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1 Focused Issue - SGLT2 inhibitors 부산의대부산대학교병원내분비내과김원진, 김상수 The Side Effects of Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Won Jin Kim, Sang Soo Kim Department of Internal Medicine, Pusan National University Hospital, Busan, Korea Abstract 158 Anti-diabetic drugs for effectively lowering glucose with limited side effects are necessary in providing patientcentered diabetic management. Sodium glucose cotransporter 2 (SGLT 2) inhibitors provide a novel therapeutic approach for managing type 2 diabetic patients by lowering glucose levels by increasing urinary excretion of glucose independently of insulin secretion or action. Several SGLT 2 inhibitors were recently approved and available in the US, European and Korean markets. SGLT 2 improved glycemic control with low propensity of hypoglycemia. Through the clinical trials, most SLGT2 inhibitors were generally well tolerated. Genital tract infections were more frequent in most clinical studies of SGLT2 inhibitors and urinary tract infections were slightly increased in some studies. This review will describe the main safety issues that have been uncovered in clinical trials of SGLT 2 inhibitors. (J Korean Diabetes 2014;15: ) Keywords: Type 2 diabetes mellitus, Sodium glucose cotransporter 2, Safety 서론 인슐린저항성과인슐린분비부족을포함한여러다양한기전에의해발생하는제 2 형당뇨병의병태생리적인특성으로인해, 여러기전의경구약제와인슐린등의사용에도불구하고당뇨병이진행할수록상당수의환자에서혈당조절이불량한것이현실이다 [1]. 이런이유로임상의사들은현재임상에서사용할수있는여러약제에도불구하고, 새로운당뇨병치료약제의사용을기대하게된다. 신장에서포도당의재흡수는 Sodium glucose cotransporter (SGLT) 에의해이루어지고, 대부분은 SGLT2 에의해이루어지는것으로알려져있다 [2]. 이 SGLT2 를선택적으로억제하여소변으로포도당배출을증가시켜혈당을조절하고자하는목적으로선택적 SGLT2 억제제가개발되었다. 약제의큰장점은인슐린과비의존적으로혈당을감소시키고베타세포의기 능장애와인슐린저항성에큰영향을받지않는다는것이다. 약제개발의모체가되었던 phlorizin 의경우 SGLT2 에대한낮은선택성과강력한 Glucose transport 1 (GLUT1) 억제에따른부작용등의이유로임상약제로개발되지않았으나, 최근 SGLT2 에선택적이며약리적우수성과안전성을보이는여러약제들이개발되었다. 대표적인 SGLT2 억제제로는 dapagliflozin, canagliflozin, empagliflozin 등이있으며, 많은다국적제약회사들에서후속적인약제개발과임상연구를진행중에있다. 최근에개정된미국당뇨병학회와유럽당뇨병학회가공동으로발표한권고지침의가장큰변화는제 2 형당뇨병환자의혈당관리전략으로혈당목표치와혈당강하전략을환자에따른개별화에초점을두고있다는것이다 [3]. 환자개별화에따른약제선택을위해서무엇보다중요한것은사용하고자하는약제의부작용과안전성을잘이해하고적절한약제를선택하는것일것 교신저자 : 김상수, 부산시서구구덕로 179 부산대학교병원내분비대사내과, drsskim7@gmail.com

2 이다. 본원고에서는새롭게출시되어그사용이기대되는 SGLT2 억제제의여러임상연구를통해확인된부작용및안전성측면을요약하였다. 본론 가장많은임상결과를가지고있는 Dapagliflozin 을포함한여러 SGLT2 억제제들은부작용측면에서위약군과대비하여전체적으로큰차이점을보이지않는다고보고하고있다. Dapagliflozin 을사용한임상연구에서흔히보고된부작용으로는두통, 설사, 요통, 기관지염, 인후두염및상기도감염등이있으나, 이는다른치료군에비교해의미있는발생빈도의차이를보이지않았다 [4-6]. 대부분의 SGLT2 억제제의임상연구의시작단계에서부터안전성측면의특별한관심을갖고관찰한저혈당과요로생식기감염 (Table 1) 등을포함한일부우려되는안전성에대해살펴봐야겠다. 1. 저혈당 (Table 1) Dapagliflozin 은단독투여또는 Metformin 및 Pioglitazone 과병용하였을때저혈당의발현빈도는높지않았고, 위약과대비하여그위험성이증가하지않았다 [4,5,7]. 하지만, 비록심한저혈당발생이증가하지않았다할지라도, Sulfonylurea 와인슐린에추가하였을때는저혈당발현빈도가증가하였다 [6,8]. 따라서이런경우 SGLT2 억제제를추가하였을때는기존인슐린또는 Sulfonylurea 의용량을감량하는것을충분히고려하여야할것이다. 