The National Lipid Association proposed the most recognized definition of statin intolerance (SI) in 2014, defining SI as a clinical syndrome incapable of tolerating at least two statins (one at the lowest starting daily dose and another at any daily dose) due to either objectionable syndromes (subjective or objective) or abnormal laboratory results, which occurred upon exposure to statin treatment, and is reversible after statin discontinuation and reproducible by statin rechallenge [28].

Statin-associated muscle symptoms (SAMS) are responsible for the vast majority of SI. Hence, most studies and guidelines, including our review, equate SAMS with SI [2, 3, 29]. SAMS are characterized by myalgias, and weakness with or without elevated serum muscle enzymes [26], and ranges from 7–29% among all patients on statin therapy and has become the predominant cause for discontinuation in 62% of patients [5, 30, 31].

A retrospective cohort study of 20,760 patients demonstrated that SAMS contributes to poor LDL-C goal attainment (OR = 1.85; [95% CI: 1.60–2.16]; p 0.0001), higher medical costs (cost ratio = 1.20; [95% CI: 1.11–1.28]; p 0.0001), and a higher risk for revascularization procedures compared with control groups [32]. Females, the elderly, patients with concurrent conditions (e.g., liver or renal dysfunction, diabetes), or concomitant interacting medications (e.g., anti-HIV, anti-HCV, immunosuppressive drugs) are at higher risk for developing SAMS [33, 34, 35].

Several large RCTs on statins have reported much lower rates of SAMS than observational studies, based on which “nocebo” effect has been proposed [36]. Some of the muscle symptoms of statins may be caused by the patients’ psychological expectations of harm from treatment rather than by the drug itself. At present, there is no effective method to distinguish between the patients who develop muscle symptoms due to the “nocebo” effect and the statin itself [37]; and a double-blind study is neither practical or ethical.

In the significant number of statin users who exhibit muscle symptoms in the clinical setting, traditional solutions have been to adjust statin therapy by dose reduction/intermittent dosing, or changing to another statin. Despite these efforts, about 30% of these patients still cannot tolerate statins [38]. Furthermore, many non-statin lipid lowing drugs, such as ezetimibe, bile acid sequestrants, fibrates, and niacin, have significant limitations. Their lipid lowering properties are limited, and they have a high incidence of AEs, thereby questioning their qualifications as an alternative LLT [39].

PCSK9 inhibitors are associated with a low incidence of muscle-related AEs (generally 10%). Myalgia is the most common form of PCSK9 inhibitor-induced muscle-related AEs. In addition, PCSK9 inhibitors have a favorable safety and tolerability profile in SI patients in a series of large clinical trials (Table 2, Ref. [8, 9, 10, 11, 12, 15]).

Based on the above studies, PCSK9 inhibitors are now incorporated in the latest updated guidelines as an acceptable alternative therapy for patients with SI [2, 3]. A real-world cohort study in the Netherlands indicated that among patients prescribed PCSK9 inhibitors, 42.9% (n = 102) were SAMS. SAMS has become the leading indication for PCSK9 inhibitor therapy [29]. Most current studies of PCSK9 inhibitors in SAMS patients are short-term follow-up trials (the longest 4 years) [11]. Therefore, the long-term safety of PCSK9 inhibitors as an alternative to statins remains to be studied.

In conclusion, since SAMS has become a common issue associated with poor clinical outcomes, current studies suggest PCSK9 inhibitors are a safe and generally well-tolerated alternative LLT for SAMS patients [8, 9, 10, 11, 12, 15]. Additional well-designed long-term clinical trials are required to confirm the long-term safety of PCSK9 inhibitors’ monotherapy.

In March 2012, the FDA updated statin labeling and added concerns about the risk of statin-induced elevated blood glucose levels and new-onset diabetes mellitus (NODM) [16]. This update is based on well-designed clinical studies and epidemiological data, indicating a 9% non-negligible risk of statin-induced Type 2 diabetes (T2D) in patients who received statins [40, 41, 42]. The mechanisms of statin-induced NODM are not fully understood. Multiple mechanisms, including pancreatic $\beta$-cell dysfunction, peripheral insulin resistance, and modulation of microRNAs expression, have been found to contribute to statins’ diabetogenic effects [43].

