Despite the widespread use of statins, cardiovascular disease (CVD) remains the leading cause of mortality, globally. 

MDLinx spoke with Marschall S. Runge, MD, PhD, cardiologist and Dean of the Medical School at the University of Michigan, and Alok Mohta, MD, MBBS, geriatrician and infectious disease physician, about current challenges and the future of lipid-lowering therapies. Here’s what they had to say.

Limitations of statins in CVD prevention

Statins primarily function by inhibiting HMG-CoA reductase, leading to reduced LDL-C levels. Recent studies suggest that over 45 million Americans are eligible for statin therapy, yet a significant proportion of patients continue to experience CV events despite optimal LDL-C reduction.

Thompson-Paul AM, Gillespie C, Wall HK, et al. Recommended and observed statin use among U.S. adults – National Health and Nutrition Examination Survey, 2011-2018. J Clin Lipidol. 2023 Mar-Apr;17(2):225–235.

According to Dr. Runge, “Statins have been among the most impactful cardiovascular therapies ever developed, but for some individuals with heart disease, lowering LDL cholesterol may not provide as much cardioprotection as initially expected. Statins do not reverse atherosclerosis; they slow its progression but do not eliminate existing plaque.”

He emphasizes the need for additional therapeutic interventions targeting other lipid fractions and pathways involved in atherogenesis. “Cardiovascular disease is also influenced by factors beyond LDL, including inflammation, triglycerides, lipoprotein(a), and insulin resistance, which is common in metabolic syndrome and diabetes,” Dr. Runge says. 

Emerging therapies of note

Cholesteryl ester transfer protein (CETP) inhibitors

CETP facilitates the transfer of cholesteryl esters from HDL to apolipoprotein B–containing lipoproteins. Inhibiting CETP activity has been proposed to elevate HDL-C levels and reduce LDL-C levels. After failed attempts with older CEPT inhibitors due to safety and efficacy concerns, a newer drug from the class, obicetrapib, has shown promising results. In recent studies, the drug reduced LDL-C significantly and caused a 21% decrease in major adverse cardiovascular events (MACE) at 1 year. Ongoing phase 3 trials aim to elucidate its clinical utility further.

NewAmsterdam Pharma announces positive topline data from pivotal Phase 3 BROADWAY clinical trial evaluating obicetrapib in patients with atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia [press release]. New Amsterdam Pharma. December 10, 2024.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

PCSK9 inhibitors, such as evolocumab and alirocumab, lower LDL-C levels by enhancing hepatic clearance of LDL particles. 

• In the OSLER trial, evolocumab reduced LDL-C by 61% compared to standard therapy alone, decreasing median LDL-C from 120 mg/dL to 48 mg/dL.

  Waters DD, Hsue PY. PCSK9 Inhibition to lower LDL-cholesterol and reduce cardiovascular risk: great expectations. Circ Res. 2015 May 8;116(10):1643–1645.

• The ODYSSEY LONG TERM study reported a 62% reduction in LDL-C levels at 24 weeks with alirocumab treatment, achieving a mean LDL-C of 48 mg/dL.

  Waters DD, Hsue PY. PCSK9 Inhibition to lower LDL-cholesterol and reduce cardiovascular risk: great expectations. Circ Res. 2015 May 8;116(10):1643–1645.

"Inhibiting PCSK9 is a powerful method for lowering LDL-C," says Dr. Runge. "Early clinical studies have shown significant LDL-C reductions with mostly minor side effects in small study groups. Larger trials will be needed to confirm whether these reductions translate into a meaningful decrease in cardiovascular events."

Bempedoic acid

Bempedoic acid is an ATP-citrate lyase inhibitor that reduces cholesterol synthesis upstream of HMG-CoA reductase. A clinical trial of 13,970 participants showed a 30-mg/dL LDL-C reduction, lowering LDL-C by approximately 21% and significantly reducing major CV events in high-risk patients. It also reduced heart attack risk by approximately 30%. However, the study found it may slightly increase gout risk and liver enzyme levels.

Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2023 Jul 11;330(2):131–140.

Dr. Mohta says, “PCSK9 inhibitors and bempedoic acid could be worth exploring in patients with familial hypercholesterolemia or statin intolerance, but we still need more robust data.”

Lipoprotein(a) lowering therapies

Lipoprotein(a) [Lp(a)] is an independent CV risk factor linked to atherosclerosis and thrombosis, with trials showing a 90% reduction in Lp(a).

Manzato M, Wright RS, Jaffe AS, et al. Lipoprotein (a): Underrecognized risk with a promising future. Rev Cardiovasc Med. 2024 Nov 6;25(11):393.

Pelacarsen, an antisense oligonucleotide targeting Apo(a) mRNA, has been shown to reduce Lp(a) by up to 71.6% in a phase 2 trial with weekly 300-mg doses. Phase 3 trials—LP(a) HORIZON (NCT04023552), assessing pelacarsen’s impact on CV events, and APO(a)-LRx apheresis (NCT05305664), assessing whether there is a reduced need for apheresis—are ongoing.

Manzato M, Wright RS, Jaffe AS, et al. Lipoprotein (a): Underrecognized risk with a promising future. Rev Cardiovasc Med. 2024 Nov 6;25(11):393.

However, Dr. Mohta clarifies, “While effective, pelacarsen requires frequent dosing and has modest LDL-C effects compared to siRNA-based therapies.”

Inclisiran

Inclisiran is a small interfering RNA (siRNA) molecule that targets hepatic PCSK9 synthesis, leading to sustained LDL-C reduction. Administered biannually, inclisiran has demonstrated significant efficacy in lowering LDL-C levels.​ Dr. Mohta adds, “Inclisiran’s unique mechanism and dosing schedule may improve patient adherence and outcomes.”

A pooled analysis of three phase 3 studies, ORION-9, ORION-10, and ORION-11, revealed that inclisiran achieved a mean LDL-C reduction of approximately 51% at day 510 compared to placebo.

Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021 Mar 9;77(9):1182–1193.