Focused Issue - 인크레틴계약물의최신지견 DPP-4 억제제의췌장외영향 ( 심혈관질환, 암, 췌장염등 ) 강원대학교의학전문대학원내과학교실조은희 Effect of DPP-4 Inhib

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1 DPP-4 억제제의췌장외영향 ( 심혈관질환, 암, 췌장염등 ) 강원대학교의학전문대학원내과학교실조은희 Effect of DPP-4 Inhibitors on the Cardiovascular System, Cancer and Pancreatitis Eun-Hee Cho Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea 138 Abstract Recently, dipeptidylpeptidase-4 (DPP-4) inhibitors have been widely used as a second-line therapy for type 2 diabetes because of their glucose-lowering efficacy, weight neutral effects and minimal hypoglycemia. However, there have been concerns regarding the lack of evidence of the long-term consequences of DPP-4 inhibitors on cardiovascular disease, acute pancreatitis and cancers; therefore, the effects of DPP-4 inhibitors on these three major diseases are reviewed in this article. A growing body of evidence demonstrates the cardioprotective role of DPP-4 inhibitors in animal and small clinical studies. However, clearly conflicting data regarding the effects of DPP-4 inhibitors on cancers and pancreatitis have been presented in preclinical and epidemiologic studies. The forthcoming long-term clinical studies on cardiovascular safety will provide more conclusive answers relating to the safety of DPP-4 inhibitors, including their effects on cancer and pancreatitis. (J Korean Diabetes 2013;14: ) Keywords: Dipeptidyl-peptidase IV inhibitors, Cardiovascular diseases, Neoplasms, Pancreatitis 서론 D P P-4 억제제는혈당강하효과외에도체중에중립적이고, 저혈당이별로없는장점으로인해현재제 2 형당뇨병의 2 차병합요법으로많이쓰이고있다. 당뇨병은만성병으로장기간의약제투여가필수적이기때문에새로운약제사용시그장기적인안정성에대해서는충분한주의가요구된다. 하지만현재까지일부세포및동물실험그리고소규모의임상실험이나메타분석에서 DPP-4 억제제의심혈관질환및암그리고췌장염과관련된효과가보고되고있을뿐, DPP-4 억제제의장기간사용시이들질환에대한안정성에대한임상연구는별로없다. 본종설에서는현재까지알려진 DPP-4 억제제의심혈관질환및암, 그리고췌장염등에대한연구결과를제시하고자한다. 본론 1. DPP-4 억제제의심혈관질환에대한효과 1) DPP-4 억제제의심혈관보호효과관상동맥질환환자에서 sitagliptin 을투여하여 glucagon-like peptide-1 (GLP-1) 을증강하면 dobutamine- 유도성스트레스심장초음파상좌심실의기능을회복시키는것이보고되었다 [1]. 또한골수에서유래된 endothelial progenitor cells (EPCs) 는혈관의재생과내피세포로의분화에관여하며, stromalderived factor-1α (SDF-1α) 에의해조절을받는다. EPCs 는제 2 형당뇨병환자에게감소됨이알려져있는데, Gian 등은 sitagliptin 투여가제 2 형당뇨병환자에서 EPCs 를증가시키고, SDF-1 α 증가시키며, monocyte chemotactic protein-1 을감소시킴을보고하여 DPP-4 억제제가심혈관질환에유익할수 교신저자 : 조은희, 강원도춘천시강원대학길 26 강원대학교의학전문대학원내과학교실, ehcho@kangwon.ac.kr

2 DPP-4 억제제의췌장외영향 ( 심혈관질환, 암, 췌장염등 ) 있음을제시한바있다 [2]. 또다른연구에서는 sitagliptin 과 vildagliptin 을 12 주간제 2 형당뇨병환자에게투여시혈당의변동폭, 내중막두께 (intima-media thickness) 및염증이감소함을보고하였다 [3]. DPP-4 억제제는혈청내 CRP, TNF-α 와같은 cytokines 을감소시키고, 말초단핵구내 IL-10 을증가시키며 [4], 쥐모델에서는지방조직의염증반응및지방간을예방하는등다양한항염증효과가보고되고있다 [5-7]. 하지만, 다른연구에서는제 2 형당뇨병환자에서 sitagliptin 를 6 주간투여시 flow-mediated vasodilatation 를감소시켜혈관내피세포의기능을감소시킨다고상반된보고도있다 [8]. 2) DPP-4 억제제의심혈관위험인자에대한효과 Zubair 등은혈관내피세포 (HUVEC) 에 alogliptin 을투여시 GLP-1 과는독립적으로 Src-Akt-eNOS 를통한 Nitric oxide 을방출하여혈관의이완을보임을보고하여 [9], 혈압강하효과의가능성을제시하였다. 