J Korean Diabetes 2019;20:1-5 Vol.20, No.1, 2019 ISSN 2233-7431 설상훈인제대학교의과대학해운대백병원심장내과 Heart Failure: Complications of Type 2 Diabetes Sang-Hoon Seol Division of Cardiology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea Abstract There is a close relationship between diabetes mellitus and heart failure, both of which are known to increase morbidity and mortality. Diabetes can cause or aggravate heart failure, and heart failure can precipitate diabetes. Diabetes mellitus causes structural and functional changes in the heart, such as fibrosis of the myocardium and left ventricular dysfunction. The mechanisms of diabetic cardiomyopathy are metabolic disturbance, myocardial fibrosis, microvascular disease, and autonomic dysfunction. Improper blood glucose control leads to deterioration of heart failure, but the role of strict glycemic control in reducing heart failure is unclear. The role of SGLT2 inhibitors in reducing the incidence of heart failure is of great importance in the treatment of diabetic patients. However, further long-term follow-up and safety studies are needed. Keywords: Diabetes complication, Heart failure 서론 당뇨병은전세계적으로증가하고있는당의대사장애를 특징으로하는질환이다. 심부전은다양한병인과임상적인 양상을나타내는증후군이며사망률이높은질환이다. 당뇨병은관상동맥질환이나고혈압과관계없이심부전발생의위험을증가시키며, 심근증의원인이되기도한다. 심부전도아직명확한원인이밝혀지진않았지만포도당대 Corresponding author: Sang-Hoon Seol Division of Cardiology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, 875 Haeun-daero, Haeundae-gu, Busan 48108, Korea, E-mail: hacemed@hanmail.net Received: Jan. 12, 2019; Accepted: Feb. 1, 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright c 2019 Korean Diabetes Association The Journal of Korean Diabetes 1
사에부정적인영향을미칠수있다. 심부전과당뇨병은흔히동반되고, 사망률을증가시키므로각각질환의병리학적인측면과영향을이해하고적절한조기진단및효과적인약물치료가필요하겠다. 적인변화를일으킨다. 심실기능의변화는초기에는좌심실이완기장애가있으며증상이없는심부전을동반한경우도많이있다. 하지만후기에는수축기심부전으로진행된다 (Fig. 1). 본론 3. 진단 1. 역학당뇨병환자에서심부전의유병률은 20% 전후로나타난다 [1]. 발병률은 Framingham 연구에의하면정상인에비해 2.4배, 특히여성인경우에는 5.1배까지증가한다 [2]. 2 형당뇨병에서심부전의주요위험인자는관상동맥질환과고혈압이지만당뇨병자체도심근에악영향을줄수있다. 당뇨병에서심부전의발생을증가시키는원인은추가적으로고령, 당뇨병의유병기간, 인슐린사용유무, 미세단백뇨, 신부전, 부적절한혈당조절, 말초혈관질환이있다 [3]. 역학연구에서당뇨병은수축기심부전이외에도이완기심부전을일으킬수도있다. 당뇨병성심근증은고혈압이나관상동맥질환, 판막질환과같은구조적인심장질환이없이심장기능이감소한것으로정의한다. 당뇨병성심근증환자는반복적인심부전으로인한입원및입원기간의증가와관련이있으며사망률도높다 [4]. 당화혈색소증가와부적절한혈당조절이심부전의악화와관련된연구는있으나, 아직까지적극적인혈당조절이심부전의발생을감소시킨다는연구는없다 [5]. 2. 기전및병태생리심근에대한인슐린저항성증가, 고혈당및지방산의이용증가로인한대사이상, 심근섬유화, 내피세포하증식과혈관주위섬유화로인한미세혈관질환, 자율신경이상으로인한맥박의변이성감소, renin-angiotensin-aldosterone system (RASS) 이상, 부적절한면역반응이있다 [6]. 당뇨병성심근증은심장의구조적인변화 ( 심근섬유화 ) 와기능 심부전의진단은임상증상과심장초음파의역할이중요하다. 하지만초기에는증상이없는경우도많으며, 심장초음파는심장의구조적및기능적인이상을판단하는중요한검사법으로도플러및 strain 같은다양한기법을이용한다 [6]. 추가적으로 brain natriuretic peptide가도움이되지만나이, 비만, 신기능등에영향을받는다 [7]. 4. 심부전치료에서당뇨병에대한영향심부전을가진당뇨병환자에서심혈관약물을이용한무작위임상연구는아직까지진행되지않았지만당뇨병에관계없이예후를향상시키는것으로알려져있다 [8]. 베타차단제와앤지오텐신전환효소 (angiotensin converting enzyme) 억제제는심부전환자의사망률과입원율을감소시켰다. 앤지오텐신수용체억제제는당뇨병과상관없이심부전환자에서비슷한효능을가지고있다. 베타차단제는당뇨병의악화와인슐린저항성을증가시킬수있지만특별한문제가없으면반드시사용해야하는약제이다. 최근에개발된 carvedilol, nebivolol 같은약제는상대적으로부작용이적다. 이뇨제중 thiazide는인슐린저항성이증가될수있고, 미네랄코르티코이드약제는특히좌심실수축기능이저하된환자에서효과가있으나당뇨병성신증이동반한경우에전해질과신기능을관찰해야한다. 5. 심부전과당뇨병을동반한환자에서당뇨병약물치료초기당뇨병성심근증은미세혈관의구조와기능의이상으로인해발생하므로혈당의조절이도움이될수도있 2
