Atherosclerotic cardiovascular disease (ASCVD) poses a major threat to patients with type 2 diabetes, even without prior events. While aspirin is recommended for primary prevention in high-risk diabetic individuals, its benefits are offset by increased bleeding risks, particularly gastrointestinal (GI) bleeding. Clopidogrel, a P2Y12 inhibitor, has shown fewer GI events in secondary prevention trials, but its role in primary prevention remains unclear. This study aimed to compare the effectiveness and safety of clopidogrel versus aspirin in high- and very high-risk diabetic patients without ASCVD, using real-world data from the Korean National Health Insurance Service–National Sample Cohort (NHIS-NSC) from 2010-2019.
From 133,534 diabetic patients, 10,453 high-/very high-risk individuals (9,550 on aspirin, 903 on clopidogrel) receiving single antiplatelet therapy for ≥90 days were identified after exclusions for prior ASCVD or incomplete data. High-risk was defined as diabetes ≥10 years plus factors like age ≥50, hypertension, dyslipidemia, smoking, or BMI ≥25 kg/m²; very high-risk included target organ damage or ≥3 factors. Propensity score matching (1:1) balanced covariates including age, gender, hypertension, and comorbidities, yielding 902 pairs. Primary endpoint: net adverse clinical events (NACEs; all-cause death, myocardial infarction [MI], stroke, intracranial hemorrhage [ICH], GI bleeding). Secondary endpoints: efficacy (death, MI, stroke) and bleeding (GI, ICH). Cox regression and Kaplan-Meier analyses were used, with follow-up until first event or December 31, 2019.
Mean age was 66 years (51% male). Post-matching, no significant NACE difference (HR: 0.97; 95% CI: 0.79–1.19). Efficacy endpoints were similar (HR: 1.02; 95% CI: 0.82–1.26), including MI (HR: 0.52; 95% CI: 0.10–2.83), stroke (HR: 1.22; 95% CI: 0.60–2.48), and death (HR: 1.07; 95% CI: 0.86–1.33). Clopidogrel trended toward lower GI bleeding (HR: 0.48; 95% CI: 0.23–1.01; p=0.053), with similar ICH (HR: 1.36; 95% CI: 0.64–2.88). Subgroup analysis showed significant NACE reduction with clopidogrel in males (HR: 0.73; 95% CI: 0.54–0.99; p-interaction=0.0015), but not females or other subgroups (age, BMI, diabetes duration).
Clopidogrel offers comparable efficacy to aspirin for primary ASCVD prevention in high-risk diabetic patients, with a potential safety advantage in reducing GI bleeding. It may be preferable for males or those at elevated bleeding risk, supporting personalized antiplatelet strategies. Limitations include retrospective design, residual confounding, and underpowering for rare events; prospective trials are needed.