Statins are still recommended as the first line LLT for patients with high to very-high CV risk by international guidelines regardless of the risk of developing NODM [2, 3, 44]. This is because the benefits of LDL-C reduction on CVD prevention exceed the absolute risk of the incidence of NODM. In a meta-analysis including 5 statin trials with 32752 patients, intensive statin therapy accounted for 2 additional cases of NODM per 1000 patient-years, whereas 6.5 cases fewer CVD events were observed [45].

Unfortunately, real-world data revealed a gap between therapeutic guidelines and clinical treatment. Among 72136 patients with diabetes at very-high CV risk in Italy, 35% did not receive statin therapy, while only 15% of those patients receiving statin therapy reached the guideline-recommended LDL-C level (LDL-C 1.4 mmol/L) [35]. In addition to concerns about the effect of statins on plasma glucose, diabetes as a risk factor for SAMS, is also thought to be a reason for this low prescription rate [35]. These issues highlight the need for improvement in LLT for these patients.

Although genetic data suggest that patients carrying loss-of-functionPCSK9 genetic variants are at higher risk of developing T2D (OR = 1.29; [95% CI: 1.11–1.50]) [46], results in clinical trials and meta-analysis are at variance with the genetic studies and found that PCSK9 inhibitors do not increase the risk of NODM [47, 48, 49].

A prespecified analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial included 11,031 patients with diabetes and 16,533 patients without diabetes at baseline, and demonstrated that evolocumab neither increases the risk of NODM in patients without diabetes at baseline (8.0% versus 7.6%; HR = 1.05; [95% CI: 0.94–1.17]) nor in patients with prediabetes at baseline (11.3% versus 11.2%; HR = 1.00; [95% CI: 0.89–1.13]) during a median follow-up of 2.2 years. Evolocumab also showed no influence on glycemic control. Levels of glycosylated hemoglobin Type A1C (HbA1c) and fasting plasma glucose were similar between the evolocumab and placebo groups [47]. Similarly, a pooled analysis of 10 ODYSSEY Phase 3 trials (n = 4974) showed no evidence of alirocumab-induced NODM compared with placebo- (HR = 0.90; [95% CI: 0.63–1.29]) and ezetimibe- (HR = 1.10; [95% CI: 0.57–2.12]) controlled groups during a follow-up period of 6–18 months [48]. Moreover, these two studies showed a similar incidence of AEs between the evolocumab/alirocumab and placebo groups.

The inconsistent outcomes in NODM risk between genetic findings and clinical trials of PCSK9 inhibitors may be attributed to two factors: (1) PCSK9 inhibitor treatment has a shorter duration on PCSK9 concentrations compared with genetic variants. (2) mAb mainly targets circulating PCSK9s. Hence, unlike genetic variants that affect both intracellular and extracellular PCSK9 concentrations, mAbs have a limited effect on intracellular PCSK9 concentrations in pancreatic beta cells, resulting in an insignificant effect on glycemia [47, 48].

In summary, statins still play an important role in the LLT of prediabetic and diabetic patients. However, since PCSK9 inhibitors do not affect blood glucose levels and do not increase the incidence of NODM, additional studies are necessary to determine those patients who will be the beneficiaries of alternative PCSK9 inhibitors therapy among prediabetic/diabetic patients with dyslipidemia.

Drug-induced liver injury (DILI) refers to a rare (0.0001–0.00001% for any single medication) but life-threatening type of hepatitis, which is the most common etiology for acute hepatic failure. 75% of patients with DILI result in mortality or liver transplantation [50]. Data between 1994 and 2012 from the Spanish Hepatotoxicity Registry showed that 5.5% (n = 47) of DILI were attributable to statins [51].

All statins have been reported to trigger DILI [51]. The mechanism of statin-induced DILI remains unclear. Yu, Geng, et al. [52] indicated that drugs metabolized by CYP450 enzymes (including all FDA-approved stains except for pravastatin) had a 4 fold higher possibility (OR = 3.99; [95% CI: 2.07–7.67]) of causing DILI compared with placebos, and were significant predictors for DILI (OR = 5.04; [95% CI: 2.34–10.9]).

