Elevated Aspirin Nonresponsiveness in Type 2 Diabetes

Use of enteric-coated (EC) aspirin therapy has been linked to incomplete absorption and “aspirin resistance” in patients with obesity and type 2 diabetes, according to research published in the Journal of the American College of Cardiology.

Deepak L. Bhatt, MD, from Brigham & Women’s Hospital Heart and Vascular Center and Harvard Medical School in Boston, Massachusetts, and colleagues conducted a randomized, single-blind, triple-crossover study comparing the onset and offset of antiplatelet activity following immediate-release aspirin therapy.

The study population included 40 patients with obesity and type 2 diabetes (age: 52.95 ±10.12 years; 65% men) and a body mass index (BMI) of 30 to 40 kg/m² (mean: 34.45 ±2.72 kg/m²). Patients were exposed to three 325-mg formulations of aspirin: plain aspirin, PL2200 (a modified-release lipid-based aspirin), and delayed-response EC aspirin. Of the patients enrolled, 87.5% (n = 35) completed all 3 crossover phrases.

Dr Bhatt and colleagues defined aspirin nonresponsiveness as “a level of residual serum thromboxane B₂ [TXB₂] associated with elevated thrombotic risk (<99% inhibition or TXB₂ >3.1 ng/mL) within 72 hours after 3 daily aspirin doses.”

Time-to-response for all 3 aspirin formulations was 16.7, 12.5, and 48.2 hours for plain aspirin (n = 38), PL2200 aspirin (n = 37), and EC aspirin (n = 36), respectively. Plain aspirin was associated with significantly faster TXB₂ inhibition when compared to EC aspirin

(P <.0001), while PL2200 aspirin reached 99% TXB₂ inhibition significantly faster than EC aspirin (P <.0001); the rate of PL2200 aspirin was similar to that of plain aspirin (P =.41).

Rates of aspirin responsiveness were 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200 aspirin, and EC aspirin, respectively (P <.001 for plain aspirin vs EC aspirin and PL2200 aspirin vs EC aspirin; P =.30 for plain aspirin vs PL2200 aspirin). More than 55% of participants treated with EC aspirin showed serum TXB₂ levels >3.1 ng/mL (18% for plain aspirin and 11% for PL2200 aspirin; P <.0001). The researchers found that the high rate of nonresponsiveness was linked to lower exposure to acetylsalicylic acid; posthoc multivariable analyses showed that female sex was a “significant independent predictor” of nonresponsiveness to EC aspirin” (P =.0414).

“The results…show that there is substantial variability in antiplatelet response to dosing with 325 mg of EC aspirin in patients with diabetes,” the researchers concluded. “Although the clinical implications need to be established, this finding does raise potential concerns that patients taking EC aspirin may not receive the full cardioprotective benefit of this important drug.”

Study Limitations

• Researchers note that a longer period of chronic dosing with EC aspirin may have resulted in less variability in results.
• Further research is necessary to see whether findings apply to patients without diabetes or patients without obesity.

Disclosures: Dr Bhatt has received honoraria from the American College of Cardiology, the Duke Clinical Research Institute, the Harvard Clinical Research Institute, and the Journal of the American College of Cardiology, among others. Dr Grosser has received consulting fees from PLx Pharma Inc, Bayer Healthcare, and Aralez Pharmaceuticals, and is an Associate Editor for Circulation: Cardiovascular Genetics. Dr Angiolillo has received payments consulting fees or honoraria from Sanofi, Eli Lilly and Company, AstraZeneca, Merck, Abbott Vascular, Amgen, Bayer, Pfizer, and PLx Pharma, among others. Dr Jeske is the principal investigator on a research grant to Loyola University Chicago from BioData Corporation, and is a consultant to PLx Pharma Inc., Machon Diagnostics, and Repros Therapeutics. Dr Grelinger is the principal or co-investigator on research grants to Boston Children’s Hospital from Baxalta, Bristol-Myers Squibb, Eli Lilly, GE Healthcare, and Pfizer, among others. Dr Marathi is an investigator, officer, and employee of PLx Pharma Inc., as well as the co-inventor of the PL2200 technology, and holds equity and options to buy equity in 7 Hills Pharma.

For a complete list of disclosures for Drs Bhatt, Angiolillo, and Frelinger, visit www.onlinejacc.org. 

Reference

Bhatt DL, Grosser T, Dong J-f, et al. Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus [published online January 9, 2017]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2016.11.050