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Randomized Controlled Trial
. 2026 Jan 6;33(1):132-142.
doi: 10.1093/eurjpc/zwaf562.

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

Kwok Leung Ong  1 , Andrzej S Januszewski  1   2 , Habib Francis  1 , Rachel L O'Connell  1 , Abubakar Mangani  1   2 , Liping Li  1 , Peter G Colman  3 , David R Sullivan  1   4   5 , James D Best  6 , Russell S Scott  7 , Alicia J Jenkins  1   8 , Anthony C Keech  1   9
Affiliations
Randomized Controlled Trial

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

Kwok Leung Ong et al. Eur J Prev Cardiol. .

Abstract

Aims: 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.

Methods and results: 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.

Conclusion: 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.

Lay summary: 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.Fenofibrate benefit on CVD did not differ by HP phenotype and baseline or change in HP levels.

Keywords: Biomarkers; Cardiovascular disease; Haptoglobin; Macrovascular complications; Type 2 diabetes.

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Conflict of interest statement

Conflict of interest: Fournier Pharma (now part of Abbott Pharmaceuticals) sponsored the FIELD trial but had no role in data collection, analysis, or interpretation. D.R.S. has received grants or contracts from Amgen, Arrowhead, Ionis, MSD, Novartis, and Regeneron, Alirocumab samples from Sanofi, and consulting fees and honoraria from Amgen and Novartis. D.R.S. has participated as a member of the Data Safety Monitoring Board or Advisory board of the LIPID, FIELD, and Nomad studies, and clinical committee chairman of the Australian Atherosclerosis Society Executive. A.J.J. has received honoraria from CSL and GSK and travel support for conference attendance from the American Diabetes Association and CSL. A.J.J. has served as an advisory panel member for Abbott (Diabetes, Australia), CSL, and GSK, has received research support from Abbott, Abbvie, and Viatris, and grant funding from the NHMRC to support research activities, including those relating to the FIELD trial. A.J.J. has also served as a honorary board member of an international diabetes aid Insulin For Life (a non-governmental organization), member of the International Diabetes Federation Disaster Committee, and Chair-Elect of the International Diabetes Federation Western Pacific Region. A.C.K. has received programme grant and Senior Research Fellowship from the NHMRC to support all research activities. A.C.K. has received research support from Abbott, Amgen, Bayer, Mylan, Novartis, and Sanofi, honoraria from Novartis, and drugs for research trials from Viatris and Aspen. A.C.K. has participated as a member of the Data Safety Monitoring Board of the PROMINENT trial (Kowa). All other authors declare no conflict of interest.

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