Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs

Kohei Takata; Stephen J. Nicholls


Am J Cardiovasc Drugs. 2019;19(2):113-131. 

In This Article

Drugs Targeting LDL-C

LDL-C has been a major target for the primary and secondary prevention of ASCVD for 3 decades. Statins reduce CV events in proportion to LDL-C lowering, leading to their current position as the cornerstone of LLTs. However, there still remain many patients at high ASCVD risk, who fail to achieve the optimal LDL-C levels despite using statins, including high-intensity statin therapy (HIST). Hence, there is an unmet need for LDL-C lowering to reduce CV risk.

Cholesterol Absorption Inhibitor: Ezetimibe(Zetia®)

Ezetimibe (Zetia®) acts at the brush border in the small intestine by binding to the Niemann-Pick C1-Like 1 (NPC1L1) for inhibiting cholesterol absorption. This action leads to the reduced delivery of cholesterol to the liver and subsequent upregulation of hepatic low-density lipoprotein (LDL) receptor (LDLR), resulting in increased clearance of circulating LDL-C.[4] Given the compensatory cholesterol absorption in statin-treated subjects,[5] the addition of ezetimibe to statin therapy can achieve further lowering of LDL-C levels and CV risk reductions. Indeed, the combination therapy provides an incremental LDL-C reduction of 15–20% and higher attainment of LDL-C goal.[4,6] In clinical studies (Table 1), ezetimibe added to statin therapy has largely proven its beneficial effects on ASCVD outcomes. The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial showed 22% risk reductions in ischemic CV events in the ezetimibe (10 mg/day) plus simvastatin (40 mg/day) combination treatment group, although it failed to show the beneficial effects on major CV events, including the disease progression of aortic stenosis (AS).[7] This study was designed to examine the effects of the combination therapy on ASCVD risk in patients with mild-to-moderate AS. The advanced age at enrollment (mean 68 years) might influence the efficacy of LDL-C levels in the disease condition of AS. Meanwhile, the SHARP (Study of Heart and Renal Protection) trial, comprising chronic kidney disease patients with or without hemodialysis, generated evidence of LDL-C lowering in patients with renal impairment.[8] Before that, other statin trials failed to show the benefits on those primary outcomes in patients undergoing hemodialysis.[9,10] In contrast, simvastatin (20 mg/day) plus ezetimibe (10 mg/day) reduced LDL-C levels by 55% (versus placebo) and major CV events risk by 17% in the SHARP trial. These incremental benefits of ezetimibe were also confirmed in the setting of acute coronary syndrome (ACS). The IMPROVE-IT trial, comprising 18 114 high-risk patients following ACS, demonstrated the additional benefit of ezetimibe (10 mg/day) added to simvastatin (40 mg/day) in reducing major CV risk compared to simvastatin alone, although the combination therapy did not reduce mortality.[2] While the absolute risk reduction was 2.0%, the relative risk reduction of ASCVD events per millimole of LDL-C reduction was consistent with that of LDL-C lowering by statins. The subgroup analyses clarified that these benefits were particularly enhanced in diabetes mellitus (DM) and older (> 75 years) individuals. Furthermore, the incremental effects were associated with the burden of risk factors in the exploratory analyses, indicating a greater degree of modifiable CV risk in high-risk patients.[11] Above all, this landmark study provided evidence for the addition of ezetimibe to statin therapy with respect to the LDL-C hypothesis. Given the median LDL-C levels at baseline were below 100 mg/dl in the IMPROVE-IT trial, the positive results supported the direction of further lipid lowering using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In addition, a mechanistic study using intravascular ultrasound (IVUS) confirmed the incremental benefits of ezetimibe in coronary artery disease (CAD) patients. In the PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial, the combination of ezetimibe (10 mg/day) with the uptitrated atorvastatin showed greater regression of coronary atherosclerosis with lower LDL-C levels compared to atorvastatin monotherapy.[12] Taken together, the current guidelines recommend ezetimibe for statin-intolerant patients and further LDL-C lowering in the setting of background statin therapy.[4,13]

PCSK9 Monoclonal Antibody: Alirocumab(Praluent®) and Evolocumab (Repatha®)

