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“Aspirin Resistance” in Type 2 Diabetes

The reason may be simpler than first thought.

There is no doubt among clinicians that the risk of cardiovascular disease in people with diabetes is very high. And in all patients with cardiovascular risks, based on past medical history or the family tree, it is accepted that once-daily low dose aspirin is an important measure in reducing this risk. This is especially important in the diabetes population where, even without a family history, cardiovascular complications run high. Yet there is a segment of the population who display “resistance” to the antiplatelet effects of low dose aspirin.  Noncompliance due to untoward effects, such as GI distress and bleeding events, is certainly one explanation for aspirin failure, but it does not explain this issue in patients who indeed take their doses every day.

It is recognized that the antiplatelet effects of aspirin are due to inhibition of cyclooxygenase-1 (COX-1), which is responsible for the formation of prostaglandins as well as the platelet aggregation effects of thromboxane (TX). Aspirin’s effects on COX-1 are dose dependent, with low doses (81-325 mg daily) showing preferential inhibition of TX formation. It is this suppression that imparts aspirin’s cardioprotective effect. Over time, some have suggested that aspirin failure may be in part due to enteric coatings or selected dose, especially in people with diabetes who have been shown to overcome “resistance” with increased dosing, it could be counterproductive to achieving cardioprotection due to inhibition of vascular dilating prostacyclins, and the occurrence of adverse effects.  With regard to coated versus regular aspirin, there has been some variability in aspiring bioavailability in enteric-coated products, although no large scale studies have been performed. To further muddy the waters, the pharmaceutical company PLx Pharma developed PL2200, a lipid-based aspirin capsule, which was approved by the FDA in 2012 under the name PL-Aspirin. A study was recently released comparing the effects of three aspirin formulations on thromboxane activity, as well as their absorption properties, in obese diabetic subjects.

This was a single site, randomized active control, single-blinded (all study staff), triple-crossover (all subjects received all tested drugs), pharmacokinetic and pharmacodynamic study, utilizing three products, immediate release aspirin, enteric-coated aspirin, and PL2200 aspirin.  Subjects were ages 21-79, obese with BMI 30-40, no cardiovascular history, had insulin dependent type 2 diabetes. Study drug was given as a single dose once weekly for 3 weeks. Baseline platelet function was obtained within 3 hours of administration of each study drug. Measured data included serum TX, serum salicylic acid and acetylsalicylic acid, and platelet aggregation. Complete aspirin responsiveness was indicated by at least 99% TXB2 inhibition over baseline, or a non-adjusted measurement up to 3.1 ng/ml. Non-responsiveness was the absence of one or both of the responsiveness criteria.

Forty subjects met enrollment criteria, with five subjects had to drop out prior to completion. With regards to a complete aspirin response, time to achieve 99% inhibition of TXB2 was obtained for all 3 products: PL2200 12.5 ± 4.6 hrs, plain aspirin 16.7 ± 4.6 hrs, and enteric-coated aspirin 48.2 ± 4.6 hrs. Both PL2200 and plain aspirin showed significantly faster inhibition time than enteric-coated aspirin (p<0.0001 for both comparisons), where no significant difference was seen between PL2200 and plain aspirin (p=0.41). The incidence of non-responsiveness was: PL2200=8.1%, plain aspirin=15.8%, and coated aspirin=52.8%.  Again, the differences between PL2200 or plain aspirin when compared to coated aspirin were significant (p<0.0001 for both comparisons), but not significant between PL2200 and plain aspirin (p=0.63).  Plasma aspirin concentration profiles were similar between PL2200 and plain aspirin, with a slower time to peak and decreased AUC for coated aspirin. Recovery of platelet activity was similar with all three formulations.  A post-hoc analysis showed females to have a higher risk of non-responsiveness (p=0.0414), while all other variables were not shown to be independent predictors.

In this small study, the comparisons of aspirin pharmacokinetics and pharmacodynamics clearly favor PL2200 and plain aspirin over enteric-coated aspirin. The authors purport that enteric-coated aspirin has a clinically significant reduction in absorption, which lends an explanation to treatment failure. While PL2200 and plain aspirin are considered equivalent with regard to measured outcomes, PL2200 may be favorable due to tolerance. One of the negitives is that PL2200 contains phosphatidylcholine which has shown to increase arherosclerosis. However, the exclusion of subjects with cardiovascular history, non-obese subjects, and the lack of chronic administration studies may limit the findings of this study. Furthermore, several of the investigators have ties to PLx Pharma, which lends a strong degree of bias. As always, further studies on this subject are warranted.

Practice Pearls:

  • Aspirin remains an important piece of the therapeutic puzzle when preventing cardiovascular complications.
  • Enteric-coated aspirin displays diminished absorption compared to other aspirin formulations, which may lower its effectiveness in cardiovascular prophylaxis.
  • PL2200 contains phosphatidylcholine as an excipient, which has been shown to contribute to atherosclerosis, and may lessen its attractiveness as a treatment option.

References:

Bhatt DL, Grosser T, Dong JF, Logan D, Jeske W, Angiolillo DJ, et al. Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2017;69(6):603-12.

Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63.

 

Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD