되어있어 [7], 이상반응을최소화하기위해서는 DPP-4 에대한선택적억제능력이요구된다. 대부분의 DPP-4 억제제가높은 DPP-4 선택성을가지고있으나, vildagliptin, saxagliptin 에비해 alogliptin, linagliptin, gemigliptin, sitagliptin 이보다높은선택성을보여주었다. 하지만이러한선택성의차이가어떠한임상적차이로나타나는지는아직까지불분명하다. 혈장 DPP-4 활동성억제의측면에서는치료적용량을사용하였을때모든약제가 70% 이상의높은억제력을보여주었으며, GLP-1 혈장레벨또한 1.5 배에서 3 배까지증가하였다. 다만 vildagliptin 의경우치료적용량 ( or 100 mg) 을사용하였을때 24 시간째에 DDP-4 억제력이급속히감소하여하루두번복용을해야한다. 약물대사 다른 DPP-4 억제제와는달리, saxagliptin 의경우일차적으로간의 cytochrome P450(CYP) 3A4/3A5 를통해대사되므로약제간상호작용에주의해야한다 [17]. 특히강력한 CYP3A4 억제제인 ketoconazole 과같이투여할경우용량을 2. 으로제한해야하며, itraconazole, clarithromycin, atazanvir 등의약제와의동시사용에도주의해야한다. 대부분의 DPP-4 억제제가주로신장을통해제거되는반면, linagliptin 의경우극히일부분 (6% 내외 ) 만신장을통해배설되며대부분 (85%) 은담즙을통해위장관으로배설된다 [18]. 따라서신장애환자의경우에도용량조절이필요없는장점을지니며최근이와관련된임상연구도보고되었다. Sitagliptin 은 70% 이상이신장으로배설되고, vildagliptin, saxagliptin, alogliptin 은간과신장을통해제거되므로신장기능에따라용량조절이필요하다 (Table 2). Gemigliptin 의경우마찬가지로간과신장을통해제거되나신장의존도가상대적으로낮아약동학적연구에서용량조절이필요없는것으로나왔으나신장애환자를대상으로한임상연구는아직없다. 대부분의 DPP-4 억제제를대상으로한약동학연구에서간장애의정도가약물대사에심각한영향을주지않는것으로보고되었다. Vildagliptin 의경우유럽에서시행된임상데이터의메타분석에서 100 mg 1 회사용이간효소수치의경미한상승과연관이있는것으로나타났다. 약동학연구에서는경도, 중등도, 중증의간질환환자에서 vildagliptin 및대사물질의최대농도및약동학의변화가있었으나통계적으로유의하지않았다 [19]. 하지만약제의허가사항에따라간장애가있는경우 (ALT/AST > 정상상한치의 2.5 배 ) vildagliptin 의사용은권고되지않는다. 같은이유로 saxagliptin 의경우에도중증의간장애환자에서사용은 Table 1. Structure-activtiy relationship and pharmacodynamics of dipeptidyl peptidase (DPP)-4 inhibitors IC50 DPP-4 Inhibition of plasma Increase in active Drug (ref.) Structure (nmol/l) selectivity a DPP-4 activity (%) GLP-1 levels Half-life (hr) Sitagliptin [8] Vildagliptin [9,10] Saxagliptin [11] Linagliptin [12,13] Alogliptin [14,15] Gemigliptin [16] b Piperazine Cyanopyrrolidine Cyanopyrrolidine Xanthine-based Pyrimidine Pyrimidopiperidine 18 3.5 0.5 1 7 6.3 > 2600 100 100 > 10000 > 14000 > 3400 a vs. DPP-8 or DPP-9. b also from unpublished data of LG Life Science. GLP-1, glucagon like peptide-1; NA, not available. 80 80 70 70 > 75 NA 2-fold 3-fold 1.5 to 2-fold 2 to 3-fold 2 to 2-fold 2 to 3-fold 8-14 2-3 2.5 113-131 12.4-21.4 17-21