실제임상에서저혈당발생이문제가되는 Sulfonylurea 를활성대조군으로비교한임상에서 Dapagliflozin 은 10 배정도적은빈도로저혈당이발생하였다 [9]. Canagliflozin 또한그자체로는저혈당발생을증가시키지않으나 [10,11], 인슐린또는인슐린분비촉진제를병용하였을때는저혈당발생이증가하였다 [12,13]. 인슐린분비촉진제를병용한연구를제외한 Empagliflozin 의경우에도여러용량의치료에서저혈당발생의증가는없었다 [14-16]. 저혈당증상을느끼게되는혈중포도당농도이하로떨어지면, 남은 SGLT2 와 SGLT1 활성화를통해배설된포도당을다시재흡수하거나추가적인소실을막아줄수있기때문에 SGLT2 억제를통한저혈당의발생은흔치않지않으며, 흔히큰문제가되지않는다. 따라서, Table 1. Adverse events of special interest associated with sodium glucose cotransporter 2 (SGLT2) inhibitors. Study design Dapagliflozin Add-on to metformin (vs. placebo) Add-on to pioglitazone (vs. placebo) Add-on to glimepiride (vs. placebo) Add-on to metformin (vs. glipizide) Canagliflozin Add-on to metformin + sulfonylurea (vs. placebo) Monotherapy (vs. glimepiride) Monotherapy (vs. sitagliptin) Empagliflozin Add-on to metformin (vs. placebo) Add-on to metformin + pioglitazone (vs. placebo) Duration, wk Reference Hypoglycemia a, % [4] [5] [7] [6] [8] [9] [10] [12] [13] [20] [11] [14] [15] [16] [29] 0-3 (3) 2-4 (3) 0-2 (0) 7-8 (5) () 3.4 (39.7) 3-4 (3) (15) 49 (37) 5-6 (34) 43 (41) 0 (1.2) (0.5) 36.1 (35.3) (1.8) Genital infection a, % 8-13 (1) 8-13 (5) 7-8 (3) 4-7 (1) 6-11 (3) 12.3 (2.7) 6-7 (2) (3) 7-9 (1) 9-11 (5) 12 (2) (0) (0) (1.8) (2.4) Urinary tract infection a, % 5-13 (4) 4-8 (8) 4-8 (6) 4-7 (6) 8-11 (5) 5.9 (7.6) 5-7 (4) 6 (5) 2-3 (2) 6 (5) 4(6) (1.2) (4.9) (8.8) (16.4) 159 a Ranges are given for each SGLT2 inhibitor if available.

3 Focussed Issue - SGLT2 inhibitors SGLT1 의활성화는정상혈당이하로혈당이떨어지는것에대한안전장치일수있다. 현재개발중인 SGLT1 활성화를동시에가지고있는약제들에서는저혈당을방지할수있는이런효과를기대하기는힘들수있겠다. 심한경우는거의없었다 [4-7]. 방광에대한우려로 pioglitazone 과의병용을실제로아직고려하고있지않더라도, SGLT2 억제제사용에따른삼투성이뇨는 pioglitazone 사용에따른말초부종에도움이될것으로여겨진다. 2. 요로생식기감염 (Table 1) 4. 종양발생 160 SGLT 억제를통한소변으로의과다한포도당배설은요로감염의기회를증가시켜줄것이다. 소변의포도당은생식기진균들의성장을위한물질로사용될것으로생각되기때문에감염의기회가증가할것을생각된다. 위약군과비교하여 Dapagliflozin 을사용한대부분의연구에서생식기감염과관련한증상및증후의빈도는증가하였고, 요로감염의경우는일부연구에서증가함을보고하고있다 [4-6,8,9]. 생식기감염의경우, 특히여성에서흔히나타나는것으로알려져있으나, 대부분임상적으로큰문제를일으키지않으며일반적인항진균치료에잘치료되며, 이로인해약제를중단하는경우는매우드문것으로보고하고있다 [4,5]. 12 개의 Dapagliflozin 의 2 상및 3 상임상연구의통합분석 (pooled analysis) 에서미리기술된광범위한목록을가지고적극적인질문을통해확인한 의심되는사건 에비해 실제진단된사건 의빈도는낮았다 [17]. 또한이런생식기감염은증상을조기에발견하여예방적으로치료함에따라시간이지남에따라발생률이점차감소하는것같다. 요로감염의경우에는임상연구에따라다소차이를보이나전체적인발생률은약 1/3 까지보고되기도한다. 혈당조절이불량한환자에서는무증상세균뇨도드물지않다. SGLT2 억제제사용에따른요로감염원인세균의분포는일반인의요로감염과크게다르지않다고보고하고있다 [17]. 요로감염의경우에도표준치료제에잘반응하였고, 신우신염을포함한심한감염의위험성은증가하지않았다 [17-19]. Canagliflozin 과 Empagliflozin 임상에서도거의모든임상에서생식기감염의빈도는증가하나, 요로감염은일부연구에서증가하는것으로보고하고있다 [10-16,20]. 3. 체액량감소 소변으로포도당의과다한배설을통한삼투성이뇨로인해수분소실로인해탈수및저혈압으로인한문제가발생할수있을것으로여겨진다. Dapagliflozin 임상에서체액량감소에따른기립성저혈압의발생은위약군과비교하여차이가없었으며, 발생한경우에도 개발과정과전임상에서 Dapagliflozin 은돌연변이를유발하거나발암성특성을갖고있는것으로보이지않으며, 알려진 off-target effect 도가지고있지않은것으로알려져있으나 [21], 임상연구에서유방및방광암의발생이조금높게관찰되었다 [22]. Dapagliflozin 연구에서유방암은 10 명의환자에서발생하였고 ( 대조군, 3 명 ), 방광암이 9 예에서발생하였다 ( 대조군, 1 예 ). 