Author + information
- Received August 5, 2019
- Revision received November 22, 2019
- Accepted November 23, 2019
- Published online February 3, 2020.
- Allie S. Carew, MSca,b,
- Andrew P. Levy, MD, PhDc,
- Henry N. Ginsberg, MDd,
- Steven Coca, DO, MSe,
- Orit Lache, MScc,
- Thomas Ransom, MSc, MDa,b,
- Robert Byington, PhDf,
- Eric B. Rimm, ScDg,h,
- John Sapp, MDa,b,
- Martin Gardner, MDa,b and
- Leah E. Cahill, PhDa,b,g,∗ ( )(, )@leahcahill@HarvardChanSPH@NSHAResearch
- aDepartment of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
- bQueen Elizabeth II Health Sciences Centre, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada
- cRappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
- dDepartment of Medicine, Columbia University, New York, New York
- eDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- fDepartment of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
- gDepartment of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- hDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Leah E. Cahill, Department of Medicine, Dalhousie University, 5790 University Avenue, Halifax, Nova Scotia B3H 1V7, Canada.
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.
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 U.S. National Institutes of Health. The funding sources were not involved in data collection, data analysis, or manuscript drafting. Dr. Levy is the author of a patent owned by his university regarding use of haptoglobin genotype to predict susceptibility to cardiovascular disease in individuals with diabetes. Dr. Coca is one of the (equity-owning) scientific cofounders of RenalytixAI, which is an artificial intelligence development company not involved in the present project; he has also received consulting fees from Goldfinch Bio, CHF Solutions, Quark Biopharma, Janssen Pharmaceuticals, Takeda Pharmaceuticals, RenaltyixAI, and Relypsa. Dr. Ransom has served as a trial investigator for Sanofi, Bristol-Myers Squibb, Sepracor, Lilly, Abbott, Novartis, and Novo Nordisk; and has received speaking or travel honoraria from Sanofi, Bristol-Myers Squibb, Sepracor, Lilly, Abbott, Novartis, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P.K. Shah, MD, served as Guest Editor for this paper.
- Received August 5, 2019.
- Revision received November 22, 2019.
- Accepted November 23, 2019.
- 2020 American College of Cardiology Foundation
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