The association of haptoglobin levels and phenotype with cardiovascular disease in Type 2 diabetes: a Fenofibrate Intervention and Event Lowering in Diabetes sub-study

Haptoglobin (HP) 2-2 phenotype has been suggested as a risk factor for cardiovascular disease (CVD) and to modulate fenofibrate benefit on CVD risk in Type 2 diabetes. However, little is known as to whether HP levels modulate CVD risk and fenofibrate response.

Haptoglobin phenotype and levels were determined in 8047 Fenofibrate Intervention and Event Lowering in Diabetes trial participants at baseline and randomization (after a 16 week run-in period, including a 6 week fenofibrate therapy) and their association with new on-trial total CVD events over 5 years was assessed. Higher baseline HP levels were associated with total CVD events in the placebo group {n = 4030, hazard ratio [95% confidence interval (CI)] = 1.30 [1.02–1.66] for HP level Tertile 3 vs. Tertile 1, P = 0.035}. This was driven by participants with HP 1-1 phenotype (P for interaction = 0.011). Participants with the lowest baseline HP level tertile and HP 1-1 phenotype tended to have the lowest CVD risk, whereas CVD risk was similar in other participants, regardless of HP phenotype and levels. Fenofibrate benefit on total CVD events did not differ significantly by HP phenotypes, baseline HP level tertiles, or tertiles of change in HP levels by fenofibrate during active run-in.

Higher baseline HP levels were associated with a higher CVD risk, especially in participants with HP 1-1 phenotype. A lower CVD risk is found only in Type 2 diabetes participants with both the HP 1-1 phenotype and low baseline HP levels. Fenofibrate benefits on CVD risk reduction did not differ by HP levels or phenotype.

We evaluated the relationship of different forms or phenotypes of the blood protein, haptoglobin, and its circulating levels with the risk of developing CVD and fenofibrate benefit in patients with Type 2 diabetes, and showed that both HP phenotype and levels are important to assess CVD risk in patients with Type 2 diabetes, although fenofibrate did not modulate CVD risk via HP phenotype or level.

Higher baseline HP levels were associated with higher CVD risk, especially in participants with HP 1-1 phenotype.