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1 대한내과학회지 : 제 92 권제 5 호 In-depth review SGLT2 억제제와케톤산증 : 발생기전과대처 원자력병원내분비내과 구윤희 SGLT2 Inhibitors and Ketoacidosis: Pathophysiology and Management Yun Hyi Ku Division of Endocrinology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea Sodium-glucose cotransporter 2 inhibitors are antidiabetic drugs that increase urinary glucose excretion by inhibiting proximal tubular reabsorption of glucose in the kidney. Some sodium-glucose cotransporter 2 inhibitors have been shown to afford effective glycemic control and to decrease the risks of major adverse cardiovascular events. However, these drugs may increase the risk of diabetic ketoacidosis. This is a rare complication that occurs in less than 0.1% of treated patients with type 2 diabetes. The condition may be euglycemic, and is triggered by controllable precipitating factors such as surgery, infection, and insulin reduction or omission. It is important to understand individual patient profiles and to prevent diabetic ketoacidosis by appropriate prescribing, by withholding sodium-glucose cotransporter 2 inhibitors when indicated, and by counseling patients on sick day management. (Korean J Med 2017;92: ) Keywords: Sodium-glucose transporter 2; Diabetic ketoacidosis; Ketone bodies 서론나트륨-포도당공동수송체 2 (sodium-glucose cotransporter 2, SGLT2) 억제제는최근개발된경구당뇨병약제이다. 이약제는신장사구체의근위세뇨관에서포도당이재흡수되는것을억제하여포도당을소변으로배출시킴으로써혈중포도당농도를낮추고, 혈압강하, 체중감소등을동반하면서혈당조절에기여한다 [1]. 현재까지사용중이거나, 개발중인 SGLT2 억제제는세계적으로약 8종류정도가있으며, 우리나라에서는다파글리플로진, 이프라글리플로진, 엠파글리플 로진이제2형당뇨병환자에서처방가능하다. SGLT2 억제제는효과적인혈당조절및심혈관질환에대한예방효과등으로널리쓰이고있으나, 2015년에미국식품의약국안전청 (Food and Drug Administration, FDA) 에서 SGLT2 억제제와당뇨병성케톤산증과의연관성에대해우려를제기한바있으며, 실제임상상황에서도이에대한우려를완전히배제할수없는상황이다. 임상상황에서 SGLT2 억제제로인해당뇨병성케톤산증이발생하였을때에어떻게진단하고, 치료하며, 이러한질환이발생하는것을어떻게예방할수있는지에대해알아보고자한다. Correspondence to Yun Hyi Ku, M.D. Division of Endocrinology, Department of Internal Medicine, Korea Cancer Center Hospital, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea Tel: , Fax: , kyh@kirams.re.kr Copyright c 2017 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 - The Korean Journal of Medicine: Vol. 92, No. 5, SGLT2 억제제의작용기전포도당은신장사구체의근위세뇨관에서나트륨-포도당공동수송체 (SGLT) 에의해재흡수된다. 