Inclisiran sustains LDL-C reduction in high-risk patients with ASCVD

Treatment with inclisiran consistently reduced low-density lipoprotein cholesterol (LDL-C) levels in patients with, or at high risk of, atherosclerotic cardiovascular disease (ASCVD), regardless of glycaemic status, based on a pooled analysis of the ORION-10* and ORION-11** studies presented at AHA 2021.

“[D]iabetes is a highly prevalent disease and individuals with disorders in glucose metabolism, both prediabetes and diabetes, have a high risk of ASCVD, … [A previous study showed that treatment with inclisiran appears to be] well tolerated and … sustained LDL-C lowering [in this population],” said study author Professor Lawrence Leiter from the Li Ka Shing Knowledge Institute, St Michael’s Hospital at the University of Toronto in Toronto, Ontario, Canada.

In this post hoc analysis, a total of 3,174 patients with ASCVD or ASCVD risk equivalent were analysed and categorized according to their baseline glycaemic status: normoglycaemia (n=833), prediabetes (HbA_1c 5.7–6.4 percent; n=1,094), and diabetes (HbA_1c ≥6.5 percent; n=1,247). Participants were randomized in a 1:1 ratio to receive either inclisiran sodium 300 mg (equivalent to 284 mg of inclisiran) or placebo at days 1 and 90, followed by every 6 months, over the 540-day study treatment period. [AHA 2021, abstract P336]

At day 510, a significant reduction in LDL-C levels was observed among inclisiran-treated patients with normoglycaemia, prediabetes, or diabetes compared with placebo-treated patients (least squares [LS] mean difference, -49.0 percent, -51.8 percent, and -52.1 percent, respectively; p<0.0001 for all).

At days 90–540, those on inclisiran also achieved a significant reduction in time-adjusted percent change in LDL-C levels from baseline, irrespective of glycaemic status, than those on placebo (LS mean difference, -49.1 percent [normoglycaemia], -52.6 percent [prediabetes], and -52.3 percent [diabetes]; p<0.0001 for all).

A consistently lower LDL-C level from baseline to day 510 was observed with inclisiran than with placebo across all glycaemic subgroups stratified by age, sex, diabetes medication, background lipid-lowering treatment, BMI, and waist circumference at baseline.

The rates of treatment-emergent adverse events (AEs) and serious AEs were similar between the two treatment arms, regardless of glycaemic status. However, more injection-site AEs occurred in the inclisiran arm than the placebo arm (4.1 percent vs 1.2 percent, 4.7 percent vs 0.0 percent, and 0.8 percent vs 0.3 percent for patients with normoglycaemia, prediabetes, and diabetes, respectively), which were mostly considered mild-to-moderate in severity.

“[In conclusion,] a significant difference between treatment arms was observed with … inclisiran when administered twice-yearly, after the initial and 3-month doses … [Inclisiran] provides effective and sustained LDL-C lowering, irrespective of glycaemic status,” said Leiter.

“Inclisiran was generally well tolerated, … and therefore inclisiran may represent a new therapeutic option for LDL-C lowering in patients with prediabetes or diabetes who often require more intensive lipid-lowering measures to attain guideline-recommended LDL-C goals,” he added.

*ORION-10: Inclisiran for participants with atherosclerotic cardiovascular disease and elevated low-density lipoprotein cholesterol

**ORION-11: Inclisiran for subjects with ASCVD or ASCVD-risk equivalents and elevated low-density lipoprotein cholesterol