PCSK9 is a serine protease that promotes the degradation of hepatic LDLR, resulting in decreased clearance of circulating LDL-C.[14] Genetic studies have shown that gain of function in PCSK9 results in elevated LDL-C levels and associates with increased risk of CAD, whereas loss-of-function (LOF) mutations in PCSK9 lead to low LDL-C levels and reduced CAD risk.[15,16] Since these discoveries, investigators have focused on PCSK9-targeting drugs and made dramatic gains. Monoclonal antibodies (mAbs) to PCSK9 have been shown to be the most developed approach so far to PCSK9 inhibition and LDL-C lowering. Above all, alirocumab (Praluent®) and evolocumab (Repatha®) are now on the market after US Food and Drug Administration (FDA) approval in 2015 (Table 1).

Alirocumab is the first FDA-approved treatment in a class of PCSK9 inhibitors for patients with heterozygous familial hypercholesterolemia (HeFH) or clinical ASCVD who require additional LDL-C lowering. In 2012, the first study of alirocumab in humans was reported, in which the association of concomitant statin treatment with LDL-C lowering was tested. Notwithstanding concomitant atorvastatin use, subcutaneously administered alirocumab appeared to show comparable LDL-C reduction at 2 weeks after administration, with no drug-related adverse events in non-FH subjects (treatment difference vs. placebo: with atorvastatin − 65%; without atorvastatin − 57%).[17] The presence of HeFH did not appear to influence the efficacy in this phase 1 trial (with HeFH − 56%; without HeFH − 65%). In a phase 2 trial, non-FH patients with LDL-C ≥ 100 mg/dl on stable atorvastatin were enrolled, and a dose-dependent reduction in LDL-C of up to 72% was observed after 12 weeks of subcutaneously injected alirocumab.[18] These beneficial effects on LDL-C levels were greater in patients on the biweekly (Q2W) low-dose regimen than in those on the high-dose 4-weekly (Q4W) regimen (150 mg Q2W vs. 300 mg Q4W; − 72% vs. − 48%), and were not associated with atorvastatin dose, indicating the mechanisms of the statin and PCSK9 mAb regarding LDL-C lowering are independent of each other. The increases of LDLR with alirocumab resulted in enhancement of apolipoprotein B (apoB)-containing lipoproteins clearance {apoB up to − 56%; non–high-density lipoprotein cholesterol (non–HDL-C) up to − 63%; lipoprotein (a) [Lp(a)] up to − 29%}. Despite a high frequency of the combination treatment of statins and ezetimibe (≈ 70%), another phase 2 trial of alirocumab reported similar reductions in apoB-containing lipoproteins [LDL-C up to − 68%; apoB up to − 50%; non–HDL-C up to − 58%; Lp(a) up to − 23%] in 77 HeFH patients with a mean baseline LDL-C of 155 mg/dl.[19] The ODYSSEY FH I and FH II trials, two phase 3 trials of alirocumab over 78 weeks in 735 HeFH patients with elevated LDL-C levels despite maximally tolerated LLT, showed an up to 52% LDL-C reduction after 78 weeks of treatment. Alirocumab enabled up to 60–68% of patients to achieve LDL-C < 70 mg/dl at week 24, even though the dose regimen was increased at week 12 from 75 mg Q2W to 150 mg Q2W if LDL-C levels at week 8 were ≥ 70 mg/dl.[20]

