Prevention of Diabetes and Hypertension

NCT00456963 | Terminated Phase 4 DMC

• 1 other identifier: 09A502
• Study Type: interventional
• Target: 3,000
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Diabetes Mellitus; Hypertension

Keywords

angiotensin converting enzyme inhibitors; angiotensin receptor blockers; diabetes; hypertension; therapeutic strategies

Outcome Measures

Primary Outcomes (2)

• Time to first event of: new diabetes or initiation of any antidiabetic treatment during the treatment period of the trial

• new hypertension or initiation of any antihypertensive treatment during the treatment period of the trial.

Secondary Outcomes (10)

• Time to first event (during the treatment phase) of: new diabetes or new hypertension, which comes first

• major cardiovascular events (myocardial infarction, stroke, cardiovascular death, heart failure, new documented angina,

• revascularization procedures ) plus death by non-cardiovascular causes

• variations of SBP and DBP during the treatment phase and, separately, during the withdrawal phase

• variations fasting blood glucose during the treatment phase and, separately, during the withdrawal phase

Study Arms (3)

Diet, exercise and Enalapril

EXPERIMENTAL

one Enalapril 10mg tablet and one Losartan placebo tablet once daily for four weeks. Subsequentely one Enalapril 20mg tablet and one Losartan placebo tablet once daily until the end of the randomized treatment phase. After this one Enalapril placebo tablet and one Losartan placebo tablet once daily for six months.

Behavioral: Diet; Behavioral: Moderate exercise; Drug: enalapril tablets

Diet, Exercise and Losartan

ACTIVE COMPARATOR

one Losartan 50mg tablet and one Enalapril placebo tablet once daily for four weeks. Subsequentely one Losartan 100mg tablet and one Enalapril placebo tablet once daily until the end of the randomized treatment phase. After this one Losartan placebo tablet and one Enalapril placebo tablet once daily for six months.

Behavioral: Diet; Behavioral: Moderate exercise; Drug: Losartan Tablets

Diet, exercise and Placebo

PLACEBO COMPARATOR

one Enalapril placebo tablet and one Losartan placebo tablet once daily until study end.

Behavioral: Diet; Behavioral: Moderate exercise; Drug: placebo tablets

Interventions

Diet BEHAVIORAL

total fat \< 5%, saturated fat \< 10%, vegetables, fruit

Diet, Exercise and Losartan; Diet, exercise and Enalapril; Diet, exercise and Placebo

Moderate exercise BEHAVIORAL

30 min at least 5 times/week

Diet, Exercise and Losartan; Diet, exercise and Enalapril; Diet, exercise and Placebo

enalapril tablets DRUG

one Enalapril 10mg tablet once daily for four weeks. Subsequentely one Enalapril 20mg tablet once daily until the end of the randomized treatment phase

Diet, exercise and Enalapril

placebo tablets DRUG

one Enalapril placebo tablet and one Losartan placebo tablet once daily until study end.

Diet, exercise and Placebo

Losartan Tablets DRUG

one Losartan 50mg tablet once daily for four weeks. Subsequentely one Losartan 100mg tablet once daily until the end of the randomized treatment phase.

Diet, Exercise and Losartan

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men or women of any racial background
• Age \>= 40 years and \<= 75 years
• SBP\>= 130 mmHg and \< 140 mmHg or DBP \>= 85 mmHg and \< 90 mmHg, average of screening and randomisation visits (in absence of any antihypertensive medication)
• FG \>=100 mg/dl (5.6 mmol/l) and \< 126 mg/dl (7.0 mmol/l) between screening and randomisation (in absence of any antidiabetic medication)
• Waist circumference \>= 102 cm in men and \>= 88 cm in women.

You may not qualify if:

• SBP \>= 140 mmHg or DBP \>= 90 mmHg
• Any antihypertensive, antidiabetic or antiobesity medication at the time of or during the 6 months previous to randomisation
• Any current or previous cardiovascular or renal disease requiring continuous administration of Ds, ßBs, ACEIs, ARBs, CAs, and any other antihypertensive medication
• Any medical condition preventing adherence to lifestyle measures included in the protocol
• Hepatic disease as AST (SGOT) or ALT (SGPT) values equal or greater than two times the upper limit of normal
• Chronic renal dysfunction as serum creatinine \> 2.0 mg/dl
• Any gastrointestinal disorder interfering with drug absorption
• Known allergy or contraindications to ACEIs or ARBs
• Pregnant or lactating women; women in reproductive age not using recognized contraceptive methods
• Malignancy within the last 5 years
• Clinically significant autoimmune disorders
• Drug abuse or alcohol abuse within the last 5 years
• History of noncompliance to medical regimens
• Incapacity or unwillingness to sign the informed consent
• Participation in any investigational clinical trial within the last 3 months

Sponsors & Collaborators

• Istituto Auxologico Italiano: lead
• Italian Society of Hypertension: collaborator
• Italian Society of General Practitioners: collaborator
• Yghea: collaborator

Study Sites (1)

Istituto Auxologico Italiano.

Milan, 20145, Italy

Location

Related Publications (23)

• 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.

  PMID: 12409940 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.

  PMID: 15983291 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.

  PMID: 16331092 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.

  PMID: 17240286 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.

  PMID: 15619390 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.

  PMID: 12714861 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.

  PMID: 11728544 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.

  PMID: 15238567 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.

  PMID: 12485966 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.

  PMID: 12777938 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.

  PMID: 11333990 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.

  PMID: 11832527 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.

  PMID: 15614015 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.

  PMID: 16997664 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.

  PMID: 16980380 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.

  PMID: 16986230 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.

  PMID: 12628950 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.

  PMID: 16365190 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.

  PMID: 17324743 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.

  PMID: 15076172 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.

  PMID: 12195132 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.

  PMID: 16794491 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.

  PMID: 12086760 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus; Hypertension

Interventions

Diet; Enalapril; Losartan

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena; Dipeptides; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Study Officials

• Alberto Zanchetti, MD

  Istituto Auxologico Italiano. Milan. Italy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2007
• First Posted: April 5, 2007
• Study Start: September 1, 2007
• Primary Completion: March 1, 2010
• Study Completion: March 1, 2010
• Last Updated: February 20, 2024

Record last verified: 2024-02

Locations

IT (1)