설상훈 다. 적극적인혈당조절은미세혈관합병증을감소시킬수는있으나, 대혈관합병증을감소시킨다는연구는없다. Metformin과 sulfonylurea는심부전환자에서대부분안전하게사용할수있다. 하지만 thiazolidinedione은체액의증가를가져올수있기때문에체중의변화와부종여부를반드시관찰하면서사용하여야한다. DPP4 억제제는저혈당의위험을획기적으로낮추고최근가장많이사용되는약제이다. 심혈관사건위험의증가와무관하지만심부전에대해서는약제에따라다른결과를보였다. Saxagliptin 의 SAVOR-TIMI 53 연구에서심혈관사망, 심근경색, 뇌졸중의발생은차이가없었으나심부전으로인한입원율은 1.27배높았다 [9]. Alogliptin과 sitagliptin의연구에서는심부전의발생증가는보이지않았다 [10,11]. 최근 linagliptin을사용한 CARMELINA 연구에서도심부전으로인한입원율이증가되지않아 DPP4 억제제가심부전발생위험을증가시킨다는아직명확한근거는없는상태이다 [12]. 비슷한인크레틴계열약제인 GLP-1 agonist 도장기간데이터는없지만, 심부전에대한영향을미치지는않았다 [13]. SGLT2 억제제는췌장과는무관하게콩팥에서당과 sodium의재흡수를억제하고소변으로배출을증가시켜혈당저하와혈압을감소시킨다. EMPA-REG OUTCOME (empagliflozin) 과 CANVAS (canagliflozin) 연구는 SGLT2 억제제군에서심혈관사건의감소를보였고특히심부전으로인한입원이감소하였다 [14,15]. 최근에발표된 dapagliflozin을사용한 DECLARE TIMI-58 연구에서는심혈관질환뿐만아니라위험성을가진환자에서도 Fig. 1. Pathophysiological mechanisms of diabetes mellitus and heart failure. Adapted from the article of Lee and Kim. (Korean J Intern Med 2017;32:404-21) [5] with original copyright holder permission. RAAS, renin-angiotensin-aldosterone system; AGE, advanced glycation end product; FA, fatty acid; TGF-β, transforming growth factor-β. www.diabetes.or.kr 3
심부전으로인한입원의감소를보여 SGLT2 억제제의심부전에대한효과는더욱더의미가있다 [16]. 하지만하부요로감염의위험성과빈도는낮지만당뇨병성케톤증발생의위험이있기때문에주의가필요하겠다. 결론 당뇨병은다양한기전으로심장의구조적및기능적감소를가져온다. 심부전을포함한여러심혈관질환의발병을높이고사망률을증가시킨다. 부적절한혈당조절은심부전의악화를가져온다. 하지만심부전감소에대한엄격한혈당조절의역할은아직불분명하다. 최근심부전의발생감소에대한 SGLT2 억제제의역할이상당한의미가있지만장기적인추적관찰과안정성에대한주의가필요한상태이다. REFERENCES 1. Rydén L, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Packer M, Poole-Wilson PA. Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J 2000;21:1967-78. 2. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974;34:29-34. 3. Wang Y, Negishi T, Negishi K, Marwick TH. Prediction of heart failure in patients with type 2 diabetes mellitusa systematic review and meta-analysis. Diabetes Res Clin Pract 2015;108:55-66. 4. Cubbon RM, Adams B, Rajwani A, Mercer BN, Patel PA, Gherardi G, Gale CP, Batin PD, Ajjan R, Kearney L, Wheatcroft SB, Sapsford RJ, Witte KK, Kearney MT. Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diab Vasc Dis Res 2013;10:330-6. 5. Lee WS, Kim J. Diabetic cardiomyopathy: where we are and where we are going. Korean J Intern Med 2017;32:404-21. 6. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 2004;25:543-67. 7. Epshteyn V, Morrison K, Krishnaswamy P, Kazanegra R, Clopton P, Mudaliar S, Edelman S, Henry R, Maisel A. Utility of B-type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients with diabetes. Diabetes Care 2003;26:2081-7. 8. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 2016;69:1167. 9. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, Udell JA, Mosenzon O, Im K, Umez- Eronini AA, Pollack PS, Hirshberg B, Frederich R, Lewis BS, McGuire DK, Davidson J, Steg PG, Bhatt DL. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 2015;132:e198. 10. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35. 11. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, 4
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