Current and emerging PCSK9‐directed therapies to reduce LDL‐C and ASCVD risk: A state‐of‐the‐art review

Abstract

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Lowering low‐density lipoprotein cholesterol (LDL‐C) levels is a primary strategy to reduce ASCVD risk. Although statin therapy remains the initial therapy of choice to reduce LDL‐C and ASCVD risk, statin intolerance and suboptimal LDL‐C lowering response prompts the need for additional non‐statin therapies. Ezetimibe and bempedoic acid are reasonable options but they modestly reduce LDL‐C levels (15% to 25%). Therapies directed at the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, however, reduce LDL‐C levels by 50%–60% when added to background statin therapy. PCSK9 is an enzyme synthesized by the liver that facilitates the degradation of LDL receptors and prevents their recycling to the hepatocyte surface to remove LDL‐C from circulation. Approaches to inhibit this effect have centered on monoclonal antibodies (mAbs) (alirocumab, evolocumab) targeting PCSK9 functionality and small interfering RNA (siRNA) therapies (inclisiran) targeting the hepatic synthesis of PCSK9. Randomized controlled trials have demonstrated beneficial cardiovascular outcomes of PCSK9 mAbs, but such evidence is not yet available for inclisiran. Current clinical practice guidelines generally recommend PCSK9‐directed therapies for higher‐risk patients with established ASCVD and those with familial hypercholesterolemia. This approach is, in part, due to their cost and uncertain economic value, but also because these therapies require subcutaneous administration, which is not preferred by some patients. Oral therapies targeting PCSK9 are, however, in development. This scoping review covers the development of current and emerging PCSK9‐directed therapies, their efficacy, safety, and role in clinical practice.

1. INTRODUCTION

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide, accounting for 17.9 million people dying from cardiovascular diseases in 2019, representing 32% of all global deaths. ¹ These deaths and related ASCVD events like myocardial infarction (MI) and stroke, result from the accumulation of atherosclerotic plaque in the artery walls. Low‐density lipoprotein cholesterol (LDL‐C) reduction is the primary target for reducing ASCVD events, as elevated levels of LDL‐C is a well‐established cause of ASCVD. ² , ³ Statins are the mainstay of therapy for lowering LDL‐C and reducing ASCVD risk. Statins inhibit the enzyme, 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, leading to decreased cholesterol synthesis in the liver and increased upregulation of LDL‐C receptors that enhance the clearance of LDL‐C from the bloodstream. Statins are available in various doses and LDL‐C‐reducing potencies. At high‐intensity doses, statins can reduce LDL‐C up to 50%. However, some patients may not experience optimal LDL‐C‐reducing effect. Statin intolerance, typically due to muscle symptoms, is reported in as many as 5%–30% of patients with prescribed statin therapy and may lead to the inability to achieve the patient‐specific LDL‐C target. Patients may experience partial or complete statin intolerance, thereby limiting statin dose or the ability to take any statin altogether. ⁴ Additionally, some patients are unable to achieve adequate LDL‐C reduction with statin therapy alone, particularly those who have high baseline levels of LDL‐C or in individuals with very high ASCVD risk and a desire to achieve lower LDL‐C targets. Thus, patients taking statin therapy may remain with residual ASCVD risk. It is believed that there is a proportional benefit in the degree and duration of plasma atherogenic lipoprotein reduction. Therefore, non‐statin pharmacologic therapies are often needed as an adjunct or as an alternative to statin therapy to achieve therapeutic targets. ² , ⁴

Historically, limited evidence supported the role of non‐statin therapies in combination with statins to reduce ASCVD risk; however, this shifted in 2015. First, the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE‐IT), compared the combination of simvastatin plus ezetimibe or simvastatin plus placebo in a randomized, double‐blind, placebo‐controlled study of over 18,000 patients hospitalized within the previous 10 days for acute coronary syndrome. When added to a statin, ezetimibe incrementally reduced LDL and significantly improved cardiovascular outcomes. Furthermore, ezetimibe has the practical advantage of being orally dosed once daily, is relatively inexpensive, and has a low risk of adverse effects. ⁵ The same year as IMPROVE‐IT, two self‐injectable, fully humanized monoclonal antibodies (mAb) that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), evolocumab and alirocumab, were brought to the market with approval by the United States Food and Drug Administration (FDA). ⁵ , ⁶ , ⁷ , ⁸ The PCSK9 inhibitors demonstrated reductions in LDL‐C levels of as much as 60% when added to background statin therapy. Additionally, in randomized controlled trials they lowered ASCVD risk, particularly in high‐risk patients necessitating secondary prevention of ASCVD. ⁹ , ¹⁰ In 2020, the FDA approved bempedoic acid, another non‐statin agent found to reduce LDL‐C. In 2023, bempedoic acid was shown to reduce cardiovascular outcomes when studied in a randomized placebo‐controlled trial of nearly 14,000 patients with or at high risk for ASCVD and unable or unwilling to take statins related to adverse effects. Bempedoic acid is orally administered once daily, more costly than generic ezetimibe, and is generally well tolerated. However, it does carry an increased risk of gout and cholelithiasis. ¹¹ , ¹² In 2021, a small interfering ribonucleic acid (siRNA) therapy targeting the synthesis of PCSK9, inclisiran, was approved by the FDA as another injectable, non‐statin option to lower LDL‐C, by an estimated 50%.

