J Korean Diabetes 2018;19:140-146 Vol.19, No.3, 2018 ISSN 2233-7431, 가톨릭대학교의과대학여의도성모병원내분비내과 Pharmacological Intervention for the Prevention of Diabetes Mellitus Han-nah Joung, Hyuk-Sang Kwon Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Abstract Diabetes mellitus is rapidly increasing worldwide, especially in Africa and Asia. According to the Diabetes Fact Sheet in Korea 2018, the prevalence of diabetes in adults 30 years and older is 14.4% (5.01 million), indicating that nearly 1 in 7 Korean adults have diabetes. Another approximately 25% of adults 30 years and older (8.71 million people) have impaired fasting glucose, so-called prediabetes. Thus, 1 in 3 adults are diabetic or at risk for diabetes. The diabetic population is expected to reach approximately 6 million in 2050, representing two-fold growth over the next 40 years. Although the etiology of diabetes mellitus is multifactorial, obesity is suspected to be a main factor for the increasing prevalence in Korea. The average body mass index of diabetics is around 25 kg/m 2. Prevention is the best way to decrease the global burden of diabetes. Many trials on the prevention of type 2 diabetes mellitus (T2DM) have been performed. Lifestyle modification is one of the most powerful strategies for the prevention of T2DM, but medications are believed to be effective in certain populations. These preventive effects can vary according to ethnicity, sex, and genetic background. Although there is little evidence of potential pharmacotherapy for diabetes prevention in Korea, this lecture will review available medications in the context of T2DM prevention. Keywords: Diabetes, Prevention Corresponding author: Hyuk-Sang Kwon Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Korea, E-mail: drkwon@catholic.ac.kr Received: Aug. 13, 2018; Accepted: Aug. 14, 2018 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 2018 Korean Diabetes Association 140 The Journal of Korean Diabetes
정한나외 서론 최근서구화된생활습관과비만인구의급증으로전세계 적으로당뇨병이급증하고있다. 올해대한당뇨병학회에서발표한 Diabetes Fact Sheet in Korea 2018 [1] 에따르면 2016년기준으로 30세이상성인의 14.4% ( 약 501만명 ) 가당뇨병환자로, 당뇨병전단계상태인공복혈당장애인구는 30세이상성인의 25.3% ( 약 871만명 ) 였다. 따라서 2016 년기준당뇨병및공복혈당장애를보이는성인은총 1,372 만명으로추정되며향후당뇨병전단계가당뇨병으로진행할가능성이매우높은것을감안하면 당뇨병대란 이올것이라는추측이절대과장이아님을쉽게예상할수있다. 본고에서는이러한당뇨병대란을막기위한최선의방법인당뇨병예방에있어서약제의역할에대해최근까지발표된여러문헌을고찰하여각약제별로리뷰하고자한다. 메트포민 : 예방연구를통한효과 - 어느정도인가? 그기전은? 