Novel Lipid Therapies: 5 Things to Know

Alan P. Jacobsen, MB, BCh, BAO; Eamon Y. Duffy, MD, MBA; Seth S. Martin, MD, MHS

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June 23, 2020

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2. Randomized clinical trial data have demonstrated that the investigational agent inclisiran effectively reduces LDL levels in patients with ASCVD or heterozygous familial hypercholesterolemia (HeFH).

Inclisiran is a small interfering RNA molecule that targets the PCSK9 messenger RNA, thus decreasing the hepatic synthesis of PCSK9. A triantennary N-acetylgalactosamine (GalNAc) modification of the inclisiran molecule permits rapid hepatic uptake through the asialoglycoprotein receptors, which are expressed exclusively on hepatocytes, such that inclisiran is no longer detectable in blood plasma after 24-48 hours.

Recently published results from three phase 3 trials (ORION-9, ORION-10, and ORION-11) have demonstrated the effectiveness of inclisiran in reducing LDL levels.

In the ORION-9 trial, 482 patients with HeFH were randomized to receive 300 mg of inclisiran or placebo on days 1, 90, 270, and 450 of the study. Results from this trial showed a reduction of LDL level of 39.7% in patients who received inclisiran compared with an increase in LDL level of 8.2% in patients who received the placebo.

The ORION-10 trial enrolled 1561 patients with ASCVD and a mean LDL level of 104 mg/dL, and the ORION-11 trial enrolled 1617 patients (203 of whom were risk-equivalent patients) with a mean LDL level of 105 mg/dL. Patients in both ORION-10 and ORION-11 were randomized to receive four injections of inclisiran or placebo on days 1, 90, 270, and 450. The difference in change in LDL levels from baseline to day 510 between the inclisiran and placebo groups was −52.3% (95% CI, −55.7 to −48.8; P < .001; ARR, −54.1 mg/dL) in ORION-10. Similar findings were demonstrated in ORION-11. Adverse event profiles in ORION-10 and ORION-11 were similar between the inclisiran and placebo groups. Although injection-site reactions were more common in the inclisiran group, they occurred in < 5% of participants. There was less occurrence of exploratory CV endpoints in the inclisiran group in both trials, but the total number of events was low.

Results of the pivotal ORION-4 trial, a clinical outcomes study of the effects of inclisiran among people with cardiovascular disease, are expected to be published in 2025.

3. Physicians should consider prescribing high-dose icosapent ethyl (IPE) to high-risk individuals who have elevated TG levels despite statin therapy.

IPE is a high-dose, highly purified synthetic derivative of EPA, which was initially approved for patients with severe hypertriglyceridemia; however, studies on IPE have demonstrated other benefits to its use. The REDUCE-IT trial randomized 8179 high-risk patients with elevated TG levels receiving statin therapy to also receive a total of 4 g IPE (2 g twice daily) or placebo for a mean of 4.9 years. This study demonstrated that the relative risk for major adverse CV events was 25% lower (absolute reduction, 4.8%) among patients who received 4 g IPE than patients who received a placebo. The reduction in CV events seen in REDUCE-IT was greater than that predicted by the reduction in TG levels alone, suggesting benefits of IPE beyond that of lowering TG (eg, anti-inflammatory, antioxidative, plaque-stabilizing, membrane-stabilizing properties). Based on these findings, in December 2019, the US Food and Drug Administration (FDA) approved IPE as an adjunct therapy to reduce the risk of CV events in adult patients with elevated TG levels. The European Medicines Association (EMA) is expected to complete its review of EPI for this secondary indication by the end of 2020.

The results of REDUCE-IT emphasize the role of TGs in the development of ASCVD and may have considerable practice-changing implications for cholesterol management. Although further trials are underway, the revised 2019 ESC/EAS guidelines have been updated to advise consideration of IPE in high-risk patients who have TG levels between 135 and 499 mg/dL despite statin treatment.

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