정상적으로포도당은사구체에서 125 mg/min 의속도로여과되고최대 375 mg/min의속도로재흡수되기때문에 [2] 혈당이정상인경우에는여과된포도당은거의모두재흡수된다. 그러나혈당이증가하여재흡수할수있는한계를넘어가면신장은소변으로포도당을내보내게된다. 혈당이 mg/dl 정도에이르면이러한현상이나타나기시작한다. 제2형당뇨병환자에서는포도당배설에대한신장의역치가증가되어있으며, 또한 SGLT2 발현도증가되어있다 [3]. SLGT에는몇몇종류가있으며, 이중 SGLT2가신장에서포도당을흡수하는데에 90% 정도를담당하며 SGLT1은약 10% 를담당한다. 포도당재흡수의 90% 를담당하는 SGLT2 에대한억제제가약제로개발되었으며, 현재다파글리플로진, 엠파글리플로진, 이프라글리플로진, 카나글리플로진, 루제오글리플로진, 토포글리플로진등이사용중이다. 단일요법으로 SGLT2 억제제는공복혈당을 mg/dl 정도, 당화혈색소를 % 정도감소시킨다 [4-6]. 다른약제와의비교연구결과를참조하면 SGLT2 억제제는설폰요소제, DPP4 억제제, 메트포르민과비슷한정도의혈당강하효과를나타낸다 [7,8]. 다만 SGLT2 억제제는신장기능이저하되어있는환자에서혈당강하효과가감소하기때문에사구체여과율 (glomerular filtration rate) 이 45 ml/min/1.73 m 2 미만인경우에는권장되지않는다. SGLT2 억제제는혈당강하효과외에 주에걸쳐약 2-3 kg 정도의체중감소효과를나타내며 [6,9] 이는대부분지방조직감소에서기인한다 [10]. 지방조직이감소하는것은하루에약 g 정도, 약 kcal에해당하는포도당이소변으로배출되기때문이다. 체중감소는지속적으로일어나지는않는데, 이는배설된포도당에대해보상적으로칼로리를더섭취하기때문이다 [11]. 이외에도 SGLT2 억제제를복용하면혈압이감소하며, 삼투성이뇨때문에수축기혈압이 3-4 mmhg, 이완기혈압이 1-2 mmhg 정도감소한다 [12,13]. 또한요산분비가촉진되어혈청요산농도가약간감소한다 [14]. 혈중지질수치에도영향을미치는데대략저밀도콜레스테롤은 3-5% 증가, 고밀도콜레스테롤은 2-3% 증가, 중성지방은 6-7% 감소하는변 화를보인다 [1,9]. 그리고소변으로배설되는알부민을 20-30% 정도감소시키기때문에당뇨병성신장병증이악화되는것을억제할수있을것으로기대된다 [15]. SGLT2 억제제의부작용대부분의연구에서 SGLT2 억제제는부작용으로인해투약을중단하는비율은높지않았다. 가장일관되게나타나는부작용은소변량증가와소변횟수증가, 생식기감염이었다 [1]. 생식기감염은남자보다는여자에서더흔하였다 [1]. 이것은소변에포도당농도가증가해서나타나는것으로사료된다. 몇몇연구에서는요로감염이증가한다고보고하기도하였다. 기립성저혈압이보고된바도있다 [1]. 혈중크레아티닌증가및사구체여과율감소도관찰되었으나, 이는가역적이었다. 사구체여과율이감소하는것은직접적으로는삼투성이뇨가발생하면서혈장량이감소되어생기는것같다. 그러나세뇨관사구체되먹임 (tubular glomerular feedback) 기전에의해수입세동맥 (afferent arteriole) 의긴장도가증가하면서, 2차적으로발생하였을수도있다. 이러한현상이잠재적으로는당뇨병성신병증의진행을늦출수있을것으로보고된바있다 [9,16]. SGLT2 억제제는인슐린에독립적으로작용하기때문에단독요법으로사용하거나, 저혈당을일으키는약제와의병합요법이아니라면저혈당발생은드물다 [1,8]. 그러나설폰요소제나인슐린과병합요법시에는저혈당발생이증가하는경향이있다 [17]. 최근 SGLT2 억제제를복용하는환자에서당뇨병성케톤산증이발생하는경우가보고되었다 [18,19]. 특히혈당이정상인경우에도케톤산증이발생할수있어서주목을받았다. SGLT2 억제제로인한당뇨병성케톤산증은제1형당뇨병환자에서더욱흔하게발생하나, 제2형당뇨병환자에서도발생할수있다. 임상적으로심한급성질환과같은스트레스상황, SGLT2 억제제를사용하면서인슐린용량을감량하였는데, 인슐린펌프가오작동되는경우처럼인슐린용량이급격하게감소된경우에서주로발생한다. SGLT2 억제제복용시당뇨병성케톤산증의위험도가어느정도증가하는지는불명확하다. 미국 FDA는 SGLT2 억제제로인한이러한잠재적인위험상황이발생할수있는것에대해경고한바있다 [18,19]

