Haptoglobin genotype and cardiovascular outcomes in diabetes mellitus — natural history of the disease and the effect of vitamin E treatment. Meta-analysis of the medical literature

Abstract

Background Diabetes mellitus carries a high risk for vascular events. Diabetics with different haptoglobin (Hp) types may carry different risk profiles, and may respond differently to vitamin E treatment. We aim to summarize the evidence about cardiovascular risk in diabetic patients, according to their Hp type, and the effect of vitamin E treatment on these sub-groups. Methods We searched MEDLINE and on-going trials’ databases until February 2011; gray literature; reference lists of identified articles; and experts. Two investigators screened and selected studies that prospectively followed cardiovascular outcomes in diabetic patients with different Hp types (natural history analysis), and randomized controlled trials reporting the effect of vitamin E on cardiovascular outcomes in diabetics, in which Hp typing was performed (interventional analysis). Results Five and three studies, comprising 1829 and 2110 patients, were eligible for the natural history and the interventional analyses, respectively. The percentage of diabetic patients experiencing non-fatal MI, stroke, or cardiovascular death was significantly higher in the Hp 2–2 population (odds ratio (OR) 2.03 (95% confidence interval (CI) 1.46 to 2.81)). In patients with Hp 2–2 genotype, the OR for a combined endpoint was 0.66 in favor of the vitamin E treated group (95% CI 0.48 to 0.9). This effect was not shown in other Hp types. Conclusion Hp type 2–2 carries a high risk of cardiovascular events in diabetic patients. A pharmacogenomic approach towards treatment of diabetic patients with vitamin E may be warranted.

Presence of Haptoglobin-2 Allele Is Associated with Worse Functional Outcomes After Spontaneous Intracerebral Hemorrhage

“…No specific drug has been successful in targeting the Hp phenotype to date. A meta-analysis not only showed a higher incidence of cardiovascular events in patients with Hp 2-2 phenotype but also suggested a beneficial effect of using vitamin E in these patients (OR of cerebrovascular events ¼ 0.66) (15). This seems to be a controversial area, particularly with a more recent prospective cohort study of 123 subjects showing no difference in cardiovascular risk in individuals with Hp 2-2 with and without diabetes (13).…”

Haptoglobin genotype and cerebrovascular disease incidence in type 1 diabetes

“…Conversely, the greater antioxidant and anti-inflammatory capacity of Hp 1-1 (9) may account for the observed protection it confers against CAD and kidney dysfunction. Furthermore, the diverse effects of Hp genotype on CAD and cerebrovascular disease may relate to the observation that vitamin E protects against CAD only in those with diabetes carrying the Hp 2 allele but may have little or even a harmful effect in the non-Hp 2-2 individuals (18-20, 40). Administration of vitamin E may thus exacerbate the risk of stroke, especially in the Hp 1-1 group.…”

An enzyme linked immunosorbent assay (ELISA) for the determination of the human haptoglobin phenotype

“…For example, an ELISA result of Hp 2-1 or Hp 1-1 also indicates a negative result for Hp 2-2. This is particularly important for individuals who are not Hp 2-2 and should not receive high dose vitamin E supplements, as this treatment may be detrimental in non-Hp 2-2 individuals [2, 14]. …”

“…Specifically, it has been shown that diabetic individuals of the Hp 2-2 phenotype are at significantly increased risk of developing vascular complications including myocardial infarction, stroke, and kidney disease. Furthermore, recent work has shown that Hp 2-2 diabetic individuals experience a 30%–40% decrease in cardiovascular complications following treatment with vitamin E [2]. We therefore sought to develop a rapid and accurate enzyme linked immunosorbent assay (ELISA) for the determination of Hp phenotype.…”