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1 한국임상약학회지제 28 권제 3 호 Korean J Clin Pharm, Vol. 28, No. 3, 2018 Clinical information Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy pissn eissn X Korean journal of clinical pharmacy (Online) URL: Metformin 에추가로병용되는 SGLT2 inhibitors 의효능과안전성에관한고찰 정경혜 * 중앙대학교약학대학 (2018년 8월 8일접수 2018년 9월 18일수정 2018년 9월 20일승인 ) A Review on Efficacy and Safety of SGLT2 Inhibitors as Addon Therapy with Metformin Kyeong Hye Jeong* College of Pharmacy, ChungAng University, Seoul 06974, Republic of Korea (Received August 8, 2018 Revised September 18, 2018 Accepted September 20, 2018) ABSTRACT Background: The new type of diabetes treatment, SGLT2 inhibitors, has been approved for monotherapy and combination therapy, but medical insurance is only allowed in combination therapy with metformin, which is the first choice for type 2 diabetes treatment. Methods: The SGLT2 inhibitors prescribed in Korea are dapagliflozin, empagliflozin and ipragliflozin. A review was conducted using Pubmed to evaluate efficacy and safety for these medications with metformin combination therapy. 10 studies were selected by searching for keywords and related references and were reviewed in full. The mechanism of action, pharmacokinetics, and the economics of treatment with SGLT2 inhibitors were examined. Results: SGLT2 inhibitors had moderate glycemic control when added to the treatment of patients with type 2 diabetes who were not being regulated by metformin monotherapy. They also showed positive effects such as weight loss, as well as the lowering of blood pressure. Hypotension and serious side effects were relatively low. However, the risk of genital infection was increased. Conclusion: The SGLT2 inhibitors are a new class of drugs that promote glucose excretion in the urine. They are a good choice for combination therapy with metformin for the treatment of type 2 diabetes, with weight loss and very low risk of serious side effects. KEY WORDS: SGLT2 inhibitors, metformin, dapagliflozin, empagliflozin, ipragliflozin 2016년, 30세이상국내당뇨병유병률은전체인구의약 13% 이었으며 65세이후에는 27.3% 로나타났다. 1) 당뇨병환자의대다수는제 2형당뇨병이며혈당조절을하지않으면심장, 뇌혈관, 말초혈관질환의대혈관합병증과신장변증, 망막변증, 신경변증의미세혈관합병증등의유발위험이증가한다. 특히비만인당뇨병환자가고혈압이나이상지질혈증이있는경우심장질환유발위험은더커진다. 그러므로당뇨병치료제로혈당조절뿐만아니라체중조절과심혈관질환위험을감소시킬수있는약제의개발이필요하다. 