PCSK9 is a serine protease that is predominantly synthesized and secreted by hepatocytes [24]. The only known human function of PCSK9 is to regulate the cell membrane low-density lipoprotein (LDL) receptor (LDLR) in the liver [24]. Following free PCSK9 binding, the LDLR is degraded instead of being recycled, leading to higher circulating LDL-C levels [24]. The potential role of PCSK9 in LDL-C metabolism was first recognized in 2003 via genetic mapping in patients with autosomal dominant hypercholesterolemia [25]. Subsequent case reports of healthy patients homozygous for loss-of-function variants and LDL-C levels of ~0.4 mmol/L (15 mg/dL) demonstrated the crucial role of PCSK9 in LDL metabolism [26]. Indeed, in an analysis of the Atherosclerosis Risk in Communities (ARIC) study in 2006, patients carrying a nonsense, or loss-of-function, variant (specifically either PCSK9 p.Tyr142Ter or p.Cys679Ter) had 28% lower LDL-C as well as significantly lower total cholesterol and triglycerides compared with non-carriers [27]. During the 15-year follow-up period, only ~1% of carriers experienced a coronary event compared with ~10% of non-carriers [27].

Several clinical trials studying the safety and efficacy of evolocumab were launched in 2010 (Table 2, Ref. [11, 28, 29, 30, 31, 32]; Table 3, Ref. [11, 33]; Table 4, Ref. [11, 34, 35]; Table 5, Ref. [11, 16, 36]; Table 6, Ref. [11, 37, 38, 39, 40, 41, 42, 43]; Table 7, Ref. [11, 44, 45, 46]) [47], taking evolocumab from bench to bedside in ~7 years. Over the years, the program of evolocumab data generation, known as the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations (PROFICIO), has grown to include 50 clinical trials and RWE studies to date, enrolling $>$51,000 patients. [48, 49] Most clinical trials conducted within the PROFICIO program investigated evolocumab added to maximally tolerated statin therapy, compared with a matching injectable subcutaneous placebo and maximally tolerated statin therapy, with background LLT being balanced across evolocumab and control arms. The PROFICIO program has also included a focus on special patient populations, including those with peripheral arterial disease (PAD), diabetes mellitus, recent/prior MI, heterozygous FH (HeFH), homozygous FH (HoFH), pediatric HeFH, and human immunodeficiency virus (HIV), from study sites across the world (Table 6). The results across all trials included support consistent and statistically significant LDL-C reduction with evolocumab across different trial settings and in various patient population. Ultimately, evolocumab was approved in North America and Europe in 2015 as an add-on to statin therapy, alone or in combination with other LLTs, and in those with statin intolerance, for LDL-C reduction in adult patients with primary hyperlipidemia (Table 2) [24]. More recent approvals for evolocumab are for the LDL-C reduction in pediatric patients aged $\ge$10 years with HeFH or HoFH and for the prevention of CV events (MI, stroke, coronary revascularization) in patients with ASCVD [24].

Evolocumab is administered subcutaneously, with a recommended dose of either 140 mg every 2 weeks (Q2W) or 420 mg once monthly (QM) [20]. It can be administered using a prefilled syringe or prefilled autoinjector, and is intended for patient self-administration or administration by a caregiver [20]. In the phase III Trial for HOMe-use of prefilled Auto-injector pen and 3.5 mL Personal Injector in AMG 145 administrationS (THOMAS)-I and THOMAS-II studies (Table 3), patients were confirmed to be successful at self-administering evolocumab in both the clinic and at-home settings, regardless of the dosing schedule or injection device [33].

Following a single subcutaneous dose of evolocumab (140 mg or 420 mg) administered to healthy adults, peak circulating drug concentrations are reached in 3–4 days, with an estimated absolute bioavailability of 72% and half-life of 11–17 days [20, 50]. Evolocumab exerts even more rapid pharmacodynamic effects, with 100% PCSK9 suppression within 4 hours of administration and reductions in LDL-C observed as early as day 1 in clinical trials [20, 42, 50]. Following a single 420 mg intravenous (IV) dose of evolocumab, the mean systemic ($\pm$ standard deviation) clearance is estimated to be 12 $\pm$ 2 mL/hr, with co-administration of statins increasing the clearance of evolocumab by ~20% [20]. Peak LDL-C reduction is generally observed at 1–2 weeks after evolocumab administration, with mean reductions ranging from 50–81% in the clinical trial setting (Tables 2,3,4,5,6,7) [50]. Patient characteristics, including mild/moderate hepatic impairment, kidney impairment or failure, body weight, race, sex, or age, do not contribute to clinically meaningful differences in pharmacodynamic effects of evolocumab on LDL-C reduction [50]. Further, PCSK9i mAbs are very specific, including evolocumab which binds to PCSK9 with a high affinity of 16 pM, and they are not known to bind to other members of the PCSK enzyme superfamily [51]. Across 17,992 adults patients treated with evolocumab in clinical studies, only 0.3% tested positive for the development of anti-evolocumab binding antibodies, with none of these patients developing neutralizing antibodies [20]. Finally, no adverse drug-drug interactions have been reported for evolocumab to date [20].

