European Journal of Cardiovascular Medicine

Atherosclerotic cardiovascular disease (ASCVD) and its clinical manifestations are the leading cause of morbidity and mortality throughout the world.

Evidence from genetic, epidemiological, and randomized clinical studies have established the key causal role of LDL-C and other apo-B-containing lipoproteins in the development of atherosclerotic disease.1

Although global guidelines suggest the concept of lower the better for LDL-C management, there are still gaps that needs to be uncovered for the effective prevention of CV events due to dyslipidemia.

It has been reported that more than 50% of coronary artery disease (CAD) associated deaths in India occur before the age of 50 years and 25% of myocardial infarctions (MIs) occur before the age of 40 years.2

Mendelian randomization studies suggests that a small change in the LDL – C achieved at younger age and maintained over a decade leads to greater reductions in the risk of having ASCVD.3 Lack of awareness among the patients, physician inertia and failure to escalate to advanced therapies necessitates the need for stringent

methods to be adopted for making improved treatment decisions and prevention of CV events in young population.4

Scientific evidence and current international guidelines recommend lowering the LDL-C to very low levels since it is associated with fewer CV events and prevention of future hospitalizations. However, these targets cannot be achieved with the aid of statins alone.

While statins are the primary pharmacological intervention for ASCVD treatment, a substantial and considerable risk persists, pressing the need for more effective treatment strategies. There remains a lack of progress in reducing CV deaths, despite having decades of robust data and in presence of good number of lipid lowering therapies.

LDL-C is the most readily modifiable cause of ASCVD from population health perspective. The liver regulates LDL-C levels by the expression of LDL- receptors which can clear LDL particles from the blood stream. The number of LDL receptors available on the liver cells can be reduced by PCSK9 proteins.

Production of these proteins can be halted by targeting the messenger RNA encoding these proteins through a natural mechanism called RNA interference. SiRNA therapies have been developed to harness the natural pathway of RNA interference.

Inclisiran is the first and only novel small interfering RNA molecule with PCSK9 targeted action. The molecule has two strands – Guide strand and a passenger strand. The passenger strand is attached to a molecule called GaINAc to provide targeted action towards hepatocytes.5,6,7 In the cytoplasm, Inclisiran binds to RNA interference machinery called RNA induced silencing complex (RISC). The RISC detaches the two strands of Inclisiran and retains the guide strand. The guide strand directs RISC to its specific target mRNA. Once the complex has found its complementary mRNA, the mRNA gets cleaved with one RISC complex cleaving multiple copies with its target mRNA thereby preventing the production of respective protein. The reduction in the production of these proteins results in increased uptake of LDL-C by the hepatocytes. Inclisiran also increases the number on LDL receptors on the hepatocytes parallelly.

Results from pivotal phase three studies, Orion 10 (in ASCVD patients) and Orion 11 (in ASCVD risk equivalent) showed that Inclisiran reduced LDL-C by more than 50% on top of oral LLTs.8 Results from long term safety study (Orion 8) shows approximately 50% reduction in the LDL-C levels from the baseline for a period of 6.8 years.9

The molecule is a pre-filled syringe with a dosing schedule of 3 doses in the first year (0, 90, 180 days) and once in 6 months every year thereafter. This eases the burden of treatment non-adherence or compliance issues which are the major concerns in the management of ASCVD disease due to multiple medications prescribed.

This study aims to measure the efficacy of Inclisiran in reducing LDL-C in patients with ASCVD in addition to oral lipid lowering agents from day 0 to day 90 following the first dose. Also, adverse events if any are also observed during the study period.

This is a real-world retrospective observational study performed to assess the efficacy and safety of Inclisiran in reducing LDL-C from day 0 to day 90 in 16 Indian ASCVD patients post the first dose.

The study also focusses on the number of patients achieving the ESC 2019 guideline recommended target LDL-C goals of < 40 mg/dl and < 55mg/dl by extreme risk and very high-risk individuals respectively.

The inclusion and exclusion criteria are as follows,

Inclusion criteria:

1.         Patients with established ASCVD

2.         Age >18 years

3.         Patients on maximally tolerated background oral LLTs atleast for a period of 3 months post an ASCVD event.

4.         Patients who are unable to achieve the guideline recommended LDL-C targets despite being on background oral lipid lowering therapies.

5.         Patients with statin intolerance.

Exclusion criteria:

1.         Patients on prior PCSK9i.

2.         Patients with NYHA class IV HF or LVEF 25%.

3.         Severe concomitant non-CV disease.

4.         HoFH.

A detailed history of each patient was taken including demographic data (current age, age at the time of diagnosis, gender, occupation, residence), history of presenting symptoms, comorbid conditions, and the patient’s treatment history followed by detailed clinical investigations and examination.