The purpose of this scoping review is to discuss the current and emerging landscape of drug therapies specifically targeting PCSK9 to reduce LDL‐C levels and ASCVD risk. This includes an evaluation of the evidence supporting the efficacy, safety, and role in clinical practice for the management of patients with elevated cardiovascular risk.

2. METHODS

2.1. Search strategy

We conducted a comprehensive search for published peer‐reviewed English language literature addressing the use of PCSK9‐directed therapies. In this scoping review, the databases searched included OVID Medline, Embase (OVID), and Web of Science. These databases were queried from January 1, 2015, through May 31, 2024. The search employed a combination of keywords, including “randomized controlled trials” and the terms for PCSK9‐directed therapies. The search strategies can be found in Appendix A. Additionally, clinicaltrials.gov was searched for PCSK9‐directed therapies in the drug development pipeline.

3. DISCOVERY AND FUNCTION OF PCSK9

In 2003, PCSK9 was discovered and identified as a serine protease synthesized and secreted by and expressed primarily within hepatocytes (Figure 1). The formation of PCSK9 is derived from a precursor (proPCSK9) that undergoes autocatalytic cleavage in the endoplasmic reticulum. With the pro‐domain still attached at the catalytic subunit, PCSK9 is secreted as an inactive protease complex which then binds to the epidermal growth factor A domain of the LDL receptor. The bound PCSK9‐LDL receptor is directed to the lysosome of the hepatocyte where its degradation occurs. ¹³ PCSK9 thereby reduces the clearance of serum LDL‐C and increases circulating LDL‐C levels in the plasma. Conversely, the inhibition of PCSK9 can lead to an increase in LDL receptors on the surface of the hepatocytes, resulting in increased LDL‐C clearance and a reduction in plasma levels. ¹³ , ¹⁴ It was later learned that PSCK9 is a cholesterol‐regulated gene, evidenced by strong upregulation of PCSK9 transcription and LDL receptor mRNA production by low dietary cholesterol and statin treatment. ¹³

FIGURE 1.

Mechanism of action for PCSK9‐directed therapies and their approach to modulating PCSK9 via (1) inhibiting the function of PCSK9 or (2) by interrupting PCSK9 synthesis. Both mechanisms result in less LDL receptor degradation by the lysosome and increased presence of LDL receptors on the surface of the hepatocytes to remove LDL‐C from circulation. alNAc, N‐acetylgalactosamine; ASGPR, asialoglycoprotein receptor; LDL‐C, low‐density lipoprotein cholesterol; LDLR, low‐density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; RISC, RNA silencing complex.

Research evaluating genetic mutations, leading to loss‐of‐function, has provided additional insight into the role of PCSK9 in lipid metabolism. Overexpression of orthologues in mouse models resulted in reduced LDL receptors and an increase in LDL‐C levels. ¹⁵ , ¹⁶ The opposite was found in mice lacking PCSK9, whereby there was an increase in LDL receptors and a more rapid clearance of LDL from the plasma. ¹⁷ A longitudinal study comparing the incidence of coronary heart disease revealed that populations with loss‐of‐function mutations in the PCSK9 gene exhibited significantly lower levels of LDL‐C and a reduced risk of ASCVD compared to those without such mutations. ¹⁸ The molecular mechanisms by which these sequence variations in PCSK9 reduce LDL‐C are unknown. Yet, these findings provided clear evidence that inhibiting the function of PCSK9 could reduce LDL‐C and the occurrence of ASCVD. These data also suggest that the degree and sustained reduction of LDL‐C are important in lowering the incidence of ASCVD. These discoveries spurred the development of therapeutic agents targeting PCSK9.

4. DEVELOPMENT OF THERAPIES TARGETING PCSK9

An appreciation for the role of PCSK9 in LDL‐C regulation incited the pharmacologic development of subcutaneously delivered mAb therapies that specifically target PCSK9 and block its ability to facilitate LDL receptor degradation. The mAb approach to drug development was reasonable as the PCSK9 complex lacked a clear pharmacologic binding site for smaller drug molecules that could be administered orally. ¹⁹ Alirocumab and evolocumab were the first PCSK9 inhibitors approved by the FDA in 2015. These agents are fully human mAb and self‐administered by subcutaneous injections at biweekly or monthly intervals (Table 1). ⁷ , ⁸ , ²⁰ Another PCSK9 mAb therapy, bococizumab, was developed as a humanized mAb. However, high rates of immunogenicity, along with high‐titer formation of anti‐drug antibodies that neutralized the durability of the LDL‐C effect, led to the halting of further drug development. ²¹ , ²²

TABLE 1.