In addition to marked reductions in LDL-C, imaging studies have demonstrated the efficacy of evolocumab at the level of coronary plaque [34, 35, 52]. In the phase III GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound (GLAGOV) (Table 4) study in patients with angiographic CAD, LDL-C reductions from baseline after 78 weeks of evolocumab (+statin) were linearly associated with reductions in the percent atheroma (atherosclerotic plaque) volume (PAV) (Fig. 1A, Ref. [34]). The clinical significance of this is clear from a comprehensive systematic review and meta-regression analysis of LLT trials representing data from over 6000 patients, including some on evolocumab, which showed that for every 1% reduction in mean PAV, there is a ~20% reduction in the risk of major CV events (Fig. 1B) [53]. In the GLAGOV study, evolocumab (+statin) reduced PAV by an absolute 0.95% from baseline and resulted in a greater proportion of patients with plaque regression compared with placebo (+statin; 64.3% vs. 47.3%, respectively) [34]. Interestingly, further analysis showed that achieving LDL-C 1.5 mmol/L (58 mg/dL) resulted in plaque regression, deceleration of progression, or lack of progression (Fig. 1A), all of which were associated with plaque stabilization and reduced CV risk [54]. Likewise, in the phase III High-ResolUtion Assessment of CoronarY Plaques in a Global Evolocumab RaNdomized Study (HUYGENS) study in patients with a non-ST-segment elevation MI (NSTEMI), 52 weeks of evolocumab (+statin) therapy resulted in even greater reductions in PAV compared with placebo (+statin; –2.3% vs. –0.6%, respectively) [35].

Fig. 1.

Correlation of LDL-C reduction, change in PAV and MACE outcomes. (A) Post-hoc Analysis of the Relationship Between Achieved LDL-C and Change in PAV After Evolocumab (+Statin) Treatment in GLAGOV. Local regression (LOESS) curve illustrating post-hoc analysis of the association (with 95% confidence intervals) between the achieved LDL-C levels and change in PAV in all patients undergoing serial IVUS evaluation. Curve truncated at 0.5 mmol/L and 2.8 mmol/L (20 and 110 mg/dL) owing to the small numbers of values outside that range. (Figure permission obtained from [34]). (B) Association Between Mean Change in PAV and MACE in Various LLT Trials. Each square represents a single study arm. The size of the square is proportional to the sample size of that study arm. The MACE proportion was converted to log odds and a constant 0.5 was added to zero counts to allow the conversion of log odds. The regression line is based on the adjusted mixed-effects logistic regression model. (Figure permission obtained from [53]). GLAGOV, GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; MACE, major adverse cardiovascular event (myocardial infarction, stroke, transient ischemic attack, unstable angina or all-cause mortality); PAV, percent atheroma volume.

Plaque stability can be characterized by the thickness of the thin-cap fibroatheroma, with an inverse relationship between the thickness of the fibrous cap covering the lipid plaque and risk of plaque rupture [55]. Plaques at high risk of rupture have a fibrous cap thickness 65 µm [56]; therefore, the ability to improve plaque stability in a vulnerable high-risk patient may reduce the risk of plaque rupture and CV events. In the HUYGENS study (Table 4) of NSTEMI patients, evolocumab (+statin) increased the minimum fibrous cap thickness at week 50 from baseline by +42.7 $\pm$ 10.3 µm vs. +21.5 $\pm$ 10.6 µm in the placebo (+statin) group [35], representing an 81.8% vs. 44.3% improvement, respectively. A greater proportion of patients achieved a minimum fibrous cap thickness $\ge$65 µm in the evolocumab group compared with the placebo group [35]. Likewise, in the phase IV Reduction in YEllow Plaque by Aggressive Lipid LOWering Therapy (YELLOW)-III study in patients with stable CAD, evolocumab (+statin) increased fibrous cap thickness from 70.9 $\pm$ 21.7 µm at baseline to 97.7 $\pm$ 31.1 µm at week 26 [52]. Collectively, these results point to relatively rapid improvements in plaque stability to reduce the risk of rupture as a potential mechanism underlying the clinical benefits of evolocumab, regardless of ASCVD severity.

