Decline in LDL-C control in patients with dyslipidemia treated with PCSK9-inhibitors: The role of obesity in LDL-C target achievement

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-Is: alirocumab and evolocumab) have improved dyslipidemia management in patients with high cardiovascular risk. However, some patients fail to reach low-density lipoprotein cholesterol (LDL-C) targets. OBJECTIVE: To evaluate factors influencing PCSK9-I therapy effectiveness. METHODS: A retrospective study (2018-2023) analyzed adults treated with a PCSK9-I for at least 6 months with heterozygous familial hypercholesterolemia (He-FH) in primary prevention, dyslipidemia in secondary prevention, or diabetes with associated complications. Clinical, anthropometric data and lipid profiles were collected at baseline and after 6, 12, 24, and 36 months. The primary outcome was LDL-C target achievement according to European Society of Cardiology/European Atherosclerosis Society guidelines. RESULTS: Among 180 patients, approximately 45% achieved the LDL-C target. Patients with overweight and obesity showed significantly lower LDL-C reductions compared to normal-weight patients. Those reductions for overweight patients were 47.8%, 50.0%, and 44.0%, and for obese patients were 25.6%, 29.4%, and 28.6%, whereas normal-weight patients achieved reductions of 54.5% (P = .021), 62.5% (P = .024), and 65.4% (P = .024), respectively. Multivariate analysis confirmed these findings (odds ratio [OR]: 0.18, 95% CI, 0.06-0.53, P = .002) and highlighted that He-FH was associated with lower likelihood of achieving LDL-C targets (OR: 0.35, 95% CI, 0.15-0.82, P = .015). Conversely, patients with coronary artery disease (CAD) were more likely to reach LDL-C targets (OR: 4.54, 95% CI, 1.98-10.41, P < .0001). Concomitant oral lipid-lowering therapy was linked to a higher probability of achieving LDL-C targets compared to PCSK9-I monotherapy (OR: 14.5, 95% CI 2.26-92.9, P = .005). CONCLUSION: Overweight, He-FH, CAD, and concomitant oral lipid-lowering therapy could influence the achievement of LDL-C target in patients treated with PCSK9-Is.