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1 Focused Issue - SGLT2 inhibitors SGLT2 억제제의혈당조절과무관한작용 원광대학교병원내과학교실이대호 The Non-glycemic Effects of SGLT2 Inhibitor Dae Ho Lee Department of Internal Medicine, Wonkwang University School of Medicine & Hospital, Iksan, Korea Abstract Sodium glucose cotransporter 2 (SGLT2) inhibitors have recently been introduced as a new class of antidiabetic agents. In addition to their glycemic action, SGLT2 inhibitors also have a number of non-glycemic effects that may contribute to renal and/or cardiovascular benefits. These include effects on tubuloglomerular feedback in the kidney, body weight, blood pressure, and serum uric acid. Other non-glycemic effects of SGLT2 inhibitors that need to be further studied include the effects on lipid profiles, food intake, and secretion of hormones such as leptin, incretins, and aldosterone. Also, the exact mechanisms of various non-glycemic actions should be further studied. Additionally, SGLT2 inhibitor therapy in combination with other drugs may have beneficial glycemic and non-glycemic effects. (J Korean Diabetes 2014;15: ) Keywords: Diabetes mellitus, Sodium glucose cotransporter 2, Antidiabetic agent 151 서론 신장의근위세뇨관 (proximal convoluted tubule) 의 S1 구획에존재하는 sodium glucose cotransporter 2 (SGLT2) 를표적으로하는 SGLT2 억제제가최근에제 2 형당뇨병치료제로도입되어임상경험이축적되어가면서혈당조절효과와낮은저혈당위험과같은혈당조절에관련된장점뿐만아니라특이적인 SGLT2 의작용때문에혈당의감소외에도당뇨병및대사증후군의병태생리에대해서도임상적으로의미있는효능을나타내고있어본고찰에서는이에대해서집중적으로논하고자한다. 신장근위관세포에대한직접작용 제 2 형당뇨병환자나당뇨병동물모델에서신장근위관세포의 SGLT2 의발현이증가되며 hepatocyte nuclear factor (HNF)-1α 에의한직접적인조절작용 이관련되어있다 [1,2]. 당뇨병을인슐린투여에의해서조절하거나 SGLT2 억제제를투여하면 HNF1α 및 SGLT2 유전자발현증가가억제된다 [1]. 또한 SGLT1 의발현이나세포막으로이동이증가한다는보고들도많아서고혈당하에서신장세포의 SGLT, 특히 SGLT2 는근위관세포의포도당흡수에중요한역할을하는것으로여겨진다 [3,4]. 신장근위관세포가고농도의포도당에노출되면서당뇨병의초기부터세포증식이발생하는데여러가지성장인자, 안지오텐신 II, mtor, protein kinase C (PKC) 등을통하여활성이증가된 ornithine decarboxylase (ODC) 를통한 polyamine 증가가세포의증식에관여하며이어서세포비후와세포의노화가발생하는데여기에는특히 transforming growth factor β1 (TGFβ1) 과 cyclin-dependent kinase (CDK) 억제단백들이관여하는것으로보인다 [4]. 최근근위세뇨관세포를이용한실험보고에서도세포가고농도의포도당에노출되고포도당흡수가증가되면 교신저자 : 이대호, 전북익산시무왕로 895 원광대학교병원내분비대사내과, drhormone@naver.com

