Implications of Haptoglobin Genotype and Cardiovascular Risk in Patients with Diabetes

Abstract

Haptoglobin (HAP) is genetically polymorphic with three primary genotypes, HAP 1-1, 2-1 and 2-2. Each genotype differs phenotypically in HAP structure and ability to perform its main function, scavenging free hemoglobin (Hb) released from old red blood cells. Patients with both diabetes and the genotype 2-2 appear to be at an increased cardiovascular risk than those with the other genotypes or patients without diabetes. This risk appears elevated with worse glycemic control. The exact mechanism for this increased risk is unknown but there are several proposed causes. Vitamin E has shown to reduce cardiovascular events in patients with both diabetes and the 2-2 genotype but the safety of implementing such therapy remains unknown. Recent post-hoc evaluation of a landmark study originally designed to assess the benefits and risks of more aggressive glycemic control suggests there may be a cardiovascular benefit in patients with diabetes and the 2-2 genotype that is not seen in those with the other genotypes. This information, if confirmed with post-hoc evaluation of other similar landmark studies as well as evaluation of genotype differences in recent cardiovascular safety studies with glucagon-like peptide agonists or sodium-glucose cotransporter inhibitors, could provide clinicians with an avenue to better identify patients most at risk for cardiovascular events and who may benefit the most from more aggressive glycemic control or use of other antihyperglycemic agents.