Pharmacologic information and indications of currently available PCSK9 inhibiting therapies. ⁷ , ⁸ , ²⁰

Characteristic	Alirocumab (Praluent)	Evolocumab (Repatha)	Inclisiran (Leqvio)
Class	PCSK9 inhibitor	PCSK9 inhibitor	siRNA inhibitor of PCSK9
Mechanism of action	Monoclonal antibody	Monoclonal antibody	Double‐stranded small interfering RNA
FDA labeled indications
Adults with HeFH	Yes	Yes	Yes
Adults with HoFH	Yes	Yes	No
Adults, secondary prevention of ASCVD	Yes	Yes	No a
Pediatric with FH	Yes b	Yes c	No
Contraindications	Hypersensitivity to drug or components of the formulation
Absorption (peak)	3–7 days	3–4 days	4 h
Onset of action	4–8 h	4 h	Not established
Distribution	~0.04–0.05 L/kg	~3.3 L	~500 L
Metabolism	Proteolysis, no CYP450 involvement	Proteolysis, no CYP450 involvement	Nucleases, no CYP450 involvement
Drug Interactions	None known
Elimination (half‐life)	17–20 days; reduced to 12 days when administered with statin	11–17 days	9 h, 16% renal elimination
Dosing	75 mg SC every 2 weeks; 150 mg SC every 2 weeks or 300 mg SC every 4 weeks	140 mg SC every 2 weeks or 420 mg SC every 4 weeks	284 mg SC initially, again at 3 months, then every 6 months
Dosage form	75 mg/mL single‐use, prefilled pen 150 mg/mL single‐use, prefilled pen	140 mg/mL single‐use, prefilled pen 140 mg/mL single‐use, autoinjector 420 mg/3.5 mL Pushtronex system (discontinued June 2024)	284 mg/1.5 mL single‐use, prefilled syringe
Drug average wholesale price	75 mg/mL ($304) 150 mg/mL ($304) ~$7300/year	140 mg/mL ($337) ~$8000/year	284 mg/1.5 mL ($2733) ~$13,600 year 1, $5500/year thereafter

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CYP450, cytochrome P450; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; kg, kilograms; L, liters; LDL‐C, low‐density lipoprotein cholesterol; LP(a), lipoprotein (a); mg = milligrams; ml, milliliter; PCSK9, proprotein convertase subtilisin/kexin type 9; SC, subcutaneously; siRNA, small interfering RNA molecule; TG, triglycerides.

^a Indication is for lowering LDL‐C in adults with clinical ASCVD.

^b Indication is for ages 8 years of age and older, including HeFH.

^c Indication is for ages 10 years of age and older, including HeFH and HoFH.

In 2021, inclisiran, a siRNA molecule against PCSK9, received FDA approval. Different from the PCSK9 mAbs, inclisiran works by silencing the gene responsible for PCSK9 synthesis in the liver. Inclisiran is composed of two nucleotide strands attached to two moieties that are becoming a target for developing advanced gene silencing therapies: (1) N‐acetylgalactosamine, (GalNAc), a sugar molecule that can recognize and bind to (2) the asialoglycoprotein receptor (ASGPR), a cell‐surface protein which is predominantly expressed on the hepatocytes. As such, once inclisiran is taken up by the hepatocyte, it associates with the RNA‐induced silencing complex. This complex cleaves the PCSK9 messenger RNA, preventing the synthesis of the PCSK9 protein. The absence of PCSK9 protease allows the LDL receptors to avoid degradation and be recycled to the hepatocyte surface, thereby lowering the levels of LDL‐C in the plasma. One of the main benefits of inclisiran is its prolonged effect, which allows a maintenance administration frequency of every 6 months, as opposed to the biweekly or monthly dosing required for PCSK9 mAbs; however, it must be administered by a healthcare professional. ²³

5. CARDIOVASCULAR CLINICAL OUTCOMES TRIALS

PCSK9‐directed therapies effectively reduce LDL‐C levels and have a favorable safety profile; however, it is imperative to demonstrate that these therapies also reduce ASCVD risk and are beneficial in preventing cardiovascular outcomes (Table 2). ⁹ , ¹⁰ , ²⁴

TABLE 2.

Landmark cardiovascular outcomes trials of the PCSK9‐directed therapies. ⁹ , ¹⁰ , ²⁴ , ²⁵

