Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes

Allie S. Carew, Andrew P. Levy, Henry N. Ginsberg, Steven Coca, Orit Lache, Thomas Ransom, Robert Byington, Eric B. Rimm, John Sapp, Martin Gardner, Leah E. Cahill

Résultat de recherche: Articleexamen par les pairs

33 Citations (Scopus)

Résumé

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.

Langue d'origineEnglish
Pages (de-à)512-521
Nombre de pages10
JournalJournal of the American College of Cardiology
Volume75
Numéro de publication5
DOI
Statut de publicationPublished - févr. 11 2020

Note bibliographique

Funding Information:
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.

Publisher Copyright:
© 2020 American College of Cardiology Foundation

ASJC Scopus Subject Areas

  • Cardiology and Cardiovascular Medicine

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