당뇨병치료제로 insulin, GLP1 agonists와같은주사제제와경구제제인 metformin, sulfonylureas, meglitinides, thiazolidinediones, αglucosidase inhibitors, dipeptidyl peptidase4 (DPP4) inhibitors, sodium glucose cotransporter2 (SGLT2) inhibitors 등이있다. 2) SGLT2 inhibitors는신장에서포도당재흡수에중요한역할을하는 SGLT2를차단함으로써포도당의소변배설을촉진하는작용을하는약물군이다. Canagliflozin, dapagliflozin, empagliflozin, ipragliflozin이여기에속한다. Canagliflozin 은 2013년 3월에 FDA 에서처음으로승인한 SGLT2 inhibitor이다. 3) Dapagliflozin은 2012년 1월에처음개발되었고유럽에서는 2012년 11월에승인되었으나, FDA에는 2014년 1월에승인되었다. 4) Empagliflozin 은유럽에서는 2014년 4월에, FDA에는 2014년 8월에승인되었다. 4,5) Ipragliflozin은일본에서최초로승인된 SGLT2 inhibitor이다. 6) 국내에서는 2013년 11월에 dapagliflozin ( 포시가정 ) 이처음으로승인되었다. 그후로 canagliflozin ( 인보카 *Correspondence to: Kyeong Hye Jeong, College of Pharmacy, ChungAng University, 84 Heukseokro, Dongjakgu, Seoul 06974, Republic of Korea Tel: , Fax: jnkh7@cau.ac.kr 243

2 244 / Korean J Clin Pharm, Vol. 28, No. 3, 2018 나정 ), empagliflozin ( 자디앙정 ), ipragliflozin ( 슈글렛정 ) 이승인되어총 4 종류의 SGLT2 inhibitors 가승인되었으나 7) 현재 canagliflozin을제외한 3 종류의 SGLT2 inhibitors가출시되어사용되고있다. 제 2형당뇨병치료가이드라인에의하면제1요법으로 metformin 이추천되고있다. 2) 그러나 metformin 단독으로혈당조절이안되면병용요법이필요하다. 병용요법으로치료제를선택할때기전이다른약물로선택하며 8) 부작용, 체중영향등여러요소를고려한다. 국내에서 SGLT2 inhibitors는단독요법, 병용요법으로모두승인되었으나 metformin과병용할경우에급여가인정되므로대부분 metformin 병용요법으로처방될가능성이높다. Dapagliflozin은 sulfonylurea계와병용시도급여가인정된다. 9) 그러므로국내에서사용되는 dapagliflozin, empagliflozin, ipragliflozin과 metformin 병용요법의효능과안전성및 SGLT2 inhibitors의특징에대해살펴보고자한다. 연구방법 2017년 7월 24일까지접근가능한 Pubmed 자료를사용하여검색을수행하였다. SGLT2 inhibitor 검색어를사용하였고 human 연구와 English 로출판된논문으로제한하여총 282 편의문헌이검색되었다. 이중제목검토를통해동물연구, dapagliflozin, empagliflozin, ipragliflozin과관련이없는문헌, 원문을찾을수없는문헌을제외하여총 82 편의문헌을선정하였다. 이후초록을검토하여 metformin 병용요법하의효능과안전성에해당하는문헌과참고문헌에서추가로발견된문헌을추가하여총 10편의문헌을최종문헌으로선정하여효능과안전성에관해검토를하였다. 국내에서발매된 3가지 SGLT2 inhibitors의임상정보를제공하기위해 SGLT2 inhibitors 의작용기전, pharmacokinetics/pharmacodynamics, 경제성에관해정리했으며 metformin 병용요법에관한연구를수집하고비교분석했다. 연구결과및고찰 SGLT2 inhibitors 의작용기전신장에서의포도당재흡수는 glucose transporters (GLUTS) 와 sodium glucose trans cotransporter (SGLTs) 에의해이루어진다. 사구체로여과된포도당은대부분근위세뇨관에서 SGLT (sodium glucose cotransporter) 에의해재흡수되어혈액중으로들어간다. SGLT는장상피와근위세뇨관에서포도당을운송하는막단백질이다. SGLT1은주로소장에서발현되어포도당과갈락토오즈흡수에중요한역할을하며신장의근위세뇨관 S3에서도발현되어여과된포도당의 10% 의재흡수를담당한다. SGLT2는주로신장의근위세뇨관 S1에서발현되어포도당의 90% 를재흡수하는역할을담당한다. 제2형당뇨병환자는건강한사람에비해 SGLT2와 GLUT2를훨씬많이발현하는것으로알려져있어신장에서포도당재흡수가증가한다. 10,11) SGLT2 inhibitors는 SGLT2를차단해서포도당재흡수억제로소변배설을촉진해서혈당을낮추는약물로, 췌장의 β cell 기능과관련없이인슐린비의존적으로작용하는새로운기전의당뇨병치료약물이다. SGLT2 inhibitors의 pharmacokinetics/pharmacodynamics SGLT2 inhibitors 세약물은복용후흡수되어 12시간내에최대혈중농도를나타내며반감기는약 1213 시간이다 (Table 1). Dapagliflozin은고지방음식과복용하면공복시와비교해서최고혈중농도 (Cmax) 가 50% 까지감소하고, 최고혈중농도에도달하는시간 (Tmax) 은약 1시간연장되나 AUC는변하지않는다. 12) 그러나소변중당배설 (urinary excretion) 에는영향을주지않아임상적으로의미를찾기어려우므로음식과상관없이복용할수있다. 13) Empagliflozin 또한고지방음식과복용하면 AUC와 Cmax가각각약 16%, 37% 감소하나임상적으로의미있다고간주되지않으므로음식과상관없이복용할수있다. 5) 세약제는환자의 CrCl가 60 ml/min 미만인경우치료시작이권장되지않는다. 이약제들을복용하는동안 CrCl가계속해서 60 ml/min 미만일경우에는 dapagliflozin, ipragliflozin 은중단하며, empagliflozin은 1일 1회 10 mg으로용량을조절하여사용하고 CrCl가 45 ml/min 미만일경우에중단한다. Dapagliflozin, empagliflozin은경증의신장이상일경우는용량조절이필요하지않다. 세가지약제모두경증또는중등도의간장애환자에서용량 Table 1. Pharmacokinetics and pharmacodynamics of dapagliflozin, empagliflozin and ipragliflozin Absolute bioavailability (%) Tmax (hours) Halflife (hours) Protein binding (%) 24hr urinary glucose excretion (g) SGLT2:SGLT1 selectivity 30) Dapagliflozin 12) 78 < Empagliflozin 5) 78 31) mg: mg: Ipragliflozin 32) Metformin 33) negligible

3 Metformin 에추가로병용되는 SGLT2 inhibitors 의효능과안전성에관한고찰 / 245 조절이필요없다. Dapagliflozin 은중증의간장애환자에는 5mg 의용량으로치료를시작하고, empagliflozin 과 ipragliflozin 은중증의간장애환자대상으로사용이권장되지않는다. 14) Metformin요법에추가된 SGLT2 inhibitors의효능 SGLT2 inhibitors의사용용량은 dapagliflozin 1일 5mg~ 10 mg, empagliflozin 10 mg~25 mg, ipragliflozin 50 mg이다. 이용량을기준으로 metformin과병용요법의혈당, 체중, 혈압변화를보았다. Nauck 등의연구 1517) 는 dapagliflozin 각각용량에관한연구가아니므로제외하고 Bailey등의연구는 102주 연구 18) 를반영했다. 평균 hemoglobin A1c (HbA1c) 는 dapagliflozin, empagliflozin, ipragliflozin병용군이 baseline으로부터각각 0.3~0.78%, 0.55~0.77%, 0.65~0.87% 유의하게감소했으며공복혈당 (fasting plasma glucose, FPG) 은각각 0.96~1.47 mmol/l, 1.11~1.5 mmol/l, 0.79~1.23 mmol/l 유의한감소를보였다. 또한체중은 baseline으로부터각각 1.7~1.74 kg, 2.08~2.7 kg, 2.1 kg~2.33 kg 유의하게감소되었다. 수축기혈압은 dapagliflozin, empagliflozin군에서각각 0.3~1.1 mmhg, 4.5~5.2 mmhg 유의하게감소되었으며이완기혈압은 empagliflozin군이 1.6~2.0 mmhg 유의하게감소되 Table 2. Efficacy of metformin combination therapy with dapagliflozin, empagliflozin and ipragliflozin Study/ duration(weeks) Group Change from baseline HbA1c(%) FPG (mmol/l) Weight (kg) SBP (mmhg) DBP (mmhg) Dapagliflozin n Baily et al 19) 2010 / MET MET+DAP 2.5 mg MET+DAP 5 mg MET+DAP 10 mg * 0.7 * 0.84 * * 1.19 * 1.30 * * 3.0 * 2.9 * Baily et al 18) 2013 / MET MET+DAP 2.5 mg MET+DAP 5 mg MET+DAP 10 mg * 0.58 * 0.78 * * 1.36 * * 1.70 * 1.74 * * 0.3 * Bolinder et al 20) 2014 / MET MET+DAP 10 mg * 0.96 * 4.54 Nauck et al 15) 2011 / MET+DAP MET+GLP 0.52 * 0.52 * 3.22 * 4.3 * * * 0.4 Nauck et al 16) 2014 / MET+DAP MET+GLP 0.32 * 1.12 * 3.7 * 0.14 * 0.68 * * +1.2 Nauck et al 17) 2015 / MET+DAP MET+GLP * * * 0.02 Empagliflozin Rosenstock et al 34) 495 MET MET+EMP 1 mg MET+EMP 5 mg MET+EMP 10 mg MET+EMP 25 mg MET+EMP 50 mg MET+SIT # mg * 0.56 * 0.55 * 0.49 * 0.45 * * 1.2 * 1.5 * 1.6 * 0.7 * * 2.7 * 2.6 * 2.9 * Haering et al 35) 2014 / MET MET+EMP 10 mg MET+EMP 25 mg * 0.77 * * 1.24 * * 2.46 * * 5.2 * * 1.6 * Ipragliflozin Wilding et al 36) 343 MET MET+IPR 12.5 MET+IPR 50 MET+IPR 150 MET+IPR * 0.65 * 0.72 * 0.79 * * 1.35 * 1.54 * * 1.99 * 2.21 * * * Kashiwagi et al 37) 2015 / MET MET+IPR * 1.23 * 2.33 * MET=Metformin;DAP=Dapagliflozin; GLP=Glipizide; EMP=Empagliflozin; SIT=Sitagliptin; IPR=Ipragliflozin; SBP=systolic blood pressure; DBP=diastolic blood pressure *Statically significant difference (p < 0.05 vs from baseline)

4 246 / Korean J Clin Pharm, Vol. 28, No. 3, 2018 었다 (Table 2). Metformin 단독으로혈당이조절되지않는제2 형당뇨병환자에 SGLT2 inhibitors를추가하는것은혈당조절과체중감소에도움이되며, 혈압에도긍정적인결과를나타냈으나유의하지않은결과를나타낸연구가많았다. Nauck 등에의한연구 1517) 에서 dapagliflozin은 baseline에비교하여 HbA1c 감소를보였으며, glipizide와비교시지속적으로혈당이조절되는결과를나타내었다. 체중은 dapagliflozin 은 baseline에비해감소를보였고, glipizide는증가를보였다는점은일반적으로알려진두약물의특징과일치했다. Bailey 등의연구결과 18,19) 에서 24주에 baseline으로부터평균 HbA1c는 0.67~0.84%, 102주에 0.48~0.78% 로감소했으며 Nauck 등에의한연구 1517) 에서도 52주, 104주, 208주연구에서각각 0.52%, 0.32%, 0.1% 로감소했다. Bolinder 등의 102주연구 20) 에서도 0.3% 감소로장기로 dapaglifozin을복용했을때혈당강하효과가감소하는것으로나타났다. 한메타분석연구 21) 에의하면 metformin, SGLT2 inhibitors 병용요법은첫 6개월동안 HbA1c와 FPG, 체중, 혈압개선에유의한결과를나타냈으나, 1년또는 2년후의결과는일정하지않았으며 FPG 와체중은유의하게감소했으나 HbA1c는유의성이없었다. 그러나민감도분석은병용요법이 HbA1c 감소에유의한효과를얻었다는결과를나타냈다. 그러므로 SGLT2 inhibitors 의장기간혈당조절에관해더연구가필요할것같다. Table 3. Safety of metformin combination therapy with dapagliflozin, empagliflozin and ipragliflozin Study/ duration(weeks) Group (n) Genital infection Urinary tract infection Adverse events, % (n) Hypoglycemia Diarrhea Hypotension Serious adverse events Dapagliflozin Baily et al 19) 2010 / 24 MET (137) MET+DAP 2.5 (137) MET+DAP 5 (137) MET+DAP 10 (135) 5 (7) 13 (18) 9 (12) 4 (6) 7 (10) 2 (3) 5 (7) 2 (3) 7 (10) <1 (1) 1 (2) Baily et al 18) 2013 / 102 MET (137) MET+DAP 2.5 (137) MET+DAP 5 (137) MET+DAP 10 (135) 5.1 (7) 11.7 (16) 14.6 (20) 12.6 (17) 8.8 (12) 13.3 (18) 5.8 (8) 3.6 (5) 5.1 (7) 5.2 (7) 7.3 (10) 5.1 (7) 6.6 (9) 11.9 (16) 1.5 (2) 2.2 (3) 1.5 (2) 10.2 (14) 10.9 (15) 6.6 (9) 10.4 (14) Bolinder et al 20) 2014 / 102 MET (91) MET+DAP 10 (91) 1.1 (1) 2.2 (2) 7.7 (7) 6.6 (6) 5.5 (5) 4.4 (4) 4.4 (4) 3.3 (3) 1.1 (1) 15.1 (14) 17.6 (16) Nauck et al 15) 2011 / 52 MET+DAP (406) MET+GLP (408) 12.3 (50) 2.7 (11) 10.8 (44) 6.4 (26) 3.4 (14) 39.7 (162) 4.7 (19) 6.4 (26) 1.5 (6) 0.7 (3) 8.6 (35) 11.3 (46) Nauck et al 16) 2014 / 104 MET+DAP (406) MET+GLP (408) 14.8 (60) 2.9 (12) 13.5 (55) 9.1 (37) 4.2 (17) 45.8 (187) 1.5 (6) 1.7 (7) 12.6 (51) 15.2 (62) Nauck et al 17) 2015 / 208 MET+DAP (406) MET+GLP (408) 14.3 (58) 2.9 (12) 13.5 (55) 9.3 (38) 5.4 (22) 51.5 (210) 8.6 (35) 10.3 (42) 18.5 (75) 19.9 (81) Empagliflozin Rosenstock et al 34) MET (71) MET+EMP 1 (71) MET+EMP 5 (71) MET+EMP 10 (71) MET+EMP 25 (70) MET+EMP 50 (70) MET+SIT 100 (71) 5.6 (4) 9.9 (7) 2.9 (2) 5.7 (4) 4.3 (3) 2.9 (2) 4.3 (3) Haering et al 35) 2014 / 24 MET (207) MET+EMP 10 (217) MET+EMP 25 (213) 3.7 (8) 4.7 (10) 4.9 (10) 5.1 (11) 5.6 (12) 0.5 (1) 1.8 (4) 1.4 (3) 3.4 (7) 3.2 (7) 2.3 (5) Ipragliflozin Wilding et al 36) MET (66) MET +IPR 12.5 (69) MET +IPR 50 (68) MET +IPR 150 (67) MET +IPR 300 (72) 1.5 (1) 4.3 (3) 3.0 (2) 6.1 (4) 2.9 (2) 6.0 (4) 6.9 (5) 3.0 (2) 5.9 (4) 4.5 (3) 1.5(1) 1.5 (1) Kashiwagi et al 37) 2015 / 24 MET(56) MET+IPR 50 (112) (2) 1.8 (2) MET=Metformin; DAP=Dapagliflozin; GLP=Glipizide; EMP=Empagliflozin; SIT=Sitagliptin; IPR=Ipragliflozin

5 Metformin 에추가로병용되는 SGLT2 inhibitors 의효능과안전성에관한고찰 / 247 일본인을대상으로한 52주연구에서 22) sulfonylurea, metformin, thiazolidinedione, αglucosidase inhibitor, DPP4 inhibitor, glinide에 empagliflozin을추가했을때 HbA1c 감소가 52주까지유지되었고 FPG, 체중, 수축기혈압, 확장기혈압감소로나타나, 다른당뇨병치료제와병용했을때임상적으로의미있는결과를나타냈다. 경구용당뇨병치료제에 dapaglifozin 추가요법에대한 Archimedes model을사용하여 20년심혈관위험과미세혈관합병증시뮬레이션연구 23) 에서제2형당뇨병과관련된심혈관질환과사망률, 당뇨병성망막변증, 신장변증발생률을낮추었다는결과가나왔다. 심혈관질환을가진제2형당뇨병환자들을대상으로시행한대규모임상실험인 EMPAREG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) 24) 연구결과에서 empagliflozin은비치명적심근경색, 또는비치명적뇌졸중에대해서는유의한차이를보이지않았으나심혈관질환사망률 38%, 심부전으로인한입원율 35%, 사망률 ( 원인과관계없이 ) 32% 유의하게감소시켰다. SGLT2 inhibitors가심혈관질환위험을감소시키는주요기전으로혈당감소, 체중감소, 혈압감소, 및죽상동맥경화과정에관여하는인자감소 25) 로제안되었으나심근경색, 뇌졸중위험에유의한차이를보이지않았다는 EMPAREG OUTCOME 연구결과이후 empagliflozin의심혈관사망률감소는대사작용보다는혈압감소, 이뇨효과와세포외액부피감소, 혈관강직감소등의혈역학적작용때문일가능성에중심을둔이론이제안되었다. 26) Metformin에추가된 SGLT2 inhibitors은혈당조절과체중, 혈압에긍정적영향을주어대사증후군과 27) 과심혈관계합병증감소 23,24) 에도움이될수있는당뇨병치료제의하나가될것을기대해볼수있겠다. Metformin요법에추가된 SGLT2 inhibitors의안전성 SGLT2 inhibitors는저혈당발생률이낮은당뇨병치료제이며, 주요부작용은생식기감염, 요로감염, 소변배출로인한저혈압, 탈수등 14) 이다. 