Aspirin, clopidogrel and prasugrel monotherapy in patients with type 2 diabetes mellitus: a double-blind randomised controlled trial of the effects on thrombotic markers and microRNA levels

Abstract

Background: Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM. Materials and methods: 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions. Results: Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/ mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083). Conclusions: Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM.

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

“…The three miRNAs responsive to P2Y12 inhibition (miR-197, miR-223 and miR-223*) have previously been described as being enriched in platelets [23]. Also, a crossover study including 56 patients with type 2 diabetes mellitus found plasma levels of miR-197 and miR-223 alongside miR-191 and miR-24 to be lower in diabetic patients on the P2Y12 inhibitor prasugrel, compared with aspirin [26]. We have previously reported a decrease of these platelet-related miRNAs in plasma of healthy volunteers upon treatment with P2Y12 inhibitors [23].…”

“…When miRNA levels were compared before and 6 hours after endotoxin administration, leukocyte-enriched miR-150 was found to have the strongest decrease ( Figure 2, Table S2) [24]. In contrast, miRNAs previously implicated as markers of platelet activation (miR-197, miR-223, miR-26b, miR-191, miR-24; [23,25,26]) showed higher levels after endotoxin treatment. Leukocyte-enriched miR-150 showed strongest fall in abundance, while platelet-enriched miR-197 and miR-223 showed the strongest rise.…”

PAR-4/Ca2+-calpain pathway activation stimulates platelet-derived microparticles in hyperglycemic type 2 diabetes

“…We also observed no influence on circulating levels of PMP by antiplatelet therapy in agreement with others [ 37 , 38 ], who showed that aspirin treatment did not change the level of PMP in T2DM. None of the study subjects assumed prasugrel, which shows the most potent effect on platelet inhibition in T2DM [ 39 ]. On the other hand, TF-MPs appeared to be significantly lower in antiplatelet treated patients [ 37 ].…”

Anesthetics may modulate cancer surgical outcome: a possible role of miRNAs regulation

“…Aspirin regulated miR-155/eNOS (endothelial nitric oxide synthase) pathway and suppressed endothelial cell dysfunction under the inflammation [ 104 ]. Also, aspirin suppressed the expression of miR-24, − 191 and − 197 in plasma [ 105 ].…”