또한 Ogawa 등은제 2 형당뇨병환자 (17 명 ) 에게 sitagliptin 을투여시혈압이감소함을보고하였고 [10], M i s t r y 등은비당뇨병고혈압환자 (19 명 ) 에게 sitagliptin 을투여시 24 시간 ambulatory BP 가감소했다는보고하는등 [11], 현재까지소규모임상연구만있을뿐 DPP-4 억제제의혈압강하효과에대한일치하는결과는없다. 또한 Marney 등은 sitagliptin 을 enalapril 10 mg 과병용시 enalapril 의 Angiotensin converting enzyme (ACE) inhibition 효과가둔화됨을보고하여 DPP-4 억제제와고용량의 ACE 억제간에혈역동학적인상호작용이있음을밝혔다 [12]. DPP-4 억제제의지질대사에대한임상연구는일부에서총콜레스테롤을감소시킨다는보고가있으나임상연구간의결과가상충한다. General Electric Centricity research database 를이용한후향적연구에서 sitagliptin 사용시총콜레스테롤과중성지방이감소함이보고되었고 [13], 제 2 형당뇨병환자 (20 명 ) 를대상으로 vildagliptin 을 1 주일투여한연구에서는 DPP-4 의억제가식후에지방조직의지방분해를증가시키고, 지방산산화는증가시키며, 교감신경계가항진됨을보였다 [14]. Matikainen 등의보고에서는제 2 형당뇨병환자에서 vildagliptin 을 4 주간투여시고지방식이후식후혈장중성지방과, apolipoprotein B-48 이감소함을보였다 [15]. 하지만대부분의 DPP-4 억제제임상연구는지질에대한효과를 1 차결과지표로삼지않아서 DPP-4 억제제의혈중지질에대한효과를증명하는데충분하지않고, 향후지질의변화를 1 차결과지표로한전향적인연구가요구된다. 3) DPP-4 억제제의심혈관질환에대한효과현재까지 DPP-4 억제제의실제심혈관질환의발생에대한임상연구는매우제한적이다. Engel 등이 25 개무작위이중맹검임상연구를이용해 14,611 명의환자를대상으로한통합분석에서심혈관질환의발생은 sitagliptin 군에서환자 100 명당 1 년에 0.65 가발생한반편, sitagliptin 비노출군에서는 0.74 로 sitagliptin 이심혈관질환의위험을증가시키지않음을보고하였다 [16]. Frederich 등이발표한 8 개의무작위 2 상 /3 상임상연구로이뤄진 4,607 명을대상으로한메타분석에서심혈관질환의발생은 saxagliptin 군에서 1.1%, saxagliptin 미사용군에서는 1.8% 로 saxagliptin 이약 41% 의심혈관질환발생의상대위험도를감소시킴을보고하여 saxagliptin 이심혈관질환에위해가없고, 오히려유익할수도있음을보고한바있다 [17]. Linagliptin (764 명 ) 과 glimepiride (755 명 ) 를 2 년간비교한무작위이중맹검임상연구에서는 linagliptin 이 glimepiride 군에비해심혈관질환의발생이유의하게감소됨 (12 명대 26 명 ) 이보고되었다 [18]. 하지만현재까지 DPP-4 억제제의심혈관질환의발생에대한전향적인무작위연구가없다. 다행히현재 sitagliptin 은 TECOS, saxagliptin 은 SAVOR-TIMI 53, a l o g l i p t i n 은 E X A M I N E, l i n a g l i p t i n CAROLINA 라는이름으로다양한 DPP-4 억제제가심혈관질환의발생에미치는영향에대한전향적인임상연구들이진행중이다. 2. DPP-4 억제제의암에대한효과 Glucagon-like peptides 가세포의증식과세포자멸사및생존에관여하며, 췌장의베타세포및신경세포의수명을연장시킴이보고되고있으며 [19], 이는 GLP 가향후종양을유발할가능성을시사한다 년 USFDA adverse event database (AERS) 를분석한연구에의하면, 췌장암의발생은 sitagliptin 군 (16 회발생 ) 이대조군 (13 회발생 ) 에비해 2.7 배가높았다고보고 (P = 0.008) 하였고, 갑상선암이나다른암의발생률에는차이가없음을보고하였다 [20]. 또다른독일의이상보고데이터연구에서는 DPP-4 억제제가췌장암의증가와는관련이없다는보고가있으며, 인간췌장세포혹은동물의종류에따라서췌장의 GLP-1 의발현이없거나존재하는등실험적차이로그해석에어려움이있어, 현재까지도 DPP-4 억제제의췌장세포에대한증식효과에대해서는논란이있다 [21]. 최근, 췌장암의전암병변을유발하는 KrasG12D 쥐 139

3 140 모델에 exendin-4 를투여시전암성병변이증가하고, 만성췌장염을악화시킴이보고되었고, 인체에서 GLP-1 receptor 가췌장의전암성병변과췌장암에서발현됨이보고되었다 [22]. 또한제 2 형당뇨병환자 (7 명 ) 의공여된췌장을비당뇨병대조군 (14 명 ) 과비교한연구에서 [23], sitagliptin 투여환자군에서췌장의외분비세포의증식과이형성 (pancreatic intraepithelial neoplasia; PanIN, 췌장의상피세포내종양 ) 이증가하고, 알파세포의과증식및글루카곤을분비하는미세선종과신경내분비종양이관찰되었다. 과증식이일어나거나, 전종양성변화가보이는것이반드시췌장암으로진행하지는않지만, 암의잠재적인위험성에대한장기적인연구가필요하다 [24]. 갑상선의 C 세포과증식및갑상선수질암에서 GLP-1 receptor 가발현하였고, 갑상선유두암의 18%, C 세포의 33% 에서도 GLP-1 recptor 가보고되어 [25], GLP-1 의세포증식효과가전암성병변의암으로의진행을유발할지에대한우려가제기되었다. 현재까지 exenatide 군에서는갑상선암이증가하였으나 sitagliptin 군에서는갑상선암이증가하지않음이보고되었다 [20]. 