저혈당발생위험은 metformin 단독요법에비해크게차이나지않았으며저혈당발생위험과용량과의관련성은나타나지않았다. 또한저혈당위험은 glipizide 병용에비해현저히낮았다 (Table 3). 생식기감염발생은 SGLT2 inhibitors 병용투여군에서 metformin 단독투여군보다높았으며이는다른연구에서의결과와도일치한다 28). 그러나용량과의관련성은나타나지않았다. 요로감염은 SGLT2 inhibitors 병용투여군에서대조군과유사하거나약간높았으나큰차이를보이지않았다. 저혈압발생은유의하게높지않았으나 SGLT2 inhibitors는배뇨증가로인해혈압저하, 체액량감소가발생하므로, 이뇨제를사용하고있거나체액량이감소된환자는주의가필요하다. 14) Bailey 등의연구결과 18,19) 에서 dapagliflozin 10mg에서설사발생률이 metformin 단독투여군보다높았으나 Bolinder 등의연구 20) 에서는그렇지않아일정한결과를보여주지않았다. 또한 dapagliflozin병용군보다 glipizide 병용군에서설사발생률이높았다. Metformin의주요부작용인위장장애가 SGLT2 inhibitors 투여후에변화했는지를보기위해서는이연구의자료가제한적이다. 그러나한메타분석연구 8) 에의하면, metformin에 SGLT2 inhibitors를추가했을때위장장애발생률은중요한차이가없었고설사위험은유의하게감소했다는결과를보여주었다. 심각한부작용발생률은 metformin 단독투여군에비해유사하거나높지않았다. 동물실험은 SGLT2 inhibitors와종양발생과의관련성을제시하지못했다. 29) Nauck 등의연구 16) 에서 dapagliflozin 병용 Table 4. Recommended daily doses and prices of antidiabetics Drug class Antidiabetics Brand name Usual daily dose (mg) Strength Price(won) 14) /tablet Biguanides Metformin Diabex 1000~ mg mg 112 Dapagliflozin Farxiga mg 784 SGLT2 inhibitors Empagliflozin Jardiance mg 689 Ipragliflozin Suglat mg 705 Alogliptin Nesina mg 759 DPP4 inhibitors Linagliptin Trajenta 5 5mg 752 Sitagliptin Januvia mg 910 Thiazolidinedione Pioglitazone Actos mg 627 1mg 124 Sulfonylureas Glimepiride Amaril 1~4 2mg 183 4mg 283 Meglitinides Nateglinide Fastic mg 173

6 248 / Korean J Clin Pharm, Vol. 28, No. 3, 2018 투여군에서 7건 ( 전립선 3, 유방, 1, 위 1, 췌장2), glipizide 병용투여군에서 3건 ( 전립선 1, 피부 1, 폐 1) 의악성종양이발생했다. 2013년까지 22개의임상연구에서방광암으로진단된경우는 dapagliflozin 복용그룹은 6045명중 10명 (0.17%), 비교그룹에서는 3512명중 1명 (0.03%) 이었다. 12,29) 방광암과 dapagliflozin 과의관련성은불확실하다. 그러나방광암환자는 dapagliflozin 복용을피해야하며, 당뇨병치료제중방광암위험증가와관련있는 pioglitazone과 dapagliflozin의병용또한피하는것이좋다. 12,14) Metformin요법에추가된 SGLT2 inhibitors의경제성 Metformin에병용요법으로사용되는대표적경구용당뇨병치료제의약가를비교했다 (Table 4). Sulfonylurea인 glimepiride 나 meglitinide인 nateglinide를사용하는것이다른약제에비해경제적이나당뇨병환자에서문제가되는저혈당, 체중증가의부작용을일으킬수있다. 다른계열약제의가격은 SGLT2 inhibitors를사용했을때와큰차이를보이지않았다. 결 SGLT2 inhibitors는 insulin과관련없는작용기전을갖고있는약물이다. Metformin으로혈당조절이안되는제 2형당뇨병환자에서 SGLT2 inhibitor의병용은중등도의혈당감소를보여주며추가로체중감소및혈압저하효과를나타내므로제 론 2 형당뇨병치료의중요한선택이될수있다. 