Consistent with alirocumab, subcutaneously administered evolocumab, a second PCSK9 mAb, was well-tolerated in two phase 1 trials and achieved up to 75% LDL-C reduction in healthy and HeFH patients.[21] The MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy For Easing Lipid Levels) trial, a phase 2 trial under assumption of statin intolerance, but not designed for those patients, tested evolocumab as monotherapy, and observed dose-dependent LDL-C reduction in LLT-untreated patients with baseline LDL-C of 100–190 mg/dl and a low-risk Framingham score (140 mg Q2W up to − 51%; 420 mg Q4W up to − 48%).[22] In the MENDEL trial, no difference in LDL-C reductions among different dose regimens was observed, whereas the LAPLACE (LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy)-TIMI 57 trial, another phase 2 trial with a larger population (n = 631) with LDL-C ≥ 85 mg/dl on background statins with or without ezetimibe, confirmed a dose-dependent and greater LDL-C reduction in patients with Q2W (− 66% by 140 mg Q2W), even though they were treated with lower dosage, than those with Q4W (− 50% by 420 mg Q4W).[23] Evolocumab has further been investigated as a combination therapy with statins or ezetimibe. The LAPLACE-2 trial, a phase 3 study in 1826 patients with hypercholesterolemia, demonstrated that the addition of evolocumab to baseline statins yielded comparable reductions in LDL-C levels, regardless of statin dose or intensity (moderate-intensity statin up to − 66%; high-intensity statin up to − 65%).[24] Subsequently, the MENDEL-2 trial assessed the efficacy of evolocumab with ezetimibe or placebo in 614 patients with the same background as those of the MENDEL trial.[25] The investigators designed the study to compare evolocumab with ezetimibe as second-line therapy to statins, resulting in greater LDL-C reduction in the evolocumab arm at week 12 (treatment difference vs. ezetimibe: 140 mg Q2W − 39%; 420 mg Q4W − 38%).

Alirocumab and Evolocumab: Outcomes Trials

In parallel with ≈ 60% LDL-C reductions, all early phase trials of alirocumab and evolocumab were generally well-tolerated and not associated with serious adverse events. Subsequently, two important phase 3 trials evaluated long-term efficacy and safety {the ODYSSEY LONG TERM trial with alirocumab[26] (Table 2) and the OSLER (Open-Label Study of Long-Term Evaluation against LDL Cholesterol) trial with evolocumab[27]}, and suggested CV benefits. In comparison with placebo or standard care, patients with alirocumab or evolocumab experienced ≈ 60% LDL-C reduction. No serious adverse events were observed in the intervention arm, even in the subgroup with on-treatment LDL-C < 25 mg/dl. Post hoc analyses demonstrated ≈ 50% reduction in composite CV events at 1–1.5 years. The investigation into this therapy's potential for great LDL-C lowering and CV benefits, along with its favorable safety profile, was expanded into ongoing longer and larger CV outcome trials (CVOTs) (Table 2).

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial in 27 564 patients with LDL-C ≥ 70 mg/dl and stable ASCVD is the first completed CVOT with PCSK9 inhibitors[28] (Table 2). Compared to placebo, evolocumab (140 mg Q2W or 420 mg Q4W) on background moderate-to high-intensity statins lowered LDL-C levels by 59% and reduced the incidence of major CV events by 15% (event rate 9.8% vs. 11.3%, hazard ratio 0.85). While no reduction in all-cause mortality or CV deaths was observed with evolocumab, evolocumab reduced the risk of myocardial infarction (MI) (27%), stroke (21%), and coronary revascularization (22%). Given that the beneficial effect of lowering LDL-C on CV benefits requires time,[29] the relatively short follow-up period (median 2.2 years) may have limited the ability to detect the therapy's full capacity. Indeed, the magnitude of the risk reduction was greater in the second year of the FOURIER trial (major vascular events: first year 10%; second year 17%).

A CVOT of alirocumab, ODYSSEY Outcomes, evaluated the impact of alirocumab (75 mg or 150 mg Q2W) or placebo in addition to optimal statin treatment on CV events in 18 924 patients with LDL-C ≥ 70 mg/dl and recent history of ACS (< 52 weeks).[30] The median follow-up period was 2.8 years. On-treatment LDL-C levels at 4 years were lower by 54.7%, and a significant 15% risk reduction in major CV events (event rate 9.5% vs. 11.1%; hazard ratio 0.85) was observed in the alirocumab arm. Consistent with the FOURIER trial, alirocumab significantly reduce the risk of MI (14%) and ischemic stroke (27%) irrespective of the different population. While the beneficial effect of evolocumab on CV risk reductions was observed consistently across the baseline LDL-C levels in the FOURIER trial, a prespecified subgroup analysis of the ODYSSEY Outcomes trial demonstrated a significantly different CV risk reduction according to the baseline LDL-C levels. The beneficial effect regarding the primary efficacy endpoint was observed only in patients with baseline LDL-C ≥ 100 mg/dl. The study protocol for the ODYSSEY Outcomes attempted to maintain patients within the target LDL-C range (25–50 mg/dl).[31] Indeed, 730 of the 9462 alirocumab-treated patients (7.7%) were blindly switched to placebo due to two consecutive LDL-C levels of < 15 mg/dl. Given a higher frequency of this situation in patients with lower baseline LDL-C levels, the involvement of the blinded switch in the inconsistent results across baseline LDL-C levels in the ODYSSEY Outcomes trial was suggested.[32]

