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1 대한내과학회지 : 제 87 권제 1 호 특집 (Special Review) - 최신당뇨병치료약제 Sodium Glucose Co-Transporter 2 (SGLT2) 억제제 인제대학교의과대학내과학교실, 백인제기념임상의학연구소 김미경 박정현 Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor Mi-kyung Kim and Jeong Hyun Park Paik Institute for Clinical Research, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea Sodium glucose co-transporter 2 (SGLT2) inhibition is a new therapeutic approach for the treatment of type 2 diabetes mellitus, independent of insulin secretion and activity. SGLT2 inhibitors have a unique mechanism of action via inhibition of renal glucose reabsorption, which is different from the mechanisms of prior medications. Clinical trials have supported the efficacy of SGLT2 inhibitors in the reduction of HbA1c as monotherapy or add-on therapy with other existing medications, including insulin. In addition to their glucose-lowering effect, SGLT2 inhibitors can significantly reduce blood pressure and body weight. The most concerning side effects are genital and urinary tract infections, especially in females. SGLT2 inhibitors offer a promising potential strategy for diabetes treatment because they can be combined with nearly any existing anti-diabetic medication, cause less hypoglycemia, and possess additional metabolic benefits beyond glucose level reduction. (Korean J Med 2014;87:14-18) Keywords: Type 2 Diabetes; Renal glucose reabsorption;sglt2 inhibitors; Urinary tract infection; Genital infection 서론당뇨병의치료는인슐린의발견이후지난 90여년동안많은발전을하였고특히최근 20년동안에는더욱다양한혈당강하약제들이소개되었다. 그러나아직까지당뇨병환자의대사조절은만족스럽지못한상태로, 대한당뇨병학회의자료에의하면당화혈색소 7% 미만으로조절이되고있는환자는 43% 정도이다 [1]. 제2형당뇨병역시유병기간이경과할수록인슐린을분비하는췌장의베타세포기능이점 차감퇴되기때문에여러가지약제를조합해서쓰더라도혈당조절이점점되지않고종국에는합병증의발생을피할수없는진행성질환이다. 현재사용되고있는다양한혈당강하제들은각각장단점을가지고있지만그어느약물도혈당강하능력과부작용의측면에서완벽한것은없어서여전히우리는더다양하고효과적이며부작용의측면에서더안전한당뇨병치료제를필요로한다. 최근제2형당뇨병의병태생리가많이밝혀지면서새롭게주목받게된것중의하나가당뇨병에서신장의역할이 Correspondence to Jeong Hyun Park, M.D., Ph.D. Paik Institute for Clinical Research, Department of Internal Medicine, Pusan Paik Hospital, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan , Korea Tel: , Fax: , pjhdoc@chol.com Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Mi-kyung Kim, et al. Sodium glucose co-transporter 2 (SGLT2) inhibitor - 다. 이와함께신장에서포도당재흡수에관여하는 sodium glucose co-transporter 2 (SGLT2) 억제제가개발되어더욱큰관심을받게되었으므로신장이정상적으로포도당항상성에미치는영향및당뇨병상태에서의변화, SGLT2 억제제의효과및부작용등에대한간략히살펴보기로한다. 신장이정상적인포도당항상성 (glucose homeostasis) 에미치는영향신장은세가지의각기다른방식으로혈액속포도당농도를일정하게유지하는데기여하게된다. 그세가지기전은포도당을생합성하여혈액속으로내보내고 (gluconeogenesis), 혈액속포도당을신장에서에너지로이용 (glucose utilization) 하며, 사구체에서여과된포도당을재흡수 (glucose reabsorption) 하는것이다. 신장의포도당생성 (renal gluconeogenesis) 약 14-16시간동안공복상태가지속되면인체에서필요한포도당량의절반은간에서 glycogen을분해해서생성되고나머지반은간과신장에서새로운포도당생성즉 gluconeogenesis를통해충당된다 [2]. 