3 - Yun Hyi Ku. SGLT2 inhibitors and ketoacidosis - 당뇨병환자에서케톤산증발생 당뇨병성케톤산증은당뇨병환자에서발생할수있는응급상황중에하나이며, 사망률은 % 정도로알려져있다 [20]. 제1형당뇨병환자에서대부분발생하지만, 제2형당뇨병환자에서도발생할수있다 [21,22]. 스웨덴에서는모든당뇨병성케톤산증환자중제2형당뇨병환자가 3분의 1까지차지한다고보고된바있다 [22]. 당뇨병성케톤산증은예방가능하다. 특히, 인슐린생략, 음식물섭취감소, 수분흡수감소, 감염, 수술, 외상, 갑상선기능항진증, 과도한음주, 특정약제사용 ( 코카인, 스테로이드, 항정신병약제, 인터페론등 ) 등과같은유발인자에대해주의가필요하다 [23]. 당뇨병성케톤산증은상대적또는절대적으로인슐린이결핍된상태에서코티솔, 에피네프린, 성장호르몬, 글루카곤과같은 counter-regulatory 호르몬이증가되면서발생한다 [23]. 이러한호르몬불균형이발생하면간에서포도당신생합성이증가하고글리코겐분해가증가하며, 지방분해가촉진된다. 반면에세포내로포도당유입이감소하여결과적으로고혈당이발생하고, 혈중유리지방산이증가한다. 간에서유리지방산을산화시키는능력이한계에다다르면, 케톤체가축적되고대사성산증이발생한다. 일반적으로당뇨병성케톤산증을진단하는기준은케톤이존재하면서 ph < 7.3, 혈청 bicarbonate 15 mmol/l, 음이온차 12 mmol/l인경우 이다 [24]. 많은경우에혈장포도당농도는 250 mg/dl (14 mmol/l) 이상이지만, 포도당농도가 250 mg/dl 미만인경우에당뇨병성케톤산증이발생하는경우도제1형당뇨병및임신부에서보고되었다 [25,26]. SGLT2 억제제사용자에서발생하는당뇨병성케톤산증은제1형당뇨병환자에서주로발생하는전형적인당뇨병성케톤산증과는병태생리가조금다르다. SGLT2 억제제로인한당뇨병성케톤산증에서가장중요한점은정상또는경미하게증가된혈당농도에서도발생할수있다는점으로, 이로인해진단이늦어질수있어주의를요한다. 제 2 형당뇨병환자와 SGLT2 억제제연관당뇨병성케톤산증 다파글리플로진, 카나글리플로진, 엠파글리플로진을이용한제2형당뇨병환자의임상시험모두에서부작용으로 당뇨병성케톤산증을보고하였다 [23,27,28]. 이임상시험들에서는총 44,000 환자-년의 SGLT2 억제제를복용하였고, 당뇨병성케톤산증의발생빈도는 1,000 환자- 년당 이었다. 카나글리플로진임상시험에서는카나글리플로진으로치료받은 10,687명의환자중 10명에서당뇨병성케톤산증이발생하였으며, 이는카나글리플로진 100 mg을복용하였던환자에서 1,000 환자-년당 0.52에해당한다. 반면에카나글리플로진을복용하지않은군에서는 0.24였다 [18]. 다파글리플로진연구에서는 5,936명의다파글리플로진을복용한환자중 1명에서당뇨병성케톤산증이발생하였고, 이는 1,000 환자-년당 0.16에해당한다 [27]. 엠파글리플로진의경우엠파글리플로진 10 mg을복용한군에서 1,000 환자-년당 0.6, 25 mg을복용한군에서 0.5의빈도로당뇨병성케톤산증이발생하였다 [28]. 10개의무작위대조연구를대상으로한, 13,134명의환자를포함한메타분석에서 14회의당뇨병성케톤산증이발생하였고, 이중 SGLT2 억제제복용군에서 11회 (0.1%), 대조군에서 3회 (0.06%) (odds ratio 1.71, 95% CI ) 의케톤산증이발생하여통계적으로유의한차이를보이지는않았다 [29]. 다만당뇨병성케톤산증의발생빈도가너무적었다는한계가있어서, 추후지속적인연구가필요하며, 어떠한환자에서당뇨병성케톤산증이발생하는지환자의프로필을이해하는것이중요하겠다. 제 1 형당뇨병환자와 SGLT2 억제제연관당뇨병성케톤산증 인슐린과독립적으로혈당을낮추는약제라는측면에서 SGLT2 억제제는제1형당뇨병환자에서매력적인약제가될수있겠으나, 당뇨병성케톤산증의발생위험도가증가하기때문에, 아직은사용하지않도록권고하고있다. 제1형당뇨병환자를대상으로한임상연구는코호트가작다는단점이있지만, 제2형당뇨병환자를대상으로한연구보다당뇨병성케톤산증이더많이발생하는경향을보인다 [30-36]. 엠파글리플로진을복용한제1형당뇨병환자는 8주동안의연구에서 40명중 2명에서당뇨병성케톤산증이발생하였다 [33]. 인슐린용량을감량한것이영향을미친것으로보인다. 소타글리플로진을이용한한파일럿연구에서는 16명의제1형당뇨병환자중 2명에서당뇨병성케톤산증이발생하였다 [35]. 두경우모두감염또는인슐린감량이라는유발

