Clinical, laboratory and procedural characteristics of patients with diabetes type 2 and non-diabetic patients receiving prasugral or ticagrelor are shown in Table 1.
The study cohort comprised 121 patients on prasugrel and 99 patients on ticagrelor. In the prasugrel and the ticagrelor group 26 and 29 patients had type 2 diabetes, respectively. Diabetic patients treated with either prasugrel or ticagrelor were younger than non-diabetic individuals (P= 0.03, and P=0.05 respectively), indicating their earlier onset of atherosclerosis. Patients on ticagrelor had significantly higher serum creatinine levels (P<0.001). As expected, diabetic patients in both, prasugrel and ticagrelor groups, had significantly higher HbA1c levels (P<0.001).
Residual platelet aggregation in response to ADP/ SFLLRN / AYPGKF
We first evaluated residual platelet response to ADP in prasugrel- and ticagrelor-treated patients. Patients on prasugrel responded similarly to platelet activation by ADP as patients on ticagrelor (p=0.349, Figure 1a). Among the patients on prasugrel, diabetic patients responded similarly as non-diabetic patients (p=0.148). Of note, 2 non-diabetic patients had HRPR ADP as their levels of AU was >47, the cut-off for adequate platelet inhibition by ADP P2Y12 receptor antagonists. Their responses to SFLLRN was 92 AU and 106 AU and to AYPGKF 62 AU and 100 AU, respectively.
Interestingly, among patients on ticagrelor, patients with type 2 diabetes had significantly lower MEA ADP AU values than non-diabetic patients (p=0.019, Figure 1a).
Patients on prasugrel responded similarly to platelet activation by SFLLRN as patients on ticagrelor (P=0.227, Figure 1b). Furthermore, there were no significant differences regarding the response to SFLLRN between diabetic and non-diabetic patients in both treatment groups (prasugrel: p= 0.7129, ticagrelor: p=0.144, Figure 1b).
Patients on prasugrel responded similarly to platelet activation by AYPGKF as patients on ticagrelor (p=0.861, Figure 1c). Moreover, there were no significant differences between diabetic and non-diabetic patients in both treatment groups (prasugrel: p=0.399, ticagrelor: p=0.175 Figure 1c).
In the prasugrel group 119 patients had on-treatment residual platelet reactivity below the cut-off for HRPR ADP. Of these, 51 patients (43%) had HRPR SFLLRN and 71 (60%) had HRPR AYPGKF. In the diabetic population we identified 12 patients (46%) with HRPR SFLLRN and 16 patients (62%) with HRPR AYPGKF.
All ticagrelor-treated patients had on-treatment residual platelet reactivity below the cut-off for HRPR ADP. Of these patients 30 (30%) had HRPR SFFLRN and 55 (56%) had HRPR AYPGKF. In the diabetic population, 7 patients (24%) had HRPR SFLLRN and 11 patients (38%) had HRPR AYPGKF.
As P2Y12 inhibition also affects the response to PAR stimulation we subsequently assessed the correlations between on-treatment residual platelet reactivity in response to ADP and in response to both PAR agonists, SFLLRN and AYPGKF. Again, diabetic patients were evaluated separately from non-diabetic patients. We observed a similar correlation between the responses to ADP and SFLLRN in diabetic patients and in non-diabetic patients on prasugrel and ticagrelor (all r= 0.556, p<0.001). There was also a significant correlation between the response to ADP and AYPGKF in diabetic patients on prasugrel and ticagrelor (r= 0.273, p=0.048), as well as in non-diabetic patients (r= 0.527, p=0.001).
The two platelet thrombin receptors PAR-1 and PAR-4 play a significant mutual role in platelet activation. Therefore, it was of interest to determine if the residual responsiveness to the specific PAR agonists SFLLRN and AYPGKF correlates similarly in diabetic patients compared to non-diabetic patients treated with prasugrel or ticagrelor. We observed significant correlations between the responses to SFLLRN and AYPGKF in diabetic patients (r=0.711, p<0.001) and in non-diabetic patients (r= 0.556, p<0.001).
Residual platelet aggregation in response to ADP/ SFLLRN / AYPGKF and the correlation to HbA1c
Metabolic control may influence the responsiveness to DAPT. We therefore correlated levels of HbA1c, as a measure of a long-term blood glucose control, with on-treatment residual platelet aggregation in response to ADP. There was no significant correlation between levels of HbA1c and the response to ADP in the study population. (r=0.07, p>0.05, Figure 2a).
Based on the assumption that impaired diabetic control influences particularly thrombin-inducible platelet activation, we also assessed the correlation of HbA1c levels with the platelet response to the PAR-1 and -4 agonists SFLLRN and AYPGKF, respectively.
There were no significant correlations between levels of HbA1c and the response to SFLLRN (r= 0.09, p>0.05, Figure 2b) or the response to AYPGKF (r= 0.07, p>0.05, Figure 2c) in the study population.
Residual platelet aggregation in response to ADP/ SFLLRN / AYPGKF and the correlation to the BMI
As high BMI levels may impair the response to treatment with prasugrel or ticagreleor we assessed the correlation between BMI and the residual response to. There was no significant correlation between levels of the BMI and the response to ADP (r= -0.02, p>0.05, Figure 3a) in the study population.
High levels of BMI have been associated with increased thrombin generation and PAR-1-mediated platelet aggregation [16]. We therefore anticipated a correlation between BMI and the responsiveness to the PAR-1 and PAR-4 agonists. However, there was no significant correlation between BMI and the response to SFLLRN (r=0.06, p>0.05 Figure 3b), or the response to AYPGKF (r= 0.07, p>0.05 Figure 3c) in the study population.