Prevention of Cardiovascular Complications in Diabetic Patients With Vitamin E Treatment

Condition(s) targeted: Diabetes; Myocardial Infarction; Cardiovascular Disease

Intervention: Natural source Vitamin E 400IU/day (Drug)

Phase: Phase 2/Phase 3

Status: Terminated

Sponsored by: Technion, Israel Institute of Technology

Official(s) and/or principal investigator(s):
Uzi Milman, MD, Principal Investigator, Affiliation: Clalit Health Services
Chen Shapira, MD, Study Chair, Affiliation: Clalit Health Services
Shany Blum, MD MSc, Study Chair, Affiliation: Laboratory of Vascular Medicine, the Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology.
Andrew P Levy, MD PhD, Study Chair, Affiliation: Laboratory of Vascular Medicine, the Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology.

The purpose of this study is to determine whether Vitamin E treatment to Diabetic patients, who carry the Haptoglobin 2-2 Phenotype, prevents cardiovascular complications such as acute MI and Stroke.

Official title: Prevention of Diabetic Cardiovascular Complications With Vitamin E 400 IU Treatment to High Risk Patients by Haptoglobin Phenotype (I CARE – Israel Cardiovascular Atherosclerosis Risk and Vitamin E)

Study design: Interventional, Prevention, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: A combination of CVD mortality non fatal MI and Stoke at a 4 year follow up.

Secondary outcome:

Cardiac Interventions (Angioplasty, Bypass surgery

etc…), all cause mortality, heart failure, at a 4 year follow up.

Detailed description: Haptoglobin is a free Hemoglobin scavenger protein. Hemoglobin is an oxidant due to the Fe it carries by the Fenton reaction. Thus it is believed that Haptoglobin is an antioxidant, especially in the site of vascular injury.

Haptoglobin has three phenotype easily identified by a method of gel electrophoresis.

The three phenotype denote as 1-1, 2-1 and 2-2. We have found in several in vitro studies in our lab that Haptoglobin 1-1 is a superior antioxidant over 2-2.

In several large retrospective studies we found that Diabetic patients who are Haptoglobin typed 2-2 have a 5 time risk of having cardiovascular complications (acute MI, CVA, CVD death) over the ones who are Haptoglobin 1-1.

2-1 patients are probably at intermediate risk. While retrospectively typing consecutive serums from patients who participate the HOPE study we found that taking Vitamin E decreased by 50% the CVD incidences of Diabetic patients with the Haptoglobin 2-2 phenotype.

Based on these findings we wish to perform the I CARE study. 5000 diabetic patients aged 55 and above, will be tested for Haptoglobin phenotype.

Knowing the distribution of the different Haptoglobin phenotypes in the Israeli population we estimate that about 2000 will be of the phenotype 2-2.

These 2000 patients will be enrolled in a prospective, doubled blind, randomized and placebo controlled clinical study and will be randomly divided into 2 groups, one receiving Vitamin E 400IU per day and the other receiving matching placebo.

All patients will be followed routinely by their primary physicians in Clalit HMO (the biggest HMO in Israel) in a routine diabetes follow up and treatment (HbA1c, blood pressure control, Lipids, renal function, eye exam for retinopathy etc…) The study steering committee will get anamnestic data and routine tests results every 3 months.

Primary Outcomes: a combination of CVD mortality and non fatal MI and Stroke. Secondary Outcomes: Cardiac Interventions (Angioplasty, Bypass surgery etc…), all cause mortality, heart failure.

Exclusion criteria: 1) patient who takes antioxidant treatment will be asked to stop, or can't be included in the study.

2) Patients who had a CVD incident (MI, Stroke, TIA), Unstable angina pectoris, Uncontrolled HTN, will have to wait a month after stabilization to be included in the study.

3) Allergy to Vitamin E. Follow up duration – 4. 5 years. 5% percent of all vitamin receivers will be tested at base line and a year after enrollment, for Vitamin E plasma concentration.

Minimum age: 55 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Diabetic patients aged 55 and above

Exclusion Criteria:

- Patient who takes antioxidant treatment will be asked to stop, or can't be included in the study

- Patients who had a CVD incident (MI, Stroke, TIA), Unstable angina pectoris, Uncontrolled HTN, will have to wait a month after stabilization to be included in the study

- Allergy to Vitamin E

Clalit Health Services, Haifa and West Galilee - primary health care clinics, in the north of Israel And the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel., Haifa, Israel

Related publications:

Melamed-Frank M, Lache O, Enav BI, Szafranek T, Levy NS, Ricklis RM, Levy AP. Structure-function analysis of the antioxidant properties of haptoglobin. Blood. 2001 Dec 15;98(13):3693-8.

Levy AP, Roguin A, Hochberg I, Herer P, Marsh S, Nakhoul FM, Skorecki K. Haptoglobin phenotype and vascular complications in patients with diabetes. N Engl J Med. 2000 Sep 28;343(13):969-70. No abstract available.

Nakhoul FM, Marsh S, Hochberg I, Leibu R, Miller BP, Levy AP. Haptoglobin genotype as a risk factor for diabetic retinopathy. JAMA. 2000 Sep 13;284(10):1244-5. No abstract available.

Nakhoul FM, Zoabi R, Kanter Y, Zoabi M, Skorecki K, Hochberg I, Leibu R, Miller B, Levy AP. Haptoglobin phenotype and diabetic nephropathy. Diabetologia. 2001 May;44(5):602-4.

Roguin A, Hochberg I, Nikolsky E, Markiewicz W, Meisel SR, Hir J, Grenadier E, Beyar R, Levy AP. Haptoglobin phenotype as a predictor of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol. 2001 Feb 1;87(3):330-2, A9.

Levy AP, Hochberg I, Jablonski K, Resnick HE, Lee ET, Best L, Howard BV; Strong Heart Study. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J Am Coll Cardiol. 2002 Dec 4;40(11):1984-90.

Hochberg I, Roguin A, Nikolsky E, Chanderashekhar PV, Cohen S, Levy AP. Haptoglobin phenotype and coronary artery collaterals in diabetic patients. Atherosclerosis. 2002 Apr;161(2):441-6.

Levy AP, Gerstein HC, Miller-Lotan R, Ratner R, McQueen M, Lonn E, Pogue J. The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Diabetes Care. 2004 Nov;27(11):2767. No abstract available.

Starting date: April 2005
Ending date: December 2009
Last updated: February 28, 2007