Dual Therapy With Statins and Antioxidants Is Superior to Statins Alone in Decreasing the Risk of Cardiovascular Disease in a Subgroup of Middle-Aged Individuals With Both Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Abstract

Diabetes Mellitus (DM) is associated with a state of increased oxidative stress. 1 Paradoxically, however, antioxidants have not been found to provide CVD benefit to DM individuals in several prospective clinical trials. [2][3][4][5][6][7][8][9][10][11] However, the inability to demonstrate benefit may have been attributable to inadequate patient selection as antioxidants may only benefit those with particularly high levels of oxidative stress. 12 A polymorphism in the Haptoglobin (Hp) gene, an antioxidant protein, appears to permit identification of individuals with high oxidative stress and who may benefit from antioxidant therapy. 13 There exists 2 classes of alleles at the Hp genetic locus, 1 and 2, and the antioxidant capacity of the Hp 2 protein is inferior to the Hp 1 protein. 14 -18 Robust clinical data has shown that individuals homozygous for the Hp 2 allele (Hp 2-2 genotype), 40% of DM individuals, have an up to 500% increased risk of CVD. 19 -22 A vast amount of basic science, animal, and epidemiological data has provided the logic for targeting vitamin E administration specifically to DM individuals with the Hp 2-2 genotype. 13 Most importantly we have recently reported in the ICARE study (Israel CArdiovascular events Reduction with vitamin E [ClinicalTrials.gov# NCT00220831]) a prospective randomized placebo controlled trial of vitamin E therapy in DM individuals with the Hp 2-2 genotype, that vitamin E therapy results in a 50% reduction in CVD events. 22 However, only about half of the Hp 2-2 DM participants in ICARE received statin therapy. Because statin therapy is currently recommended for all DM individuals we sought to determine whether antioxidant therapy could still be demonstrated to provide benefit to Hp 2-2 DM individuals also taking statins in ICARE. We believed that this analysis would be of particular interest and importance because of previous work demonstrating that the addition of antioxidant vitamins to simvastatin-niacin therapy blunted the rise in protective subfractions of HDL with an apparent adverse effect on the progression of coronary artery disease. 23,24 Research Design and MethodsThe study protocol of the ICARE study has previously been reported in detail. 22 Briefly, participants were drawn from 47 primary health clinics of the Clalit Health Services in the northern sector of Israel. Patients were eligible for the study if they had Type II DM and were 55 years of age or older. 3054 individuals underwent Hp genotyping, and of these 1434 were found to have the Hp 2-2 genotype. These Hp 2-2 individuals were randomly assigned to treatment with either vitamin E or placebo. Hp 1-1 and Hp 2-1 individuals were not enrolled in the treatment phase of the study but were followed in a study registry for all major cardiovascular events using the same methodology for outcomes adjudication as for individuals with the Hp 2-2 genotype. The major study outcomes (MI, stroke, CVD death) were identified prospectively in this population over an 18-month period. A preplanned secondary analy...

Polymorphisms at Cytokine Genes May Determine the Effect of Vitamin E on Cytokine Production in the Elderly , ,

“…Recent reports have shown that response to vitamin E supplementation in diabetics may be modulated by variants of HaptoglobulinA (34,41,42) and plasminogenA-1 (43,44) genes. These reports support the idea that genetic factors modulate responses to supplemental E. We have observed that the effect of vitamin E supplementation on TNFa production was dependent on TNFa -308G .…”

The LDL modification hypothesis of atherogenesis: an update

“…The primary composite end point of cardiovascular death, nonfatal myocardial infarction, or stroke was reduced by 47% in the treated group (P 5 0.01). In a later study, again in a cohort of diabetics with the haptoglobin 2-2 genotype, it was shown that adding vitamin E to statin therapy reduced risk by over 60% compared with statin-only treatment (49). These are striking results suggesting that oxidative modification does indeed occur in the human disease but that the benefit of vitamin E (and perhaps the other natural antioxidants) is only apparent in populations under unusual oxidative stress.…”

Type 1 Diabetes Mellitus and Cardiovascular Disease

“…119 What is particularly exciting about these observations is the potential for preventing CVD with vitamin E in those with haptoglobin 2-2, as may occur in T2DM. [120][121][122][123] The relevance of these observations to patients with T1DM remains unexamined, and the haptoglobin 2-2 genotype has not been identified by genome-wide association studies.…”