DDP- 4 억제제의비교 권고되지않는다. 이상의약동학과결과와별개로중증간장애환자에게이들약제의실제사용예나임상연구결과는아직보고되지않았다. 혈당강하능력 혈당강하능력 (glucose-lowering efficacy) 의측면에서봤을때, 개별적인임상연구의대상자및연구조건, 연구기간에따라차이를보이나대략적으로당화혈색소 0.5~1.2% 강하능력을가지는것으로조사되었다. 각각의약제의비교를위해서는일대일대응연구가필수적이나아직까지혈당강하능력을주요결과변수로설정하여시행된일대일대응연구는많지않은실정이다. 따라서비슷한조건의임상연구를비교하여그차이를보고자한다. 1. D r u g-n a ï v e 환자를대상으로한단독요법 (monotherapy) 의효과 (24 주이상연구 ) 대부분의단독요법연구는약제출시초기에진행되었으며, 혈당강하능력이외에도용량에따른효과평가와부작용의확인이라는목적으로시행되었다. Table 3 에서보듯이단독요법으로약 0.5~1.0% 의당화혈색소감소효과를보여주고있으며약제간두드러진차이는보이지않는다. 대부분의연구에서초기당화혈색소가높을수록혈당강하효과가큰것으로나타났다. 출시된지오래된 sitagliptin 과 vildagliptin 이가장많은임상경험과근거를가지고있다. Table 2. Dosage adjustments for kidney disease Renal impairment Drug Usual dose (daily) Ccr > 50 ml/min Ccr 30-50 ml/min Ccr < 30 ml/min Sitagliptin Vildagliptin Saxagliptin Linagliptin Alogliptin Gemigliptin a 100 mg 100 mg 2 100 mg 100 mg 2 2. 12. a KFDA approved based on pharmacokinetic/pharmacodynamic data but not clinical data. 2 2. 6.2 113 Table 3. Efficacy of dipeptidyl peptidase (DPP)-4 inhibtors as an initial monotherapy in drug-naïve type 2 diabetic patients Baseline Reduction Reference Drug No. of patients Study duration HbA1c level Study group Control of HbA1c no. Sitagliptin Vildagliptin Saxagliptin Linagliptin Alogliptin Gemigliptin a Includes patients who were either drug-naïve or had previously received one oral antihyperglycemic drug (with washout). 741 1091 354 632 401 503 329 180 26 wk 8.0% 8.8% 8.4% 8.4% 7.9% 8.0% 7.9% 8.2% Sita 100 mg Sita 200 mg Sita 100 mg Vilda qd Vilda bid Vilda 100 mg qd Vilda qd Vilda bid Vilda 100 mg qd Saxa 2. Saxa Saxa 10 mg Lina Alo 12. Alo 2 Gemi -0.79% -0.94% -0.83% -0.7% -0.9% -0.6% -0.52% -0.55% -0.63% -0.69% -0.58% -0.61% -0.71% [20] [21] [22] [23] [24] [25] a [26] [27]
114 2. 기존메트포르민사용자에추가병합요법 (add on to metformin) 의효과 실제임상에서는메트포르민단독요법으로치료중조절되지않는경우에추가약제로서 DPP-4 억제제를선택하는경우가많다. 대부분의약제에서이러한치료알고리즘에따라시행한임상연구의근거들이있는데이들결과는 Table 4 와같다. 메트포르민에 DPP-4 억제제를추가한경우적게는 0.5% 에서많게는 1.1% 까지의추가적인당화혈색소감소효과를보인다. Vildagliptin 이상대적으로좋은혈당감소효과를보여주고있으나다른연구에비해기저당화혈색소가높았다는점이고려되어야한다. 3. 설폰요소제와의비교연구 설폰요소제와일대일대응비교연구에대한근거를가진 DPP-4 억제제는 sitagliptin, vildagliptin, linagliptin, saxagliptin 이며, 모두설폰요소제에비해열등하지않은결과 (non-inferiority) 를입증하였다 (Table 5). 또한모든연구에서설폰요소제에비하여저혈당과체중증가가적었다. 하지만다른측면에서보자면, 연구기간이 1 년에서 2 년에달했음에도불구 하고어느약제도설폰요소제보다우월한혈당강화효과나지속성 (durability) 를입증하지는못하였다. 여기에대해서는보다장기적인연구나연장연구결과가필요할것이다. 