당뇨병예방약제로가장오래전부터시도되고많은연구결과를가지고있는약제가바로메트포민 (metformin) 이다. 사실메트포민은이미중세유럽에서항염증, 해열등을목적으로사용한 Galega officinalis 라는약용식물에서유래한약제로, 미국에서시행된당뇨병예방연구인 Diabetes Prevention Program (DPP) 연구 [2] 에서사용된이후전세계적으로도당뇨병예방목적으로가장많이시도되었으며그결과각종진료지침에서가장우선적으로추천되는당뇨병예방약제이다. 한편 1996년부터시작되었던 DPP 연구는 2001년종료이후에도연구에참여했던약 88% 의대상자를포함시킨 Diabetes Prevention Program Outcome Study (DPPOS) 연구 [3] 로연장되어메트포민의장기예방효과에대한귀중한정보를준바있다. 잘알려진바처럼 DPP 연구에서메트포민은위약군대비당뇨병발생을 31% 나유의하게감소시켰지만생활습관개선군의효과 (58%) 에는미치지못했다. 생활습관개선은성별, 연령, 체질량지수에관계없이 모두효과적이었는데, 메트포민투여와비교할때고령과체질량지수가낮을경우더효과적이었다. 반면메트포민은상대적으로체질량지수가높은군에서위약군에비해효과적이었다. DPP 연구에서사용되었던메트포민의용량은 850 mg 1일 2회투여로적지않은용량이었음에도연구기간중 70% 이상의복약순응도를나타냈다. 그러나위약군및생활습관개선군에비해서는월등히많은위장관계부작용을유발시켰다 (77.8% vs. 30.7% vs. 12.9%). 한편 DPPOS 연구는 DPP 연구종료후 10년및 15년추적결과까지발표되었는데생활습관개선군은각각 34%, 27% 의당뇨병발생감소, 메트포민군은각각 18%, 18% 의예방효과를보여주었다 [3]. 특히 DPPOS 연구종료시점까지당뇨병이발생하지않은군은연구시작전에비해평균 7% 의체중감량을유지한것으로분석되어당뇨병예방을위해서는약제복용여부와상관없이적어도 7% 이상의체중감량을목표로해야한다는일종의마지노선을제공한셈이다. 실제로도메트포민의당뇨병예방효과의절반이상이체중감량에의한인슐린감수성개선이었다는연구결과가있었기때문에결국체중감량이당뇨병예방의핵심이라고말할수있겠다. 메트포민 : 당뇨병을예방함으로써합병증을줄일수있을까? 중단해도효과가지속되나? 과연생활습관개선군보다우월하진않았지만대조군에비해유의하게당뇨병발생을감소시킨메트포민의당뇨병예방효과는당뇨병성만성합병증의발생감소로이어질까? 이역시 DPPOS 연구를통해확인된바에의하면메트포민군이나생활습관개선군, 그리고대조군간미세혈관합병증의유병률은차이가없었다 [4]. 다만당뇨병이발생하지않은경우발생군에비해미세혈관합병증유병률이 22% 유의하게낮았다 (P < 0.001). 또한여성의경우는생활습관개선군 (8.7%), 메트포민군 (11.2%), 위약군 (11.2%) 의순서로생활습관개선군이 21~22% 가량유의하게미세혈관합병증유병률이낮았다. 즉메트포민은당뇨병발생은감소시켰지만미세혈관합병증을줄이지는못했다. 그러면메트포민을 www.diabetes.or.kr 141
중단해도당뇨병예방효과가지속될까? DPP 연구에서는당뇨병예방효과가약물에의한일시적인억지효과인지를확인하기위해연구종료시점에서메트포민투여를중단한후 1~2주에경구당부하검사를시행하여재확인하도록하였더니첫분석상 31% 의당뇨병발생감소효과가다소경감되어 25% 로나타났다 [5]. 한편내당능장애환자를대상으로한메트포민군 (500 mg 1일 2회 ) 20명, 위약군 20명의소규모연구에서는메트포민중단후에도약 6개월까지당불내성개선효과가관찰되었다고보고한바있다 [6]. TZD: 강력한당뇨병예방효과 당뇨병예방약제중가장강력한효과를보여준약제로는티아졸리딘디온 (thiazolidinediones, TZDs) 을빼놓을수없다. 대표적인인슐린저항성개선제인 TZD는인슐린감수성을높임으로써인슐린분비를최소화시키면서소위 β-cell rest 의기전으로당뇨병을예방하는것으로알려져있다. 즉메트포민의대부분의당뇨병예방효과가앞서체중감량효과에서기인된다고하였는데 TZD를복용하면오히려체중증가가되지만인슐린감수성이개선되면서인슐린분비능도호전되는것이다. 우선 TRoglitazone In Prevention Of Diabetes (TRIPOD) 연구 [7] 에서는 236명의임신성당뇨병병력을가진여성을대상으로하여트로글리타존 (troglitazone) 을 1일 400 mg 복용시킨결과위약군에비해 55% 의당뇨병발생예방효과를관찰하였다 ( 발생위험도 [hazard ratio, HR] 0.45, 95% confidence interval [CI] 0.25~0.83; P = 0.009). 또한앞서소개한 DPP 연구에서도사실트로글리타존투여군이배정되었는데위약군대비 75% 의당뇨병발생감소효과를나타내었다 (P < 0.001) [8]. 한편로시글리타존 (rosiglitazone) 을투여하여당뇨병발생여부를관찰한 Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) 연구 [9] 에서는로시글리타존이위약군대비 60% 의당뇨병발생감소를나타내었다 (HR 0.40, 95% CI 0.35~0.46; P < 0.0001). 