또한현재까지건강한사람에서 DPP-4 억제제투여후췌장암이나갑상선암이발생하였다는직접적인증례보고는아직까지는없다. 3. DPP-4 억제제의췌장에대한효과 USFDA adverse event database (AERS) 를분석한연구에의하면, 췌장염의발생이 sitagliptin 군에서대조군에비해서 6 배가높았다고보고하였고 [20], 미국보건부데이터베이스를활용한 337,067 의제 2 형당뇨병환자를동수의비당뇨병환자와비교시, 제 2 형당뇨병환자군에서는급성췌장염의빈도가 2.83 배, 담도질환이 1.9 배가비당뇨군에비해증가함을보고하여 [26], 제 2 형당뇨병이췌장염의위험인자임을제시하였다. 하지만미국건강보험데이터베이스를이용한연구에서는 16,276 명의 sitagliptin 사용군에서다른 metformin, glyburide 군과비교시급성췌장염의빈도는증가하지않았고 [27], 또다른후향적코호트연구에서도 sitagliptin 군에서급성췌장염의빈도는차이가없었으며 [28], 수십개의이중맹검임상연구를통합분석한연구에서도 s i t a g l i p t i n 군에서췌장염의빈도가증가하지는않았다 [29,30]. 결론 제 2 형당뇨병은장기간의약제투여가필수적이기때문에새로운약제사용시그장기적인안정성에대해서는충분한주의가요구된다. 하지만현재까지세포및동물실험그리고소규모의임상실험이나메타분석을종합하면, DPP-4 억제제가심혈관질환에대해서는보호효과의가능성을보여주었으나, 갑상선암이나췌장암그리고췌장염에는상충된결과들이알려져있을뿐이다. 현재 DPP-4 억제제의장기간사용시이들질환에대한임상연구는별로없어향후 DPP-4 억제제의장기간사용시그안정성에대한임상연구가필요하다. 참고문헌 01. S Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging 2010;3: S Fadini GP, Boscaro E, Albiero M, Menegazzo L, Frison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromalderived factor-1alpha. Diabetes Care 2010;33: S Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A, Paoliss o G. D e c re a s e d ca ro t i d atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis 2013;227: S Satoh-Asahara N, Sasaki Y, Wada H, Tochiya M, Iguchi A, Nakagawachi R, Odori S, Kono S, Hasegawa K, Shimatsu A. A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients. Metabolism 2013;62: S Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, Sakamoto E, Koganei M, Sasaki H, Nagashima Y, Amo K, Aoki K, Morimoto C, Takeda E, Terauchi Y. Dietinduced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes 2011;60: S Dobrian AD, Ma Q, Lindsay JW, Leone KA, Ma K, Coben J, Galkina EV, Nadler JL. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab 2011;300:E S Ferreira L, Teixeira-de-Lemos E, Pinto F, Parada B, Mega C, Vala H, Pinto R, Garrido P, Sereno J, Fernandes R, Santos P, Velada I, Melo A, Nunes S, Teixeira F, Reis F. Effects of sitagliptin treatment on

4 DPP-4 억제제의췌장외영향 ( 심혈관질환, 암, 췌장염등 ) dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediators Inflamm 2010;2010: S Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T, Iizuka M, Takiguchi S, Yakushiji E, Nakaya K, Yogo M, Ogura M, Takase B, Murakami T, Ikewaki K. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc 2013;2:e S Shah Z, Pineda C, Kampfrath T, Maiseyeu A, Ying Z, Racoma I, Deiuliis J, Xu X, Sun Q, Moffatt-Bruce S, Villamena F, Rajagopalan S. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vascul Pharmacol 2011;55: S Ogawa S, Ishiki M, Nako K, Okamura M, Senda M, Mori T, Ito S. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. 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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract