Paradoxical LDL-C Increase after Switching from PCSK9 Inhibitors to Inclisiran: A Real-World Case Series

Abbreviations

ASCVD, Atherosclerotic cardiovascular disease

ASGPR, Asialoglycoprotein receptors

LDL-C, Low-density lipoprotein cholesterol

PCSK9i, PCSK9 inhibitors

RNA, Ribonucleic acid

PCSK9 inhibitors (PCSK9i) are widely used for managing hyperlipidemia in patients with atherosclerotic cardiovascular disease (ASCVD), offering significant reductions in low-density lipoprotein cholesterol (LDL-C) and proven cardiovascular benefits. The monoclonal antibodies evolocumab and alirocumab have demonstrated robust cardiovascular risk reduction in landmark trials: the FOURIER trial showed evolocumab reduced major adverse cardiovascular events by 15%,¹ while the ODYSSEY OUTCOMES trial demonstrated alirocumab reduced cardiovascular events by 15% in post-acute coronary syndrome patients.²

Inclisiran (Leqvio), a small interfering ribonucleic acid (RNA) targeting hepatic PCSK9 synthesis, has emerged as an alternative with a convenient biannual dosing schedule.³ While clinical trials have shown durable LDL-C reductions with inclisiran,⁴ real-world data on switching from PCSK9 monoclonal antibodies to inclisiran remain limited.

We followed 9 ASCVD patients at our center who transitioned from PCSK9i-based regimens (alone or in combination with statins/ezetimibe) to inclisiran primarily for convenience. All patients were previously treated with PCSK9i administered every 2 weeks, according to standard regimens (either evolocumab 140 mg Q2W or alirocumab 75 mg Q2W). LDL-C levels were recorded at baseline (final value on PCSK9i) and 3 months after the first inclisiran injection. At the time of the 3-month LDL-C measurement, all patients had received only the first dose of inclisiran. The second injection, typically scheduled at Month 3, had not yet been administered.

Surprisingly, mean LDL-C increased from 50.8 mg/dL at baseline to 77.9 mg/dL at 3 months — a 53.4% average increase (p = 0.07, paired t-test). This trend-level difference, while not statistically significant, was consistent: 7 of 9 patients experienced an LDL-C increase, including those previously on combination therapy. A spaghetti plot of individual trajectories is shown in Figure 1.

Figure 1.

Individual low-density lipoprotein cholesterol (LDL-C) trajectories before and 3 months after switching from PCSK9 inhibitors (PCSK9i) to inclisiran (Leqvio). Each line represents one patient. The baseline value corresponds to the last LDL-C measurement under PCSK9i (administered every 2 weeks). The 3-month value was measured after the first inclisiran injection, but before the second scheduled dose, which is typically given at month 3.

These findings diverge from the expected lipid-lowering effects reported in the ORION-10 and ORION-11 trials⁴ and align with other real-world observations showing LDL-C increases when switching from PCSK9 monoclonal antibodies to inclisiran.⁵ This may reflect differences in pharmacokinetics and pharmacodynamics between these therapeutic approaches. PCSK9 monoclonal antibodies achieve immediate systemic inhibition, while inclisiran relies on hepatic uptake via Asialoglycoprotein receptors (ASGPR), intracellular RNA silencing mechanisms, and hepatic processing, which may delay its full effect.^6,7

We hypothesize that this early LDL-C rebound may be due to a pharmacologic gap between the waning effect of PCSK9i and the onset of inclisiran action. The mechanism of inclisiran involves hepatic uptake through ASGPR, followed by intracellular processing to achieve PCSK9 mRNA degradation, processes that may require several weeks to reach maximum efficacy.³ In contrast, PCSK9 monoclonal antibodies provide immediate circulating PCSK9 protein inhibition with a rapid onset of action.

In high-risk patients requiring tight lipid control, clinicians may consider strategies such as overlapping PCSK9i therapy during the transition period or timing inclisiran initiation earlier to maintain continuity in LDL-C suppression. The clinical significance of this temporary LDL-C elevation in high-risk ASCVD patients warrants careful consideration, particularly given the established relationship between LDL-C exposure and cardiovascular risk.

Further real-world studies with larger populations and longer follow-up periods are warranted to evaluate optimal switching strategies, confirm this early LDL-C increase, and determine whether LDL-C levels normalize at later time points as inclisiran reaches steady-state efficacy.

LEARNING POINTS

• LDL-C may paradoxically increase 3 months after switching from PCSK9 monoclonal antibodies to inclisiran, especially if only the first dose has been administered.

• Clinicians should consider bridging strategies when transitioning high-risk ASCVD patients from PCSK9i to inclisiran to avoid transient LDL-C rebound.

DECLARATION OF CONFLICT OF INTEREST

All the authors declare no conflict of interest.

FUNDING

None.