Are We “statin” to have New Options for ASCVD Risk Reduction?

Madeleine Davies, PharmD, Open Cities Health Center

Background: In the five years since the American Heart Association (AHA) and American College of Cardiology (ACC) published their updated Guideline on the Management of Blood Cholesterol, there have been a slew of new non-statin therapies gaining evidence for their ability to reduce low-density lipoprotein cholesterol (LDL-C) without causing myopathy. This article intends to summarize these updates and consider what they mean for the future of cholesterol management.

Evidence: Around the time of the 2018 AHA/ACC guideline update, proprotein convertase subtilisin–kexin type 9 (PCSK9) targeting therapies were newly introduced. Among these therapies were two humanized monoclonal antibodies administered as biweekly or monthly subcutaneous injections, alirocumab (Praluent) and evolocumab (Repatha). PCSK9 inhibitors promote degradation of LDL-C by hepatocytes, resulting in additional reduction of LDL-C by 50-60% in patients already on maximally tolerated statins. Additionally, in 2019 Nishikido and Ray noted that PCSK9 inhibitors may reduce major adverse cardiovascular events (MACE) by 15% when used for two to three years, without the risk of statin-associated muscle symptoms and impaired glucose metabolism. For patients who are needle-averse, an oral PCSK9 inhibitor, MK-0616 (Merck), demonstrated a reduction in LDL-C by up to 60.9% without any major safety concerns in phase II clinical trials, based on an article by Ballantyne et al.

A novel method of reducing circulating PCSK9 levels came from the development of inclisiran (Leqvio), a small interfering ribonucleic acid (siRNA) that prevents the translation of PCSK9 messenger RNA into functional protein. Inclisiran is injected subcutaneously at day 1, day 90, and every six months thereafter. In 2020, Ray et al. published the results of two phase 3 trials showing the effectiveness of inclisiran to reduce LDL-C by approximately 45-51% from baseline in patients with atherosclerotic cardiovascular disease (ASCVD), approximately 73% of whom were on a high intensity statin at baseline. ORION-4, anticipated end date in 2026, is studying the effect of inclisiran on MACE.

A non-statin, non-PCSK9 targeting therapy that is proven to reduce cardiovascular outcomes is bempedoic acid (Nexletol). Positive cardiovascular benefit was demonstrated in the 2023 CLEAR trial published by Nissen et al. Bempedoic acid is a hepatically-activated prodrug that works upstream of statins, inhibiting the actions of ATP citrate lyase. Oral administration of bempedoic acid 180 mg daily compared to placebo resulted in fewer events of a four-component composite MACE (hazard ratio, 0.87; 95% CI 0.79 to 0.96). Of note, this trial targeted patients indicated for primary or secondary prevention of ASCVD who were unable to tolerate low intensity statin therapy due to myopathies, though nearly a quarter of patients were on intermittent statin therapy. Mean adjusted LDL-C reductions at 6 months were 21.1% from baseline, with no concerns for myalgias, and the main adverse event was hyperuricemia.

Discussion & Clinical Impact: In 2018, the AHA/ACC cholesterol guidelines noted that the $14,000 annual cost of PCSK9 inhibitors may limit the cost-effectiveness of these powerful medications, and instead recommending the less expensive ezetimibe as add-on to maximally-tolerated statin therapy to further reduce LDL-C and ASCVD risk. Since 2018, the cost of PCSK9 inhibitors has halved to $7,000-9,000 yearly based on average wholesale price (AWP), while inclisiran and bempedoic acid cost <$6,000 per year. In comparison, statins cost <$2,500 annually based on the Red Book and as low as $20 annually at Mark Cuban Cost Plus Drug Company. Much of the cost-effectiveness seen for these medications relies on estimates that a 40 mg/dL reduction in LDL-C corresponds with a 22% 10-year reduction in MACE, as repeated by Nishikido and Ray, which then translates to reduced overall healthcare costs. However, a Lancet article by Ridker et al. raises the point that chronic inflammation, as measured by high-sensitivity C-reactive protein (CRP) ≥2 mg/L, may impact an individual’s ASCVD risk more than having an LDL-C >70 mg/dL. To back up this claim, they cite studies of canakinumab and colchicine that have shown reductions in MACE, in addition to their own meta-analysis, and studies of statins, SGLT-2 inhibitors, GLP-1 RAs, and bempedoic acid that show reductions in CRP and ASCVD risk. The extent to which residual inflammation increases ASCVD risk is unclear, and there may be a need for future ASCVD risk scores to include high-sensitivity CRP levels. Until then, statins remain the most cost-effective method for reducing LDL-C and ASCVD risk, with bempedoic acid becoming an exciting novel therapeutic agent to reduce ASCVD risk in statin-intolerant patients, while avoiding the monetary and administrative costs of PCSK9 inhibitors.


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