Inclisiran safely reduces LDL-C in primary prevention patients with elevated levels: Study

The study found inclisiran, a small interfering ribonucleic acid (siRNA) targeting the production of hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9), to be generally well-tolerated in primary prevention patients with increased LDL-C; the patients derived significant decrease in the levels of atherogenic lipoprotein with twice-yearly maintenance dosing.

Most cardiovascular events occur in patients without a prior atherosclerotic cardiovascular disease (ASCVD) history. Therefore, practical strategies for primary prevention are critical for reducing the global burden of ASCVD. Considering the multi-factorial causes of ASCVD, policies directed at lifestyle and behaviour and individualized approaches to control conventional risk factors such as blood pressure and lipid levels are complementary strategies to promote public health.

Apart from lifestyle and diet, the main pharmacological approach for lowering atherogenic lipoproteins in primary prevention patients is to lower LDL-C with statins. Other lipid-lowering therapies are considered if lowering LDL-C with statins is insufficient for the level of individual risk.

Kausik K Ray, Imperial College London, London, UK, and colleagues conducted a pre-specified analysis of the ORION-11 trial. The study included 203 patients at risk of, but without prior, CV events and LDL-cholesterol ≥2.6 mmol/L, despite maximally tolerated statins. 284 mg inclisiran was administered on days 1, 90, and after that, every six months up to 540 days.

Safety assessment was done over 540 days. The researchers assessed the percentage LDL-C change from baseline to Day 510 and the time-adjusted change from baseline after Day 90 and up to Day 540 (co-primary endpoints). Also, the researchers noted the percentage and absolute changes in atherogenic lipoproteins (key secondary endpoints).

The authors reported the following findings:

• The mean baseline (SD) LDL-cholesterol was 3.6 (1.5) mmol/L.
• The placebo-corrected LDL-C change with inclisiran at Day 510 was −43.7%, with a corresponding time-adjusted change of −41.0%.
• At Day 510, the placebo-corrected absolute change in LDL-C with inclisiran was −1.5 mmol/L, and the time-adjusted change was −1.3 mmol/L.
• Inclisiran remarkably decreased apolipoprotein B (apoB) and non-HDL cholesterol at Day 510 compared to placebo, with a greater probability of attaining the goals of lipoprotein and apoB, and was well-tolerated other than mainly mild, adverse events emerging from treatment at the injection site.

To conclude, the twice-yearly administration of inclisiran (following the initial and 3-month doses) by subcutaneous (SC) injection was generally well-tolerated. It provided an effective and sustained decrease in multiple atherogenic lipoproteins across a wide range of high-risk primary prevention patients with increased LDL-C despite maximally tolerated statins.

Reference:

Kausik K Ray, David Kallend, Lawrence A Leiter, Frederick J Raal, Wolfgang Koenig, Mark J Jaros, Gregory G Schwartz, Ulf Landmesser, Lorena Garcia Conde, R Scott Wright, for the ORION-11 Investigators, Effect of inclisiran on lipids in primary prevention: the ORION-11 trial, European Heart Journal, 2022;, ehac615, https://doi.org/10.1093/eurheartj/ehac615