Haptoglobin Genotype Found to Affect the Impact of Intensive Glucose-Lowering Therapy on CV Outcomes in T2DM

intensive glucose-lowering therapy associated with a reduced risk for coronary heart disease in patients with type 2 diabetes with hp2-2 genotype.

Intensive glucose-lowering therapy was found to be associated with a reduced risk for incident coronary heart disease (CHD) and cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) and a haptoglobin (Hp) Hp2-2 genotype, but not in patients with an Hp1 genotype, according to a study published in the Journal of the American College of Cardiology.

The study is a reanalysis of the Action to Control Cardiovascular Risk in Diabetes (ClinicalTrials.gov identifier: NCT00000620) double-blind 2 x 2 factorial trial, in which 5806 white adult participants from the United States and Canada (mean age, 63.1±6.3 years; 36% women; median T2D duration at baseline, 9 years) were enrolled. In this cohort, 15%, 48%, and 37% of participants had the Hp1-1, Hp2-1 and Hp2-2 subtypes, respectively. For the analysis, the Hp1-1 and Hp2-1 were combined into a single Hp1 allele carrier group (n=3673) for comparison with the Hp2-2 genotype group (n=2133).

The study’s outcomes included incidence rates for major CHD (unstable angina, nonfatal myocardial infarction [MI], or fatal CHD), CVD (CV death, non-fatal stroke, or non-fatal MI), fatal CVD, non-fatal MI, and all-cause mortality.

The mean study duration was 4.9 years. Participants with the Hp2-2 genotype treated with intensive vs standard therapy were at lower risk for incident CHD (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.55-0.91; P =.006), CVD (aHR, 0.71; 95% CI, 0.54-0.93; P =.013), and nonfatal MI (aHR, 0.64; 95% CI, 0.46-0.89; P =.008). Participants with an Hp1 genotype had comparable risks for CHD (aHR, 0.85; 95% CI, 0.79-1.13; P =.550), CVD (aHR, 0.91; 95% CI, 0.75-1.12; P =.392), and nonfatal MI (aHR, 0.83; 95% CI, 0.65-1.07; P =.144) whether they were receiving intensive or standard therapy.

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Patients with an Hp1 — but not Hp2 — genotype and treated with intensive vs standard therapy had an elevated risk for fatal CVD (aHR, 1.50; 95% CI, 1.00-2.25; P =.049) and all-cause mortality (aHR, 1.40; 95% CI, 1.08-1.81; P =.011).

Study strengths include its large sample size, randomized controlled design, comprehensive follow-up, blinded CVD outcome adjudication, and use of a validated assay. Study limitations include an underpowering of the ability to examine the effect of intensive therapy on stroke, which has been associated with the Hp1 but not the Hp2 genotype.

“The findings from the present study support acquiring the Hp [genotype] status of patients with T2DM for better precision management of glycemic control to mitigate their high risk for CVD events,” noted the authors. They recommended that future research look to replicate and confirm their findings, as well as investigate other ethnic and racial groups.

Disclosures: The present analysis was funded by a Dalhousie University Department of Medicine Ad Hoc Operating Grant and a Nova Scotia Health Authority Research Fund grant to Dr Cahill. Additional funding in part from the Israel Science Foundation (grant 190/16) to Dr Levy. The original ACCORD study was funded by the US National Institutes of Health.

Please see original article for conflict of interest declarations.


Carew AS, Levy AP, Ginsberg HN, et al. Haptoglobin phenotype modifies the influence of intensive glycemic control on cardiovascular outcomes. J Am Coll Cardiol. 2020;75(5):512-521. doi:10.1016/j.jacc.2019.11.051