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Originally published February 8 2008

Antioxidants Are Lifesaving for Diabetics with Cardiovascular Disease

by Helmut Beierbeck

(NaturalNews) Atherosclerosis starts with the deposition of low-density lipoproteins (LDL or "bad cholesterol") in blood vessel walls. However, LDL deposits by themselves do not cause atherosclerosis. LDL lipids have to be oxidatively damaged before cardiovascular disease (CVD) develops (1).

Given the role of oxidative damage in the development of CVD, antioxidant therapy seemed the obvious thing to try. It was therefore surprising that several large-scale clinical trials of patients with cardiovascular disease failed to show any benefit from antioxidant supplementation (2). There were indications, however, that a subset of patients in these trials might have derived a benefit from taking antioxidants. These patients had two things in common, namely diabetes and a particular form of the haptoglobin protein (3,4).

That this type of patient indeed benefits from antioxidant therapy has now been confirmed in a clinical trial (5). 1,434 diabetics with haptoglobin phenotype Hp 2-2 were randomly assigned to receive either 400 IU per day of vitamin E or placebo. After eighteen months the vitamin E group had less than half the number of heart attacks, strokes or cardiovascular deaths as the placebo group (2.2% vs 4.7%). These results were significant enough to halt the trial.

Since it is the primary role of haptoglobin to bind free hemoglobin and remove it from circulation, free hemoglobin and the oxidative damage it can cause had to be the critical factors.

When an atherosclerotic plaque breaks, red blood cells penetrate the arterial wall. This risk is magnified in diabetes due to more rapid red blood cell turnover and increased damage to the blood vessel wall. The red blood cells entering the arterial wall break down and release their hemoglobin, which ultimately generates free iron. Divalent iron can cause the generation of hydroxyl radicals and lipid peroxidation, especially the peroxidation of polyunsaturated fatty acids. It is the role of haptoglobin to bind the free hemoglobin for removal by macrophages, before peroxidation can damage the lipoproteins and their contents. The effectiveness with which haptoglobin can do this depends on its structure.

We have two copies (alleles) of the haptoglobin gene, type 1 and 2. Since we have two sets of chromosomes, we may carry two type 1 copies (phenotype Hp 1-1), two type 2 copies (Hp 2-2), or one copy of each type (Hp 2-1). The resulting haptoglobin molecules aggregate via disulfate bonds. Type 1 haptoglobin has only one cysteine residue and can only bind to one other haptoglobin monomer, whereas type 2 has two cysteines. This means that patients with different haptoglobin phenotypes form polymers of different sizes. The Hp 1-1 phenotype permits at most dimers, the Hp 2-1 phenotype produces linear dimers, trimers and tetramers, and the Hp 2-2 phenotype results in cyclic trimers and tetramers (6).

In vitro the different haptoglobin polymers all bind free hemoglobin equally well, but the larger haptoglobins cannot penetrate the arterial wall to the same extent as the smaller Hp 1-1 dimers. Patients with the Hp 1-1 phenotype therefore neutralize free hemoglobin much more effectively than Hp 2-1 and especially Hp 2-2 patients. It is not surprising then that Hp 2-2 patients have much more oxidized lipoprotein in their blood vessel walls.

Higher blood glucose levels in diabetes compound the problem. Glucose exists as a cyclic compound in equilibrium with an open-chain aldehyde form. In its open-chain form glucose is very reactive and causes damage in various ways.

First, aldehydes are reducing agents, and an abundance of glucose will ensure that free iron is kept in the reduced (divalent) state in which it contributes to lipid peroxidation. Secondly, aldehydes react with the amino groups of N-terminal and lysine residues of proteins in a non-enzymatic reaction called glycation, damaging the proteins in the process.

Hemoglobin damaged by glycation doesn't bind the heme group as tightly, and releases iron more readily, than undamaged hemoglobin. Glycation can damage haptoglobin as well, adversely affecting the binding between haptoglobin and hemoglobin. This haptoglobin-hemoglobin (Hp-Hb) complex must be eliminated by binding to, and take-up by, macrophages. Binding to the macrophage receptor is also adversely affected by glycation, i.e. damaged Hp-Hb complexes are cleared much more slowly.

Diabetics who can only make type 2 haptoglobins (Hp 2-2 phenotype) therefore have two strikes against them. The larger Hp 2-2 haptoglobin polymers are less effective at reaching free hemoglobin at sites of hemorrhage inside arterial walls. This problem is compounded by protein glycation resulting from high blood glucose levels. Even if haptoglobin does reach free hemoglobin, it will be less effective at binding and removing it.

The net result for Hp 2-2 diabetics is an increased rate of lipoprotein peroxidation. It is therefore not surprising that vitamin E antioxidant should have a significant impact on cardiovascular outcomes in this type of patient. It is estimated that up to 40% of people with advanced atherosclerotic plaques may suffer hemorrhages inside blood vessel walls, and that Hp 2-2 phenotypes may make up as much as a third of the population (6). This is therefore a significant concern for a large number of patients. If you are diabetic and suffer from cardiovascular disease, your doctor needs to know about these findings. This knowledge could literally save your life.


1. D. Steinberg. Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime. Nat. Med. 2002;8(11):1211-1217.

2. D. Steinberg and J.L. Witztum. Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation 2002;105:2107-2111.

3. R. Asleh. S. Marsh, M. Shilkrut, O. Binah, J. Guetta, F. Lejbowicz, B. Enav, N. Shehadeh, Y. Kanter, O. Lache, O. Cohen, N.S. Levy, and A.P. Levy. Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ. Res. 2003;92:1193-1200.

4. A.P. Levy, H.C. Gerstein, R. Miller-Lotan, R. Ratner, M. McQueen, E. Lonn, and J. Pogue. Effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Diabetes Care 2004;27:2767.

5. U. Milman, S. Blum, C. Shapiro, D. Aronson, R. Miller-Lotan, Y. Anbinder, J. Alshiek, L. Bennett, M. Kostenko, M. Landau, S. Keidar, Y. Levy, A. Khemlin, A. Radan, and A.P. Levy. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both diabetes mellitus and the haptoglobin 2-2 genotype. A prospective double-blinded clinical trial. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007. Published online before print November 21, 2007.

6. A.P. Levy, J.E. Levy, S. Kalet-Litman, R. Miller-Lotan, N.S. Levy, R. Asaf, J. Guetta, C. Yang, K.R. Purushothaman, V. Fuster, and P.R. Moreno. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler. Thromb. Vasc. Biol. 2007;27:134-140.

About the author

Helmut Beierbeck has a science background and a strong interest in all scientific aspects of health, nutrition, medicine, weight loss, or any other topic related to wellness. You can follow his ruminations on his blog and leave comments on this or any other health-related topic.

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