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Trials of Inclisiran in Patients With Elevated LDL Cholesterol
Study Questions:
Does intermittent dosing of inclisiran provide sustained low-density lipoprotein (LDL) cholesterol lowering?
Methods:
Participants with atherosclerotic cardiovascular disease (ASCVD) or with ASCVD risk equivalents and elevated LDL cholesterol despite receiving maximum tolerated statin therapy were enrolled in either the ORION-10 or ORION-11 trials. For ORION-10, US patients with ASCVD and LDL levels of ≥70 mg/dl were eligible. For ORION-11, European or South African patients with ASCVD or risk equivalents (diabetes mellitus, familial hypercholesterolemia, or 10-year CVD risk of ≥20%) and LDL levels of ≥70 mg/dl were eligible. All participants were required to be on stable, maximally tolerated statin therapy for ≥30 days prior to enrollment. Participants were randomized to either inclisiran (284 mg) or placebo, given by subcutaneous injections on day 1, day 90, and every 6 months after that for a period of 540 days, in a blinded fashion. Primary endpoints included placebo-corrected percent change in LDL cholesterol from baseline to day 510 and time-adjusted percent change in LDL cholesterol from baseline to after day 90 and up to day 540.
Results:
A total of 1,561 patients from ORION-10 and 1,617 patients from ORION-11 were randomized. Mean LDL cholesterol at baseline was 104.7 ± 38.3 mg/dl and 105 ± 39.1 mg/dl, respectively. At day 510, inclisiran lowered LDL cholesterol by 52.3% (95% confidence interval [CI], 48.8-55.7) in the ORION-10 trial and 49.9% (95% CI, 46.6-53.1) in the ORION-11 trial. Corresponding time-adjusted reductions were 53.8% (95% CI, 51.3-56.2) and 49.2% (95% CI, 46.8-51.6). Adverse events were similar between the inclisiran and placebo groups for each trial, except for injection-site adverse events that were more frequent in the inclisiran groups (2.6% vs. 0.9% in ORION-10, and 4.7% vs. 0.5% in ORION-11). Injection site reactions were generally mild, and none were severe or persistent.
Conclusions:
The investigators concluded that reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran administered every 6 months. More injection-site adverse events were reported with inclisiran than placebo.
Perspective:
These data suggest that inclisiran, which inhibits hepatic synthesis of PCSK9, administered intermittently, provides significant, sustained LDL lowering.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins
Keywords: Atherosclerosis, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Proprotein Convertases, Primary Prevention
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