The development of novel pharmacotherapies targeting low-density lipoprotein (LDL), lipoprotein a, and triglycerides (TG) to help prevent patients' risk of atherosclerotic cardiovascular disease (ASCVD) has accelerated during the past decade. Some of these therapies have been approved as an adjunct to primary dyslipidemia therapies. Major societal guidelines, including those from the American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS), continue to recommend the highest tolerated statin as first-line therapy to lower LDL levels, as well as the addition of ezetimibe for patients considered to be at very high risk for ASCVD. In addition to these recommendations, the ACC/AHA and ESC/EAS guidelines now support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to reduce patients' LDL levels and risk for ASCVD.
There are multiple additional therapies to discuss. Clinical outcomes data now support the use of a high-dose, highly purified form of omega-3 fatty acid, eicosapentaenoic acid (EPA), for patients with elevated TG levels. Furthermore, several novel therapies with innovative mechanisms to target hepatocytes and minimize off-site adverse effects have shown promising results in phase 3 trials, with clinical outcomes data on the horizon.
Here are five things to know about novel lipid therapies.
The PCSK9 protein promotes the degradation of the LDL receptor, resulting in diminished clearance of LDL from the bloodstream. The PCSK9 inhibitors alirocumab and evolocumab are monoclonal antibodies that target the PCSK9 protein and increase LDL receptor activity, and they have been shown to decrease circulating LDL levels by an average of 60%.
The ODYSSEY OUTCOMES and the FOURIER trials were two large randomized controlled trials of patients with clinical ASCVD who, despite statin therapy, had baseline LDL levels ≥ 70 mg/dL. The ODYSSEY OUTCOMES trial demonstrated a 15% relative reduction (absolute risk reduction [ARR], 1.6%) of cardiovascular (CV) events in patients receiving alirocumab during a median follow-up of 2.8 years. Similarly, in the FOURIER trial, evolocumab significantly reduced the risk primary composite outcome by 15% (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001; ARR, 1.59%) during a median follow-up of 2.2 years.
Although the ESC/EAS and AHA/ACC support the use of PCSK9 inhibitors, the class of recommendation/strength of recommendation differs between the two guidelines. Although the ESC/EAS guidelines outline a more aggressive strategy regarding the use of PCSK9 inhibitors in patients with ASCVD, the strength of recommendation for use of PCSK9 inhibitors in the AHA/ACC guidelines is based on concerns over the cost-benefit ratio (which continues to be an issue despite a 60% reduction in the cost of these drugs). The current AHA/ACC guidelines recommend considering PCSK9 inhibitors in patients striving to have optimal LDL control (LDL level ≥ 70 mg/dL for very high-risk secondary prevention or LDL level ≥ 100 mg/dL for high-risk primary prevention).
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.
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.
Approved by the FDA and EMA in February 2020, bempedoic acid is another nonstatin agent shown to lower LDL. An inhibitor of adenosine triphosphate citrate lyase, bempedoic acid reduces cholesterol synthesis and upregulates LDL receptors in the liver, promoting cholesterol clearance from the blood.
Two phase 3 studies, CLEAR Harmony and CLEAR Wisdom, evaluated the safety and efficacy of bempedoic acid as an adjunct to maximally tolerated statin therapy in patients with ASCVD and/or HeFH versus placebo. The CLEAR Harmony trial assessed patients for 1 year, and the CLEAR Wisdom trial assessed participants for 12 weeks. Both studies showed significant reductions in LDL levels in patients receiving add-on bempedoic acid compared with those given placebo. A notable safety finding in the Clear Harmony trial was an increased risk of gout flare in the treatment arm.
The enzyme required to activate bempedoic acid is liver specific and not present in muscle tissue, so bempedoic acid is a potential option for patients intolerant to statin therapy due to muscle-related side effects. A 12-week study, CLEAR Tranquility, assessed the safety and efficacy of bempedoic acid plus ezetimibe versus ezetimibe plus placebo in patients with a history of statin intolerance and elevated LDL levels. Results from the trial showed that bempedoic acid plus ezetimibe reduced LDL levels 28% more than placebo plus ezetimibe. Pending cost considerations, this oral combination therapy may represent an effective alternative for patients intolerant to statin therapy.
The ongoing CLEAR Outcomes trial, comprising an estimated 12,600 patients at high CV risk with elevated LDL levels who are intolerant to statin therapy, is assessing the effectiveness of bempedoic acid as monotherapy versus placebo. This trial is expected to conclude in 2022.
Several novel antisense oligonucleotide agents capable of silencing key regulatory proteins in the lipoprotein a and apolipoprotein CIII (apo CIII) pathways are currently under investigation, most notably TQJ230 (AKCEA-APO(a)-LRx) and ISIS 678354 (AKCEA-APOCIII-LRx). In a similar manner as inclisiran, these agents are hepatocyte-specific due to the presence of a GalNAc modification.
A randomized, placebo-controlled dose-ranging trial of 286 participants with ASCVD and elevated lipoprotein a levels demonstrated an 80% reduction in lipoprotein a among patients who received the highest dosing schedule of TQJ230 (AKCEA-APO(a)-LRx) (20 mg weekly) compared with a 6% reduction among patients who received placebo. There were no significant adverse effects, the most common of which was injection-site reaction. Moreover, there were no significant differences in platelet count or liver and renal function between the TQJ230 (AKCEA-APO(a)-LRx) and placebo groups. Similar dramatic reductions were seen in apo CIII and TG levels in another randomized controlled trial that evaluated ISIS 678354 (AKCEA-APOCIII-LRx). These promising early data have led to much anticipation of the findings from ongoing phase 3 clinical trials for both therapies.