26Trial	Study design	N	Study population	Baseline LLT	Intervention	Median follow‐up	Mean LDL‐C reduction	Primary endpoint	Results	Adverse events
FOURIER 10	R, DB, PC	27,564	40–85 years with ASCVD and ≥1 major CV risk factor or 2 minor CV risk factors and fasting LDL‐C ≥ 70 mg/dL on a statin	HIS (69.3%) MIS (30.4%) Ezetimibe (5.2%)	Evolocumab 140 mg every 2 weeks or 420 mg every 4 weeks vs. placebo	26 mos.	59%	Composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization	9.8% evolocumab vs. 11.3% placebo HR 0.85; 95% CI 0.79–0.92; p < 0.001	Any adverse events 77.4% evolocumab vs. 77.4% placebo Serious adverse events 24.8% evolocumab vs. 24.7% placebo
ODYSSEY OUTCOMES 9	R, DB, PC	18,924	≥ 40 years., hospitalized with ACS 1–12 mos prior, LDL‐C ≥ 70 mg/dL or non‐HDL‐C ≥ 100 mg/L or apoB ≥80 mg/L on HIS or max tolerated statin	HIS (88.8%) Ezetimibe (2.8%)	Alirocumab 75 mg (or 150 mg) every 2 weeks vs. placebo	2.8 years	54.7%	Composite of CV death, non‐fatal MI, fatal or non‐fatal ischemic stroke, or UA requiring hospitalization	9.5% alirocumab vs. 11.1% placebo HR 0.85; 95% CI 0.78–0.93; p < 0.001	Any adverse events 75.8% alirocumab vs. 77.1% placebo Serious adverse events 23.3% alirocumab vs. 24.9% placebo
ORION‐4 24	R, DB, PC	Planned >16,000	≥40 years. (men) ≥55 years. (women) with prior MI, ischemic stroke, or PAD	TBD	Inclisiran 300 mg at baseline, at 3 mos, then every 6 mos vs. placebo	TBD	TBD	Composite of CV death, MI, fatal or non‐fatal ischemic stroke, or urgent coronary revascularization	TBD	TBD
VICTORION‐2P 25	R, DB, PC	Planned 15,000	≥40 years., on HIS therapy with LDL ≥70 mg/dL and prior MI, ischemic stroke, or symptomatic PAD	TBD	Inclisiran 300 mg at baseline, at 3 mos, then every 6 mos vs. placebo	TBD	TBD	Composite of CV death, non‐fatal MI, and non‐fatal ischemic stroke	TBD	TBD

Abbreviations: ACS, acute coronary syndrome; apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CV, cardiovascular; DB, double‐blinded; HIS, high‐intensity statin; HR, hazard ratio; LDL‐C, low‐density lipoprotein cholesterol; LLT, lipid‐lowering therapy; MI, myocardial infarction; MIS, moderate‐intensity statin; non‐LDL‐C, non‐high‐density lipoprotein cholesterol; PAD, peripheral artery disease; PC, placebo‐controlled; Pts, patients; R, randomized; TBD, to be determined; UA, unstable angina.

The FOURIER trial included 27,564 adult patients with history of MI, non‐hemorrhagic stroke, or symptomatic peripheral artery disease (PAD), in addition to at least one major CV risk factor (diabetes, age ≥ 65 years, MI, or non‐hemorrhagic stroke within 6 months of screening, additional diagnosis of MI, non‐hemorrhagic stroke or PAD excluding qualifying criteria, or daily cigarette smoking) or two minor risk factors (non‐MI related coronary revascularization, residual coronary artery disease (CAD), high‐density lipoprotein cholesterol (HDL‐C) < 40 mg/dL in men or <50 mg/dL in women, high‐sensitivity C‐reactive protein (hsCRP) > 2 mg/L, LDL‐C ≥ 130 mg/dL or non‐HDL‐C ≥ 160 mg/dL and metabolic syndrome) and a fasting LDL‐C ≥ 70 mg/L while on a statin. ¹⁰ Results showed a 59% mean percentage reduction in LDL‐C in evolocumab versus placebo (95% confidence interval [CI] 58%–60%; p < 0.001) and the drop in LDL was apparent within 4 weeks of therapy. LDL‐C was reduced to ≤70 mg/dL in 87% of the patients, ≤40 mg/dL in 67% of the patients, and ≤25 mg/dL in 42% of patients. The primary endpoint of the study, a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina (UA), or coronary revascularization occurred in 9.8% of the evolocumab group versus 11.3% in the placebo (hazard ratio [HR] 0.85; 95% CI 0.79–0.92; p < 0.001). The secondary end point of CV death, MI, or stroke was reduced from 7.4% in placebo to 5.9% evolocumab (p < 0.001). Benefits were consistent across major subgroups and regardless of baseline LDL‐C. There was no difference in the evolocumab dosing regimen of every 2 weeks or once monthly. In terms of safety and adverse events, there were no significant differences between the groups, except for minor injection site reactions being higher in the evolocumab group. In this trial, a reduction in lipoprotein(a) (Lp(a))was also observed with evolocumab, with a median decrease of 26.9% (interquartile range: from −6.2% to −46.7%) compared with placebo. ²⁶