The potential for the effects of evolocumab on LDL-C to translate into CV benefits was explored in the phase III FOURIER trial (Table 5), the largest dedicated CV outcomes trial with a LLT to date (N = 27,564) [16]. FOURIER was an event driven trial that investigated the efficacy and safety of evolocumab vs. placebo added to high- or moderate-intensity statin therapy in patients with clinically evident ASCVD with an LDL-C $>$1.8 mmol/L (70 mg/dL) or a non-HDL-C $>$2.6 mmol/L (100 mg/dL), with a median follow-up of 2.2 years. At 48 weeks, evolocumab reduced LDL-C by 59% compared with placebo, which was maintained over time. Further, LDL-C was reduced below thresholds of $\le$1.8 mmol/L ($\le$70 mg/dL) in 87% of patients and $\le$1.0 mmol/L ($\le$40 mg/dL) in 67% of patients on evolocumab, compared with 18% and 0.5% of patients on placebo, respectively. A post-hoc analysis of the interindividual variation in LDL-C reductions from baseline during the first year post-evolocumab initiation in FOURIER showed 94.7% of patients achieved $\ge$50% LDL-C reduction, 97.9% achieved $\ge$30% reduction and 99.5% achieved any reduction in LDL-C [57]. Evolocumab also significantly reduced concentrations of other atherogenic lipoproteins, including non-high-density lipoprotein C (HDL-C), apolipoprotein B-100 (ApoB), and lipoprotein (a; Lp(a)), compared with placebo (Table 8, Ref. [16]). A pre-planned analysis of the FOURIER results showed patients with higher baseline Lp(a) levels had greater absolute reductions in Lp(a) and CV risk post-evolocumab treatment, with a 23% reduction in the risk of coronary heart disease death, MI or urgent coronary revascularization compared with only 7% in patients with lower baseline Lp(a) [58].

Findings from the FOURIER trial highlighted the benefit of reducing LDL-C to levels lower than those shown in previous LLT trials, with a median achieved LDL-C of 0.78 mmol/L (30.2 mg/dL) [16]. Importantly, this significant LDL-C reduction with evolocumab resulted in reduced CV events which can be visualized in the Kaplan-Meier curved from the FOURIER, which showcase a 15% reduction in the risk of the prespecified primary composite endpoint of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (Fig. 2A, Ref. [16]), and a 20% reduction in the risk of the key secondary composite endpoint of major adverse CV events (MACE; i.e., CV death, MI, or stroke; Fig. 2B, Ref. [16]). Differences in CV risk between the evolocumab and placebo groups were observed early, at approximately 6 months, and increased over time. The Kaplan-Meier curves from the FOURIER analysis demonstrate the magnitude of MACE risk reduction was 16% during the first year that increased to 25% beyond the first year post-evolocumab initiation, collectively highlighting a rapid onset of MACE risk reduction that grew over time, considering the relatively short duration of follow-up (Supplementary Fig. 4 in [16]). Further, MACE risk reductions were consistent across levels of background statin intensity and ezetimibe use and regardless of baseline LDL-C. Among patients in the top quartile for baseline LDL-C (n = 6829), evolocumab reduced median LDL-C from 3.3 mmol/L (126 mg/dL) to 1.1 mmol/L (43 mg/dL) and the risk of MACE by 17%. Among patients in the lowest quartile for baseline LDL-C (n = 6961), evolocumab reduced median LDL-C from 1.9 mmol/L (73 mg/dL) to 0.57 mmol/L (22 mg/dL) and the risk of MACE by 22%. Further, in a subset of patients who had baseline LDL-C 1.8 mmol/L (70 mg/dL), a significant 30% reduction in MACE was shown, reinforcing the importance of further LDL-C reduction even in high-risk ASCVD patients who are close to the recommended LDLC threshold [59]. Finally, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions [16], even at the lowest achieved LDL-C levels [59], as described in detail in section 9 on evolocumab safety.

Fig. 2.

Impact of evolocumab vs. placebo on CV death, MI, or stroke in high- and very high-risk patients in the FOURIER trial. (A) Overall FOURIER [16]. (B) Prior PCI [63]. (C) PAD [64]. (D) Diabetes Mellitus [65]. ${}^1$Composite of coronary death, MI, or coronary revascularization. ARR, absolute risk reduction; CV, cardiovascular; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; NNT, number needed to treat; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; RRR, relative risk reduction; MI, myocardial infarction.