In parallel, development of a humanized PCSK9 mAb, bococizumab, was terminated due to the emergence of neutralizing antibodies reducing the lipid-lowering impact of this agent in many patients.[33] Despite early study termination, the SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events)-2 outcome trial, performed in high-risk patients with LDL-C > 100 mg/dl or non–HDL-C > 130 mg/dl, demonstrated a significant reduction in CV events with bococizumab.[34] This supports the importance of targeting patients with higher lipid levels. In addition, a recent analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration demonstrated that PCSK9 mAbs and statins are likely to have similar effects on CV event risks for the same duration of therapy.[35] Similarly, given the associations of statins with diabetes, there was a similar concern regarding treatment with PCSK9 inhibitors. Consistent with a meta-analysis on 1.5 years of follow-up or a prior study,[36,37] the analyses from phase 3 trials of alirocumab and evolocumab confirmed that PCSK9 mAbs were not associated with worsening or new onset of diabetes over 1.5–2 years,[38,39] whereas LOF mutations in PCSK9 were associated with the risk of diabetes.[40] The authors of the Mendelian randomization study suggested that the biological effects of PCSK9 mAbs may not be similar to those of PCSK9 genetic variants.

The GLAGOV (Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial, a mechanistic study using IVUS, investigated the impact of evolocumab or placebo on coronary atheroma burden in moderate- or high-intensity statin-treated patients with CAD[41] (Table 2). After 1.5 years, the evolocumab treatment arm (420 mg Q4W) achieved lower LDL-C levels (37 vs. 93 mg/dl), resulting in significant regression of coronary plaque burden (percent atheroma volume − 0.95% vs. 0.05%; total atheroma volume − 5.8 mm3 vs. − 0.9 mm3). This beneficial effect on coronary atheroma was greater in patients with baseline LDL-C < 70 mg/dl compared to the whole cohort (difference between treatment groups − 1.6% vs. − 1.0%). Of interest, the linear relationship between on-treatment LDL-C levels and the rate of coronary atheroma progression was observed even in patients with achieved LDL-C levels as low as 20 mg/dl. These findings support the risk-reduction effects of the FOURIER trial, in which 87 or 42% of the patients achieved LDL-C levels < 70 or 25 mg/dl. In response to the positive data of the FOURIER trial, the FDA approved evolocumab as the first PCSK9 inhibitor for secondary prevention in ASCVD patients in December 2017.

Alirocumab and Evolocumab: Effects on Lp(a) Levels

An unexpected finding of the 30% Lp(a) reduction with PCSK9 mAbs in early clinical trials[18,21] was confirmed by phase 2 and 3 trials.[26–28,42–44] Although the absolute reduction in Lp(a) level is very small, this distinct effect from statins on Lp(a) is noteworthy. In a kinetic study with healthy volunteers, alirocumab showed acceleration of apolipoprotein (a) [apo(a)] catabolism (24.6%) without any change in its production.[45] Epidemiological and genetic studies have demonstrated the positive association between elevated Lp(a) levels and ASCVD risk. However, the clinical significance of this Lp(a) reduction on ASCVD risk requires further robust investigations.

