doi: 10.1161/ATVBAHA.107.159905
© 2008 American Heart Association, Inc.
Letters to the Editor |
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
From the Technion Faculty of Medicine (S.B., R.M.L., A.P.L.), Technion-Israel Institute of Technology, Haifa, Israel; Clalit Health Services (U.M., C.S., L.B., M.K., A.K., A.R.), Haifa and Western Galilee, Israel; Internal Medicine (S.K., Y.L.), Rambam Medical Center, Haifa, Israel; and PharmaBrains Israel (M.L.), Tel Aviv, Israel.
Correspondence to Andrew P. Levy, MD, PhD, FACC, Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel 31096. E-mail alevy{at}tx.technion.ac.il
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.2–11 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 Methods
The 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 analysis of ICARE was used to assess the ability of vitamin E therapy to influence outcomes in those ICARE participants who were also taking statins. Statin use as prospectively defined in ICARE was based on the use of statins by the participant in at least 8 of the 12 months preceding enrollment of the participant in the study. The decision to use statins for a particular participant was under the discretion of the patient’s primary care physician and was in no way influenced by the patient’s participation in the ICARE study.
Results
Of the 801 Hp 2-2 individuals taking statins in the ICARE cohort, 386 were randomized to vitamin E and 415 to placebo. There was no significant difference in the baseline characteristics, concurrent medications, or diabetes characteristics between those individuals taking statins who were randomized to placebo or vitamin E. We found that dual treatment with statins and vitamin E dramatically reduced the event rate compared with statin treatment alone. (1.3% 5/386 for vitamin E versus 4.1% 17/415 for placebo, hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.15 to 0.83, P=0.017 by log-rank Figure, A). This magnitude of the beneficial affect of vitamins in those taking statins was unchanged if the definition for statin use was widened to include those patients taking statins in at least 1 of the 12 months preceding enrollment of the participant in the study (1.7% (9/538) for vitamin E versus 4.2% (23/543) for placebo, P=0.013).
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We also sought to determine, similar to what was demonstrated in the entire ICARE cohort, whether dual therapy with statins and vitamin E in Hp 2-2 DM individuals could reduce the rate of cardiovascular events to that observed in Hp 2-1 and Hp 1-1 DM individuals taking statins followed in the study registry. The event curves for Hp 1-1 and Hp 2-1 individuals taking statins superimposed on the event curves for Hp 2-2 individuals taking statins (randomized to placebo) and Hp 2-2 individuals taking statins (randomized to vitamin E) are shown in the Figure (B). Whereas the event rate was increased 2- to 3-fold in Hp 2-2 individuals randomized to placebo as compared with Hp 1-1 and Hp 2-1 individuals, the event rate in Hp 2-2 individuals randomized to vitamin E was remarkably similar to that of Hp 1-1 and Hp 2-1 individuals (Figure, B).
Conclusions
We conclude that dual therapy with antioxidants and statins appears to have provided superior cardiovascular protection to middle-aged Hp 2-2 DM individuals as compared with statins alone. These data provide further support for the role of Hp genotyping in individuals with DM to determine the optimal treatment regimen.
Acknowledgments
Sources of Funding
This study was supported by grants from the Binational Science Foundation, the Israel Science Foundation, and the Kennedy Leigh Charitable Trust all to A.P.L.
Disclosures
Dr Levy is a consultant for Synvista Therapeutics.
Footnotes
S.B. and U.M. contributed equally to this study.
References
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