Relative Efficacy of Alirocumab, Evolocumab, Inclisiran, and Bempedoic Acid on Lipids in Patients with Cardiovascular Disease or Familial Hypercholesterolaemia

<b>Background:</b> Lowering lipid levels after an acute coronary syndrome is critical for preventing recurrent adverse cardiovascular events. Multiple medications are now available, but there is limited evidence comparing how frequently they lead to the achievement of guideline-recommended lipid targets. <b>Methods and Results:</b> This observational study evaluated the impact of novel lipid-lowering therapies (alirocumab, evolocumab, inclisiran, and bempedoic acid) in patients with a history of atherosclerotic cardiovascular disease or familial hypercholesterolaemia treated with maximum-tolerated doses of high-intensity statin therapy with or without ezetimibe. Our primary assessment was the achievement of LDL-C below 1.4 mmol/L as per the European Society of Cardiology guidelines. The study comprised of 256 patients. Reduction in LDL-C was greatest with alirocumab and evolocumab, achieving a reduction of 62% (95% confidence interval [CI], 51 to 93; <i>p</i> < 0.001) and 58% (95% CI, 47 to 88; <i>p</i> < 0.001) after 12 months, respectively. This was followed by inclisiran with a reduction of 47% (95% CI, 37 to 78; <i>p</i> < 0.001) and bempedoic acid with a reduction of 36% (95% CI, 22 to 69; <i>p</i> < 0.001). Patients treated with alirocumab and evolocumab started from a higher baseline LDL-C than inclisiran, due to the higher LDL threshold required for initiation of alirocumab and evolocumab in the UK. Despite this, inclisiran, evolocumab, and alirocumab were all associated with similar proportions of patients achieving LDL targets: 35%, 42%, and 37% of patients achieved a guideline-recommended LDL-C target of <1.4 mmol/L. Patients with a baseline LDL-C > 4 mmol/L were more likely to reach the ESC target when treated with alirocumab or evolocumab compared to inclisiran, with results of 33.3% vs. 24.1% (<i>p</i> = 0.016) and 35.7% vs. 24.1% (<i>p</i> = 0.05). <b>Conclusions:</b> Alirocumab and evolocumab were associated with the greatest reductions in LDL-C, followed by inclisiran and bempedoic acid. Overall, alirocumab, evolocumab, and inclisiran led to approximately 40% of patients reaching ESC targets for LDL-C. In patients with a baseline LDL-C > 4 mmol/L, significantly more patients achieved LDL-C targets when treated with alirocumab or evolocumab compared to inclisiran. <b>Strength and limitations:</b> This was the first study to comprehensively compare the efficacy of novel lipid-lowering therapies in achieving guideline-recommended LDL targets within a high-risk cardiovascular population. The sample size was relatively small, especially for patients treated with bempedoic acid.