2 Focussed Issue - SGLT2 inhibitors 152 세포의노화가진행되는데 SIRT1 감소 p21 증가 CDK 활성의감소등의기전이관련이있으며 SGLT2 을억제하면고혈당에의한근위세뇨관세포의노화를억제할수있는것으로나타났다 [5]. 또한근위관세포역시다른세포들과마찬가지로포도당독성에의해서세포의산화스트레스증가및세포괴사가발생하는데고농도포도당조건하에서산화스트레스나최종당화산물에의한세포괴사도 SGLT2 억제에의해서감소된다 [6]. 그외에세포수준의실험조건하에서나당뇨병성실험동물모델에서신장근위관세포가고혈당에노출되면염증반응이나섬유화를증가시키는기전이활성화되는데, SGLT2 억제제는이기전의활성을억제하는효과가있다 (Fig. 1)[7,8]. 근위세뇨관에서의과흡수 (hyperreabsorption) 와 tubuloglomerular feedback 의이상의교정 당뇨병에서근위세뇨관이고농도의포도당에노출되면근위관세포의증식과비후를일으킨다. 또한신장의크기증가및 SGLT2 증가는포도당및나트륨의재흡수의증가와관련이있다 [4]. 당뇨병에서근위관에서재흡수의증가는원위관의 Na-Cl-K 농도를유의하게감소시키며이러한감소는 macula densa 에서감지되어 tubuloglomerular feedback 이감소하고사구체의 afferent arteriole 이확장되어사구체의과여과 (hyperfiltration) 를초래한다 [4]. Tubuloglomerular feedback 은실시간으로사구체의 afferent arteriole 의혈관저항성을혈관수축물질인아데노신을통하여유지조정하는기전이다 [9]. 당뇨병에서 SGLT2 억제제투여에의해서이러한과여과를줄일수있다는실험연구와임상연구결과들은많이보고되었다 [4,8,10]. 즉, SGLT2 억제제가근위세뇨관에서과흡수를억제하면원위세뇨관으로나트륨전달이증가하고염분의증가가 macula densa 에서감지되면 afferent arteriole 을수축시키는 tubuloglomerular feedback 이작동하여사구체의과여과가개선되어사구체여과율이감소하며당뇨병환자에서 empagliflozin 투여에의한과여과의감소정도는레닌 - 안지오텐신 - 알도스테론축 (renin-anigotensin-aldosterone system, 이하 RAAS) 의억제효과와비슷할정도라고보고되었다 (Fig. 1)[10]. 사구체과여과는당뇨병성신증의진행위험을크게증가시키므로 SGLT2 억제제의효과가 RAAS 억제제에비할수있을정도로사구체과여과를억제시킬수있다면향후 RAAS 억제제와병합요법을비롯하여신기능보존효과에대해서더많은관심과연구가필요해보인다 [10-12]. 신장기능에대한 SGLT2 억제제의장기적인효과 근위세뇨관세포의증식, 비후, 노화와동반된신장의크기증대및사구체과여과등이 SGLT2 억제제에의해개선된다는실험연구결과와일부임상연구결과에부합하여장기적인신기능보존효과가나타나는지아직 Fig. 1. Potential role of sodium glucose cotransporter 2 (SGLT2) inhibitor in renoprotection for patients with type 2 diabetes. PKCβ, protein kinase C β; ODC, ornithine decarboxylase; TGFβ, transforming growth factor β; CDK, cyclin-dependent kinase.

3 SGLT2 억제제의혈당조절과무관한작용 결론을내릴만한임상연구결과는부족하다. 하지만 db/db 생쥐에서시행한동물모델에서는 dapagliflozin 12 주간투여결과혈청크레아티닌농도나크레아티닌청소율의변화없이단백뇨를유의하게감소시키고신장조직의 mesangial matrix 축적, 간질섬유화, 염증성 M1 대식세포의침윤, 염증성싸이토카인발현, 산화스트레스표지자, 세포괴사역시유의하게감소시키는결과를보였다 [13]. 또한가지흥미로운연구에서는 BTBR ob/ob 생쥐를이용하여안지오텐신 II 를만성적으로주입하면서고혈압을동반한당뇨병성신증모델에대한실험에서 empagliflozin 은다른당뇨병성신증관련변수들이나염증표지자, 조직학적변화들은개선시키지는못하였지만이와는별개로저명한단백뇨감소효과를보였다 [14]. 