이런암들은임상의초기에대부분발견되고대개진행한상태로발견되었다. 방광암이발생한대부분에서는기저상태에혈뇨가이미존재하고있어이런종양이 SLGT2 억제제사용이후새롭게발생하였다고보기힘든경우들이었다 [22]. 게다가, SGLT2 는인간의유방이나방광조직에서발견되지않는다 [23]. 고용량의장기간전임상연구들을통해판단해볼때, 지속적인고혈당에대한노출이요로상피에손상을유발하거나종양의발생을조장하였을가능성은매우낮아보인다. 임상기간동안보다관심을기울여부작용을관찰하게되고, 빠른체중감소로인해유방암의이른발견과배뇨의변화및혈뇨의발견등으로방광암을빨리발견하는계기를제공해주었을가능성도생각해볼수있다. 또한가족성신장성당뇨 (familial renal glucosuria) 환자들에서이런종양의발생을포함한요로계부작용의거의관찰되지않는다는점도약제의안전성을뒷받침해준다 []. 5. 골절 중등도신기능저하 ( 예측사구체여과율, ml/ min/1.73m 2 ) 가있는환자에서 Dapagliflozin 을장기간사용 (104 주 ) 한경우에골절이 13 예 (7.7%) 발생하였다 ( 위약군 0 예 )[25]. 이연구에서골절이증가한원인은아직명확하지않다. Dapagliflozin 군에서기저상태에신경병증과기립성저혈압을많이갖고있어, 많이넘어져발생하였을가능성을먼저고려할수있겠다. Dapagliflozin 을사용한신기능이정상이거나만성신부전 3A 를포함한연구들의통합분석에서골절의위험은증가하지않았다. 또한 Dapagliflozin 은정상또는경미한신기능저하를가지고있는당뇨병환자에서골

4 밀도와골대사의생화학지표에영향을미치지않았다 [26]. 하지만만성신부전 3B 이상의환자에서골밀도및골대사생화학표지자의변화에대한연구가아직없기때문에골절위험성증가에대한우려를갖고연구를진행하여야할것이다. 6. 특수상황에서안전성 고령에이미심혈관질환을갖고있는제 2 형당뇨병환자를대상으로 Dapaglifozin 10 mg 을 주간투여는혈당, 혈압및체중감소에효과를나타내면서저혈당의위험성이증가시키지않았고심혈관계안전성에악영향을미치지않았다 [27]. 중등도신기능저하 ( 예측사구체여과율, ml/min/1.73m 2 ) 가있는환자에서 Dapagliflozin (5 mg, 10 mg) 의장기간사용 (104 주 ) 은위약과비교하여전체적인부작용을증가시키지않았다 [25]. 신기능이정상인경우와유사하게요로감염의발생은위약군과비슷한빈도로발생하였으나, 생식기감염은증가하였다. 전해질장애나신기능의악화는드물었으나, 체액량감소에따른사건은좀더많이관찰되었다. 무엇보다이연구에서 Dapagliflozin 군이위약군에비해혈당조절의향상을보이지않았기때문에, 이런중등도신기능저하를동반한환자에서의사용은아직추천되지않을것으로보인다. 반면, 만성신질환 3 단계 ( 예측사구체여과율, ml/min/1.73m 2 ) 의제 2 형당뇨병을대상으로 canagliflozin 100 mg, 300 mg 을 26 주간사용하였을때는, 전반적인부작용발생은위약군과유의한차이없이비교적양호한편이었다 [28]. 이연구에서는위약군대비유의한혈당감소효과를보여주었다. 결론 최근여러임상연구를통해 SGLT2 억제제들은비교적큰부작용없이사용할수있을것으로기대된다. 여성에서생식기감염과신기능저하및고령에서의체액량저하에대한주의점을갖고주의깊게사용할필요가있겠다. 다양한기전을통해발병하는제 2 형당뇨병환자들에게기존약제와차별화된기전을가진약제를추가적으로사용할기회를가짐으로써제 2 형당뇨병환자의개별화된치료에한걸음더다가갈수있을것으로기대된다. 참고문헌 1. Jeon JY, Kim DJ, Ko SH, Kwon HS, Lim S, Choi SH, Kim CS, An JH, Kim NH, Won JC, Kim JH, Cha BY, Song KH; Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Current status of glycemic control of patients with diabetes in Korea: the fifth Korea national health and nutrition examination survey. Diabetes Metab J 2014;38: Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 2010;95: Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35: Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33: Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375: Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, -week, doubleblind, placebo-controlled trial. Diabetes Obes Metab 2011;13: Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012;35: Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 2012 Mar 20;156: Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, Parikh SJ. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, -week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34: Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 161