Alirocumab was evaluated for cardiovascular outcomes in the ODYSSEY OUTCOMES trial, which included 18,924 patients who were hospitalized in the previous year for MI or UA with LDL‐C ≥ 70 mg/L, or non‐HDL‐C ≥ 100 mg/L, or apolipoprotein B (apoB) ≥ 80 mg/L while on a high‐intensity statin. ⁹ This study included two doses of alirocumab (75 and 150 mg administered every 2 weeks) which were adjusted based on LDL‐C levels. Patients were increased from the 75 mg dose to 150 mg if the LDL‐C was >50 mg/dL at week 4. Additionally, if LDL‐C decreased to <15 mg/dL at any time during the trial, the alirocumab dose was decreased from 150 to 75 mg dose or if on the 75 mg dose, was switched over to placebo. At the study end, alirocumab led to a mean LDL‐C reduction of 54.7% from baseline, with significant reductions observed at 4 weeks after initiation. The primary composite end point of CV death, non‐fatal MI, fatal or non‐fatal ischemic stroke, or UA requiring hospitalization occurred in 9.5% in alirocumab compared with 11.1% in placebo (HR 0.85; 95% CI 0.78–0.93); p < 0.001. This benefit of reduced CV outcomes was observed in a greater number of patients who had a baseline LDL‐C ≥ 100 mg/dL compared with those having lower baseline LDL‐C. There were no significant differences in safety or adverse effects between the groups, except for a higher incidence of minor injection site reactions in the alirocumab group. Alirocumab also led to reduced Lp(a) levels at month 4, lowering it by 23% (interquartile range, −47% to 0%). ²⁷

The other FDA‐approved PCSK9‐directed therapy, inclisiran, is currently undergoing two cardiovascular outcomes trials, ORION‐4 (NCT03705234) and VICTORIAN‐2P (NCT05030428). ²⁴ , ²⁵ ORION‐4 is a phase 3 study, expected to be completed in 2026 that will examine over 16,000 patients with prior MI, ischemic stroke, or PAD and randomize them to inclisiran 300 mg injection or to placebo. The primary endpoint will be major adverse cardiac events (MACE) composite (first occurrence of CV death, MI, fatal or non‐fatal ischemic stroke, or urgent coronary revascularization) assessed at a median of 5 years. The VICTORION‐2P study is a similar design looking at 15,000 patients with a history of ASCVD and on high‐intensity statin. This is an event‐driven study with a primary endpoint of time to the first occurrence of a 3‐point MACE (CV death, non‐fatal MI, or non‐fatal ischemic stroke).

6. LONG‐TERM SAFETY AND TOLERABILITY

PCSK9‐directed therapies result in favorable lipid profiles, particularly driven by reduced LDL‐C and Lp(a), in addition to potential reduction in CV outcomes; however, the initial trials had a follow‐up study duration of approximately 2 to 3 years. This may not have been long enough to observe clinically meaningful changes in cardiovascular mortality. Furthermore, the long‐term tolerability and safety were unclear. The ability to achieve very low levels of LDL‐C (<25 mg/dL) raised concern regarding the potential risk of cognitive deficits or increased risk for hemorrhagic stroke.

Historically, agents that significantly reduce LDL‐C levels, such as statins, led to concerns of impaired cognitive function. In fact, some small studies previously led the FDA to issue a warning in 2012 that is still in the package labeling for statins. ²⁸ The FDA notes that any minor risk of non‐serious reversible cognitive side effects, such as memory loss or confusion, are outweighed by the significant CV benefits of statin use. Nevertheless, similar concerns have translated over to PCSK9‐directed therapies.

The EBBINGHAUS trial aimed to determine the safety of long‐term evolocumab use on cognitive effects. ²⁹ This study followed 1974 patients enrolled in FOURIER and prospectively evaluated cognition, using validated tests. There were no differences in baseline characteristics between the evolocumab and placebo groups, and 71% of patients were on high‐intensity statins with 29% on moderate‐intensity statins. Patients were followed for a median of 19.4 months, and the primary endpoint showed no significant differences between evolocumab or placebo in terms of spatial working memory index of executive function. Additionally, there were no between‐group differences observed on other cognitive tests including executive function, working memory, paired associated learning test, median 5‐choice reaction time test, and psychomotor speed. Further, no direct relationship was observed between cognitive effects and LDL‐C levels.

Additional long‐term, larger‐scale safety data with evolocumab was published with the open‐label extension trial of FOURIER (FOURIER OLE) which continued to follow 6635 patients from the FOURIER trial to assess long‐term adverse events. ³⁰ The median follow‐up was 5 years, therefore, resulting in a maximum exposure to evolocumab of up to 8.4 years. Just 12 weeks into this trial, the median LDL‐C was 30 mg/dL and 63.2% of patients achieved LDL‐C < 40 mg/dL while taking evolocumab, which was sustained throughout. High‐intensity statins were taken by 77% of patients enrolled. There were no differences in serious adverse events, muscle‐related events, new‐onset diabetes, cataracts, hemorrhagic stroke, or neurocognitive events with evolocumab compared with placebo. Patients taking evolocumab maintained a 15% reduced risk of CV death, MI, stroke, or hospitalization for UA or coronary revascularization (HR 0.85; 95% CI 0.75–0.96; p = 0.008). Interestingly, the clinical benefit of reducing MACE was more apparent in the first 3 years of evolocumab use.

