NEW ORLEANS — The cardiovascular mortality rate was more than fivefold higher in type 2 diabetic patients who possessed the haptoglobin 2-2 genotype than in those who did not in a large, prospective, Israeli study.
Another analysis based on the same study population showed that tight glycemic control reduced the incidence of myocardial infarction—but only in those type 2 diabetic patients with the haptoglobin 2-2 genotype.
Taken together, these findings suggest an important role for haptoglobin genotyping in assessing cardiovascular risk and guiding management strategies in patients with type 2 diabetes, Dr. Uzi Milman said at the annual scientific sessions of the American Heart Association.
Haptoglobin is a serum protein that binds extracellular hemoglobin, a potent source of oxidative tissue damage in the bloodstream and in vascular endothelium. The haptoglobin arising from the haptoglobin (Hp) 2-2 genotype is a much less efficient antioxidant than are the forms of the protein present in individuals who are Hp 1-1 or Hp 1-2. Thus, haptoglobin typing permits identification of a diabetic subgroup with chronically high oxidative stress, explained Dr. Milman, a family physician at Clalit Health Services and the Technion-Israel Institute of Technology, Haifa.
The Hp 2-2 variant is quite common. In most Western populations, its prevalence is 36%, compared with 16% for Hp 1-1 and 48% for Hp 1-2.
Dr. Milman reported on 2,241 type 2 diabetes patients age 55 years or older who participated in a registry created at 47 primary care clinics in northern Israel as part of the Israel Cardiovascular Events Reduction with Vitamin E (ICARE) study. The double-blind randomized portion of ICARE, which was presented at the 2007 scientific sessions of the American Heart Association, showed a halving of cardiovascular death, MI, and stroke with 18 months of 400 IU/day of vitamin E, compared with placebo.
The 2,241 registry participants were not part of the vitamin E randomized trial. They underwent haptoglobin genotyping, then were followed prospectively for 3 years, with all treatment decisions left to the discretion of their primary care physicians. Patients in the three groups with regard to haptoglobin genotype did not differ in terms of baseline duration of diabetes, glycosylated hemoglobin values, or prevalence of known cardiovascular disease, which was roughly 25% across the board.
The key finding was that the incidence of cardiovascular death during the 3-year follow-up was 1.1% in the 708 Hp 2-2 patients, more than fivefold greater than the 0.2% rate in Hp 1-1 or 1-2 individuals. The rate of nonfatal MIs was 3.9% in the Hp 2-2 patients and 2.5% in the others, a difference that did not reach statistical significance.
The other ICARE substudy Dr. Milman presented looked at the impact of haptoglobin genotype on the success of tight glycemic control to prevent MI. He found that the rate of MI during follow-up was 5% in Hp 2-2 patients whose average glycosylated hemoglobin was greater than 7.0%, compared with 1.8% in Hp 2-2 individuals who maintained an HbA1c of 7.0% or less. The number of Hp 2-2 type 2 diabetic patients who needed to be on tight glycemic control for 3 years in order to prevent one MI was 31.
In contrast, MI rates were similar in Hp 1-1 or Hp 1-2 individuals regardless of whether their average HbA1c was greater or less than 7.0%.
This finding may explain the lack of consistent clinical trials evidence that tight glycemic control reduces cardiac events in diabetic patients. The benefit of tight control in terms of reduced macrovascular events appears to be restricted to the subgroup with high oxidative stress, as reflected in the Hp 2-2 genotype. These are the diabetic patients in whom aggressive risk factor modification is warranted; they also are the ones who will benefit from 400 IU/day of vitamin E, he continued.
Dr. Milman and coinvestigators recently demonstrated that the mechanism for vitamin E's benefit in Hp 2-2-positive patients with type 2 diabetes involves the antioxidant vitamin's ability to correct the HDL dysfunction present in such individuals (Diabetes 2008;57:2794-800).
Synvista Therapeutics is developing a simple diagnostic kit to determine haptoglobin genotype. Until the kit receives marketing clearance from the Food and Drug Administration, physicians can order haptoglobin genotype testing from ARUP Laboratories, a national clinical reference laboratory, under a license agreement with Synvista.
Interested physicians can call ARUP's 24-hour service line at 800-522-2787 and should refer to ARUP test #0040116).
The ICARE trial was sponsored by the Technion-Israel Institute of Technology.