Effective treatment of statin- and ezetimibe-resistant hyperlipidemia in a patient with active membranous nephrotic syndrome using a PCSK9 inhibitor

Background/Synopsis

Hyperlipidemia is a characteristic of nephrotic syndrome (NS), contributing to increased cardiovascular risk. Proprotein convertase subtilisin kexin 9 (PCSK9) is upregulated in NS, leading to dysregulated lipid metabolism. Consequently, PCSK9 inhibitors are emerging as promising therapeutic agents for NS-associated hyperlipidemia. This case report describes the effectiveness of a PCSK9 inhibitor in treating statin- and ezetimibe-resistant hyperlipidemia in a patient with active membranous nephropathy (MN).

Objective/Purpose

To highlight the efficacy of PCSK9 inhibitors in managing NS-associated hyperlipidemia.

Methods

A chart review was conducted.

Results

A 40-year-old male with MN-type nephrotic syndrome complicated by recurrent pulmonary emboli and chronic thromboembolic pulmonary hypertension (CTEPH), and insulin-dependent diabetes presented with severe hyperlipidemia on high-dose statin and ezetimibe. His immunotherapy for NS was delayed due to a planned pulmonary thromboembolectomy for CTEPH.

The patient did not drink alcohol and smoked half a pack of cigarettes daily. He was unable to exercise due to dyspnea from CTEPH. His lipid panel before medical therapy was total cholesterol (TC) 295 mg/dL, triglycerides (TG) 172 mg/dL, and LDL 195 mg/dL. After initiation of atorvastatin 80 mg and ezetimibe 10 mg, his lipid panel remained elevated with TC 296 mg/dL, TG 323 mg/dL, and LDL 174 mg/dL. Lipoprotein(a) was 69 mg/dL.

Given persistent hyperlipidemia, he was started on the PCSK9 inhibitor Evolocumab. Within one month, his lipid profile dramatically improved to TC 120 mg/dL, TG 131 mg/dL, and LDL 44 mg/dL, representing a 74% reduction in LDL and 59% reduction in TG. The patient underwent planned pulmonary thromboembolectomy and started NS treatment post-surgery.

Conclusions

This case highlights the efficacy of Evolocumab in managing hyperlipidemia in a patient with active MN-type nephrotic syndrome who had not yet started immunotherapy. Previous case reports have shown similar successes with PCSK9 inhibitors in immunotherapy-refractory nephrotic syndrome not responding to statins, including a Japanese report where Evolocumab reduced LDL by 78% in a patient with refractory minimal change disease (MCD) on atorvastatin. Another case series showed a 36.8% reduction in LDL with PCSK9 inhibitors in 12 patients with refractory MN-, MCD-, or focal segmental glomerulosclerosis (FSGS)-type NS not at LDL goal with statin ± ezetimibe. Our case adds to the existing literature by demonstrating that PCSK9 inhibitors can effectively treat NS-associated hyperlipidemia even before immunotherapy initiation, supporting the need for future studies on PCSK9 inhibitors as a potent therapeutic for NS-associated hyperlipidemia.