4. DPP-4 억제제간비교연구 DPP-4 억제제간에혈당강하효과는비슷한것으로보고되었다. 메트포르민단독요법으로잘조절되지않는 801 명의당뇨병환자를대상으로 sitagliptin 100 mg 과 saxagliptin 을 18 주간직접비교한연구에서두약제의혈당강하효과는비슷하였다 [40]. 이외에도 sitagliptin 과 vildagliptin 을비교하여메타분석한연구에서도두약제의혈당강하효과간에의미있는차이는없었다 [41]. 최근에출시된 gemigliptin 또한 sitagliptin 과의비교연구를진행하였고, 425 명의아시아인을대상으로한 24 주간의연구에서두군간의혈당강하효과는비슷하였다 [42]. 한편, 혈당강화효과는비슷하지만 continuous glucose monitoring system 을이용하여측정한 mean amplitude of glycemic excursion (MAGE) 는약제간에차이가있다는보고들도있다. 한연구에따르면 viltagliptin 이 sitagliptin 보다 MAGE 를효과적으로 Table 4. Efficacy of dipeptidyl peptidase (DPP)-4 inhibtors as add-on therapy to metformin in type 2 diabetic patients Baseline Reduction Reference Drug No. of patients Study duration HbA1c level Study group Control of HbA1c no. Sitagliptin Vildagliptin Saxagliptin Linagliptin Alogliptin 701 273 544 370 743 701 527 18 wk 26 wk 8.0% 7.7% 8.4% 8.5% 8.0% 8.1% 7.9% MET + Sita 100 mg MET + Sita 100 mg MET + Vilda MET + Vilda 100 mg MET + Vilda 100 mg MET + Saxa 2. MET + Saxa MET + Saxa 10 mg MET + Lina MET + Alo 12. MET + Alo 2 MET + MET + MET + MET + MET + MET + MET + -0.65% -0.51% -0.7% -1.1% -0.83% -0.73% -0.83% -0.72% -0.64% [28] [29] [30] [31] [32] [33] [34] Table 5. Comparison of dipeptidyl peptidase (DPP)-4 inhibitors with sulfonylureas in type 2 diabetic patients No. of Study Baseline Reduction Reference Drug patients duration HbA1c level Study group Control of HbA1c no. Sitagliptin Vildagliptin Saxagliptin Linagliptin 1172 2789 1007 858 1552 52 wk 52 wk 52 wk 52 wk 96 wk 7.5% 7.3% 8.5% 7.7% 7.7% Sita 100 mg + MET MET + Vilda 100 mg MET + Vilda 100 mg MET + Saxa MET + Lina Glipizide + MET MET + glimepiride (~6 mg) MET + gliclazide (~320 mg) MET + glipizide (~20 mg) MET + glimepiride (~4 mg) -0.67% vs. -0.67% -0.44% vs. -0.53% -0.81% vs. -0.85% -0.74% vs. -0.80% -0.16% vs. -0.36% [35] [36] [37] [38] [39]
DDP- 4 억제제의비교 감소시켰으며, 산화스트레스나염증관련지표역시더호전시켰다 [43]. 그러나이런결과가약제간수용체결합력의차이에서유발된것인지아니면복용법의차이에서유래한것인지는분명치않으며, 이런결과의임상적의의도아직은불불명하다. 부작용및안전성 일반적으로 DPP-4 억제제는내약성이우수하고약제부작용이적은것으로알려져있다. 약제출시초기의한메타분석에서 DPP-4 억제제는저혈당의위험을증가시키지않았으며, 구역, 구토, 설사와같은위장관계부작용도대조군에비해차이를보이지않았다 [44]. 다만이분석에서두통과요로감염의빈도가증가하는것으로나타났으나이후의대규모분석에서는이러한부작용의증가가관찰되지않았다 [45]. 