Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes
Allie S Carew1, Andrew P Levy2, Henry N Ginsberg3
1Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Queen Elizabeth II Health Sciences Centre, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada.
Insights
Intensive glucose lowering therapy reduced cardiovascular disease (CVD) risk in patients with the Hp2-2 haptoglobin (Hp) phenotype. However, it increased mortality risk in Hp1 carriers, highlighting the importance of Hp phenotype in diabetes treatment decisions.
Area of Science:
- Endocrinology and Metabolism
- Genetics and Genomics
- Cardiovascular Medicine
Background:
- Glycated hemoglobin levels correlate with cardiovascular disease (CVD), but intensive therapy to normalize levels has yielded mixed results, increasing mortality in some trials.
- A common haptoglobin (Hp) genetic polymorphism is linked to CVD risk, particularly coronary heart disease (CHD), in individuals with hyperglycemia.
Purpose of the Study:
- To investigate if the differential effects of intensive versus standard glucose-lowering therapy on CVD events in the ACCORD study were dependent on the participant's Hp phenotype.
- To analyze the association between Hp phenotype and the efficacy and safety of intensive glucose-lowering strategies.
Main Methods:
- Hp phenotype was determined in 5,806 non-Hispanic white participants of the ACCORD study using a validated assay.
- Stratified Cox regression models were employed to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for incident CVD events based on Hp phenotype (Hp2-2 vs. Hp1 carriers).
Main Results:
- Intensive therapy significantly reduced the risk of incident coronary heart disease (CHD) in participants with the Hp2-2 phenotype (aHR: 0.71; 95% CI: 0.55 to 0.91).
- In contrast, intensive therapy did not show a significant benefit for CHD risk in Hp1 carriers (aHR: 0.95; 95% CI: 0.79 to 1.13).
- Intensive therapy was associated with increased risks of fatal CVD (aHR: 1.50) and total mortality (aHR: 1.40) among Hp1 carriers, but not in the Hp2-2 group.
Conclusions:
- Intensive glucose-lowering therapy effectively prevented incident CHD and CVD events in ACCORD participants with the Hp2-2 phenotype.
- Hp1 carriers experienced an increased risk of mortality with intensive therapy, indicating that Hp phenotype is a critical factor in guiding diabetes treatment strategies.
Background:
Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia.
Objectives:
This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype.
Methods:
Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers).
Results:
Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908).
Conclusions:
Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.
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