또다른 TZD 계열약제인피오글리타존 (pioglitazone) 을이용한 ACTos NOW for the Prevention of Type 2 Diabetes (ACT NOW) 연구 [10] 에서도피오글리타존투여는위약군에비해 72% 의당뇨병발생감소 (HR 0.28, 95% CI 0.16~0.49; P < 0.05) 를시켰을뿐아니라정상내당능상태로 48% 더많이회귀시켰다. 최근에뇌경색병력이있는인슐린저항성을동반한비당뇨병환자를대상으로피오글리타존을투여하였던 Insulin Resistance Intervention after Stroke (IRIS) 연구 [11] 에서도당뇨병발생을위약군대비 52% 감소시킨바있다 (HR 0.48, 95% CI 0.33~0.69; P < 0.001). TZD: 중단해도효과가지속되나? 당뇨병성만성합병증을줄일수있을까? 앞선메트포민에서도그랬지만당뇨병예방을위해사용한 TZD를중단하더라도예방효과가지속될까? TZD 가만약베타세포기능부전과같은근본적인제2형당뇨병의병인을교정시켜서 50~70% 의예방효과를보였다면중단후에도어느정도는그효과가지속되어야한다. 우선 TRIPOD 연구에서는약제중단후 8개월까지도당뇨병예방효과가 50% 까지보였다 [7]. 또다른 TZD 예방연구인 DREAM 연구에서는약제중단후대략 71일쯤에당뇨병발생을비교해보니로시글리타존군과위약군이같았다 ( 각각 10.6% vs. 9.8%) [12]. DPP 연구에서도트로글리타존이약 0.9년후당뇨병의발생을 75% 감소시켰지만중단후 3년뒤에는위약군과의발생률에서차이가없었다 [8]. 즉, 메트포민보다는중단후효과가더오래지속되지만결국 TZD에의한당뇨병예방효과를유지하기위해서는계속투약해야하는것이다. 한편당뇨병전단계에서 TZD를투여할경우당뇨병성만성합병증을줄일수있을지에대한해답은최근발표된 IRIS 연구 [11] 에서찾아볼수있는데, 뇌경색병력이있는인슐린저항성을동반한비당뇨병환자에서피오글리타존을투여한결과뇌경색혹은심근경색의발생을위약군대비 25% 감소시켰다 (HR 0.76, 95% CI 0.32~0.93; P = 0.007). 142
정한나외 글루카곤양펩티드 -1 수용체작용제 주요인크레틴인글루카곤양펩티드-1 (glucagon-like peptide-1, GLP-1) 이 dipeptidyl peptidase-4 에의해분해되는것을막기위한치료제인글루카곤양펩티드-1 수용체작용제 (GLP-1 receptor agonists, GLP-1 RAs) 는전임상혹은임상연구를통해베타세포의기능개선에기여하는것으로알려져있다. 그중하나인리라글루타이드 (liraglutide) 3.0 mg을비만한당뇨병전단계환자에게투여하여당뇨병진행을억제하는지를관찰한 SCALE Obesity and Prediabetes 연구 [13] 결과제2형당뇨병발생시기를위약군에비해 2.7배정도연장시켰는데, 이를 HR로환산하게되면 79% 감소효과로분석되었다 (HR 0.21, 95% CI 0.13~0.34). 한편정상내당능으로회귀하는비율도 3.6배가더많았다 (odds ratio 3.6, 95% CI 3.0~4.4; P < 0.001). 이때리라글루타이드투여후인슐린분비능과감수성변화결과를보면인슐린저항성지수 (HOMA-IR) 는위약군대비 15% 가유의하게감소하였고췌장베타세포분비기능지수 (HOMA-β) 와 disposition index는각각 18%, 20% 가유의하게증가한것으로나타났다. 한편리라글루타이드 3.0 mg 은아니지만 1.8 mg을투여하여대조군과당뇨병만성합병증의발생정도를비교한 LEADER 연구 [14] 에서는리라글루타이드가뇌경색, 심근경색및심혈관사망을종합하여 13% 의발생을유의하게감소시켰고, 심혈관사망률만따로봤을때에도 22% 의유의한감소를나타낸바있다. 또한미세혈관합병증에있어서도당뇨병성신증의발생을 22% 유의하게감소시켜당뇨병전단계에서도당뇨병성만성합병증의발생을감소시킬수있을것으로기대되고있다. 알파글루코시다제억제제 위장관계부작용과상대적으로경미한혈당강하능, 그리고하루최대 3회복용해야하는복용불편성등으로특히서양에서는많이사용되지않고있는알파글루코시다제억제제 (alpha-glucosidase inhibitor) 는탄수화물흡수를억 제하기때문에쌀을주식으로하는아시아인종에서는앞선 TZD, GLP-1 RAs만큼당뇨병예방효과가우수할수있다는예상을해볼수있겠다. 실제로아카보스 (acarbose) 를투여하였던 Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) 연구 [15], Chinese Diabetes Prevention Trial [16] 및 Early Diabetes Intervention Trial (EDIT) 연구 [17], 그리고일본인을대상으로보글리보스 (voglibose) 를투여하였던당뇨병예방연구 [18] 에서각각대조군대비 36%, 88%, 34% 및 40.5% 의유의한당뇨병발생감소를보여주었다. 