4 - 대한내과학회지 : 제 92 권제 5 호통권제 678 호 인자가있었다. 이프라글리플로진으로시행한 12주연구에서 17명의제1형당뇨병환자중 2명에서당뇨병성케톤산증이발생하였고, 대조군에서는발생하지않았다 [36]. 이경우에도모두인슐린용량을감량한것이유발인자로작용하였을것으로사료된다. 카나글리플로진을사용한 351명의환자를대상으로한연구는 18주동안진행되었는데 [30,32] 카나글리플로진군에서인슐린용량은 10-20% 정도감량하였으며, 카나글리플로진 100 mg 복용군에서는 4.3%, 300 mg 복용군에서는 6.0% 의환자에서당뇨병성케톤산증이발생하였으며, 대조군에서는발생하지않았다. 당뇨병성케톤산증이발생한환자들은대부분감염또는인슐린감량이라는유발인자를공통적으로가지고있었으며, 혈당은 mg/dl ( mmol/l) 였다. 현재까지의자료를종합해보면제1형당뇨병환자는 SGLT2 억제제로인해당뇨병성케톤산증위험도가증가하며, 빈도는약 5-12% 정도이다. 모든경우에서유발인자가존재하였다. 감염또는인슐린감량이제일흔하였으며, 정상포도당농도에서발병하는경우도있었다. 다. SGLT2 억제제에의해소변으로포도당이배출되면, 효과적으로혈장포도당농도가감소하고, 이는췌장베타세포로부터인슐린분비를감소시킨다. 또, SGLT2 억제제는신장에서나트륨재흡수를감소시켜간접적으로신장에서케톤재흡수를증가시켜서케톤의 reservoir 가증가하게된다. 최근췌장의알파세포에도 SGLT2가존재하는것이알려졌다 [40]. 이로인해 SGLT2 억제제가알파세포로부터직접적으로글루카곤분비를자극한다는것을알게되었으며 [41,42], 또한인슐린대글루카곤비율이감소하면서케톤생합성, 포도당신생합성, 글리코겐분해가증가하는것이알려졌다. SGLT2 억제제가소변으로포도당을배출시키면혈중포도당농도는감소하지만, 이와는대조적으로, 포도당신생합성및글리코겐분해에의해혈중포도당농도는증가하게된다. 따라서, 고혈당또는정상혈당에서의당뇨병성케톤산증은내인성포도당생성및신장에서포도당배설량간의균형에의해서발생하는것으로보인다. 당뇨병성케톤산증에대한대처법 SGLT2 억제제로인한케톤산증발생의병태생리단독요법이든다른약제와의병합요법이든간에, SGLT2 억제제사용시케톤증가로인한부작용이발생하는것으로알려져있다. 제1형당뇨병환자에서엠파글리플로진을복용하였던연구와비슷하게 [34] SGLT2 억제제를복용한제2형당뇨병환자에서증상은없더라도 β-hydroxybutyrate 가 12-20% 정도증가하는것이확인되었다 [37,38]. 특히저탄수화물식이를하는경우 β-hydroxybutyrate 가더욱증가한다 [39]. 이로부터 SGLT2 억제제를복용하는경우무증상이더라도케톤체발생이증가하는것으로유추할수있다. 그러나케톤이증가하는경우에도일부의환자들만이현저한당뇨병성케톤산증으로진행한다는것을고려해보면 [5,30-32,38], 당뇨병성케톤산증을발생시키는케톤의역치가있는지에대해생각해보게된다. 전형적인당뇨병성케톤산증과비슷하게 SGLT2 억제제로인한당뇨병성케톤산증에서도인슐린부족으로인해지방분해가일어나고, 혈중유리지방산이증가하며증가된유리지방산은케톤합성의재료가된다. 이러한현상이췌장의글루카곤분비증가와맞물려간에서도케톤생성이증가한 SGLT2 억제제사용과관련된당뇨병성케톤산증을예방하는가장좋은방법은, 약제를적절하게처방하고, 급성질환, 수술, 탈수, 저탄수화물식이, 과도한음주등당뇨병성케톤산증을유발할수있는상황에서적절히약제를중단하는것이다. SGLT2 억제제의반감기는약 11-13시간정도이기때문에약물을중단한후에도수일간약효가지속될수있다. 그러므로외과적수술을앞두고있는경우에는약 3일전부터약제를중단하는것이바람직하다 [23]. 제1형당뇨병환자 SGLT2 억제제는현재로서는제1형당뇨병치료에사용하지않는다. 왜냐하면제1형당뇨병환자들이 SGLT2 억제제로인해당뇨병성케톤산증이발생할위험도가더높기때문이다. 아직까지는임상시험단계에서만제1형당뇨병환자에서 SGLT2 억제제를사용하고있다. 인슐린을사용하는제2형당뇨병환자인슐린을사용하는제2형당뇨병환자는 SGLT2 억제제를시작하기전에인슐린용량이안정적이어야한다. 인슐린을사용하는것에대해지속적인치료의중요성을상담해주고, 인슐린을부적절하게감량하거나, 생략하는것에대해주의

- 구윤희. SGLT2 억제제와케톤산증 - 를주어야한다. 급성질환발생시설령혈중포도당농도가정상이더라도혈중케톤수치를측정하는것에대해고려해볼수있다. 소변에서케톤을측정하는것은바람직하지않은데, 이는당뇨병성케톤산증에서주요케톤은 β-hydroxybutyrate 인데, 소변에서측정하는것은 acetoacetate 이기때문이다.