Therefore, liver function tests are recommended before initiation of statin therapy. Unexplained persistent elevation of serum transaminases (suggesting the possibility of DILI) and acute liver diseases are FDA contraindications for statins [18].

Unlike statins and other lipid-lowering drugs, PCSK9 inhibitors appear to be relatively free of any significant hepatotoxicity and have little influence on liver function [53, 54]. No case of PCSK9 inhibitor-induced DILI has been reported. Consequently, neither monitoring of liver enzymes nor limitations on the status of a patient’s liver function are mentioned on PCSK9 inhibitors’ labels [16, 17].

The resumption of statin therapy is prohibited in patients with stain-induced DILI and patients who have experienced a severe liver injury after re-exposure to another statin [18, 55]. Therefore, PCSK9 inhibitors offer a promising option for alternative LLT after statin-induced DILI., but will need to be confirmed in large cohort and case-crossover studies.

AKI results in increased mortality and high healthcare costs. Patients with CVD are at higher risk for AKI [56].

Statins have been shown to induce AKI. There are currently three known mechanisms involved in statin-induced AKI [56, 57, 58]: direct or immune-mediated kidney interstitial injury, rhabdomyolysis-induced AKI, and suppression of coenzyme Q10. A nationwide cohort study in France which included 8,236,279 participants demonstrated that high-potency statin treatment was associated with a 72%–116% increased risk of AKI (HR = 1.72; [95% CI: 1.37–2.17] in men, and HR = 2.16; [95% CI: 1.64–2.85] in women) [56]. Therefore, statins should be immediately discontinued in patients with statin-induced AKI.

PCSK9 inhibitors are a guideline-recommended alternative LLT for patients with SAMS, including rhabdomyolysis-induced AKI [2, 3]. Dardano, Daniele et al. [59] reported that an 80-year-old male developed rhabdomyolysis-induced AKI under rosuvastatin therapy, and that ezetimibe failed to effectively reduce LDL-C levels after statin withdrawal (LDL-C: 5.9–6.6 mmol/L). Therefore alirocumab was initiated, and LDL-C levels remained under control (1.2 mmol/L) with no AEs during the 24-month follow-up period [59].

Although PCSK9 inhibitors are a safe alternative for rhabdomyolysis-induced AKI patients, unexplained alirocumab-induced acute tubular injuries have been reported in two studies [60, 61]. Although these are the only two reports of PCSK9 inhibitors-induced renal injury, the potential for nephrotoxicity needs to be monitored when considering PCSK9 inhibitors as an alternative in non-rhabdomyolysis-induced AKI.

The cognitive effects of statins in literature are highly inconsistent, reporting beneficial, detrimental, and no effects, keeping this topic in a heated debate until now.

An analysis of the FDA Adverse Event Reporting System demonstrated an increased risk of cognitive impairment among statin users, especially in lipophilic statins (proportional reporting ratios range: 1.47–3.51 in lipophilic statins versus 0.69–1.64 in hydrophilic statins) [62]. The possible mechanism responsible for this phenomenon is that lipophilic statins cross the blood-brain barrier to a greater extent than hydrophilic statins, lowering brain cholesterol levels and inducing myelin impairment, ultimately leading to cognitive impairment [63]. Moreover, statin-induced suppression of coenzyme Q10 may enhance oxidative stress, reduce cerebral energy production and contribute to cognitive dysfunction [63].

Nevertheless, several recent clinical studies and meta-analyses have shown no significant effect of statins on cognitive functions [64, 65]. A randomized trial of 18,846 patients $\ge$65 years old revealed no significant association between statins and dementia and other mild cognitive impairments compared with the non-statin group [64]. Furthermore, Schultz, B. G. et al. [63] proposed that the lipid-lowering effect of statins can result in beneficial cognitive effects by protecting cerebral vessels and reducing A$\beta$ formation, and preventing dementia and Alzheimer’s disease. However, the Cochrane Systematic Review of 26,340 participants found no protective effects of statins on dementia (including Alzheimer’s disease) compared with placebo groups [65].