In a post hoc analysis of the ODYSSEY OUTCOMES trial, a prespecified subgroup of patients were eligible for an additional 3–5 years of observation to assess the efficacy, safety, and tolerability of alirocumab use. ³¹ The analysis showed no significant difference in the number of patients that had at least one adverse event in alirocumab compared with placebo (78.3% vs. 80.2%) and no differences in any adverse events that were determined to be serious. There were no differences in the incidence of diabetes, neurocognitive effects, or changes in liver enzymes. Additionally, the reduction in MACE was upheld at 12% in alirocumab compared with 14.2% in placebo (HR 0.83; 95% CI 0.74–0.94; p = 0.003).

Inclisiran also has long‐term data on its LDL‐C lowering efficacy and safety. The ORION‐8 trial was an open‐label, long‐term extension trial. ³² , ³³ , ³⁴ This trial followed 3274 patients from four previous trials (ORION 3, 9, 10, and 11) for up to 3 additional years beyond the original study duration. The mean exposure to inclisiran in this extension trial was 3.7 years, leading to a total exposure of up to 6.8 years. The results showed that inclisiran, in addition to statin therapy, reduced LDL‐C by an average of 49% and 78.4% of patients achieved their prespecified LDL‐C target by the end of the study. Overall, inclisiran was well tolerated with minimal adverse effects, and no new safety signals were noted with the additional exposure.

7. GUIDELINE RECOMMENDATIONS FOR USING THERAPIES TARGETING PCSK9 IN CLINICAL PRACTICE

PCSK9‐directed therapies are generally reserved for secondary prevention in patients at very high risk of ASCVD events and individuals with primary severe hyperlipidemia (LDL‐C ≥ 190 mg/dL). Very high risk includes individuals with multiple major ASCVD events or one major ASCVD event plus additional high‐risk conditions, including age ≥ 65 years, heterozygous familial hypercholesterolemia (FH), prior coronary intervention, diabetes mellitus, hypertension, chronic kidney disease, current smoking, LDL‐C ≥ 100 mg/dL despite max tolerated statin and ezetimibe, and a history of heart failure. These characteristics are based on trial participants enrolled in IMPROVE‐IT, FOURIER, and ODYSSEY OUTCOMES who were most likely to benefit from PCSK9 mAb therapy. Given the uncertainty around the cost‐effectiveness of PCSK9‐directed therapies, these criteria aim to guide the use of these therapies in patients most likely to benefit. Beyond the guidelines, there are also practical considerations for selecting a PCSK9‐directed therapy.

2018 American College of Cardiology (ACC)/American Heart Association (AHA)/Multi‐Society Cholesterol Guideline

The first guideline to incorporate recommendations regarding the use of PCSK9‐directed therapies was the 2018 ACC/AHA/Multi‐Society Cholesterol Guideline. ² At the time of its publication, only alirocumab and evolocumab were approved by the FDA, so inclisiran was not mentioned in these guidelines. This guideline recommends considering a PCSK9 mAb primarily in secondary prevention for patients with clinical ASCVD who are at very high risk, on maximally tolerated statin therapy and ezetimibe, and with an LDL‐C ≥ 70 mg/dL. Additionally, a PCSK9 mAb may be reasonable in individuals with FH who continue to have an elevated LDL‐C despite maximally tolerated statin and ezetimibe. The advent of PCSK9‐directed therapies has made it possible to achieve desired levels of LDL‐C in the FH population, which historically has been a challenging population to manage given the modest LDL‐C lowering achievable with other non‐statins, such as ezetimibe.

In 2022, the ACC released an Expert Consensus Decision Pathway on LDL‐C Management to provide clinicians guidance on the use of non‐statin therapies based on new evidence and emerging therapies. ³⁵ One notable change was lowering the LDL‐C threshold from 70 to 55 mg/dL for adding ezetimibe or a PCSK9 mAb in patients with very high‐risk ASCVD. This would increase the number of patients eligible for additional non‐statin therapy, although we will have to wait and see if this recommendation is adopted by future guidelines. The PCSK9 mAbs were recommended over inclisiran due to their well‐established record of safety, efficacy, and evidence of benefit to cardiovascular outcomes.

Inclisiran was also mentioned in the 2023 ACC/AHA/Multi‐Society Chronic Coronary Artery Disease (CCD) Guideline despite the lack of data from a large clinical outcome trial, ³ although the ORION‐4 study evaluating inclisiran is currently ongoing. ²⁴ The guideline states it is reasonable to consider inclisiran as an alternative to a PCSK9 mAb in the event of ineffectiveness or poor tolerability to further reduce LDL‐C, not ASCVD risk, given the current lack of data.

Although the efficacy of the PCSK9 mAbs is well established, the 2018 ACC/AHA/Multi‐Society Cholesterol Guideline deemed them to be of low value in secondary prevention patients and of uncertain value in patients with FH given their mid‐2018 list price of approximately $14,000 per year. ² This is one reason why the guideline recommends adding ezetimibe to maximally tolerated statin therapy before adding a PCSK9 mAb. Ezetimibe is also highly affordable and a once daily, oral medication with a well‐established safety record. The list pricing for alirocumab and evolocumab was, however, subsequently reduced by approximately 60% in 2018 and 2019, respectively. ³⁶ However, the value of PCSK9 mAbs in the secondary prevention population remained uncertain in the 2023 ACC/AHA/Multi‐Society CCD Guideline. ³ The reason for this uncertainty was due to conflicting economic analyses with some projecting low economic value and others demonstrating intermediate‐to‐high economic value. This underscores the importance of prioritizing the use of PCSK9‐directed therapies for individuals at the highest ASCVD risk who are most likely to benefit.