Alirocumab and Evolocumab: Effects on the Neurocognitive Function

Although no excess adverse events in patients who achieved very low LDL-C levels with alirocumab or evolocumab were reported in recent phase 3 trials,[26,27] the potential of PCSK9 inhibitors to achieve very low LDL-C levels, especially in combination with statins, has raised interest on potential safety implications regarding neurocognitive function. Even in statin-treated patients, an increasing risk of neurological disease has been suggested.[46] Indeed, both phase 3 trials[26,27] and some meta-analyses[47,48] have suggested an increased risk of neurocognitive adverse events in patients receiving PCSK9 mAbs (ODYSSEY LONG TERM with alirocumab 1.2% vs. 0.5%; OSLER-1 and OSLER-2 with evolocumab 0.9% vs. 0.3%). However, both the FOURIER trial and the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study, assessing function with a validated assessment tool as a substudy of the FOURIER trial, reported that LDL-C lowering with evolocumab was not associated with impairment of cognitive function.[49,50] Although further investigation on neurocognitive function will be required in longer and larger CVOTs, these results are consistent with a recent genetic study [REGARDS (Reasons for Geographic and Racial Differences in Stroke)], showing that LOF mutations in PCSK9 and low LDL-C levels were not associated with neurocognitive impairment.[51] As the short follow-up period (FOURIER 2.2 years; EBBINGHAUS 1.6 years) may underestimate the full capacity of the mentioned treatments, a 5-year extension of the FOURIER trial will provide further findings on neurocognitive function.[52]

Alirocumab and Evolocumab: Familial Hypercholesterolemia and Statin Intolerance

In addition to their benefit in patients with elevated LDL-C levels despite maximally tolerated statins, PCSK9 inhibitors are especially beneficial for those with FH or statin intolerance. PCSK9 mAbs have demonstrated further and sustained LDL-C reduction on background LLTs, with a rapid response. FH is caused by genetic mutations in LDLR, apoB, and PCSK9, resulting in an increased ASCVD risk. All homozygous FH (HoFH) and many severe HeFH patients with maximum tolerated LLTs still do not achieve goal LDL-C.[53,54] Under these circumstances, PCSK9 mAbs in HeFH patients have showed comparable LDL-C reductions to those in patients without FH.[17,19–21,55] In addition, the long-term use (48 weeks) of evolocumab with standard care demonstrated sustained LDL-C reduction (54%) and its safety in an extended phase 3 study of the RUTHERFORD (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder) trial with HeFH patients.[56] By contrast, the effect of PCSK9 mAbs on LDL-C levels in HoFH patients is less effective compared to in non-HoFH patients (≈ − 20% vs. ≈ − 60%).[57,58] This ability to lower LDL-C with a PCSK9 inhibitor in HoFH suggests that many of these patients have some level of functioning LDLR. However, PCSK9 mAbs have the potential to be an effective additional option for FH management. In the ODYSSEY ESCAPE study, a phase 3 study in HeFH patients undergoing LDL apheresis, 150 mg Q2W alirocumab reduced the frequency of the apheresis by 75% and weaned 63% of alirocumab-treated patients off the invasive procedure.[59] Future studies are needed to determine the impact of PCSK9 mAbs on CV outcomes in FH patients.

Although treatment guidelines highly recommend statin use for the primary and secondary prevention of ASCVD, up to 15% of patients have shown statin intolerance due to mainly statin-associated muscle symptoms (SAMS).[60,61] In several trials designed for statin-intolerant patients [ODYSSEY ALTERNATIVE with alirocumab[62] and GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) 1–3 with evolocumab[63–65]], up to 55 or 56% LDL-C reduction with alirocumab or evolocumab was observed. Besides the fact that the underlying mechanism of SAMS remains unclear, only 43% of patients showed intolerable SAMS during the rechallenge procedure of the GAUSS-3 trial.[65] The poor reproducibility implies intricacy for patients and physicians. For statin-intolerant patients, ezetimibe was recommended as the first choice of alternative treatment to the intolerable statins or as an additional agent to maximally tolerated statin dosage.[61] Up to 38% LDL-C reduction in these studies with alirocumab or evolocumab and the lower discontinuation rate of the GAUSS-3 trial in comparison with ezetimibe (0.7% vs. 6.8%) highlight the incremental benefits of PCSK9 mAbs in the treatment of statin-intolerant patients.[62–65]