Based on these controversial results and the lack of consensus, there have been no strict limitations on statin use regarding cognitive impairments. In 2012, the FDA released a safety warning about the possible adverse cognitive side effects (such as memory loss and confusion) induced by statins. This warning was updated in 2016, describing these memory impairments as notable but non-serious, reversible after statin discontinuation, and more likely to happen in patients over 50 [18].

Current studies show no significant association between PCSK9 inhibitors and cognitive impairments. The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study evaluated cognitive function in 1974 patients from the FOURIER study and found no significant difference between evolocumab and placebo groups during a median follow-up of 19 months [66]. No impairment in cognitive function is inserted in the labels of alirocumab and evolocumab [16, 17].

Given the ability of PCSK9 inhibitors to reduce serum LDL-C to extremely low levels, there are questions as to whether this could contribute to brain cholesterol deficiency and impair cognitive function [63].

Reassuringly, large clinical trials such as the FOURIER and the ODYSSEY OUTCOMES trials demonstrated that alirocumab- or evolocumab-induced low LDL-C levels resulted in no significant differences concerning cognitive AEs compared with placebo groups [13, 14]. This most likely due to the relatively large volume which disables mAbs from directly crossing the blood-brain barrier [66].

In conclusion, current studies suggest PCSK9 inhibitor treatment has little effect on cognitive function. Nevertheless, given that most reports of cognitive impairment in statin users are mild and reversible [18, 67], further studies are needed to determine if patients can benefit from PCSK9 inhibitors as an alternative in terms of cognitive safety.

Statins have been shown to reduce the risk of ischemic stroke but increase the risk of hemorrhagic stroke (HS), which is less prevalent but more likely to be fatal.

This conclusion is mainly based on the SPARCL trial, a large-scale randomized study including 4731 patients with a previous stroke or transient ischemic attack. This study demonstrated that 80 mg of atorvastatin per day increased the risk of HS significantly by 66% (adjusted HR = 1.66; [95% CI: 1.08–2.55]) with a median follow-up period of 4.9 years [68]. This potential hemorrhagic propensity is thought to be derived from statins’ (not lipid-lowering mediated) pleiotropic effects, such as anti-thrombotic properties that decreases platelet aggregation and thrombogenesis [21].

Based on these findings, current clinical guidelines on stroke management recommend caution on statin use in patients with previous spontaneous intracerebral hemorrhage (the most common form of HS), especially before introducing a high-dose statin regimen [69].

Unlike statin’s anti-thrombotic ability, PCSK9 inhibitors were found to reduce the risk of ischemic stroke while having no association with HS (RR = 0.93; 95% CI: 0.58–1.51) in a meta-analysis involving 5 PCSK9 inhibitor RCTs (76,140 patients) [21].

In regard to safety concerns that achieving extremely low LDL-C levels might increase the risk of stroke, recent studies did not support this hypothesis and showed a consistent risk-reducing effect of lowing LDL-C levels on all strokes [21, 70]. Each 1 mmol/L decrease in LDL-C level was associated with a significant reduction of all stroke risk by 23.5% (slope = 0.235; [95% CI: 0.007–0.464]). PCSK9 inhibitors are proven to have the greatest ability to reduce stroke rates among various lipid-lowering drugs [70].

In view of these data, there is a call for consideration about to use PCSK9 inhibitors, instead of high-intensity statins, in patients at particular risk of HS [70]. In order to justify this proposal, the comparisons between PCSK9 inhibitor monotherapy and statins on the risk of HS should be further studied in well-designed large clinical trials.

Cataract, defined as loss of lens transparency, accounts for the leading cause of blindness worldwide [71].

