Prevention of Diabetes and Hypertension

Summary

Background. Antihypertensive therapy with ß-blockers (ßBs) and diureticts (Ds) is accompanied by a higher incidence of diabetes mellitus (DM) than therapy with ACE-inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs). Whether this difference is due to an antidiabetogenic action of ACEIs and ARBs or to the fact that these agents are free of the diabetogenic activity of ßBs and Ds is unknown. Prevention of DM as well as of HT is of primary health concern. Objectives. The primary objective of PHIDIAS is to test whether in individuals with components of metabolic syndrome making them predisposed to DM and HT, addition of either an ACEI or an ARB to periodically reinforced lifestyle counselling can reduce 1) onset of DM and 2) onset of HT significantly more than lifestyle plus placebo. Secondary objectives are 1) comparing the antidiabetogenic effects of ACEI and ARB, and 2) investigating whether the effects of ACEI and ARB on DM and HT persist at least 6 months after treatment withdrawal. Methods. PHIDIAS is a prospective, double-blind, placebo-controlled 3-arm comparison trial. 300 general practitioners (members of SIMG with the assistance of hospital centres of SIIA) will randomise 6000 untreated individuals aged 40-75 years, with SBP 130-139 or DBP 85-89 mmHg, fasting glucose (FG) 100-125 mg/dl, waist circumference \>= 102 (M) or \>= 88 cm (W), to three blinded treatments, given in addition to lifestyle advise: 1) Placebo; 2) the ACE Enalapril (10 mg, then 20 mg od); 3) the ARB Losartan (50 mg, then 100 mg od).Double-blind treatment will be maintained until 500 cases of DM are observed (presumably average of 36 months) (Treatment Phase: control visits, BP, FG every 6 months). This will be followed by a 6-month Withdrawal Phase (active treatment substituted by placebo). Primary outcomes are DM (FG \>= 126 mg/dl) and HT (SBP \>= 140 or DBP \>= 90 mmHg) on 2 consecutive visits. PHIDIAS will be governed by a Steering Committee assisted by a blinded Event Adjudicating Committee and an independent DMSB. Expected results. The sample size is adequate (alfa 5%, power 90%) to evaluate whether incident DM (expected rate 3.5%/year) or incident HT is reduced 25% by ACEI and ARB versus placebo (primary hypothesis) and whether either the ACEI or the ARB reduces incident DM by 30% more than the other agent.

Timeline

Start

2007-09

Primary completion

2010-03

Completion

2010-03

Publications

• Background Zanchetti A, Ruilope LM. Antihypertensive treatment in patients with type-2 diabetes mellitus: what guidance from recent controlled randomized trials? J Hypertens. 2002 Nov;20(11):2099-110. doi: 10.1097/00004872-200211000-00001.
• Background Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, Woodward M, MacMahon S; Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005 Jun 27;165(12):1410-9. doi: 10.1001/archinte.165.12.1410.
• Background Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006 Jan;24(1):3-10. doi: 10.1097/01.hjh.0000194119.42722.21.
• Background Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007 Jan 20;369(9557):201-7. doi: 10.1016/S0140-6736(07)60108-1.
• Background Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR; SHEP Collaborative Research Group. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005 Jan 1;95(1):29-35. doi: 10.1016/j.amjcard.2004.08.059.
• Background Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003 May;21(5):875-86. doi: 10.1097/00004872-200305000-00011.
• Background Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet. 2001 Nov 17;358(9294):1682-6. doi: 10.1016/S0140-6736(01)06710-1.
• Background Julius S, Nesbitt S, Egan B, Kaciroti N, Schork MA, Grozinski M, Michelson E; TROPHY study group. Trial of preventing hypertension: design and 2-year progress report. Hypertension. 2004 Aug;44(2):146-51. doi: 10.1161/01.HYP.0000130174.70055.ca. Epub 2004 Jul 6.
• Background National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 Dec 17;106(25):3143-421. No abstract available.
• Background European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003 Jun;21(6):1011-53. doi: 10.1097/00004872-200306000-00001. No abstract available.
• Background Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001 May 3;344(18):1343-50. doi: 10.1056/NEJM200105033441801.
• Background 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 Feb 7;346(6):393-403. doi: 10.1056/NEJMoa012512.
• Background Kurtz TW, Pravenec M. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. J Hypertens. 2004 Dec;22(12):2253-61. doi: 10.1097/00004872-200412000-00003.
• Background 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 frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006 Sep 23;368(9541):1096-105. doi: 10.1016/S0140-6736(06)69420-8.
• Background DREAM Trial Investigators; Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G, Diaz R, Avezum A, Lanas F, Probstfield J, Fodor G, Holman RR. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006 Oct 12;355(15):1551-62. doi: 10.1056/NEJMoa065061. Epub 2006 Sep 15.
• Background Deedwania PC, Schmieder R. Angiotensin receptor blockers: Cardiovascular protection in the metabolic syndrome. J Renin Angiotensin Aldosterone Syst. 2006 Jun;7 Suppl 1:S12-8. doi: 10.3317/jraas.2006.018.
• Background Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif JC; Studies Of Left Ventricular Dysfunction. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation. 2003 Mar 11;107(9):1291-6. doi: 10.1161/01.cir.0000054611.89228.92.
• Background Schupp M, Lee LD, Frost N, Umbreen S, Schmidt B, Unger T, Kintscher U. Regulation of peroxisome proliferator-activated receptor gamma activity by losartan metabolites. Hypertension. 2006 Mar;47(3):586-9. doi: 10.1161/01.HYP.0000196946.79674.8b. Epub 2005 Dec 19.
• Background Cuspidi C, Meani S, Valerio C, Sala C, Fusi V, Zanchetti A, Mancia G. Age and target organ damage in essential hypertension: role of the metabolic syndrome. Am J Hypertens. 2007 Mar;20(3):296-303. doi: 10.1016/j.amjhyper.2006.09.010.
• Background Niklason A, Hedner T, Niskanen L, Lanke J; Captopril Prevention Project Study Group. Development of diabetes is retarded by ACE inhibition in hypertensive patients--a subanalysis of the Captopril Prevention Project (CAPPP). J Hypertens. 2004 Mar;22(3):645-52. doi: 10.1097/00004872-200403000-00029.
• Background Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman JM, Snapinn S; LIFE study group. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens. 2002 Sep;20(9):1879-86. doi: 10.1097/00004872-200209000-00035.
• Background Kjeldsen SE, Julius S, Mancia G, McInnes GT, Hua T, Weber MA, Coca A, Ekman S, Girerd X, Jamerson K, Larochelle P, MacDonald TM, Schmieder RE, Schork MA, Stolt P, Viskoper R, Widimsky J, Zanchetti A; VALUE Trial Investigators. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens. 2006 Jul;24(7):1405-12. doi: 10.1097/01.hjh.0000234122.55895.5b.
• Background Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002 Jun 15;359(9323):2072-7. doi: 10.1016/S0140-6736(02)08905-5.

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