PCSK9 inhibitors tug of war: Compliance, adverse events and LDL-cholesterol target

Dear Editor,

We read with interest López-Miranda J.’s article titled “Efficacy, benefit and safety of inclisiran” highlighting the role of inclisiran in clinical practice.¹

In the CHOLINET Registry, a phase 4 registry of Italian patients, inclisiran was administered following reimbursement criteria established by the Italian Medicines Agency (AIFA, GU 231-03.10.2022). However, less than 10% of subjects (63/659 patients) had previously administration of monoclonal antibodies against Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (mAb PCSK9i).²

At own site, in accordance with local pharmaceutical regulations and based on partial cardiovascular outcome data² we administered inclisiran when mAb PCSK9i was discontinued due to side effects or poor patient compliance. In our cohort of subjects (see Table 1 for patient's clinical characteristics), we observed a 24% increase in LDL cholesterol l levels (LDL-c in mAb PCSK9i 115 ± 57 mg/dl vs. LDL-c in inclisiran 144 ± 59 mg/dl; p 0.043). Due to concomitant intolerance to lipid-lowering therapy, none of these patients archived the LDL-c target outlined in international guidelines. Our efficacy data align with previous experience³ although during follow-up, two patients recorded a cardiovascular event and one patient self- discontinued injectable therapy.

Table 1.

Clinical characteristic of patients.

	Patients (n 17)
Male	9/17 (53%)
Mean age (years)	67 ± 10
Inclisiran administration (n°)	4 [3–5]
Previous ischemic heart disease	13/17 (76%)
Former smokers	10/17 (59%)
Heterozygous familial hypercholesterolemia	8/17 (47%)
Arterial hypertension	7/17 (41%)
Chronic kidney disease	6/17 (35%)
Diabetes	5/17 (30%)
Hyper-Lp(a)^a	5/17 (30%)
Previous peripheral vascular disease	5/17 (30%)
Obesity (BMI > 30)	4/17 (24%)
PCSK9i discontinuation
Adverse event	12/17 (70%)^b
Low compliance	5/17 (30%)
Backbone lipid lowering therapy
Ezetimibe	7/17 (41%)
Moderate/low intensity statins^c,d	5/17 (30%)
Nutraceuticals	4/17 (24%)
Fibrates	2/17 (12%)
Omega-3	1/17 (6%)
Lipoprotein apheresis	5/17 (30%)

Legend.

a

Lipoprotein (a) > 50 mg/dl.

b

8/12 (67%) recorded adverse events with both alirocumab and evolocumab.

c

Moderate-intensity statins: atorvastatin (10 and 20 mg), rosuvastatin (5 and 10 mg), simvastatin (20 and 40 mg).

d

Low-intensity statins: simvastatin (10 mg), lovastatin (any dosage), pravastatin (any dosage), fluvastatin (any dosage).

Data from the CHOLINET Registry² partially contradict the “strike early-strike strong” strategy proposed in the AT-TARGET-IT registry⁴ as treatment with mAb PCSK9i is associated with discontinuation of oral lipid lowering therapy, leading to subsequent LDL-c worsening.⁵

This represent a tug of war between lipid lowering strategies and achieving LDL-c targets for cardiovascular prevention. It is well known that mAb PCSK9i alone cannot restore LDL-c levels in patients with inherited hypercholesterolemia and lipid-lowering therapy intolerance.⁶ The most appropriate therapeutic choice should be considered when a patient is not receiving background lipid-lowering therapy with statins and ezetimibe, especially in light of new guidelines and LDL-c targets.^1,6

Author approval

All authors have seen and approved the study submitted.

No part of the submitted work has been published or is under consideration for publication elsewhere.

Authors’ contribution

FS and BDP contributed to conception or design, drafted and critically revised the manuscript. All authors read and approved the final version of the manuscript.

Notes. Data have not been presented at any congress.

Consent for publication

The patient signed the informed consent from form for anonymous medical data usage in our paper.

Funding sources

No financial support was received.

Conflict of interest

No conflict of interest for each author.

Acknowledgements

None.