There is controversy concerning the association between cataracts and statin treatment. Cataracts developed in animal experiments in dogs given lovastatin and simvastatin in dosages well above the maximal clinical doses [72]. A propensity score-matched analysis involving 46,249 subjects from a US administrative dataset demonstrated that statin users are at higher risk of cataracts compared with nonusers (adjusted OR = 1.25; [95% CI: 1.14–1.38]), and statins acted as an independent predictor for the development of cataracts (adjusted OR = 1.43; [95% CI: 1.33–1.53]) [73]. The mechanism of statin-induced cataracts might be due to long-term inhibition of the de novo synthesis of cholesterol in the lens that can result in lens opacity. Moreover, the bidirectional effects of statins on oxidative stress may also contribute to this process [73].

On the other hand, several studies produced inconsistent results, reporting no effect or protective effect of statins on cataracts [71]. Since there is no clear conclusion, no limitation of statins in patients with or at risk of cataracts is currently indicated.

However, given the widespread prescription of statins and the irreversible loss of vision caused by cataracts, the risk of statin-induced cataracts among the elderly (old age is the most critical risk factor for cataract formation) and long-term users should not be ignored.

PCSK9 inhibitors can achieve lower LDL-C levels than statins, while no side effect leading to cataracts has been detected. A meta-analysis including 5 trials with 83,492 patients demonstrated that PCSK9 inhibitor treatment was not associated with increased cataract risk (OR = 0.96; [95% CI: 0.85–1.08]) [74]. The analysis of VigiBase found no disproportionality between PCSK9 inhibitors and cataracts (reporting odds ratios = 0.64; [95% CI: 0.48–0.85]) [75].

This phenomenon might occur because PCSK9 inhibitors could play a lipid-lowering role without inhibiting endogenous cholesterol synthesis, the dominant cholesterol synthesis pathway in the lens [75].

Hence, PCSK9 inhibitors appear to be a safer option in patients at risk for cataracts. However, it is essential to underline that there are limited studies of PCSK9 inhibitors on this issue. Therefore, coupled with statins’ unconfirmed cataract-induced capability, no definitive conclusion can be made until further investigations are performed.

Dyslipidemia in pregnancy is associated with an increased risk of AEs such as pre-eclampsia, pregnancy-induced hypertension, and gestational diabetes [76].

Nevertheless, statins are recommended to be discontinued in patients with pregnancy and lactation according to the latest update of the FDA in 2021. The mechanism of statins’ underlying fetal toxicity remains unclear, and may related to the following mechanisms [18, 77, 78, 79, 80]: Cholesterol and other products of the cholesterol biosynthesis pathway play an essential role in fetal growth and development. Statins can cross the placental barrier or pass into breast milk and cause harm to the fetus. Higher abortion rates and teratogenicity have been observed in animals (rats, mice, rabbits) exposed to high-intensity statins [77, 78]. A retrospective cohort study compared 281 statin-exposed pregnant women to 2643 controls and reported a higher rate of spontaneous miscarriage in the statin-exposed group (25.27% versus 20.81%; adjusted HR = 1.64; [95% CI: 1.1–2.46]) [79]. Currently, the option of LLT is strictly limited in pregnant and lactating patients.

There are no restriction in the labels of PCSK9 inhibitors regarding patients in pregnancy or lactation [16, 17].

The most significant potential advantages of PCSK9 inhibitors lie in the safety of mAbs in pregnant and lactating patients. First mAbs do not cross the placenta in early pregnancy. Animal experiments (rats, monkeys) demonstrated no adverse effects on embryo-fetal development despite being given concentrations tens of times higher than the maximum recommended human dose [81]. Second, current FDA-approved PCSK9 inhibitors are both IgG mAbs, which are present in breast milk but do not enter the circulation of newborns and infants in significant amounts via breastfeeding [16, 17, 26].

The current findings suggest PCSK9 inhibitors are expected to be a potential emerging therapy for pregnant and lactating patients and dyslipidemia with contraindications to statins. However, due to the lack of population-based studies, it is still in the preliminary exploration stage. At present, a prospective observational study of evolocumab on patients during pregnancy is in progress and will provide us with further data [82].

The comparison of statins and PCSK9 inhibitors in the relationship with the liver is listed in Table 3.

The comparison of statins and PCSK9 inhibitors in the relationship with the kidney is listed in Table 4.