Primary outcomes: Efficacy of Inclisiran in reducing LDL-C from baseline to 90 days.

Secondary outcomes: Safety of Inclisiran from day 0 to day 90.

16 patients with the established ASCVD with the help of clinical and imaging studies were included in the study. All the patients received maximally tolerated oral LLTs post discharge. During their follow-up visit at 3 months post discharge, the LDL-C values of the patients were checked to confirm if they have attained the guideline recommended LDL-C targets. Inclisiran 284mg SC was administered to the patients in addition to maximally tolerated background LLTs who are unable to achieve the ESC 2019 guideline recommended LDL-C targets. Direct LDL-C was measured prior to the initiation of Inclisiran at day 0 and repeated at day 90.

Risk stratification of the patients was done using ESC recommendations for LDL-C treatment goals per total ASCVD risk categories as follows,

Extreme risk:

·        Patients experiencing recurrent events within 2 years despite being on oral lipid lowering therapies.

·        These patients must be managed on an LDL-C goal of < 40 mg/dl.

Very high risk:

·        Patients with documented ASCVD

·        Significant plaques on coronary angiography or CT.

·        DM or at least 3 major risk factors.

·        Severe CKD (eGFR < 30ml/min/1.73 m²).

·        A calculated score of ≥ 10% for 10-year risk of fatal CVD.

·        FH with ASCVD.

Continuous data was presented as mean and standard deviation with the help of Microsoft excel. Categorical data was expressed as percentages.

The mean age of the patients included in the study was 53 years (SD±9.43 years) consisting of 13 males and 3 females. The age and gender distribution are depicted in graph 1 and graph 2.

Graph 1. Age distribution

Graph 2. Gender distribution:

Graph 3:

COMORBIDITIES:

The comorbidities observed in 16 patients is represented in graph 3. 8 patients had diabetes, 6 patients had hypertension, 2 patients had hypothyroidism, 1 patient had renal dysfunction and 3 patients had past history of CABG performed.

CLASSIFICATION OF RISK GROUPS:

Out of 16 patients included in the study, 7 were identified as extreme risk group and 9 belonged to very high risk patients. The graphical representation of the classification of risk groups is as shown in graph 4

Graph 4:

ORAL LIPID LOWERING THERAPIES UTILIZATION:

Patients were on combination therapy (Maximally tolerated statins plus ezetimibe) or monotherapy post discharge.

14 patients were administered with the combination of Rosuvastatin 40 and ezetimibe 10mg, 1 patient received Atorvastatin 80mg in combination with ezetimibe 10mg and 1 patient received ezetimibe monotherapy due to statin intolerance.

During their follow-up visit at 3 months post discharge, the LDL-C values were scrutinized to check if they had achieved their guideline recommended LDL-C goals.

The utilization of oral lipid lowering therapies are as depicted in the graph 5:    

Graph 5

DIFFERENCES IN LDL-C LEVELS FROM BASELINE TO DAY 90:

The baseline mean LDL-C value of the patients was 124.5 mg/dl (SD±34.41 mg/dl) prior to the initiation of Inclisiran. The differences in LDL-C (in mg/dl) observed from baseline to day 90 are as shown in the table 1. After the initiation of Inclisiran, the mean value of LDL-C at day 90 was found to be 41.56 mg/dl (SD±14.28). The mean value of the differences in LDL-C observed in 16 patients was 82.93 mg/dl (SD±26.81 mg/dl).

Table 1:

                     The range of reduction in LDL-C from the baseline to day 90 are represented in the graph 6.

                                                                                                    Graph 6:

PERCENTAGE CHANGE IN LDL-C AT DAY 90:

The follow-up LDL-C was measured at day 90 after the first dose of Inclisiran. The mean percentage reduction in LDL-C from the baseline to day 90 was found to be 66.2%. 4 patients had 50 to 60% reduction from the baseline, 7 patients had 60 to 70% reduction, 4 patients had 70 to 80% reduction and 1 patient had 91.5% reduction in LDL-C from the baseline.

Efficacy of Inclisiran at day 90:

In this study, 7 patients were identified to be at extreme CV risk and 9 patients belonged to very high risk category. 5 out of 7 extreme risk patients achieved the guideline recommended target of < 40 mg/dl. 9 out of 9 very high risk patients achieved <55 mg/dl. Out of 16 patients, 1 patient achieved an ultra-LDL-C reduction of 9 mg/dl.

The graphical representation of the number of patients achieving guideline recommended targets are as shown in the graph 7.

Graph 7:

Safety of Inclisiran:

No serious adverse events or cardiac events were reported during the study duration.