An open-label extension of the FOURIER trial (FOURIER-OLE; Table 5) was conducted to determine the long-term efficacy and safety of evolocumab [36]. Patients (N = 6635) who completed FOURIER continued or transitioned to open-label evolocumab (140 mg Q2W or 420 mg QM), with an additional median follow-up of 5.0 years. Maximum exposure to evolocumab in the parent trial plus FOURIER-OLE was 8.4 years, and patients were advised to continue other background LLT whenever appropriate during follow-up. Consistent with the parent FOURIER trial, at 12 weeks after the start of FOURIER-OLE, LDL-C was reduced by 58.4% to a median of 0.75 mmol/L (30 mg/dL), which was consistent between patients irrespective of their original treatment in the parent trial (i.e., evolocumab or placebo). An LDL-C 1.8 mmol/L (70 mg/dL) was achieved by 87.3% of patients, 1.4 mmol/L (55 mg/dL) by 80.3% and 1.0 mmol/L (40 mg/dL) by 63.2%. Further, for patients randomized to evolocumab in the parent FOURIER trial, LDL-C reductions were consistent and stable over a median follow-up of 7.1 years, with no attenuation of effect or fluctuations over time. Accordingly, these patients had a 20% reduced risk of CV death, MI, or stroke and 23% reduced risk of CV death (Table 9, Ref. [16, 36]) compared with patients originally randomized to placebo who were delayed in evolocumab initiation by approximately 2 years until the start of the OLE. The Kaplan-Meier curves for percentage of patients experiencing CV death, MI or stroke (Supplementary Fig. 4B in [36]) demonstrate the significant CV benefits associated with both earlier and longer evolocumab intervention [36]. The differences in CV outcomes based on duration of evolocumab exposure may be due to an accrued benefit of prior LDL-C reductions in patients originally randomized to evolocumab, in combination with the lag time required for LDL-C reductions to affect plaque burden in patients originally randomized to placebo and transitioned to evolocumab.

In another recent analysis of the FOURIER-OLE with a maximum follow-up of 8.6 years, there was a monotonic relationship between achieved LDL-C levels and CV risk, with every 1 mmol/L (40 mg/dL) reduction in LDL-C conferring ~20% reduction in the risk of major CV events [60]. While this finding is consistent with reports of agents from other LLT trials [7], the FOURIER-OLE uniquely confirmed these CV benefits in patients with LDL-C reductions to lower levels than previously studied, down to 0.5 mmol/L (20 mg/dL), with no apparent level below which there is no further CV risk reduction [60]. Indeed, patients who achieved LDL-C levels well below guideline-recommended thresholds (1.0 and 0.5 mmol/L; 40 and 20 mg/dL) tended to have a reduced risk of MACE compared with patients who achieved LDL-C levels within these thresholds (1.4–1.8 mmol/L; 55–70 mg/dL). These results reinforce the importance of targeting very low LDL-C levels in high-risk patients with ASCVD and suggest the most intensive European guideline-recommended LDL-C target threshold of 1.0 mmol/L (40 mg/dL) could benefit all patients with ASCVD, not just those with recurrent CV events. Further, no new adverse events emerged, even in patients with the lowest achieved LDL-C levels [36, 60], as described in section 9, evolocumab safety.

Altogether, the FOURIER and FOURIER-OLE provide the largest and longest follow-up data available to date for a PCSK9i in patients with ASCVD. The results demonstrate rapid, clinically significant, and sustained efficacy with long-term evolocumab (+statin) treatment, with compounding CV benefits at lower achieved LDL-C levels and over time. Hence, the results emphasize the importance of early and significant LDL-C reduction to achieve the greatest clinical outcomes.

Elevated LDL-C is associated with an increased risk of recurrent or adverse CV events in patients with ACS [66]. The impact of evolocumab on patients with ACS was investigated in both the EVOlocumab for Early Reduction of LDL-Cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS) and EVolocumab in Acute Coronary Syndrome (EVACS) studies (Table 6) [40, 42]. EVOPACS investigated the 8-week feasibility, safety, and LDL-C effects of evolocumab added to statin therapy during the in-hospital phase of ACS, compared with placebo, which also included statin therapy. Most patients (62%) were screened for study participation within 24 hours of patient-reported symptom onset and all within 72 hours [40]. Evolocumab treatment reduced LDL-C levels by 40.7% compared with placebo, with LDL-C reductions observed as early as 4 weeks post-ACS and maintained at 8 weeks. Additionally, 95.7% of patients treated with evolocumab upon their ACS achieved LDL-C 1.8 mmol/L (70 mg/dL) and 90.1% achieved LDL-C 1.4 mmol/L (55 mg/dL) compared with 37.6% and 10.7%, respectively, in the placebo group at 8 weeks [40]. LDL-C reductions were consistent regardless of type of ACS [40]. Further, there were no new safety issues with early post-ACS initiation of evolocumab.