Type I HIV infection can lead to lipid metabolism disorders and chronic inflammation, causing a significantly higher risk of dyslipidemia (67.3% in women and 81.2% in men) among HIV-infected patients and resulting in a higher incidence of ASCVD [104].

Nevertheless, statins are widely restricted or abandoned in patients with HIV infection [105]. On March 1st, 2012, The FDA updated a safety announcement on statins, warning about the DDIs between HIV protease inhibitors and statins [18]. Among numerous HIV-infected patients with dyslipidemia, only 5.9% acquired statin therapy [106].

There are complex interactions between statins and antiretroviral drugs. On the one hand, protease inhibitors (PIs), the first class of antiretroviral therapy in HIV-infected patients, are strong CYP3A4 inhibitors. Several PIs are also inhibitors of OATP1B1 and P-gp. Consequently, the DDIs between PIs and statins are intensive and involve multiple pathways [105]. A 30-fold increase (p 0.001) in the AUC of simvastatin was observed in patients taking saquinavir and ritonavir in the ACTG (AIDS Clinical Trials Group) A5047 study [107]. Cases of rhabdomyolysis have been reported in patients receiving both statins and PIs.

On the other hand, conversely, the non-nucleoside reverse transcriptase inhibitors, such as nevirapine, efavirenz, and etravirine, are CYP3A4 isozymes inducers, diminishing the efficiency of statins when given simultaneously [97]. The ACTG A5108 study, which included 52 HIV-infected patients, demonstrated a 60% (p = 0.003), 50% (p 0.001), and 40% (p = 0.005) decrease in the AUC of simvastatin, atorvastatin, and pravastatin when coadministered with efavirenz, respectively [108].

The metabolism and elimination of PCSK9 inhibitors are independent from the CYP450 isoenzyme system and OATP1B1 or P-gp drug transporters. No DDI has been discovered between PCSK9 inhibitors and anti-HIV drugs.

The EvolocumaB Effect on LDL-C Lowering in SubJEcts with Human Immunodeficiency VirRus and INcreased Cardiovascular RisK (BEIJERINCK) study was the first study assessing the safety and efficiency of evolocumab treatment in 464 patients under anti-HIV therapy during a 24-week follow-up period. After adjusting confounder factors, evolocumab and placebo groups showed similar treatment-emergent AEs and serious AEs (67.5% versus 61.9% and 5.1% versus 3.3%, respectively). Evolocumab also showed a consistent lipid-lowering effect despite well-performed tolerability, lowering LDL-C levels by 56.9% (95% CI: 61.6–52.3%), unaffected by antiretroviral therapy [109].

In addition to their safety and efficacy, PCSK9 inhibitors are expected to provide additional therapeutic benefits in HIV-infected patients. PCSK9 levels are 65% higher (p 0.0001) in HIV-infected patients than in uninfected patients and are associated with decreased coronary endothelial dysfunction (R = –0.51; p 0.0001) in a cross-sectional study including 48 patients [25]. The anti-inflammatory effects of PCSK9 inhibitors are thought to suppress the HIV-induced chronic inflammatory state [25].

Nevertheless, there are too few existing studies to determine the safety of PCSK9 inhibitors in HIV-infected patients, and more data is warranted.

Chronic hepatitis C virus (HCV) infection is an independent risk factor for CVD. However, only 21% of HCV infected patients who meet lipid-lowering standards received statin therapy [110].

The main reason is that statins are strictly limited in HCV-infected patients due to concerns about DDIs with anti-HCV drugs [18, 105].

Direct-acting antiviral agents (DAAs) act as the most effective anti-HCV therapy, significantly improving clinical treatment success rates to 95%. Unfortunately, many DAAs are inhibitors of CYP3A4enzymes, OATP1B1, and P-gp [83]. Patients who use DAAs in combination with statins have a 1.5–10 fold increase in statin plasma concentrations and an increase in the risk of statin-induced AEs [83, 111]. According to a large prospective cohort study in Italy analyzing 814 patients who underwent DAAs, statins rank as one of the most frequently (accounting for 20–35% of patients) suspended or replaced drugs due to DDIs [112].

