Conventionally, it is recommended that Dual antiplatelet therapy (DAPT) should be continued for at least 6 months (in stable coronary artery disease) or 12 months (in acute coronary syndrome) unless contraindications occur ^[7][12]. Early suspension of antiplatelet therapy would increase the risk of recurrent ischemic events and stent thrombosis. This concept was changed because of the advent of safer, newer-generation drug-eluting stents (DES) and the awareness of increased bleeding risk caused by prolonged DAPT. Based on these reasons, a new treatment strategy of using a very short period of DAPT followed by a potent P2Y12 inhibitor monotherapy was proposed. The results from this researchsystematic review and meta-analysis of 29136 patients from four randomized controlled trials indicate that the P2Y12 inhibitor monotherapy could significantly lower the risk of bleeding complications without increasing the risk of ischemic events compared with standard DAPT in patients without DM. Surprisingly, P2Y12 inhibitor monotherapy significantly reduced the risk of ischemic events in patients with DM, but not the risk of bleeding complications. Currently, there is no clear biological rationale to explain this clinical finding. However, ticagrelor seemed to have better clinical effects when combined with a lower dose of aspirin in a PLATO study ^[8][13]. One possible hypothesis is that aspirin reduces not only the release of thromboxane A₂, but also the release of prostacyclin ^[9][14]. The therapeutic effect of ticagrelor may be attenuated when endogenous prostacyclin production is inhibited ^[10][11][15,16]. It is possible that ticagrelor works better in monotherapy than in combination therapy with aspirin. Further investigations are needed to elucidate the complex interactions between these two drugs. These findings challenge contemporary practice guideline recommendations for DAPT as the standard treatment for post-PCI care. Other meta-analyses have been published on P2Y12 inhibitor monotherapy after PCI ^[12][13][14][17,18,19]. However, the ouresearchers' meta-analysis is unique in focusing on DM patients. This distinction is important given the growing prevalence of diabetic patients and the different prognostic nature of these patients. The TWILIGHT DM substudy was the very first randomized study to show that P2Y12 inhibitor monotherapy could have better outcomes compared to standard DAPT ^[5][10]. However, the case number was relatively small. ThisOur researchstudy is the first meta-analysis to show a decrease in the risk of ischemic events with P2Y12 inhibitor monotherapy in patients with DM compared to standard DAPT.

One of the salient findings in theour researchstudy is that patients with DM indeed had a significantly higher risk of ischemic events after PCI in the modern era. The rate of ischemic events in DM and non-DM patients treated with standard DAPT was 18.7% vs. 12.8% in the GLOBAL LEADERS trial, 3.8% vs. 1.7% in the SMART-CHOICE trial, 5.9% vs. 2.8% in the TWILIGHT trial, and 5.1% vs. 2.7% in the TICO trial. All four clinical trials had the same findings. However, the risk of bleeding complications was only slightly higher in DM patients than in non-DM patients. There are several possible explanations for these findings. First, platelet reactivity was higher in DM patients than in non-DM patients ^[15][20]. Second, the turnover rate and the number of reticulated platelets were both higher in DM patients, resulting in more endothelial cell adhesion ^[16][21]. Third, DM patients tend to be more resistant to antiplatelet agents ^[17][22]. Based on these factors, thwe researchers could assume that the bleeding risk of DM patients treated with antiplatelet agents would be similar or even lower than non-DM patients. Therefore, DM patients should be treated with a different antiplatelet regimen than non-DM patients ^[18][23].

DM also leads to endothelial dysfunction (one of the main pathophysiologic mechanisms associated with cardiovascular disease) and is described as an independent determinant of ischemic heart disease and acute coronary syndrome ^[19][24]. Several biochemical pathways have been described to demonstrate the association between endothelial dysfunction and platelet activation, such as nitric oxide (NO) and prostacyclin (PGI₂) ^[20][25]. NO, a well-known atheroprotective and vasodilating substance, may also attenuate platelet activation. Blood vessels of patients with DM have diminished NO production, enhanced NO degradation, and decreased sensitivity to NO. PGI₂ is another important regulator produced by endothelial cells that inhibits platelet activation through binding to the prostacyclin receptor on platelets. DM is associated with lower levels of prostacyclin synthase in subcutaneous arteries and possibly leads to impaired formation of PGI₂ ^[21][26]. Together, endothelial dysfunction and platelet hyperactivity make DM patients much more susceptible to cardiovascular disease than non-DM patients ^[22][27].

The success of P2Y12 inhibitor monotherapy was not a coincidence. Many in vitro and ex vivo investigations have shown that aspirin provided very limited additional platelet inhibition and anti-thrombotic effect to a potent P2Y12 inhibitor ^[23][24][25][28,29,30]. Of note, most of the patients treated with P2Y12 inhibitor monotherapy were using ticagrelor. Ticagrelor is a more potent P2Y12 inhibitor than clopidogrel and may improve endothelial function and blood viscosity ^[26][27][31,32]. In addition, clopidogrel is a prodrug that requires metabolism to transform into an active form. DM patients have a greater prevalence of being unresponsive to clopidogrel than non-DM patients ^[28][33]. Impaired drug metabolism, metabolic disorders, and competition for CYP3A4 with other drugs (e.g., statins) are possible mechanisms leading to a lower concentration of clopidogrel’s active metabolite and insufficient antiplatelet effects ^[29][30][34,35]. Therefore, it is possible the benefit of P2Y12 inhibitor monotherapy in patients who underwent PCI belongs to ticagrelor alone. In the ouresearchers' previous real-world observational study, ticagrelor monotherapy resulted in substantially lower cardiovascular risk compared to clopidogrel monotherapy in patients with acute coronary syndrome (ACS) undergoing PCI ^[31][36].

3. Conclusions

Based on this resysearchtematic review and meta-analysis, P2Y12 inhibitor monotherapy followed by a short duration of dual antiplatelet therapy could significantly decrease the risk of bleeding events without increasing the risk of stent thrombosis or myocardial infarction in the general population. The benefit of reducing bleeding events was much more significant in non-DM patients than in DM patients. Surprisingly, P2Y12 inhibitor monotherapy could lower the risk of MACCE in DM patients but not in non-DM patients. These findings support that P2Y12 inhibitor monotherapy is a feasible, alternative choice of medical treatment for patients with or without diabetes mellitus undergoing percutaneous intervention with stent implantation in the modern era.