Haptoglobin genotype may dictate success of intensive glucose control
medwireNews: The benefits and harms of intensive glucose control in people with type 2 diabetes may depend on which form of haptoglobin (Hp) they have, shows an analysis of the ACCORD trial.
There are three common haptoglobin phenotypes, determined by a copy number variant that substantially alters the size and functionality of the protein, and the researchers found that only people with the Hp2-2 phenotype benefited from being assigned to the intensive control arm of ACCORD.
These people comprised 37% of 5806 non-Hispanic White ACCORD participants, meaning that “the present study evaluates a medical management issue that could impact millions of people,” write the researchers in the Journal of the American College of Cardiology.
People with the Hp2-2 phenotype had significant 29% reductions in the risk for coronary heart disease and for cardiovascular disease (CVD), and a 46% reduced risk for nonfatal myocardial infarction if they were assigned to intensive rather than standard therapy. Their risk for fatal CVD or all-cause mortality was not affected by treatment intensity.
Leah Cahill (Dalhousie University, Halifax, Nova Scotia, Canada) and study co-authors explain that the “large cyclic Hp2-2 protein is less functional at binding and clearing free hemoglobin,” especially when hemoglobin is glycated. The consequences of this include increased oxidative damage and impaired reverse cholesterol efflux leading to increased instability of atherosclerotic plaques.
People with this haptoglobin phenotype therefore have the most to gain from intensive glucose control.
Carriers of Hp1 (encompassing the Hp1-1 and Hp2-1 phenotypes) in ACCORD derived no significant benefit from intensive versus standard therapy. On the contrary, they had a significant increase in the risk for both fatal CVD and total mortality, of 50% and 40%, respectively. These associations were independent of variables including age, gender, history of CVD, and assignment to the blood pressure or lipid trials within ACCORD.
Cahill and team suggest that the ethnic and geographic variation in haptoglobin phenotypes, as well as differences in target and attained glucose levels, may help to explain why intensive management was associated with harm in the ACCORD trial, but not in ADVANCE or VADT.
They add that if haptoglobin phenotype truly affects the risk–benefit profile of intensive glucose control, it may have implications for guideline advice to relax management in people with glycated hemoglobin below 6.5%.
“The results of the present study suggest this softening of glycemic control would be optimal for Hp1 allele carriers but could cause harm to patients with the Hp2-2 phenotype,” say the researchers.
They conclude: “If the results of the present study continue to replicate in future studies, the Hp phenotype could potentially serve as a simple one-time inexpensive biomarker to help fine-tune the appropriate intensity of blood glucose-lowering treatment in a precision medicine-based algorithm to prevent CVD in people with [type 2 diabetes].”
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