8. PRACTICAL CLINICAL CONSIDERATIONS

Clinical practice guidelines are a starting point for providing clinical care as there are frequently system and patient‐related factors that inform clinical decision‐making. ³⁷ This is particularly true when determining which of the PCSK9‐directed therapies to use for a given patient. Given that evolocumab and alirocumab have demonstrated significant reduction in LDL‐C levels and ASCVD event rates, they may be preferred over inclisiran at this time; however, inclisiran may be ideal for select patients who have had a reaction to a PCSK9 mAb or to improve medication adherence due to reduced injection administrations. At this time, there may also be cost savings to Medicare beneficiaries with supplemental coverage as inclisiran does not contribute to the coverage gap under pharmacy benefits.

Deciding between evolocumab and alirocumab often begins with determining which therapy is preferred by the payor. There are, however, some additional considerations. Alirocumab is available in two doses (75 and 150 mg), which does allow for titration based on patient response and tolerability, whereas evolocumab is only available in one dose (140 mg). This can be particularly helpful with patients who are statin intolerant and may be more receptive to a PCSK9 mAb if they have the option of starting at a lower dose. Another consideration is latex allergy because the evolocumab autoinjector contains dry natural rubber whereas alirocumab does not. Both evolocumab and alirocumab are self‐injected by the patient either on a biweekly or once‐monthly basis and not all patients are willing or able to perform self‐injection. The once‐monthly option is limited by the requirement for patients to self‐inject multiple injections to administer the appropriate dose. Inclisiran is a reasonable alternative in these situations since the maintenance dosing is administered every 6 months, and it must be administered by a healthcare professional. Additionally, even if patients are able and willing to self‐inject, they may struggle with adherence. Inclisiran is a reasonable alternative in these patients; however, this does require the patient to be adherent with attending administration appointments. ⁷ , ⁸ , ²⁰

9. PRACTICE APPLICATION

Non‐statins, such as PCSK9‐directed therapies, are a significant addition to our armamentarium to assist patients with achieving LDL‐C targets and ASCVD risk reduction. Although statins are first‐line therapy, they remain under‐utilized. One retrospective cohort found that just 50.1% of patients with established ASCVD were on any statin therapy, with only 22.5% on recommended high‐intensity statin. ³⁸ Furthermore, even in patients prescribed statin therapy, perceived or actual intolerances and nonadherence can limit their utility. This is critical since nonadherence increases the risk of adverse CV outcomes. ³⁹ PCSK9‐directed therapies are an effective option for patients given their LDL‐C‐lowering potency and favorable safety profile. However, PCSK9‐directed therapies are also often under‐utilized or have lower patient retrieval rates, as one real‐world study demonstrated, due to high copays, lack of insurance coverage, or the necessity of prior authorizations. ⁴⁰

Considering the current landscape of suboptimal LDL‐C control, clinical practice protocols evaluating the patient population for potential use of PCSK9‐directed therapies are recommended. Utilizing electronic medical record tools and resources to identify patients that meet guideline recommendations for consideration of starting a PCSK9‐directed therapy is recommended. Clinical decision support tools could utilize alerts to help improve the identification of patients who may be eligible for a PCSK9‐directed therapy. ⁴¹ , ⁴² Alternatively, utilizing a multidisciplinary team member or pharmacist to identify and evaluate patients through a targeted electronic medical health record report, and then providing recommendations, may also be a viable option. ⁴³ Additionally, peer education to providers about lipid management, current under‐utilization rates of medications, the various treatment options, and PCSK9‐directed therapies, is also valuable and recommended.

The clinical considerations noted above must be considered for therapy selection, as well as shared decision‐making between the patient and clinician. Patient education is key to review their ASCVD risk, as well as the benefits and importance of LDL‐C control. Key counseling points regarding PCSK9‐directed therapies should include how they work, how they differ from other medications, efficacy, side effect profile, administration and injection technique, and storage requirements. Additionally, conversations regarding insurance coverage, authorizations, and affordability should be initiated. Once that information is determined from the insurer, the patient should be directed to information about cost, patient assistance programs, and manufacturer resources, as applicable. Ensuring the patient can access the medication at an affordable price is vital to adherence and, therefore, successful clinical outcomes. Therefore, it is important for practices to institute supportive workflows to gain access to medication through appropriate prior authorizations and copay assistance education, as applicable. It is important to note that inclisiran, is one of the first healthcare provider to administer medication in the cardiovascular community, and this process mandates a need for logistical workflow to support ordering, potential product storage, and billing structures. ⁴⁴

Pharmacists are in a pivotal position to educate patients, as well as assist with adherence support and following up with the patient in terms of tolerability, follow‐up monitoring, and outcomes. In fact, one study showed that integrating pharmacists into a prevention cardiology clinic, led to many impactful interventions resulting in significant cost avoidance and improved medication adherence and clinical outcomes. ⁴⁵

Regardless of which member of the multidisciplinary team assists, patients need to be identified, educated, assisted, followed, and monitored. The PCSK9‐directed therapies available at this time provide important alternatives for increasing the number of patients attaining desired levels of LDL‐C and reducing ASCVD risk.