Small Interfering RNA Targeting PCSK9: Inclisiran

Various approaches for inhibiting PCSK9, including anti-PCSK9 vaccines, small molecule PCSK9 inhibitors, and small interfering RNA (siRNA) targeting PCSK9, are currently being tested at different stages in addition to the FDA-approved PCSK9 mAbs.[14,66] Inclisiran (formerly known as ALN-PCSsc), an siRNA targeting PCSK9 messenger RNA (mRNA), is a developed formulation of ALN-PCS. PCSK9 mAbs bind to extracellular PCSK9 and interact with LDLRs, whereas the specific uptake of ALS-PCS/inclisiran to hepatocytes leads the inhibition of PCSK9 synthesis and both intracellular and extracellular functions in the liver, resulting in increased numbers of LDLRs on hepatocytes and a reduction in circulating LDL-C levels.[67,68] In a small phase 1 trial of ALS-PCS with intravenous administration, the highest dose showed a reduction of 70% in plasma PCSK9 levels and 40% in LDL-C levels in healthy adults with elevated LDL-C levels.[69] In the study, no serious adverse events were observed in subjects receiving ALN-PCS, while the LDL-C–lowering effect was less than that of the highest dose in a phase 1 trial of alirocumab and evolocumab.[17,21]

In a subsequent phase 1 trial, subcutaneously administered inclisiran (ALS-PCSsc) was tested in healthy volunteers with LDL-C ≥ 100 mg/dl.[68] For inclisiran, the study reported no drug discontinuations and showed reductions in PCSK9 levels of up to 84% and reductions in LDL-C levels up to 60%. The beneficial effects of inclisiran were observed in the phase 1 trial, regardless of the presence or absence of statin use. In addition, the effect of lowering LDL-C with inclisiran was similar to the effects seen with the currently approved PCSK9 mAbs. Different from the pharmacodynamic profile of the PCSK9 mAbs, the reductions in PCSK9 and LDL-C levels were sustained for at least 6 months after administration. The findings were used to develop a phase 2 trial to evaluate the potential of inclisiran administration every 3 or 6 months.

The ORION-1 phase 2 study was designed to investigate the effects of different doses and administration intervals for inclisiran in 501 patients at high CV risk.[70] Seventy-three percent of the participants were taking the maximum possible dose of statins. Inclisiran lowered both PCSK9 and LDL-C levels dose dependently and was well-tolerated, with no symptoms of concomitant immune activation. The primary endpoint of lowering LDL-C at day 180 was 28–42% with a single subcutaneous injection and 36–53% with two injections with a 3-month interval. In addition, inclisiran-treated patients showed up to 26% Lp(a) reduction. The greatest reduction in LDL-C levels at day 180 (− 53%) was observed in patients with two injections of 300 mg inclisiran, which was equal to that of PCSK9 mAbs. The ORION-1 study showed the potential of inclisiran to maintain the LDL-C lowering effect with fewer injections in contrast to PCSK9 mAbs with frequent injections. Given the high frequency of discontinuing statin therapy,[71] the dosing regimen of inclisiran has the potential to improve adherence and provide sustained LDL-C lowering more cost-effectively in patients at high CV risk. These safety and efficacy data from ORION-1 study were used to develop four phase 3 studies: the ORION-11 trial in 1500 patients at high CV risk, the ORION-10 trial in patients with ASCVD, the ORION-9 trial in HeFH patients, and the ORION-5 trial in HoFH patients.

Cost-effectiveness of PCSK9 Inhibitors

Drug cost is one of the determinants of the final choice of drug and dose in clinical practice.[4] In addition, cost-effectiveness is essential in terms of medical economics. A recently updated cost-effectiveness analysis from the Institute of Clinical and Economic Review, based on the results of the FOURIER trial, clarified that PCSK9 inhibitors were not cost-effective at 2017 prices for ASCVD patients.[72] The incremental cost-effectiveness ratio of PCSK9 inhibitors in combination with statins was US$450 000 per quality-adjusted life-year (QALY). Given the commonly accepted willingness-to-pay thresholds, such as US$100 000 per QALY gained, 71% annual drug cost reductions were required to achieve the threshold. Owing to these analyses, the price of PCSK9 mAbs has been dramatically reduced in 2018. A preliminary cost-effectiveness analysis from the ODYSSEY Outcomes trial was presented at American Heart Association Scientific Sessions 2018. The analysis found that alirocumab may be cost-effective in maximally statin-treated patients with a history of ACS and LDL-C ≥ 100 mg/dl, although the full paper is awaited. Cost-effectiveness analyses highlight the importance of identifying cost-effective patient groups, i.e., high-risk and very high-risk patients, depending on the baseline LDL-C levels, such as clinical ASCVD patients with FH, diabetes, and chronic kidney disease (CKD), or statin-intolerant patients with clinical ASCVD.[73,74]

