Antiplatelet Therapy Resistance in Diabetes Due to Low Vitamin D

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Severe vitamin D deficiency in people with diabetes treated with dual antiplatelet therapy (DAPT) after an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) is associated with high residual platelet reactivity in patients taking the adenosine-diphosphate (ADP) antagonists ticagrelor or prasugrel, according to an exploratory study epublished on June 7 by Vascular Pharmacology. 

“Vitamin D levels among our diabetic patients…were independently associated, when severely reduced, with an increased ADP-mediated platelet reactivity and rate of high on-treatment platelet reactivity with new ADP antagonists but not clopidogrel,” wrote senior author Giuseppe De Luca, MD, PhD, chief of interventional cardiology in the Division of Cardiology at the Azienda Ospedaliera-Universitaria Maggiore della Carità in Novara, Italy, and colleagues.

High on-treatment platelet reactivity (HTPR), defined in the study as reactivity above the lower limit for normal after antiplatelet treatment, is linked to a two- to fourfold increased risk of major cardiovascular events. Previous research, the authors wrote, has identified diabetes as a potential contributor to a suboptimal response to dual antiplatelet therapy.

Vitamin D levels may also impact platelet function.

“The loss of the pleiotropic antioxidant, antithrombotic, and cardioprotective effects of vitamin D has been linked to the prevalence and extent of CAD and to an increase of platelet reactivity and cardiovascular mortality, even among DAPT-treated patients,” wrote Dr. De Luca and colleagues. 

Their analysis included 409 people with diabetes (mean age 69.2  9.7 years, 24.5% women) treated with aspirin plus clopidogrel, ticagrelor, or dose-adjusted prasugrel after an acute coronary syndrome or percutaneous coronary intervention for stable coronary artery disease. Investigators measured platelet function with whole blood impendence aggregometry 30 to 90 days after hospital discharge and performed vitamin D assays (≥30–100 ng/ml is the normal range; 10 ng/ml was considered severely deficient). Patients were divided into vitamin D level quartiles (9.4 ng/ml, 9.4–15.59 ng/ml, 15.5–21.64 ng/ml, ≥21.65 ng/ml).

The prevalence of high on-treatment platelet reactivity to ADP antagonists was associated with lower vitamin D levels (40.2%, 29.1%, 29.4%, 25.5%). The effect was significant only in the lowest vitamin D quartile and among patients taking ticagrelor or prasugrel. Vitamin D levels did not affect the response to aspirin or clopidogrel.

Vitamin D may help modify inflammatory and oxidant processes that lead to atherosclerotic progression and thrombotic events, according to the authors.

“Vitamin D could exert a regulatory effect…on platelets, since its deficiency has been associated to endothelial dysfunction and the levels of nitric oxide and moreover, vitamin D receptor [VDR] has been recently identified also in platelets, where studies in vitro and in vivo have demonstrated that the vitamin D–VDR system plays a pivotal role in antithrombogenicity,” wrote Dr. De Luca and colleagues.

Vitamin D also directly and indirectly effects insulin release and efficiency in people with diabetes, the investigators wrote.

“Insulin sensitivity is often impaired among diabetic patients, enhancing their thrombotic risk,” they noted. “Therefore, it could be hypothesized that vitamin D [supplementation] might counteract insulin resistance and increase the response to insulin in diabetic platelets, reducing then their activated status and preventing high on-treatment platelet reactivity during DAPT treatment.”

The intermediate outcomes investigated in this study don’t reveal what effect vitamin D levels may have on the occurrence of future cardiac events and the authors note that more research is needed before practicing physicians start prescribing vitamin D supplementation to enhance dual antiplatelet therapy in people with diabetes.

“Future dedicated studies are certainly needed to define the interactions between vitamin D and diabetes on platelet function and the potential benefits of its supplementation, especially in higher cardiovascular risk subsets of patients as among diabetics,” wrote the investigators.

REFERENCE:  Monica Verdoia, MD; Patrizia Pergolini, MD; Matteo Nardin, MD; et al. “Vitamin D Levels and Platelet Reactivity in Diabetic Patients Receiving Dual Antiplatelet Therapy.” Vascular Pharmacology. June 7, 2019. DOI:10.1016/j.vph.2019.106564