10. OVERVIEW OF THE PCSK9 DRUG DEVELOPMENT PIPELINE

The drug development pipeline for additional PCSK9‐directed therapies is rich with novel approaches to address known barriers with the currently available PCSK9 mAbs and inclisiran. ⁴⁵ This includes an orally administered option for those who prefer non‐injectables, a more convenient once‐monthly administered injectable therapy, and permanent genetic modification of the PCSK9 gene. At the time of this writing, all these agents are in phase II or III studies.

Developing a small molecule to inhibit PCSK9 has been challenging due to the flat nature of the PCSK9‐epidermal growth factor‐like A interface, making it difficult to bind directly to the PCSK9 enzyme. ⁴⁶ An alternative approach is to use a macrocyclic peptide that inhibits the protein–protein interaction between the PCSK9 enzyme and the LDL receptor. Two oral PCSK9 inhibitors are currently in development. Enlicitide decanoate (MK‐0616) is an experimental orally administered macrocyclic peptide that has a strong affinity for the PCSK9‐LDL receptor binding domain. A phase 2b, placebo‐controlled, randomized trial demonstrated that enlicitide decanoate 30 mg once daily significantly reduced LDL‐C levels by up to 61% at week 8. ⁴⁷ No difference in adverse event or drug discontinuation rates was noted across the four doses used in the study when compared to placebo. A phase 3 cardiovascular outcomes study evaluating enlicitide decanoate, CORALreef Outcomes, was launched in 2023 with an anticipated completion date of 2029. ⁴⁸ A second oral agent in development, AZD0780, is a small molecule targeting PCSK9 with completed phase I clinical trials and phase II program currently underway. ⁴⁹ , ⁵⁰

Although both currently available PCSK9 mAbs can be administered once monthly, alirocumab requires two injections (total of 2 mL) to achieve the 300 mg monthly dose and evolocumab requires three injections (total of 3 mL) to achieve the 420 mg monthly dose.^7,8 This may not be convenient or preferred by some patients. Lerodalcibep (LIB003) is a third‐generation PCSK9 inhibitor that offers once‐monthly dosing in a much smaller volume (1.2 mL). This is possible because lerodalcibep's anti‐PCSK9 binding domain is an adnectin, which has a smaller molecular scaffold than alirocumab and evolocumab. ⁵¹ The phase 3 trial, LIBERATE‐HR, was a randomized, placebo‐controlled study that randomized patients 2:1 to lerodalcibep 300 mg once monthly or placebo for 52 weeks. The placebo‐adjusted reduction in LDL‐C levels was 56% with lerodalcibep and adverse event rates were similar between lerodalcibep and placebo, except injection site reactions were more common with lerodalcibep (6.9% vs. 0.3%) although they were primarily mild–moderate. Several other phase 3 clinical trials evaluating lerodalcibep are underway, but a cardiovascular outcomes trial has not yet been announced. ⁵⁰ , ⁵² , ⁵³

11. CONCLUSIONS

Significant advancements in lipid management with PCSK9‐directed therapies have changed the landscape of LDL‐C management, offering additional non‐statin options for significant LDL‐C reduction and improved cardiovascular outcomes on top of background statin therapy. There is a growing body of evidence demonstrating the efficacy and safety of these therapies, particularly in individuals at high risk for ASCVD events who do not achieve adequate LDL‐C reduction with maximally tolerated statin with or without ezetimibe or bempedoic acid. Currently, available PCSK9‐directed therapies offer unique advantages, such as varying dosing regimens, favorable tolerability and safety profile, and significant ASCVD risk reduction. Integration of PCSK9‐directed therapies into clinical practice reflects a strategic shift in the approach to hyperlipidemia management, emphasizing the importance of personalized medicine in achieving optimal cardiovascular health. Ongoing development of orally administered and more convenient once‐monthly PCSK9‐directed therapies will provide important alternatives for patients.

CONFLICT OF INTEREST STATEMENT

Dr. Dixon has received grant funding from Boehringer Ingelheim, Inc. Dr. Garwood is a Scientific Editor for Pharmacotherapy. All other authors declare no conflicts of interest.

SEARCH STRATEGIES

OVID MEDLINE

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Web of science

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Garwood CL, Cabral KP, Brown R, Dixon DL. Current and emerging PCSK9‐directed therapies to reduce LDL‐C and ASCVD risk: A state‐of‐the‐art review. Pharmacotherapy. 2025;45:54‐65. doi: 10.1002/phar.4635