제 2 형당뇨병환자에서는앞에서언급한 tubuloglomerular feedback 의재활성화로인해 SGLT2 억제제투여시사구체여과율이급성기에는 14~20% 정도, 지속적으로투여시 11~15% 정도의감소가유지된다 [9,15]. Canagliflozin 을 52 주간계산된사구체여과율 > 55 ml/min/1.73m 2 인환자에서 glimepiride 와비교하기위해서메포르민에추가한 CANagliflozin Treatment And Trial Analysis versus SUlphonylurea (CANTATA-SU) 연구에서는 canagliflozin 투여군에서 glimepiride 투여군에비해서사구체여과율이초기에는감소하였다가약간회복된채로유지되었고 glimepiride 투여군에서는지속적으로감소하여약 12 주째에비슷해졌다가결국 canagliflozin 투여군에서사구체여과율이더높은상태로유지되었다 [16]. 이는 SGLT2 억제제가신장기능이유지된제 2 형당뇨병환자에서장기적으로신장기능보호효과가있을가능성을시사한다. 현재제 2 형당뇨병환자에서만성신장질환제 3a 기 (45 계산된사구체여과율 < 60 ml/min/1.73m 2 ) 인경우 canagliflozin 100 mg/ 일투여가가능한데이전에시행된당뇨병성만성신장질환제 3 기환자에대한 canagliflozin 투여임상연구결과들을수집분석한보고에의하면약 6 개월째사구체여과율은대조군의 +0.7 ml/min/1.73m 2 에비해서 Canagliflozin 100 mg/ 일투여군과 300 mg/ 일투여군에서각각 1.7 및 2.2 ml/min/1.73m 2 정도의변화를보였으며, 현성단백뇨환자에서는단백뇨가각각 19.6%, 53.1%, 그리고 44.7% 의변화를보여사구체여과율은사구체과부하에대한개선효과의해서감소되지만단백뇨는크게개선됨을보여신장기능보호효과의가능성을보였다 [17]. 계산된사구체여과율이 30~50 ml/min/1.73m 2 하인환자들을대상으로 Canagliflozin 을 1 년간투여한연구결과에서는 1 년후사구체여과율은 canagliflozin 300 mg/ 일투여군에서대조군에비해서유의하게낮았다 [18]. 따라서사구체여과율이감소된환자에서신기능보존효과는더추가적인임상연구가필요하겠지만적응증을잘고려하여사용하는것이좋겠다. 체중감소효과 대조치료군에비해서 SGLT2 억제제치료는유의한체중감소효과를일관되게보이는데대상환자에따라서다르지만최근에시행된메타분석결과대조군에비해약 1.74 kg (95% 신뢰구간 ) 의체중감소를보였다 [19]. 당뇨병환자에서 SGLT2 투여후소변으로포도당배설은 1 일약 70 그램정도배설되므로이에의한칼로리소실과삼투압성이뇨에의한체액감소가기여할것으로여겨진다 [20]. 체중감소를조사한연구결과들에의하면 CANTATA- SU 연구에서는 Canagliflozin 100 mg/ 일 (-3.7 kg) 혹은 300 mg/ 일 (-4.0 kg) 투여군에서 glimepiride 투여군 (+0.7 kg) 에비해서 52 주째체중변화가유의하게감소되었는데 canagliflozin 투여군에서는 2/3 정도의체중감소는체지방감소가, 1/3 정도의체중감소는지방조직외조직의감소가기여하였고전산화단층촬영분석에서는복부지방감소가피하지방감소보다더저명하였다 [19]. 제 2 형당뇨병환자에서체중변화를분석한 dapagliflozin 연구에서도비슷한결과를보였으며체중감소는 1 주내에유의하게감소하기시작하여 24 주째까지서서히감소하였으며장기간유지되는것으로여러연구들에서도보고되었다 [15,21]. Dapagliflozin 투여군에서대조군에비해허리둘레의감소 (-1.52 cm; 95% 신뢰구간 : ~ -0.31; P = ) 와 5% 이상의체중감소를보인환자비율 (26.2%; 95% 신뢰구간 : 15.5 ~ 36.7; P < ) 역시유의하게높았으며회귀분석에서소변의포도당배설과체중감소나체지방감소량과유의한상관관계를보였다 [21]. 추가적으로이연구에서 MRI 검사를통하여간지방의변화를측정하였는데간지방은대조군에비해서더감소하는경향만보였고통계적으로유의하지는않았으며, 혈청렙틴의농도는기저치에비해 dapagliflozin 투여군에서 2.6 ng/ ml 감소하였고대조군에서는 0.09 ng/ml 증가하여두군사이에차이의경향을보였다 (P = )[21]. Canagliflozin 과 dapagliflozin 직접비교연구는없지만체중감소에대한효과는 canagliflozin 은 1 일 300 mg 투여하는경우소장에서 SGLT1 을억제하는효능도기대할수있기때문에향후이에대한임상연구도필요해보인다. 153

