By Jacob Victor, Ph.D., Executive Director, Product Development, Synvista Pharmaceuticals, Inc.
Dated: 1/1/2008
Both robust clinical evidence and conventional wisdom suggest that tight glycemic control in patients with Type 1 or Type 2 diabetes mellitus (DM) will reduce morbidity from microvascular complications, such as retinopathy and nephropathy. However, the literature does not consistently demonstrate the same benefit with regard to larger vessel complications. Yet, it is these complications associated with DM that can be identified as the cause of death in approximately 80% of individuals with the disease.
In a poster at the American Heart Association’s 2007 Scientific Sessions, Shany Blum, MD, Andrew Levy , MD, PhD, et al, Rappaport Institute, Technion University, Haifa, Israel, demonstrated the role of Haptoglobin (Hp) typing in determining the risk of cardiovascular complications in patients with DM. Hp is a normal serum protein that is polymorphic in humans. It occurs as one of three genotypes, Hp1-1, Hp1-2 and Hp2-2.
In multiple independent prospective longitudinal studies of more than 20,000 individuals, it has been established that the Hp genotype is an independent risk factor for cardiovascular disease, with a specific relationship to DM patients. After accounting for conventional cardiovascular risk factors and DM characteristics in these studies, research has demonstrated that there is a two-to-five fold increased risk of cardiovascular disease in people with both DM and the Hp2-2 genotype (approximately 40% of all DM patients).
Despite the varied opinions on whether its antioxidant properties actually prevent cardiovascular disease, Blum’s team has also conducted studies on the use of vitamin E in preventing cardiovascular disease. A previous retrospective analysis showed that while vitamin E may actually harm other patients, there is a demonstrated cardiovascular benefit to patients with both DM and the Hp2-2 genotype.
Based on these combined findings, Blum’s team reported the results of a prospective, double blind, placebo controlled, randomized population-based study of more than 3,000 individuals age 55 and older with DM who were tested for Hp type and followed for two years in a registry. In the study, called ICARE, more than 1,400 patients with Hp2-2 were randomized to receive either Vitamin E 400IU/day or placebo.
It was observed that DM patients with Hp2-2 had a significant increase in the incidence of non-fatal myocardial infarction, stroke and cardiovascular death compared with all DM patients. Further, only those patients with the Hp2-2 genotype (compared to those with genotypes Hp1-1 and Hp1-2) were shown to demonstrate a significant decrease in major cardiovascular events if their HbA1c was maintained below 7.0, the generally recommended target for tight glycemic control. Finally, the study demonstrated cardiovascular risk was significantly reduced only in those patients with the Hp2-2 genotype who took vitamin E and/or maintained tight glycemic control. The best results occurred in those Hp2-2 patients who did both.
The study concluded that optimal utilization of health care resources for risk factor modification should be focused on DM individuals with the Hp2-2 genotype. Benefit from tight glycemic control only in a subset of the DM cohort defined by the Hp 2-2 genotype may explain the inability in multiple prior clinical studies to show a benefit from tight glycemic control on reducing cardiovascular events in the entire DM cohort.
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