지금까지시행된개별적 DPP-4 억제제의위약대조및타약제와의비교임상연구에서도약제자체의부작용은대조군에비하여증가하지않았으며, 전통적인인슐린분비촉진제에비하여체중증가와저혈당의위험이유의하게적은것으로보고되었다. 그러나드물게는혈관부종이나아나필락시스, 그리고 Stevens-Johnson 증후군과같은피부부작용도보고된바있으므로 DPP-4 억제제를처방할때는이런가능성도염두에두어야한다. 최근까지도이슈가되고있는것은췌장염및췌장암의발생과관련된문제제기이다. 동물실험및전임상적연구에서 DPP-4 억제제는베타세포의증식을촉진하고 apoptosis 를억제함으로써베타세포의질량을증가시켰으며 [46], 이는 GLP-1 agonist 및 DPP-4 억제제가다른당뇨병치료약제와달리베타세포기능향상에도움을줄것이라는이론적인배경이되었다. 하지만이와동시에 GLP-1 수용체가췌관세포에도풍부하게존재하며, 따라서베타세포와마찬가지로인크레틴기반치료에의해췌관세포증식이일어난다는연구결과 [47] 들은췌장염및췌장암과관련된안전성문제를제기하였다. 지금까지의실제임상데이터들을보았을때서로상반된결과들을보여주고있다. 예를들어, 2009 년에발표된약제부작용보고데이터베이스에서 exenitide 및 sitagliptin 이다른당뇨병약제에비하여급성췌장염의발생이높지않았으며 [48], sitagliptin 의전향적연구들을분석한종합자료분석 (p o o l e d analysis) 에서도대조군에비해췌장염의발생비율이올라가지않았다 [49]. 반면, exenitide 와 sitagliptin 을사용했던환자들의췌장조직을분석한연구에서췌장외분비세포의증식과전암성변화들이관찰되었으며 [50], 미국 FDA 약제부작용리포트를분석한연구에서도 exenitide 와 sitagliptin, saxagliptin, linagliptin 사용그룹에서다른당뇨병약제에비해 ( 비록넓은 95% 신뢰구간을가지고있으나 ) 췌장염혹은췌장암의빈도가유의하게증가된것을보고하였다 [51]. 이처럼상반된결과의이유는여러가지가있을수있으나, 기본적으로당뇨병환자에서췌장염및췌장암의발생빈도가일반인구에비해높고, 대부분의연구가후향적이며, 보고편향을배제할수없는점, 그리고무엇보다도인과관계를명시할수없는점등이주요한원인이라고할수있겠다. 이를극복하기위해서는전향적인, 잘매치된케이스컨트롤연구와대규모무작위연구가필요하며현재진행되고있는더욱신뢰할만한연구결과들과 FDA 등유관기관의분석결과기다려보아야할것이다. 심혈관계에미치는영향및심혈관계안전성 기본적으로 DPP-4 억제제는혈당강하효과와체중에대한긍정적인효과로인해심혈관계질환에대한위험도를낮출수있을것으로기대된다. 또한당뇨병치료제로서의역할이외에도다른장기와조직에미치는영향으로인해심혈관계에긍정적인결과를가져올수있음을시사하는여러연구들이보고되어왔다. DPP-4 억제제는 GLP-1 의농도와활성도를높임으로서심혈관보호작용을나타낼수있으나 [52], GLP-1 과독립적으로도심혈관계에좋은영향을가질수있음이보고되었다. 생리적 DPP-4 는평활근과내피세포에도존재하고있으며, DPP-4 의억제가여러혈관작용물질들, 예를들어 B-type natriuretic peptide (BNP), stromal cell-derived factor 1α (SDF-1α), neuropeptide Y, s u s b s t a n c e P 의효소적분해를억제함으로서이론적으로는심혈관계보호효과를나타낼수있다 [53]. 임상적인데이터들도아직까지는 DPP-4 억제제가심혈관계에대해유해한효과보다는좋은효과들이더많다는것을보여주고있다. Sitagliptin 의경우체질량지수감소와독립적으로수축기혈압을낮추었으며 [54], 식후 triglyceride-rich lipoprotein 혈장농도를감소시켰다 [55]. 이와유사하게지질대사에미치는좋은효과는 vildagliptin 과 alogliptin 연구에서도확인되었다 [56.57]. Linaglpitin 의경우 glimepiride 와비교한 2 년간의연구에서 major cardiovascular event 가유의하게적었는데, 이는특히뇌졸중발생을감소시키는영향을통해서였다 [39]. 현재까지의제 2 상, 3 상임상연구를후향적으로메타분석한결과역시 DPP-4 억제제들이심혈관계안전성에 115
