How Will the New Player in Dyslipidemia Therapy Change the "Rules of the Game"?
Inclisiran, as an innovative drug indicated for adult patients with primary hypercholesterolemia or mixed dyslipidemia, was registered in the European Union at the end of 2020. Internists and cardiologists can now share their first experiences with this therapy in real practice. Case reports from the Czech Republic have also been published in specialized literature.
Dyslipidemia in the Czech Republic
Epidemiological evaluation post-MONICA, among other useful data, provided us with information on the prevalence of dyslipidemia in the Czech population according to age groups. Between 2015 and 2018, dyslipidemia (even with a lenient definition) was detected in 80.5% of the male and 72.7% of the female population, and in the oldest age group (55 to 64 years), it was present in approximately 90% of individuals (women 93.7%, men 88.8%). The high occurrence of dyslipidemia in the population is certainly related to low physical activity, alcohol consumption, and smoking. Consequently, only a limited number of people have a consistently optimal lipid profile and are free from atherosclerosis, which would necessitate lifestyle adjustments.
Treatment Options After Failure of Conventional Therapy
With conventional therapy based mainly on statins, or their combination with ezetimibe, it has not been very successful in achieving target low-density lipoprotein (LDL-C) levels in our country. Previous meta-analyses of clinical studies have shown that in high-risk patients, a reduction in LDL-C by 1 mmol/l leads to a 25% reduction in coronary events and a decrease in coronary and overall mortality by 19% and 12%, respectively. Therefore, it is essential to seek more effective treatments and strive to reach target lipid profile values with patients.
A newer and more effective approach in dyslipidemia therapy involves targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). This enzyme reduces the number of LDL-C receptors present on hepatocyte membranes, which is undesirable in dyslipidemia. Its activity can be inhibited, as can be done by monoclonal antibodies alirocumab and evolocumab, or its quantity can be directly reduced by interfering with its synthesis.
Suppression of PCSK9 Synthesis
This is precisely the mechanism of action of inclisiran. The drug consists of a modified small interfering double-stranded ribonucleic acid (siRNA) that reduces the translation of mRNA for PCSK9 through RNA interference. The reduction in PCSK9 production increases the number of LDL-C receptors on the hepatocyte membrane and subsequently decreases the concentration of LDL-C in the blood. The inclisiran molecule is designed to be selectively captured in hepatocytes. Compared to older hypolipidemic agents based on RNA interference, which consisted of a single-stranded molecule, inclisiran as a double-stranded RNA is minimally immunogenic and its administration is associated with higher efficiency and safety. Results from the ORION 9, 10, and 11 clinical studies indicate that inclisiran can reduce LDL-C concentrations by approximately 50% regardless of the prior treatment.
Availability of Combination Therapy
Therapy in patients where conventional hypolipidemic treatment does not achieve acceptable results should in the future rely on a combination of standard hypolipidemic agents with drugs targeting PCSK9. Currently, used PCSK9 inhibitors are distributed through a centralized care system, which is inadequate for such a widespread issue as dyslipidemia. Therefore, three specialist societies of the Czech Medical Society of JEP (ČLS JEP) have submitted a request to the State Institute for Drug Control (SÚKL) for their prescription to be allowed also to outpatient specialists.
Inclisiran is approved by the European Medicines Agency (EMA) and its reimbursement in the Czech Republic is currently under negotiation.
First Experiences with Inclisiran in Our Country – Case Report
Inclisiran has already been administered to patients in several locations in our country. One of these places is the Cardiology Department at the Regional Hospital in Liberec, where doctors, among other things, addressed the case of a patient (born in 1957) with a family history of familial hypercholesterolemia. In 2019, the patient underwent a double bypass and subsequently underwent several interventions on coronary arteries for unstable angina pectoris. Echocardiographic examination showed lateral hypokinesis. This man had arterial hypertension since 2007, mixed hyperlipidemia (intermittently treated with statins), and slight overweight in his medical history.
The patient did not tolerate a combination of high-dose atorvastatin and ezetimibe, so a reduced dose of rosuvastatin was chosen for him and adding ezetimibe was considered, as the target LDL-C values (3.09 mmol/l) were not achieved. In December 2021, inclisiran was started, and after 3 months, an LDL-C value of 1.38 mmol/l was measured. By combining a low dose of rosuvastatin with targeted inclisiran therapy, an LDL-C reduction of 55% was achieved. This case report thus confirms that inclisiran represents a promising therapy with a good safety profile even in challenging cases of dyslipidemia patients.
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Source: Homolová Richtrová N. First Experiences with Inclisiran Treatment and Vision of Therapy Approach. Remedia 2022; 32 (3): 266−271.
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