Coadministration of statins and DAAS are not recommended because of the increased incidence of DDIs. Only the lowest statin doses are permitted, along with careful monitoring for myopathy/rhabdomyolysis [18, 83].

PCSK9 inhibitors are not metabolized by the CYP450 isoenzymes system or OATP1B1 and P-gp drug transporters. No case of DDI with DAAs has been reported [111].

Dousdampanis, Assimakopoulos et al. [113] reported that in a male patient on hemodialysis with dyslipidemia and chronic HCV infection comorbidities, atorvastatin was discontinued because of the concern for hepatotoxicity. Alirocumab was prescribed as an alternative option (150 mg every 2 weeks, 8 weeks in total), and a significant decrease in LDL-C levels was observed without side effects [113].

In addition to concerns about DDIs, impaired hepatic function in HIV-infected patients is another important reason for limiting statins. As discussed in the Liver dysfunction section, PCSK9 inhibitors are safe in patients with hepatic impairment, including HIV-infected patients [83, 87]. HCV infection is associated with high PCSK9 levels in vivo [114, 115]. Although some studies propose that PCSK9 plays a protective inhibitory role in HCV infection by enhancing LDL receptor degradation and downgrading CD81 expression (both are receptors that mediate HCV entry into hepatocytes) [116], the evidence from in vitro and in vivo studies demonstrated that inhibition of PCSK9 neither effect CD81 levels nor increase susceptibility to HCV entry [114, 117].

In summary, PCSK9 inhibitors are a potential alternative to statins in HCV-infected patients for two main reasons: (1) Freedom from interactions with HCV medications and (2) a more favorable liver safety profile. Future studies investigating the use of PCSK9 inhibitors in large cohorts of different degrees of hepatic impairment and virus loads are necessary to further clarify the safety and tolerability of PCSK9 inhibitors in HCV-infected patients.

Solid-organ transplantation (SOT) recipients have a high incidence of dyslipidemia (80% in kidney transplant recipients, over 50% in heart transplant recipients, and 30–50% in liver transplant recipients), which contributes to increased CVD events, which is one of the leading causes of mortality [118]. Hence, guidelines have placed great emphasis on LLTs, requiring LLTs as part of standard post-transplant therapies regardless of cholesterol levels [2, 3, 119].

However, statin use among SOT recipients is limited because of DDIs associated with immunosuppressive drugs [18].

Immunosuppressive drugs, especially cyclosporine, have been shown to interact with statins. Cyclosporine is an inhibitor of multiple pathways in statin metabolism and elimination (including CYP3A4, OATP1B1, and P-gp pathways). Hence, there is a strong DDI between cyclosporine and statins [120]. Cyclosporine can increase the AUC of atorvastatin and simvastatin by 7.5-fold and 8-fold, respectively [121]. Cases of rhabdomyolysis have been reported in patients receiving both statins and cyclosporines [122]. Therefore, most statins are not recommended a with cyclosporines [120].

Besides statins, other lipid-lowering drugs such as ezetimibe, gemfibrozil, and fenofibrate have also been associated with DDIs with immunosuppressive drugs, resulting in increased AEs [118].

Enthusiasm has grown for PCSK9 inhibitors as a safer alternative LLT in SOT recipients who have failed to tolerate statins.

A clinical case series involving different kinds of SOT (including heart, kidney, liver, and lung transplantation) reported no severe AEs or discontinuation in 25 participants receiving PCSK9 inhibitors (evolocumab and alirocumab) and various immunosuppressive drugs (including cyclosporine and tacrolimus) coadministration [123]. Jennings, Jackson, et al. [124] identified 5 heart transplant recipients who receive PCSK9 inhibitor therapy (evolocumab 140 mg every two weeks) because of statin-induced myositis. The duration of evolocumab ranged from 12–34 months and no AE was noted.

The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (NCT03734211) is an ongoing double-blind, randomized, placebo-controlled trial investigating the effect of evolocumab on cardiac allograft vasculopathy among heart transplant recipients [125]. This trial will further determine the feasibility of PCSK9 inhibitors as an alternative LLT in SOT patients.