참고문헌 1. Korean statistical Information Service. Available from eng/search/search01_list.jsp. Accessed July 12, American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes Diabetes Care 2018; 41(Supplement 1):S73S U.S. Food and Drug Administration. Canagliflozin prescribing information. Available from daf/index.cfm?event=overview.process&applno= Accessed July 12, European Medicines agency. Find medicine. Available from Accessed August 7, U.S. Food and Drug Administration. Jardiance prescribing information. Available from label/2017/204629s016lbl.pdf. Accessed July 12, Nainggolan L. Ipragliflozin (Suglat) First of new diabetes drug class in Japan. Available from Accessed July 12, Ministry of Food and Drug Safety. Online medicine library. Available from Accessed August 20, Kawalec P, Mikrut A, Lopuch S. The safety of dipeptidyl peptidase4 (DPP4) inhibitors or sodiumglucose cotransporter 2 (SGLT2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and metaanalysis. Diabetes Metab Res Rev 2014;30(4): Health insurance review & assessment service. Available from Accessed August 4, Fujita Y, Inagaki N. Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: Clinical data and mechanism of action. J Diabetes Invest 2014;5: Monica Reddy RP, Inzucchi SE. SGLT2 inhibitors in the management of type 2 diabetes. Endocrine 2016;53(2): U.S. Food and Drug Administration. Drugs@FDA. Farxiga prescribing information. Available from Accessed July 12, Kasichayanula S, Liu X, Zhang W, et al. Effect of a highfat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects. Diabetes Obes Metab 2011;13(8): Ministry of Food and Drug Safety. Product information. Available from Accessed July 1, Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as addon therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52week, doubleblind, activecontrolled noninferiority trial. Diabetes Care 2011;34(9): Nauck MA, Del Prato S, DuranGarcia S, et al. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as addon therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab 2014;16(11): Del Prato S, Nauck M, DuranGarcia S, et al. Longterm glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as addon therapy to metformin in patients with type 2 diabetes: 4year data. Diabetes Obes Metab 2015;17(6): Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin addon to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, doubleblind, placebocontrolled 102week trial. BMC Med 2013;11: Bailey CJ, Gross JL, Pieters A, et al. 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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