116 있어대조군에비해동등하거나좋다고보고하였다 [58]. 하지만이연구들은중대심혈관질환의발생을보기에는짧은 6 개월임상연구들을다수포함하고있고, 심혈관질환의초고위험군들을대상으로진행한연구가아니기에실제보다이익이과대평가되었을가능성을주의해야한다. Rosiglitazone 이심혈관계안전성의문제로시장에서퇴출된후, 새로출시되는약제들의심혈관계안정성의확보는승인을위한대단히중요한전제조건이되었다. DPP-4 억제제들중에서는현재총 4 개의대규모전향적연구가진행중이다. TECOS (sitagliptin), SAVOR-TIMI 53 (saxagliptin), CAROLINA (linagliptin), EXAMINE (alogliptin) 이그것이다. 모두심혈관위험도가매우높은제 2 형당뇨병환자들을대상으로하며, 모두합쳐서총 4 만명이상의환자들이연구에포함되었다. 따라서이연구들의결과는이들약제의안전성에대한신뢰도높은근거를제공할것이라고기대할수있다. 결론 현재출시되어있는 6 종의 DPP-4 억제제는동일한작용기전을가지고있으나, 약동학적프로파일, 혈당강하효과, 부작용및안전성, 심혈관계효과등의측면에서조금씩다른차이와근거를가지고있다. 하지만어떤특정한약제가다른약제보다우월하다는결론을내리기는어렵다. Sitaglipitn 이가장오래되었고따라서가장많은임상적근거들을가지고있으나, 또한췌장염등의안전성에대한문제제기가가장많은것도사실이다. Vildagliptin 은심한간장애환자에서사용이제한적이고하루두번복용의불편함이있으나혈당강하효과나혈당변이도의측면에서좀더좋은효과를보여준데이터들이있었다. Saxagliptin 의경우현재까지유일한서방복합제를가졌다는점이, 그리고 Linaglitin 은신장애나간장애환자에서용량조절없이비교적안전하게사용할수있다는점이장점으로고려될수있다. Gemigliptin 은우리나라에서개발된약제라는점이장점일수있으나아직은임상근거가적다는단점이있다. 이처럼개별적인약제들의장점과단점들이각기존재하기때문에실제처방에있어이들을고려하며개별환자들의특성에맞게약제를선택하는것이필요하겠다. 참고문헌 01.S Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964;24:1076-82. 02.S Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986;63:492-8. 03.S Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulindependent) diabetes. Diabetologia 1986;29:46-52. 04.S Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364-79. 05.S Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, Handelsman Y, Horton ES, Lebovitz H, Levy P, Moghissi ES, Schwartz SS. by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract 2009;15:540-59. 06.S Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409-39. 07.S Yazbeck R, Howarth GS, Abbott CA. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol Sci 2009;30:600-7. 08.S Herman GA, Stein PP, Thornberry NA, Wagner JA. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin. Clin Pharmacol Ther 2007;81:761-7. 09.S He H, Tran P, Yin H, Smith H, Batard Y, Wang L, Einolf H, Gu H, Mangold JB, Fischer V, Howard D. Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metab Dispos 2009;37:536-44. 10.S Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, Mangold BL, Russell ME, Hughes TE. 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]- 2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with a n t i h y p e rg ly c e m i c p ro p e r t i e s. J M e d C h e m 2003;46:2774-89. 11.S Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han SP, Abboa-Offei B, Cap M, Xin L, Tao L,
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