식사후에는우리몸에서새롭게생성하는포도당의양은급격하게줄어들게되어간에서혈액속으로유리되는포도당은거의없게된다. 그러나신장에서는식후에오히려포도당신생작용이 2배로증가되게되는데이것은아마도간에서글리코겐저장을효과적으로하게하기위함일것으로설명되고있다 [3]. 호르몬의영향을살펴보면인슐린은간과신장모두에서포도당생성을억제시키지만글루카곤은간에서만포도당유리를증가시킨다. 카테콜라민이신장의포도당생성에직접적인역할을하고 [4] 코티졸, 성장호르몬과갑상선호르몬이신장포도당생성에미치는영향은사람에게서는아직확실하지않다. 신장의포도당이용 (renal glucose utilization) 공복상태에서신장은우리몸의포도당중대략 10% 를사용하게된다. 식후에는그이용률이 3배로증가하게되는데전체적으로는포도당이용에있어서신장의역할은그리크지않다 [3]. 신장의포도당재흡수 (renal glucose reabsorption) 정상적으로신장에서는하루에약 180 g 정도의포도당이사구체를통해여과된다. 정상인에서는여과된거의모든포도당이재흡수되어소변에서는포도당이검출되지않는다. 포도당항상성에서는재흡수에관여하는신장의이기능이가장중요하다. 재흡수는근위세뇨관에있는 sodium-glucose co-transporters (SGLT1 과 SGLT2) 가주로담당한다. SGLT 는여섯종류가현재까지알려져있고여러가지장기에분포하고있지만아직그기능은다알려지지는않았다 (Table 1) [5]. 근위세뇨관에서의포도당흡수는신장에만주로발현되는 SGLT2가 90% 를담당하고장관과신장에같이발현되는 SGLT1이 10% 를담당한다고알려져있다. SGLT2나 SGLT1을통해재흡수된포도당은 basolateral membrane 에있는 glucose transporters (GLUTs) 를통해혈액속으로이동된다 (Fig. 1) [6]. 사구체를통해여과되는포도당은혈액속포도당농도에비례하여늘어난다. 여과된포도당의재흡수는정상인의경우혈액속포도당농도가약 200 mg/dl가될때까지늘어나다가그이상이되면재흡수는감소하고소변에서포도당이검출되기시작한다 (Fig. 2) [7]. 당뇨병상태에서포도당항상성에대한신장의역할변화신장의포도당생성 (renal gluconeogenesis) 당뇨병상태에서는공복시신장에서혈액속으로유리되는포도당이증가되어그양이간에서유리되는것과비슷해진다. 식후에도정상인보다포도당생성이더증가된다. 신장의포도당이용 (renal glucose utilization) 공복시신장에서의 glucose uptake는정상인에서보다당뇨병에서더증가되어신장에서증가되었던포도당생성을능가하게된다. 식후에는당뇨병환자에서신장에서의 glucose uptake는 2배로증가되지만근육에서는크게변화하지않는다 [8]. 신장의포도당재흡수 (renal glucose reabsorption) 정상인과비교해서당뇨병환자에서신세뇨관의포도당재흡수가증가되어있다고알려져있다. 정확한기전은아직밝혀지지않았지만약물로유도된제2 형당뇨병동물모델에서정상이거나내당능장애보다당뇨병모델의신장에서 SGLT2-15 -

3 - 대한내과학회지 : 제 87 권제 1 호통권제 647 호 Table 1. The sodium glucose co-transporter family Co-transporter Gene Substrate Tissue distribution SGLT1 SLC5A1 Glucose, galactose Intestine, trachea, kidney, heart, brain, prostate SGLT2 SLC5A2 Glucose Kidney, brain, liver, thyroid, muscle, heart SGLT4 SLC5A9 Glucose, mannose Intestine, kidney, liver, brain, lung SGLT5 SLC5A10 Not known Kidney SGLT6 SMIT2/SLC5A11 Glucose, myo-inositol Brain, kidney, intestine SMIT1 SLC5A3 Glucose, myo-inositol Brain, heart, kidney, lung SGLT, sodium-glucose co-transporter; SMIT, sodium-myoinositol transporter. Glucose Glucose Figure 1. Glucose reabsorption from the glomerular filtrate through a proximal tubular epithelial cell into the blood. GLUT, glucose transporter; SGLT, sodium-glucose co-transporter. 와 GLUT2 mrna의발현이증가되어있다는보고가있고 [9] lean Zucker rat에비해 obese Zucker rat에서 SGLT1과 SGLT2 발현이증가되어있었다 [10]. 사람의경우에도정상인보다제2형당뇨병환자에서 SGLT2와 GLUT2 발현이증가되어있고신세뇨관에서의포도당흡수가증가되었다는연구가있었다 [11]. SGLT2 억제제의개발 SGLT2 억제제 1835년에사과나무의뿌리껍질에서비특이적 SGLT1와 SGLT2 억제제인 phlorizin 이처음으로분리되었고이것이당뇨 (glucosuria) 를야기하여혈당을감소시키고인슐린감수성을정상화시킨다고알려졌다. 그러나이제제는경구로투여하였을때흡수율이낮고위장관에있는 SGLT1도같이억제하기때문에 glucose-galactose malabsorption과설사를야기 Figure 2. Renal glucose handling. SGLT, sodium-glucose cotransporter; T max, transport maximum. 하여당뇨병치료제로사용되기에는부적절하였다. 이러한단점을보완하기위해 SGLT2에대한특이성이높은억제제를개발하게되었다. 그중에서 dapagliflozin은 2012년유럽에서승인을받았고 2014년미국 FDA에서도승인을받았으며 2013년 11월 SGLT2 억제제계열약제들중에서는아시아국가중에서한국이가장처음으로허가를하였다. Canagliflozin은 2013년미국 FDA의승인을받았으며 empagliflozine도미국과유럽에서승인절차를기다리는중이다 (Table 2). SGLT2 억제제의임상연구결과 Dapagliflozin Dapagliflozin 10 mg 단독또는 metformin, glimepiride, sitagliptin, pioglitazone 및인슐린과의병합요법에대한임상연구들에서당화혈색소는 0.5% 에서 0.8% 정도감소하였다. 공복혈당은평균 mg/dl 감소하였고식후혈당역시