4 Focussed Issue - SGLT2 inhibitors 154 칼로리섭취 여러동물모델실험에서 SGLT 억제제투여시에체중감소와더불어서칼로리섭취의유의한증가혹은증가경향이확인되었으며 [13,22,23]. 제 1 형당뇨병환자에대한한연구에서도 empagliflozin 투여후에탄수화물섭취량은더증가하였다 [13]. 따라서포도당소실과체중감소에대해서어떤보상기전에의해서식욕이나탄수화물섭취가증가하는지추가연구가필요해보이며실제로최근에발표된매우흥미로운연구에서는 SGLT2 억제제투여에의해서포도당소변배설이증가하면서포도당독성이개선되어말초인슐린감수성은개선되지만글루카곤증가에의해서간에서의포도당배출은증가한다고보고되었다 [24]. 혈압강하효과 제 2 형당뇨병과고혈압은흔히같이동반되어있는데 75% 이상의당뇨병환자에서수축기혈압이 140 mm Hg 이상이거나항고혈압제를복용중이다 [20]. 최근메타분석에서제 2 형당뇨병환자에서 SGLT2 억제제투여군에서는위약군에비해수축기혈압이약 3.77 mm Hg (95% 신뢰구간 : 2.90 ~ 4.65 mm Hg) 더낮고, 대조약치료군에비해서는 4.45 mm Hg (95% 신뢰구간 : 3.18 ~ 5.73 mm Hg) 더낮다고보고하였고, 이완기혈압은위약군에비해약 1.75 mm Hg (95% 신뢰구간 : 1.23 ~ 2.77 mm Hg) 더낮고, 대조약치료군에비해서는 2.01 mm Hg (95% 신뢰구간 : 1.39 ~ 2.62 mm Hg) 더낮다고보고하였다 [19]. 혈압감소의기전은아직잘밝혀지지않았지만약제투여후 1 주내에나타나는삼투압성이뇨는일부관여하겠지만소변으로나트륨배설증가는입증되지않았다 [20]. SGLT2 억제제치료후에소변나트륨배설량을관찰한임상연구결과들을보면소변나트륨배설량은초기투여 1 일에는 dapagliflozin 에의해서증가하였으나 2 주째에는증가가유지되지않았으며 [25], canagliflozin (300mg/day) 연구에서도 1 주및 12 주째에소변의나트륨배설은증가되지않아서나트륨배설이지속적으로증가되지는않는것으로보인다 [26]. 또한혈압의감소와체중혹은당화혈색소의감소와도상관성은없다고보고되었다 [19]. Lambers-Heerspink 등 [15] 은흥미로운연구를시행하였는데제 2 형당뇨병환자를 dapagliflozin (10 mg/ 일 ), hydrochlorothiazide (25 mg/ 일 ), 그리고위약군으로나누어서 12 주간치료후혈압을비롯하여체중, 혈장용적, 사구체여과율등을비롯한다양한변수 를비교하였다. 체중은 dapagliflozin 치료군과 hydrochlorothiazide 군모두에서감소하였으나 dapagliflozin 치료군에서는혈장용적이유의하게 7.3% 감소하였다. 또한 dapagliflozin 투여군에서혈장레닌활성도와혈청알도스테론농도가이뇨제투여군과비슷할정도로증가하였으며, 다른두군에서는변화가없었으나 dapagliflozin 투여군에서는 NT-proBNP 농도가약간증가하였다 [15]. 저자들은 NT-proBNP 농도의증가는일시적인 erythropoietin 상승이 brain natriuretic peptide 분비를증가시켜서발생했을것으로추측하였다 [15]. 하지만 canagliflozin 연구에서는투여 1 주째에유의하게혈장용적이감소하였으나 12 주째에는통계적인유의성은없었다고보고되었으며소변의나트륨배설은 1 주및 12 주에모두대조군에비해서증가하지않았다고보고하였다 [26]. 따라서 SGLT2 억제제에의한고혈압의개선에대한기전에대해서는추가연구가필요해보이며장기적인심혈관질환에대한영향을같이분석할때 RAAS 축의변화도같이분석이되어야할것으로보이며앞에서신장기능보호에대한효과에서도언급했듯이 RAAS 억제제의병용투여에대한포괄적인연구도필요하다고생각된다. 레닌 - 안지오텐신 - 알도스테론축의변화 SGLTs 와 RAAS 와의관련성도중요하다. 동물실험에서당뇨병쥐모델에서 losartan 치료에의해서 SGLT2 발현이감소했다는보고가있다 [27]. 반면에 familial renal glycosuria 환자에서는 RAAS 축의활성이증가되어있다는보고들이있으며당뇨병환자에서 SGLT2 억제제투여시혈압감소와과여과의감소등이로운혈역학적변화와동반해서레닌 - 안지오텐신알도스테론축의활성이증가한다고보고되었다 [10,28]. 또한 RAAS 차단제와 SGLT2 억제제가각약제의단독요법보다신장보호효과가더우수하다는동물실험결과가있으므로향후임상연구를통해서확인할필요가있다 [10,23]. 요산배설증가 SGLT2 억제제투여의특장점중또다른하나는혈청요산농도의감소효과이다 [29]. 당뇨병은요산혈증과밀접한관계가있는데인슐린이요산의재흡수를증가시키고, 반면에소변으로포도당배설이증가하면혈청요산은약간감소한다. 따라서요당의증가와소변