5 Focussed Issue - SGLT2 inhibitors 162 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15: Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Kawaguchi M, Canovatchel W, Meininger G. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a -week randomized trial. Diabetes Care 2013;36: Wilding JP, Mathieu C, Vercruysse F, Usiskin K, Deng L, Canovatchel W. Canagliflozin (CANA), a sodiumglucose co-transporter 2 inhibitor, improves glycemic control and reduces bodyweight in subjects with type 2 diabetes (T2D) inadequately controlled with metformin (MET) and sulfonylurea (SU) [abstract]. Diabetes 2012;61:A Matthew D, Fulcher GR, Perkovic V, de Zeeuw D, Mahaffey KW, Rosenstock J, Davies M, Capuano G, Desai M, Shaw W, Vercruysse F, Meininger G, Neal B. Efficacy and safety of canagliflozin, an inhibitor of sodium glucose cotransporter2, added on to insulin therapy with or without oral agents in type 2 diabetes [abstract]. Diabetologia 2012;55 (Suppl 1):S Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebocontrolled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab 2013;15: Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ; EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a -week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2014;37: Rosenstock J, Jelaska A, Wang F Kim G, Broedl U, Woerle HJ, Bajaj HS. Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated type 2 diabetes (T2DM). Can J Diabetes 2013;37:S Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27: Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs 2012;72: Shah NK, Deeb WE, Choksi R, Epstein BJ. Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. Pharmacotherapy 2012;32: Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382: Jones D. Diabetes field cautiously upbeat despite possible setback for leading SGLT2 inhibitor. Nat Rev Drug Discov 2011;10: Bailey CJ. Interpreting adverse signals in diabetes drug development programs. Diabetes Care 2013;36: Chen J, Williams S, Ho S, Loraine H, Hagan D, Whaley JM, Feder JN. Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther 2010;1: Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 2010;5: Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85: Ljunggren Ö, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD, Sugg J, Parikh S. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab 2012;14: Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a -week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc 2014;62: Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15: Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC; on behalf of the EMPA-REG PIO trial investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a -week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014;16:

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