ATP Citrate Lyase Inhibitor: Bempedoic Acid

Bempedoic acid is a first-in-class, once-daily, oral therapy that targets the cholesterol synthesis pathway. Bempedoic acid directly inhibits adenosine triphosphate (ATP) citrate lyase (ACL), an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the cholesterol synthesis pathway, leading to a reduction in hepatic cholesterol levels and compensatory sterol regulatory element-binding protein (SREBP)-2–mediated LDLR upregulation.[75] The upregulated LDLR results in subsequent reduction in circulating LDL-C levels. A noteworthy point on the mechanism of bempedoic acid is that ACL inhibition appears to be limited to the liver. The activity of very-longchain acyl-CoA synthease-1 (ACSVL1), which is required for conversion of bempedoic acid to its active CoA derivative, is not expressed in skeletal muscle.[76] The absence could contribute to reductions in muscle-related side effects compared to statins. Furthermore, this agent has the potential to limit the use of PCSK9 inhibitors due to its cost-effective and oral administration. These favorable properties have led to ongoing clinical studies.

After confirmation of LDL-C reduction in a dose-dependent manner by up to 36% at day 14 and a satisfactory safety profile in two phase 1 trials,[77] a first published phase 2 trial in 177 non-diabetic patients with LDL-C ranging from 130 to 220 mg/dl showed that bempedoic acid reduced LDL-C levels by up to 27% at week 12, with a generally safe profile regardless of the presence of hypertriglyceridemia.[78] A single-blind, dose-titration study of 60 diabetic patients with LDL-C ≥ 100 mg/dl demonstrated that bempedoic acid lowered LDL-C levels by 43% at day 29 without worsening glycemic control. A 41% reduction of high-sensitivity C-reactive protein (hsCRP) in the study highlighted the beneficial effects on inflammation as well as lipid metabolism.[79]

Given that both bempedoic acid and statins target the cholesterol synthesis pathway, there is considerable interest in the ability of bempedoic acid to amplify LDL-C reductions in patients with elevated LDL-C levels despite tolerated statins. Indeed, addition of bempedoic acid treatment to statin therapy demonstrated additional dose-dependent and significantly greater LDL-C reduction in 134 hypercholesterolemic patients, with good safety and tolerability compared to placebo (− 4% vs. up to − 24%).[75] This finding provided a potentially promising benefit of bempedoic acid as add-on therapy for patients with elevated LDL-C levels despite maximally tolerated statins.

Recently, two phase 2 trials examined bempedoic acid in statin-intolerant patients with hypercholesterolemia,[80,81] showing comparable results. The larger and longer study (n = 348, follow-up period 12 weeks) demonstrated that bempedoic acid up to 180 mg daily reduced LDL-C levels by up to 30% and hsCRP by up to 40% regardless of the presence of statin intolerance.[81] In addition, the incremental effect on lowering LDL-C was observed in patients with combination treatment of bempedoic acid and ezetimibe compared to ezetimibe monotherapy (LDL-C up to − 48% vs. − 21%; hsCRP up to − 38% vs. − 11%). Compared to ezetimibe monotherapy, bempedoic acid treatment did not show any increase in muscle-related adverse events and other safety concerns even in patients with statin intolerance. Considering the ≈ 17% LDL-C reductions with ezetimibe in statin-intolerant patients,[81] the beneficial effect of bempedoic acid with a good safety profile appears to be attractive for the management of statin intolerant patients.