The EVACS study included patients with NSTEMI and troponin I $\ge$5 ng/mL on background statin therapy, though not all were dose-optimized upon clinical presentation [42]. Still, LDL-C reductions from baseline were observed as early as day 1 post-evolocumab initiation, with significant reductions compared with placebo as early as day 3. LDL-C was 0.74 mmol/L (28.6 mg/dL) lower for patients on evolocumab compared with placebo at 30 days, reflecting a calculated 31% reduction. Further, 80.8% of patients on evolocumab achieved LDL-C $\le$1.8 mmol/L ($\le$70 mg/dL) and 65.4% achieved $\le$1.4 mmol/L ($\le$55 mg/dL), compared with only 38.1% and 23.8%, respectively, with placebo.

Altogether, the results from EVOPACS and EVACS demonstrate prompt addition of evolocumab in the hospital after ACS rapidly and significantly reduces LDL-C, compared with statin alone, in patients who most require LDLC reductions to reduce the risk of further CV events. Importantly, most patients were capable of achieving LDL-C levels below guideline-recommended thresholds for patients at increased CV risk prior to hospital discharge.

Patients with acute MI have higher rates of subsequent major CV events and mortality relative to patients with ASCVD in general [6]. In patients in the FOURIER trial who experienced prior MI, evolocumab demonstrated consistent LDL-C reductions of 59–61% at 48 weeks from baseline, regardless of the time since most recent MI, number of prior MIs, or the presence of residual multivessel CAD, with a median achieved LDL-C of 0.75–0.78 mmol/L (29–30 mg/dL) [61]. Indeed, the proportion of patients who achieved the LDL-C target threshold of 1.0 mmol/L (40 mg/dL) for patients with recurrent CV events was similar between patients with a recent MI $\le$1 year ago (63.8%) and $>$1 year ago (63.1%) [62]. Further, evolocumab reduced the risk of the composite of CV death, MI, or stroke by 25% in patients with a prior MI compared with placebo, over a median follow-up of only 2.2 years (Fig. 3A). This risk reduction with evolocumab compared with placebo was consistent in patients with $\ge$2 prior MIs (21%; Fig. 3B), patients with a recent MI $\le$2 years ago (24%; Fig. 3C), patients with a recent MI $\le$1 year ago (25%; Fig. 3D) and patients with residual multivessel disease (30%; Fig. 3E) [61, 62]. Collectively, these results demonstrate the significant benefit of evolocumab in reducing the residual risk of MACE in patients with prior MI, particularly in those who are at the greatest risk for a subsequent event early in the trajectory of their disease.

A blinded, post-hoc analysis of the FOURIER trial revealed evolocumab reduced the risk of any coronary revascularization by 22%, simple PCI by 22%, complex PCI by 33%, coronary artery bypass grafting (CABG) surgery by 24%, and complex revascularization (the composite of complex PCI or CABG) by 29% [67]. Hence, these results suggest evolocumab may shift the risk from more complex revascularization procedures towards simple PCI or no revascularization at all. Interestingly, the magnitude of complex revascularization risk reduction with evolocumab tended to increase over time, from 20% in the first year post-evolocumab initiation to 41% beyond the second year. Patients who have undergone PCI are at high residual risk for CV events, including subsequent MI and coronary revascularization [68]. In a prespecified analysis of patients with prior PCI in the FOURIER trial, evolocumab treatment reduced LDL-C by 60.8% at 48 weeks compared with placebo [63]. Furthermore, evolocumab reduced the risk of the composite of CV death, MI, or coronary revascularization by 18% compared with placebo, over a median follow-up of 2.2 years (Fig. 2B), which did not significantly differ based on time since last PCI. Interestingly, CV risk reduction was observed almost immediately after evolocumab initiation, before growing over time, emphasizing the importance of early LDL-C lowering, especially in vulnerable patients, for the opportunity to derive the greatest benefit in the long term.

