Loss of lipid-lowering effect of evolocumab over time: A case report

Abstract

Background/Synopsis

While real-world data on PCSK9 inhibitors (PCSK9i) indicate occasional non-response, reports of an initial strong lipid-lowering effect followed by loss of efficacy remain rare.

Objective/Purpose

To describe a case of a robust initial response to evolocumab with subsequent loss of lipid-lowering efficacy and evaluate the response to an alternative PCSK9i, alirocumab.

Methods

Review of case report.

Results

A 64-year-old woman with type 2 diabetes mellitus (T2DM), papillary thyroid cancer, prior PCI for multi-vessel coronary artery disease (CAD), and a strong family history of premature cardiovascular disease was diagnosed with heterozygous familial hypercholesterolemia. Despite treatment with rosuvastatin (40 mg) and ezetimibe (10 mg), her lipid levels remained suboptimal (non-HDL-C: 145 mg/dL, LDL-C: 125 mg/dL). Additional testing revealed an Lp(a) of 515 nmol/L and ApoB of 112 mg/dL, prompting initiation of PCSK9i therapy.

She initially received alirocumab but switched to evolocumab after several months due to insurance changes. At nadir on rosuvastatin, ezetimibe, and evolocumab, her non-HDL-C dropped to 43 mg/dL, LDL-C to 27 mg/dL, Lp(a) to 359 nmol/L and ApoB to 37 mg/dL. However, after ten months on evolocumab, her non-HDL-C increased to 90 mg/dL and LDL-C to 64 mg/dL, followed by a further rise three months later (non-HDL-C: 156 mg/dL, LDL-C: 135 mg/dL), despite confirmed adherence to all lipid-lowering therapies and proper injection technique. These findings were confirmed on repeat testing. Lp(a) remained lower than baseline at 281 nmol/L, with ApoB at 110 mg/dL. Secondary causes, including medication interactions, thyroid dysfunction, nephrotic syndrome, obstructive liver disease and dermatological absorption issues, were ruled out.

She was switched to alirocumab, leading to lipid improvement within six weeks (non-HDL-C: 93 mg/dL, LDL-C: 77 mg/dL, ApoB: 80 mg/dL). However, the degree of lipid-lowering was less pronounced than her initial response to evolocumab, with Lp(a) increasing to 369 nmol/L.

Conclusions

This case highlights an unusual loss of evolocumab efficacy despite an initially strong response. Potential mechanisms include the development of neutralizing anti-drug antibodies or acquired resistance related to PCSK9 or LDLR mutations. Given her initial robust response, a genetic loss-of-function mutation in LDLR or PCSK9 is less likely, raising the possibility of antibody-mediated drug inactivation. Further research is needed to elucidate mechanisms of variable PCSK9i efficacy and determine whether switching to an alternative PCSK9i is an effective strategy.