The LDL-C lowering with bempedoic acid was accompanied by comparable reductions in non–HDL-C, apoB, and LDL particle (LDL-P) number.[78,81] These beneficial effects in early studies have spurred the development of ongoing phase 3 CVOTs with bempedoic acid. The CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL inhibiting Regimen) Outcomes trial will be conducted to evaluate the effects of bempedoic acid in 12 600 statin-intolerant patients at high ASCVD risk[82] (Table 2). Bempedoic acid treatment has consistently reduced hsCRP levels in early clinical studies,[75,78–81] whereas no discernible effects of PCSK9 inhibitors on inflammation have been observed.[17,26,41,70] Given the reduction of hsCRP by bempedoic acid and the positive result of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial,[83] reducing inflammation with bempedoic acid could contribute to further ASCVD risk reduction in addition to the benefit of lowering LDL-C. This result is expected to be presented in early 2022.

LDLR-independent LDL-C–lowering Therapies: Mipomersen (Kynamro®) and Lomitapide (Juxtapid®)

The main cause of monogenic FH is mutations in LDLR, although > 1700 mutations have been identified. This difference leads to various degrees of remaining LDLR function.[4] Compared to those in non-FH subjects, LDL-C levels in HoFH patients are four- to eight-fold higher because of the complete loss of or striking reduction in (2–30%) LDLR function.[84] Therefore, in HoFH patients, there is a need for LDLR-independent therapy as adjunctive therapy.

Mipomersen (Kynamro®) is an FDA-approved antisense oligonucleotide (ASO) for HoFH treatment, targeting apoB mRNA (Table 1). ASOs inhibit the translation of mRNA to protein by binding to mRNA, and apoB is the principal apolipoprotein of LDL. In a long-term extension phase 3 trial in HeFH or HoFH patients on maximally tolerated LLTs, once-weekly subcutaneous administered mipomersen reduced LDL-C levels by 28% at week 104 in parallel with those of apoB by 31%.[85] The inhibition of hepatic apoB production by mipomersen injected over 12 months was associated with reductions of major CV events in a similar population.[86] Furthermore, a pooled analysis from four phase 3 trials of mipomersen consistently showed reductions of Lp(a) by 26% in various populations with hypercholesterolemia.[87] Although the mechanism in FH patients is still unknown, increased catabolism of apo(a) (27%) was observed in healthy volunteers without change in production.[88] In the abovementioned extension study, long-term mipomersen had a satisfactory safety and tolerability profile, although concerns about transaminase elevations and hepatic steatosis require further long-term observations.

Lomitapide (Juxtapid ® ) is an orally-administered FDA-approved microsomal triglyceride transfer protein (MTP) inhibitor for HoFH patients (Table 1). MTP is an intracellular endoplasmic reticulum transfer protein, engaging in apoB production and lipidation in the liver and the intestines. The inhibition of MTP leads to reduced secretion of apoB-containing lipoproteins into the circulation.[89] In a phase 3 trial in HoFH patients, lomitapide at maximally tolerated doses on top of maximally tolerated LLTs reduced LDL-C and apoB levels by up to ~ 50%.[90] Hepatic toxicity has been the same as mipomersen. Given these issues, a multicenter, prospective, observational study is currently ongoing to evaluate the long-term (10-year) safety and effectiveness of lomitapide: the LOWER (Lomitapide Observational Worldwide Evaluation Registry).[91] In common with mipomersen, lomitapide is mentioned to be a restricted option as adjunctive therapy for HoFH patients.[89]

The Potential of CETP Inhibitors

Cholesterol ester transfer protein (CETP) is an important mediator to transfer cholesterol esters and triglyceride (TG) among lipoproteins. CETP inhibition has been demonstrated to decrease LDL-C levels in addition to raising HDL-C. After all of the large outcomes trials of CETP inhibitors, there remains some hope that this may still prove to be an effective cardioprotective strategy. Pharmacogenomic analysis of the dal-Outcomes suggested potential benefit of dalcetrapib in patients with specific polymorphisms of the ADCY9 gene on chromosome 16.[92] This has led to the initiation of a new trial comparing dalcetrapib and placebo in patients with that specific genotype. In addition, Mendelian randomization data suggest that CETP deficiency can be protective, but only in the presence of HMGCR, the pharmacological target of statin therapy.[93] Accordingly, it is possible that these agents may be more effective in the absence of statins, although this has not been tested to date.