Patients with PAD have an increased risk of major CV events, including CV death, MI, and stroke, compared with patients with stable ASCVD [69, 70]. In patients with PAD in the FOURIER trial, treatment with evolocumab reduced LDL-C by 59% after 48 weeks compared with placebo, with LDL-C levels maintained over time [64]. Furthermore, evolocumab-treated patients had a 27% reduced risk of the composite of CV death, MI, or stroke compared with placebo, over a median follow-up of 2.2 years (Fig. 2C). Additionally, this was the first study to demonstrate a benefit of intensive LDL-C lowering for major adverse limb events (MALE) risk, including the composite of acute limb ischemia, major amputation, or urgent revascularization, with evolocumab treatment in all patients (with or without PAD) conferring a 42% reduced risk compared with placebo. There was a roughly linear relationship between reductions in LDL-C and the risk of MALE, down to an LDL-C of 0.26 mmol/L (10 mg/dL), highlighting the benefits of significant LDL-C lowering in patients with PAD. Further, evolocumab reduced the risk of the combination of MACE and MALE by 49%, yielding an NNT of 16 over 2.5 years for patients with PAD. Finally, there was no impact of evolocumab on any additional treatment emergent adverse events in patients with PAD.

The prevalence of diabetes mellitus has gradually increased globally over the past decades [5], and given the association of diabetes mellitus with increased risk for CV disease morbidity and mortality, there is a need for effective strategies to lower LDL-C in this population [71]. The BANTING study investigated the impact of evolocumab in patients with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia and on background statin therapy (Table 6) [39]. Evolocumab significantly reduced LDL-C by 54.3% from baseline, compared with 1.1% for placebo at week 12 [39]. Furthermore, 84.5% of patients on evolocumab achieved LDL-C $\le$1.8 mmol/L ($\le$70 mg/dL) and 65.5% achieved an LDL-C reduction of $\ge$50%, compared with 15.4% and 0.8%, respectively, for placebo [39]. A substantial proportion of patients in the FOURIER trial had diabetes (n = 11,031; 40%) [65], enhancing the CV risk in these patients with ASCVD. In these patients, evolocumab treatment reduced the risk of the composite of CV death, MI, or stroke by 18% compared with placebo (Fig. 2D). The magnitude of CV risk reduction increased over time post-evolocumab initiation, from 13% in the first year to 25% afterwards, emphasizing the importance of early LDL-C lowering in patients with diabetes mellitus, for the opportunity to derive the greatest benefit in the long term. Finally, there was no increase in incident diabetes mellitus in patients who did not have diabetes at baseline, nor did evolocumab worsen glycemic control in patients with diabetes mellitus, as described in section 9 on evolocumab safety.

Metabolic syndrome, comprising three or more of abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, and/or low levels of HDL-C, is recognized as a risk factor for major CV events [2, 3, 4, 5]. In patients with metabolic syndrome in the FOURIER trial, compared with placebo, evolocumab reduced LDL-C by 57.7% at 48 weeks as well as the risk of the composite of CV death, MI, or stroke by 24% over a median follow-up of 2.2 years [72]. Hence, these results demonstrate the benefit of evolocumab in reducing CV risk in patients with several risk factors.

FH is an autosomal dominant genetic disorder characterized by chronically elevated circulating LDL-C, which can accelerate the development of ASCVD, with an estimated 10- to 20-fold increased risk compared with normolipidemic individuals [79, 80, 81]. Patients with HeFH commonly experience LDL-C levels $>$4.9 mmol/L ($>$190 mg/dL), and HoFH is even more severe with LDL-C levels $>$13 mmol/L ($>$503 mg/dL) [82]. Clinical trials have demonstrated evolocumab added to statin therapy reduces LDL-C compared with placebo (+statin) in both adult and pediatric patients with either HeFH or HoFH [37, 41, 83]. The phase III RedUction of LDL-C With PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2 (RUTHERFORD-2) trial is the largest reported global trial of patients with HeFH treated with a PCSK9i (Table 6) [37]. Both doses of evolocumab (i.e., 140 mg Q2W or 420 mg QM) reduced LDL-C by ~60% compared with placebo at week 12, with reductions observed as early as week 2 and remaining consistent up to week 12 [37]. Furthermore, LDL-C 1.8 mmol/L ($\le$70 mg/dL) was achieved by $\ge$63% of patients receiving either dose of evolocumab, compared with 2% in each of the placebo groups [37].

Evolocumab efficacy in HeFH was also investigated in pediatric patients (aged 10–17 years) in the phase III Trial Assessing Efficacy, Safety and Tolerability of PCSK9 InHibition in PediAtric SUbjectS With GenEtic LDL DisordeRs (HAUSER) study (Table 6) [41]. Evolocumab reduced LDL-C by 38.3% compared with placebo at week 24 [41]. Furthermore, 74% of pediatric patients achieved LDL-C 3.4 mmol/L (130 mg/dL), the target LDL-C threshold within the study, and 45% achieved an LDL-C reduction of $\ge$50% [41].

