Most Read Articles
Christina Lau, 02 Jan 2020

Tolvaptan improves dyspnoea, increases sodium levels and reduces body weight in patients with acute heart failure (HF) with or without hyponatraemia, but no significant effect is seen in mortality or rehospitalization, according to a recent meta-analysis.

Pearl Toh, 15 Apr 2020
Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic stenosis who are at low surgical risk appears to be safe with low rates of death or disabling stroke at 30 days, according to a study presented at the ACC.20/WCC Virtual Meeting.

Inclisiran lowers LDL levels in patients at high risk for ASCVD

Elaine Soliven
25 Mar 2020

Treatment with inclisiran led to a significantly reduced low-density lipoprotein (LDL) cholesterol levels in patients with atherosclerotic cardiovascular disease (ASCVD), according to two phase III randomized clinical trials.

The ORION-10* and ORION-11** cohorts consisted of 1,561 and 1,617 patients aged 65–66 years (mean LDL, 104.7 and 105.5 mg/dL, respectively) with ASCVD or ASCVD risk equivalent who had elevated LDL cholesterol levels and were previously treated with statin at a maximum tolerated dose. Participants were randomized in a 1:1 ratio to receive either four subcutaneous injections of inclisiran 284 mg or placebo on day 1 and 90, and subsequently every 6 months for a 540-day treatment period. [N Engl J Med 2020;doi:10.1056/NEJMoa1912387]

Inclisiran-treated patients had significantly reduced LDL cholesterol levels compared with the placebo-treated patients at day 510 in ORION-10 (absolute change, -56.2 vs -2.1 mg/dL; between-group difference, -52.3 percent; p<0.00) and ORION-11 trials (absolute change, -50.9 vs 1.0 mg/dL; between-group difference, -49.9 percent; p<0.001).

Both trials also demonstrated significantly lower time-adjusted change in LDL cholesterol levels in patients who received inclisiran vs placebo at day 90 and until day 540 (absolute change, -53.7 vs -0.4 mg/dL; between-group difference, -53.8 percent; p<0.001 in ORION-10 and absolute change, -48.6 vs 0.3 mg/dL; between-group difference, -49.9 percent; p<0.001 in ORION-11).

Among all the participants, PCSK9*** levels decreased by 69.8 percent and 63.5 percent (p<0.001 for both) in the inclisiran arm, whereas increased PCSK9 levels were observed in the placebo arm at 13.5 percent and 15.6 percent (p<0.001 for both) in the ORION-10 and ORION-11 trials, respectively. “Inclisiran, a small interfering RNA (siRNA) therapeutic agent, reduces hepatic synthesis of PCSK9,” the researchers said.

In a prespecified exploratory analysis, the cardiovascular composite outcome occurred at a lower rate of 7.4 percent and 7.8 percent in the inclisiran arm compared with 10.2 percent and 10.3 percent in the placebo arm for both ORION-10 and ORION-11 trials, respectively.

The incidence of adverse events (AEs) were comparable between the inclisiran and placebo arms (73.5 percent vs 74.8 percent [in ORION-10] and 82.7 percent vs 81.5 percent [in ORION-11]).

However, injection-site AEs occurred more frequently in the inclisiran arm than the placebo arm for both trials (2.6 percent vs 0.9 percent [in ORION-10] and 4.7 percent vs 0.5 percent [in ORION-11]), which were mostly mild or moderate in severity. “[Of note, even] without further injections, the LDL cholesterol-lowering effects of inclisiran are reversed at the rate of approximately 2 percent per month, which means that these effects can persist for up to approximately 2 years,” the researchers noted.

Although more injection-site AEs were reported in the inclisiran group, “we found that a regimen of inclisiran every 6 months was feasible and significantly reduced LDL cholesterol levels by approximately 50 percent,” said the researchers, noting that “sustained reductions in LDL cholesterol levels are achievable [even] with an infrequent dosing schedule of inclisiran.”

“[Furthermore,] the results of our trials have the potential to move RNAi-based therapies from the realm of rare to common diseases,” they added.

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

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

***PCSK9: Proprotein convertase subtilisin-kexin type 9

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Most Read Articles
Christina Lau, 02 Jan 2020

Tolvaptan improves dyspnoea, increases sodium levels and reduces body weight in patients with acute heart failure (HF) with or without hyponatraemia, but no significant effect is seen in mortality or rehospitalization, according to a recent meta-analysis.

Pearl Toh, 15 Apr 2020
Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic stenosis who are at low surgical risk appears to be safe with low rates of death or disabling stroke at 30 days, according to a study presented at the ACC.20/WCC Virtual Meeting.