Use of Inclisiran in a Patient in Secondary Cardiovascular Prevention
Lowering LDL cholesterol (LDL-c) is one of the primary goals for reducing cardiovascular (CV) risk due to its proven mortality reduction. However, many patients with familial hypercholesterolemia or CV disease fail to reach target LDL-c levels even when given the maximum tolerated dose of conventional hypolipidemic treatment. For these patients, inclisiran—a small interfering RNA (siRNA) that lowers cholesterol—offers hope. In the following article, we present a model example of a patient after an acute coronary event for whom starting inclisiran treatment is appropriate.
Mechanism of Action and Administration of Inclisiran
As the first siRNA approved for the treatment of dyslipidemia, inclisiran induces catalytic cleavage of mRNA for PCSK9 in hepatocytes, thereby increasing the expression of LDL-c receptors on the surface of these cells, enhancing the clearance of LDL-c.1 The result is a persistent reduction in circulating LDL-c by >50%, as demonstrated in randomized controlled trials.1, 2 This reduction is consistent across various patient groups, such as those with familial hypercholesterolemia, known CV disease, or high CV risk. Administering inclisiran once every 6 months (after the second dose administered 3 months after the first dose) via subcutaneous injection, coupled with the favorable safety profile of this drug, may improve patient compliance with the treatment.2
Model Example of Use
An example of inclisiran use can be a patient in secondary cardiovascular prevention. Specifically, envision a 59-year-old man with long-term treatment for hypertension with an ACE inhibitor who suffered a myocardial infarction with ST segment elevation (STEMI). He has elevated LDL cholesterol levels (4.3 mmol/l) and has been prescribed acetylsalicylic acid, ticagrelor, a beta-blocker, and a statin. Despite not having any further issues, he fails to reach the target LDL-c values for 2 years post-coronary event. His LDL-c levels hover around 2.9 mmol/l with the maximum statin dose, while the target level for secondary prevention is <1.4 mmol/l. Even after adding ezetimibe, his LDL-c level remains around 2.3 mmol/l for a year. Therefore, this patient cannot achieve the target value as per European guidelines, and his physician justifiably fears a recurrence of CV events. For such a patient, starting inclisiran, with the advantage of twice-yearly administration, could lead to a significant reduction in LDL-c and achievement of the recommended level.
Reduction of LDL-c and CV Event Risks
An analysis of pooled data from phase III ORION-9, -10, and -11 trials, which included patients with heterozygous familial hypercholesterolemia, atherosclerotic CV disease, or high CV risk on the maximum tolerated dose of statin, showed that adding inclisiran significantly reduces the risk of major adverse cardiovascular events (MACE), including cardiovascular death, cardiac arrest, non-fatal myocardial infarction, and fatal and non-fatal stroke. After 90 days of treatment, inclisiran led to a 50.6% reduction in LDL-c compared to placebo, translating to an absolute reduction of 1.37 mmol/l (p < 0.0001). In 3655 enrolled patients randomized to inclisiran (284 mg on days 1 and 90, then every 6 months) or placebo, 8.3% experienced MACE over 18 months. Inclisiran administration was associated with a 26% reduction in the risk of this event (odds ratio [OR] 0.74; 95% CI 0.58–0.94).3
These preliminary results should be further confirmed by follow-up studies.
Indications for Inclisiran
Inclisiran is indicated for adults with primary hypercholesterolemia (heterozygous familial and non-familial forms) or mixed dyslipidemia in combination with a statin or a statin and another hypolipidemic agent in patients who fail to reach their target LDL-c levels with the maximum tolerated statin dose. Inclisiran monotherapy or combination therapy with another hypolipidemic agent is possible in cases of statin intolerance or contraindication.4
(zza)
Sources:
1. Rogula S., Błażejowska E., Gąsecka A. et al. Inclisiran-silencing the cholesterol, speaking up the prognosis. J Clin Med Jun 2; 10 (11): 2467, doi: 10.3390/jcm10112467.
2. Pirillo A., Catapano A. L. Inclisiran: how widely and when should we use it? Curr Atheroscler Rep 2022 Oct; 24 (10): 803−811, doi: 10.1007/s11883-022-01056-0.
3. Ray K. K., Raal F. J., Kallend D. G. et al.; ORION Phase III investigators. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J 2022 Nov 4: ehac594, doi: 10.1093/eurheartj/ehac594 [Epub ahead of print].
4. SPC Leqvio. Available at: www.ema.europa.eu/en/documents/product-information/leqvio-epar-product-information_cs.pdf
Did you like this article? Would you like to comment on it? Write to us. We are interested in your opinion. We will not publish it, but we will gladly answer you.