4 - 김미경외 1 인. Sodium glucose co-transporter 2 (SGLT2) 억제제 - Table 2. Selected SGLT2 inhibitors in development (data from ClinicalTrials.gov) Compound Company Dapagliflozin Bristol-Myers Squibb and AstraZeneca Canagliflozin Johnson & Johnson Empagliflozin Boehringer Ingelheim & Eli Lilly Ipragliflozin Astellas Tofogliflozin Roche & Chugai Pharmaceuticals Luseogliflozin Taisho Pharmaceuticals Ertugliflozin Pfizer 의미있게감소되었다. 체중은 kg 감소하였고수축기혈압은 2-9 mmhg, 이완기혈압도 2 mmhg 감소하였다. 평균적으로 total cholesterol은 1% 증가, HDL cholesterol 은 1.7% 증가, LDL cholesterol 은 0.8% 증가, 중성지방은 4.7% 감소시켰다 [12-15]. 전체적으로는약제에대한순응도는좋았으며가장흔한부작용은 headache, diarrhea, back pain, upper respiratory tract infection 등이었는데대조군과의미있는차이는보이지않았다. 특히여성에서는 genital infection의빈도가증가하였는데위약군이 1% 인데반해 dapagliflozin군은 4-6% 로보고되었다. 하지만중증도는심하지않아서대부분의경우항생제치료에잘반응하였다. Urinary tract infection도약간증가하는경향을보였다. 저혈당은인슐린이나 glipmepiride와의병합요법에서만대조군에서보다약간증가하였다. 10명의환자에서방광암이보고되었는데대부분은연구시작전에이미혈뇨가있었던환자였고약제사용후 6개월이내에발견되었으므로약제사용과직접적인연관성이있다고하기는어렵다. 신기능이감소되어있는환자에서는효과가적어중등도이상의신장애환자에게는권장되지않는다 [12-15]. Canagliflozin 총 504명의환자들을대상으로 26주간관찰한연구에서 canagliflozin 100 mg을사용한군에서당화혈색소가기저치에비해 0.77% 감소하였으며위약군에비해공복혈당, 식후혈당, 체중및혈압등이유의하게감소하였다고한다. 병용요법에서도유사한결과를보였다. Pooled analysis 에서 LDL cholesterol이 % 정도증가하였지만심혈관질환에대한다른위험인자들인혈압, 체중및 HDL cholesterol 등에는좋은영향을보여주었다 [16-19]. Dapagliflozin과안정성측면 에서는큰차이가나지않고역시제일흔한부작용은 female genital mycotic infection과 urinary tract infection이었다. 이뇨효과때문에기립성저혈압이나체위성현훈, 갈증및탈수가몇증례에서보고되었다. 현재심혈관합병증에대해서는 Canagliflozin Cardiovascular Assessment Study (CANVAS) 라는대규모임상연구가국내를포함해서진행중에있다. 결 SGLT2 억제제는기존의당뇨병약제와는작용기전의측면에서전혀다른약제로, 현재까지의제2형당뇨병치료에추가적으로혈당강하기능을더할수있을것으로기대된다. 인슐린에비의존적으로작용하므로당뇨병환자의베타세포기능에관계없이작용할수있고저혈당발생의위험성이적다. 현재까지의임상연구결과들을볼때단독및인슐린을포함한여러가지약제들과의병합요법에서효과적인추가혈당강하효과를보였으며혈당강하효과외에혈압및체중의의미있는감소등당뇨병치료의전체적인대사적측면에서도큰장점이있어전체적인합병증감소에의미있는이득을줄가능성이높다고사료된다. 가장큰단점은 genital infection과 urinary tract infection이특히위생상태가좋지않은여성에게늘어난다는점이며이부분은실제임상에서사용된이후장기적으로그의미가다시평가되어야할것이다. 개발과정에서우려가되었던방광암의발생위험은현재로서는생물학적인근거가없는것으로잠정결론이되어있지만이역시임상에서광범위하게사용이되면반드시재평가가필요할수도있을것이다. 결론적으로 SGLT2 억제제의등장은기존의당뇨병치료방법에더해분명히임상적으로의미가있는발전이라판단되며특히심혈관질환에대한의미있는효과를기대할수있을것으로본다. 중심단어 : 제2형당뇨병 ; 신장포도당재흡수 ; SGLT2 억제제 ; 요로감염 ; 외부생식기감염 론 REFERENCES 1. Korean Diabetes Association. Diabetes Facts Sheets in Korea KDA, Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab 2000;2:

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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