5 SGLT2 억제제의혈당조절과무관한작용 의요산배설은관련이있으며 SGLT2 억제도이러한기전을통해서작용할것으로추정할수있으며실제로 SGLT2 억제제투여후소변포도당배설량과소변의요산배설량과비례한다 [30]. 건강한성인에서시행된임상연구에서 luseogliflozin 의경우 1 일 5 mg 혹은 10 mg 투여시 1 주째에는혈청요산농도를 1.71~1.76 mg/dl 정도감소시키는효과를보였으며실제소변에서요산배설량은대개투여첫날에가장많았는데기저치에비해약제투여시투여첫날에는 mg/ day 정도배설이증가하였지만이러한배설량의증가는수일정도만유지되다가크게감소하는경향을보였다 [30]. 혈청요산농도는신장의배설에의해서도영향을받는데사구체로여과된요산의 ~90% 는근위관세포에의해서재흡수된다 [30]. 근위관세포에서요산의재흡수에관여되는 uric acid transporter 1 (URAT1, SLC22A12), organic anion transporter 4 (OAT4, SLC22A11), OAT10 (SLC22A13), GLUT9 isoform 1 (SLC2A9a) 등이알려져있고 losartan 과 salicylic acid 는 URAT1 을억제한다 [31]. 포도당수송체 GLUT9 은간과신장에서발현되고, 신장에서 GLUT9 아형 1 (SLC2A9a) 은기저측막에발현되고 GLUT9 아형 2 (SLC2A9b) 는첨막에발현되며 SGLT2 억제제에의해서근위세뇨관의소변에서포도당농도가증가하면포도당은 GLUT9 아형 2 (SLC2A9b) 에의한요산의재흡수를신장의근위세뇨관과수집관에서억제하는것으로여겨진다 [30]. 하지만 SGLT2 억제제에의한요산배설의증가에다른요산수송체들이더관여하는지에대해서는추가연구가필요해보인다. 혈청요산농도의증가는통풍뿐만아니라대사증후군, 만성신장질환, 고혈압, 심혈관질환등과도관련성이있기때문에비교적작은농도변화이기는하지만 SGLT2 억제제투여에의한혈청요산농도감소는이약제의장점이될수있다고여겨진다 [32]. 혈청지질의변화 제 2 형당뇨병환자에서 canagliflozin 투여시 HDL- 콜레스테롤농도를유의하게증가시키고 LDL- 콜레스테롤농도를증가시키며대상자에따라서중성지방농도를감소시킨다는보고도있다 [22,33]. 그러나 CKD 3 기환자에서 canagliflozin 52 주투여임상연구에서는오히려 LDL 콜레스테롤농도가대조군에비해서낮고, HDL 콜레스테롤은높은경향을보였다 [18]. Dapagliflozin 역시 HDL- 콜레스테롤농도를증가시키며 LDL 농도를증가시킨다 [29]. SGLT1 과 SGLT2 를 동시에억제하는약제들은 glucagon-like peptide-1 분비를통하여중성지방감소효과가더잘나타날가능성도제시되었다 [34]. 콜레스테롤농도변화의기전과 canagliflozin 및 dapagliflozin 외에다른 SGLT2 억제제들에서도일관된변화를보이는지향후더분석할필요가있다. 심혈관질환에대한영향 최근까지발표된임상연구결과나메타분석들에서 SGLT 억제제가심혈관질환을줄이거나증가시킨다는증거는없다. 하지만심혈관질환이있는환자에서약물투여초기에탈수등에의한부작용으로인해서심혈관질환이악화되거나초래될위험에대해서는주의할필요가있다 [19]. 결론 SGLT2 억제제는혈당조절외에도신장에서사구체과여과에의한손상과여러가지병태생리에대한작용을통하여신장보호효과가있을가능성이있으나현재는단백뇨감소외에는임상적으로입증된효능은없지만, 혈압강하, 체중감소, 그리고요산농도감소등은비교적일관되게관찰되어왔고그외에지질농도변화, 칼로리섭취에대한영향, 호르몬의변화, 그리고 RAAS 차단제와병합효과등등에대해서는더추가적인연구결과들이나와야할것으로보이며심혈관질환에대한영향과 SGLT1 에대한부분적인억제효과에대해서도향후결과가기대된다. Acknowledgements This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP) ( ) and by the Basic Science Research Program through the NRF funded by the Ministry of Education ( ). 참고문헌 1. Freitas HS, Anhê GF, Melo KF, Okamoto MM, Oliveira- Souza M, Bordin S, Machado UF. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology 2008;149:

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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