모든당뇨병약제는당뇨병예방효과를가지나? 지금까지소개한약제는모두당뇨병약제로서정도의차이는있지만모두당뇨병발생을감소시키는예방효과를가졌다. 그렇다면혈당을떨구는당뇨병약제는모두당뇨병예방효과를가질까? Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) 연구 [19] 는 2 2 연구디자인을가진무작위대조임상연구로서식후혈당개선제인나테글리나이드 (nateglinide) 를투여했을때당뇨병및심혈관질환을예방할수있는지보기위함이었다. 그러나같은식후혈당개선제인아카보스가 STOP-NIDDM 연구에서당뇨병예방효과를보여준데비해나테글리나이드는당뇨병발생을감소시키지못했을뿐만아니라저혈당의빈도만유의하게증가시켰다. Outcome Reduction With Initial Glargine Intervention (ORIGIN) 연구 [20] 는당뇨병전단계혹은당뇨병초기환자를대상으로글라진인슐린을투여하여공복혈당을철저히낮추어주면심혈관질환도예방되고당뇨병의발생도늦추지않겠냐는가정하에시작한연구로서결과적으로대조군에비해 28% 유의한감소를나타냈다. 하지만각종저혈당의빈도가글라진인슐린군에서약 3배가량유의하게증가하였고대조군이약 0.5 kg의체중증가를보여준데비해글라진인슐린군에서는 1.6 kg의체중증가를나타냈다. www.diabetes.or.kr 143
당뇨병예방을위한가장좋은방법은? 미국임상내분비학회 [21] 에서는당뇨병전단계에서당뇨병발생을예방하기위한목적으로약제를선택할경우메트포민과아카보스는약 25~30% 정도의당뇨병발생감소효과를가지고있다고밝히고있다. 반면 TZD의경우는 60~75% 의강력한당뇨병예방효과를가지고있고 GLP- 1 RAs 역시좋은효과를보여준바있어당뇨병발생위험도가보다높은환자에서처방할것을권고하고있다. 즉당뇨병전단계환자도위험도에따라약제를선택하도록하였다. 실제로각종당뇨병예방수단들에대해중단이후에도장기간효과가지속되는지를메타분석한연구결과 [22] 에따르면식생활습관개선안에서는연구종료후 5~9년간의추적관찰이후에도당뇨병예방효과가지속된데비해약제는중단후짧게는 2주에서많게는 1년간의추적관찰이후에대부분의약제가예방효과를소실하는것으로밝혀졌다. 따라서현재로서는당뇨병예방을위해서가장좋은방법은체중감량을목표로한식생활습관개선 ( 규칙적인유산소운동포함 ) 이되겠다. 당뇨병약제는결국복용하는동안에만당뇨병발생이억제되는것이므로식생활습관개선에도불구하고당뇨병발생위험도가지속적으로증가하는고위험군에한해서만사용하는것이좋겠다. 만약사용한다면어떤약제가좋을지에대해서는결국국내당뇨병전단계환자에서당뇨병예방연구를통해서확인해야할것이다. REFERENCES 1. Korean Diabetes Association. Diabetes fact sheet in Korea 2018. Seoul: Korean Diabetes Association; 2018. p6-11. 2. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. 3. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R, Venditti E, Nathan DM. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677-86. 4. Diabetes Prevention Program Research Group. Longterm effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015;3:866-75. 5. Diabetes Prevention Program Research Group. Effect of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care 2003;26:977-80. 6. Lehtovirta M, Forsén B, Gullström M, Häggblom M, Eriksson JG, Taskinen MR, Groop L. Metabolic effects of metformin in patients with impaired glucose tolerance. Diabet Med 2001;18:578-83. 7. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-803. 8. Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, Walker EA, Fowler SE, Nathan DM, Kahn SE; Diabetes Prevention Program Research Group. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 2005;54:1150-6. 9. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the 144
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