5 - 구윤희. SGLT2 억제제와케톤산증 - 를주어야한다. 급성질환발생시설령혈중포도당농도가정상이더라도혈중케톤수치를측정하는것에대해고려해볼수있다. 소변에서케톤을측정하는것은바람직하지않은데, 이는당뇨병성케톤산증에서주요케톤은 β-hydroxybutyrate 인데, 소변에서측정하는것은 acetoacetate 이기때문이다. 또, SGLT2 억제제를복용하는환자는신장에서케톤재흡수가증가되어, 소변케톤이감소하기때문이다. 급성질환자에서혈중케톤이양성반응을보이는경우매 2-4시간마다케톤증을감소시키기위해경구로탄수화물을공급하면서인슐린을주입하는것이권장된다. 그러나무증상환자에서케톤을모니터링하는것은추천하지않는다 [23]. 인슐린을사용하지않는제2형당뇨병환자인슐린을사용하지않는제2형당뇨병환자에서인슐린이 부족해지거나, 탄수화물섭취를제한하거나, 과도한음주를하는경우, 당뇨병치료를적절히받지않는경우당뇨병성케톤산증이발생할가능성이증가한다 [23]. 유발인자가없으면서인슐린을사용하지않는제2형당뇨병환자에서는당뇨병성케톤산증이발생할확률이매우낮다 [23]. SGLT2 억제제를사용하는모든환자병력에상관없이모든환자는당뇨병성케톤산증이진행하는증상을느낀다면, 모두응급실에가서검사를받아야한다. 포도당농도가정상이라하더라도당뇨병성케톤산증을배제하기위해검사를해야한다. 케톤증단독으로는당뇨병성케톤산증을진단할수없으며, 대사성산증이동반되는경우에만당뇨병성케톤산증으로진단한다. ph, bicarbonate, 음이온차, 혈청케톤등으로당뇨병성케톤산증을진단받았다면 SGLT2 억제제는즉시중단한다. 그리고전통적인당뇨병성케톤산증치료방법에준해치료를시작한다 (Fig. 1). 결 론 SGLT2 억제제는인슐린과독립적으로작용하는새로운계열의경구당뇨병치료약제로서혈당강하효과및체중감소, 혈압강하, 심혈관질환으로인한사망률감소등여러이점으로미루어환영할만한약제이다. SGLT2 억제제로인한당뇨병성케톤산증발생에대해우려가있기는하나, 이는 0.1% 미만으로발생하는드문합병증이고, 주로통제가능한유발인자가동반될때에발생한다는점을고려해야한다. 케톤산증의유발인자를통제하고적절하게처방함으로써당뇨병성케톤산증을예방하면서소기의치료목적을달성할수있을것으로기대한다. 중심단어 : 나트륨 -포도당공동수송체 2; 당뇨병성케톤산증 ; 케톤체 REFERENCES Figure 1. Prevention of diabetic ketoacidosis in sodium-glucose cotransporter 2 inhibitor (SGLT2i) users with type 2 diabetes mellitus. T2DM, type 2 diabetes mellitus; DKA, diabetic ketoacidosis; CHO, carbohydrate. Modified from Goldenber RM, et al. [23]. 1. Reddy RM, Inzucchi SE. SGLT2 inhibitors in the management of type 2 diabetes. Endocrine 2016;53: Guyton AC: Urine formation and the kidneys. Textbook of Medical Physiology, 9th ed. Philadelphia: WB Saunders; DeFronzo RA, Davidson JA, Del Prato S. The role of the

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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