Results: Aspirin is currently recommended for cardiovascular prevention in type 2 diabetes (T2DM). However, primary prevention trials failed to substantiate its efficacy in T2DM and incomplete platelet inhibition has been reported. Hyperglycemia has been often hypothesized to contribute to such an incomplete inhibition. We tested whether a faster recovery of platelet COX-1 activity and/or a suboptimal 24-hour glycemic control would account for an incomplete thromboxane (TX) A2 inhibition by low-dose aspirin during the 24-hour dosing interval. One-hundred T2DM patients on chronic low-dose aspirin (100 mg daily) were studied. Serum TXB2, an index of platelet COX-1 activity, was measured every 3 hours, between 12 and 24 hours after a witnessed aspirin administration, to characterize the kinetics of platelet COX-1 recovery (phase 1); 46 out of 100 patients underwent 24-hour continuous glucose monitoring (CGMS) as well. Thirty-three patients with the steepest COX-1 recovery slopes were subsequently randomized to receive aspirin 100 mg daily, 200 mg daily or 100 mg twice daily for 28 days (phase 2). On day 29, COX-1 recovery was reassessed over the 12 to 24 hour dosing interval. COX-1 activity displayed linear kinetics with large inter-individual variability in recovery slope. Multiple linear regression showed that mean platelet volume, higher BMI quartiles and age predicted serum TXB2 recovery slope, independently of other variables. None of the CGMS variability indices, (mean 24h glycemic value, standard deviation, MAGE and CONGA1-5) as well as HbA1c and fasting glucose correlated with serum TXB2 recovery slopes. A twice-daily aspirin regimen, but not a doubling of the dose, completely corrected the abnormal recovery slope of platelet COX-1 activity. We conclude that inter-individual variability in the recovery rate of platelet COX-1 activity during the aspirin dosing interval most likely reflects abnormal megakaryopoiesis associated with T2DM while is not influenced by 24-hr glucose control or other glycemic indices; inadequate TX inhibition can be overcome by a twice daily regimen.
Determinants of the Variability in the Recovery Rate of Platelet Cyclooxygenase Activity during Chronic Therapy with Low-Dose Aspirin in Type 2 Diabetes
SANTILLI, FRANCESCA;MUCCI, LUCIANA;VITACOLONNA, Ester;LATTANZIO, STEFANO;MATTOSCIO, DOMENICO;LIANI, ROSSELLA;VAZZANA, NATALE;FERRANTE, ELISABETTA;DAVI', Giovanni;PATRONO, Carlo
2011-01-01
Abstract
Results: Aspirin is currently recommended for cardiovascular prevention in type 2 diabetes (T2DM). However, primary prevention trials failed to substantiate its efficacy in T2DM and incomplete platelet inhibition has been reported. Hyperglycemia has been often hypothesized to contribute to such an incomplete inhibition. We tested whether a faster recovery of platelet COX-1 activity and/or a suboptimal 24-hour glycemic control would account for an incomplete thromboxane (TX) A2 inhibition by low-dose aspirin during the 24-hour dosing interval. One-hundred T2DM patients on chronic low-dose aspirin (100 mg daily) were studied. Serum TXB2, an index of platelet COX-1 activity, was measured every 3 hours, between 12 and 24 hours after a witnessed aspirin administration, to characterize the kinetics of platelet COX-1 recovery (phase 1); 46 out of 100 patients underwent 24-hour continuous glucose monitoring (CGMS) as well. Thirty-three patients with the steepest COX-1 recovery slopes were subsequently randomized to receive aspirin 100 mg daily, 200 mg daily or 100 mg twice daily for 28 days (phase 2). On day 29, COX-1 recovery was reassessed over the 12 to 24 hour dosing interval. COX-1 activity displayed linear kinetics with large inter-individual variability in recovery slope. Multiple linear regression showed that mean platelet volume, higher BMI quartiles and age predicted serum TXB2 recovery slope, independently of other variables. None of the CGMS variability indices, (mean 24h glycemic value, standard deviation, MAGE and CONGA1-5) as well as HbA1c and fasting glucose correlated with serum TXB2 recovery slopes. A twice-daily aspirin regimen, but not a doubling of the dose, completely corrected the abnormal recovery slope of platelet COX-1 activity. We conclude that inter-individual variability in the recovery rate of platelet COX-1 activity during the aspirin dosing interval most likely reflects abnormal megakaryopoiesis associated with T2DM while is not influenced by 24-hr glucose control or other glycemic indices; inadequate TX inhibition can be overcome by a twice daily regimen.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