In the open-label, single-arm TAUSSIG study (Table 6), evolocumab reduced LDL-C by 1.94 $\pm$ 3.22 mmol/L (74.9 $\pm$ 124.5 mg/dL) in patients with HoFH and by 2.33 $\pm$ 1.60 mmol/L (90.6 $\pm$ 61.9 mg/dL) in patients with severe HeFH after 4.1 years, corresponding to 24.0% and 47.2% reductions, respectively [83]. The individual variability in evolocumab response in patients with HoFH is attributed to differences in LDLR expression resulting from their disease, with the non-responders lacking functioning or available LDL receptors [84]. Furthermore, although the magnitude of LDL-C reduction may be less in homozygous or compound heterozygous double LDLR mutation carriers, the LDL-C reduction is sustained [83]. Evolocumab efficacy has also been demonstrated in patients with a rare subtype of HeFH due to PCSK9 gain-of-function mutations [83]. Additionally, a CV event rate of 2.7% per year was reported [83], which was markedly lower than expected given the high risk of CV events in patients with HoFH and HeFH reported in other studies [85]. Moreover, of the 61 patients undergoing apheresis at enrollment, 9% with HoFH and 48% with HeFH were able to discontinue apheresis, sparing on average 36 months of apheresis treatment over the course of the study [83]. Of the 26% of patients who stopped apheresis altogether, 62.5% were able to do so within 90 days of starting evolocumab treatment [83].

In summary, FH is a serious incurable disease that substantially increases the risk of primary as well as secondary ASCVD, even in pediatric patients. These results demonstrate the addition of evolocumab to background statin therapy confers clinically significant LDL-C reductions to achieve levels below guideline-recommended thresholds, in a population wherein statins alone are often insufficient. Further, no additional evolocumab safety issues were identified in these studies, as described in section 9 on evolocumab safety. Hence, evolocumab is globally indicated in patients with HeFH and HoFH and is guideline-recommended to ultimately reduce the substantial CV risk associated with lifelong exposure to elevated LDL-C [2, 3, 4, 5].

Patients with HIV are considered to be at high risk for ASCVD because of traditional risk factors such as dyslipidemia, insulin resistance, tobacco, and hypertension, and also due to the immune-mediated changes associated with HIV [86, 87, 88]. Moreover, evidence suggests certain antiretroviral therapies (ARTs) may increase the risk of ASCVD, especially first-generation protease inhibitors that can result in endothelial dysfunction or metabolic imbalances [86, 88, 89, 90]. Considering the minimal LLT studies in this high-risk patient population, the impact of LLT is not well-understood. In the phase III BEIJERINCK study (Table 6), evolocumab treatment reduced LDL-C by 56.9% at week 24 compared with placebo in patients with HIV receiving maximally tolerated statin therapy [43]. Additionally, 73.3% and 72.5% of patients on evolocumab achieved LDL-C 1.8 mmol/L (70 mg/dL) and a $\ge$50% reduction from baseline, compared with 7.9% and 0.7% of patients, respectively, with placebo. Lastly, no neutralizing antibodies were developed against evolocumab, and no safety issues were identified, as described in section 9 on evolocumab safety. Thus, these results demonstrate evolocumab is an efficacious add-on to background statin therapy to achieve LDL-C levels below guideline-recommended thresholds in patients with HIV, an immunocompromised population with complex etiology underlying their increased risk of ASCVD.

In the HEYMANS study (Table 7) of patients initiated on evolocumab as part of routine clinical care across 12 European countries (N = 1951), 41% of patients were not on background statin and/or ezetimibe therapy at evolocumab initiation and 60% had reported statin intolerance [44]. Consistent with the FOURIER trial and OLE [16, 36], evolocumab therapy was associated with a 58% reduction in LDL-C from baseline after 3 months, which was maintained over 30 months of follow-up, all despite the heterogenous patient population on varying background LLT. Approximately 60% of patients achieved $\ge$50% LDL-C reduction throughout the study. Further, 56% of patients at high CV risk achieved the guideline-recommended LDL-C goal of 1.8 mmol/L (70 mg/dL) and 60% of patients at very high CV risk achieved the more aggressive goal of 1.4 mmol/L (55 mg/dL). Overall, a greater proportion of patients achieved below LDL-C thresholds on evolocumab plus background LLT compared with those on evolocumab monotherapy, consistent with the science showing the impact of PCSK9 inhibition on LDL-C clearance is enhanced when used in combination with a statin [91].

In the ZERBINI study of patients initiated on evolocumab as part of routine clinical care in three continents and five countries (Table 7), including Canada, Mexico, Colombia, Saudi Arabia, and Kuwait (N = 578), 15% of patients were not on background statin and/or ezetimibe therapy at evolocumab initiation and 36% had reported statin intolerance (ranging 7.7–61.8% across the different countries) [46]. In the full heterogeneous cohort on varying background LLT, evolocumab therapy was associated with a 70% reduction in LDL-C from baseline, which was maintained over a 12-month period. Further, 76.0% of patients achieved $\ge$50% reduction in LDL-C, which is consistent with the FOURIER trial wherein 80% of patients achieved $\ge$50% LDL-C reduction at 4 weeks (Fig. 4, Ref. [57]), and 94.7% at 12 months [16]. In the ZERBINI study, guideline-recommended LDL-C thresholds of 1.8, 1.4, and 1.0 mmol/L (70, 55, and 40 mg/dL) were achieved by 75%, 64%, and 47% of patients, respectively [46]. Notably, these LDL-C outcomes were consistent across high- and very high-risk patients, including those with ASCVD or FH, ASCVD with FH, $\ge$2 ASCVD conditions, and ASCVD with diabetes, with $>$50% of very high-risk patients achieving the most intensive LDL-C goal of 1.0 mmol/L (40 mg/dL) recommended for patients who experienced a second CV event within the previous 2 years [3]. These real-word LDL-C reductions associated with evolocumab therapy in vulnerable patients are consistent with those from sub-analyses of the FOURIER trial [65]. Finally, all ZERBINI study outcomes were consistent across sub-analyses of the Canadian [92], Colombian [93], and Middle Eastern [94] cohorts.

Fig. 4.

Waterfall plots of the distribution of percentage change in LDL-C from baseline. (A) Week 4 in Placebo Group of FOURIER. (B) Week 4 in Evolocumab Group of FOURIER${}^{1,2}$. ${}^1$In the FOURIER trial, at 1-year post-evolocumab initiation, 94.7% of patients achieved a $\ge$50% LDL-C reduction; ${}^2$Data represent patients with an LDL-C measure at baseline (measured within 6 months prior to initiation of evolocumab) and their minimum LDL-C measure during the 12-month study follow-up period. (Figure permission obtained from [57]). FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin-kexin type 9.

Effect of EVolocumab in PatiEntS at High CArdiovascuLar RIsk WithoUt Prior Myocardial Infarction or Stroke (VESALIUS)-CV is a phase III multinational trial assessing the effect of optimized LLT intensification with evolocumab in reducing first major CV events in adults with established ASCVD or diabetes mellitus, without prior MI or stroke, compared with placebo (+optimized LLT) [104]. Inclusion criteria require elevated LDL-C and presence of at least one of the following high-risk conditions at screening: significant CAD, atherosclerotic cerebrovascular disease, PAD, and/or diabetes mellitus. Primary outcomes are time to coronary heart disease death, MI, or ischemic stroke or any ischemia-driven arterial stroke over a minimum of 4.5 years of follow-up. This study will be the first CV outcome study with a PCSK9i to include a large cohort of primary prevention patients.

The phase IV A Pragmatic, Randomized, Multicenter Trial of EVOLocumab Administered Very Early to Reduce the Risk of Cardiovascular Events in Patients Hospitalized With Acute Myocardial Infarction (EVOLVE-MI) open-label trial is evaluating the effect of early treatment with evolocumab plus routine LLT vs. routine LLT alone to reduce MI, ischemic stroke, arterial revascularization, and all-cause mortality in adult patients hospitalized for an acute MI (NSTEMI and STEMI) [105]. This is a pragmatic study to assess the impact of evolocumab initiated within 10 days of the index MI in the acute setting compared with standard of care. The primary outcome is the total (first and subsequent) composite of MI, ischemic stroke, any arterial revascularization procedure, and all-cause mortality over approximately 3.5 years of follow-up.

NEWTON-CABG is a phase IV trial evaluating the effect of evolocumab added to routine statin therapy on vein graft patency after CABG surgery compared with placebo (+statin) [106]. The primary outcome is saphenous vein graft disease rate (VGDR) 24 months post-CABG, with VGDR defined as the proportion of vein grafts with significant stenosis or total occlusion ($\ge$50%) on 64-slice (or greater) cardiac computed tomography angiography (CTA) or clinically indicated coronary angiography.

Taken together, the results of these novel studies will advance the current understanding of the impact of LLT intensification with evolocumab on major CV outcomes in vulnerable patients. Further, these studies will address a data gap and may help shape clinical practice for certain patient types for whom current guidelines are unclear, such as those with diabetes mellitus without established ASCVD.