Current Atherosclerosis Reports (2020) 22: 26

https://doi.org/10.1007/s11883-020-00844-w

STATIN DRUGS (R. CESKA, SECTION EDITOR)

Clinical Pharmacology of Statins: an Update

Nicola Ferri 1 & Alberto Corsini 2,3

Published online: 3 June 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review Statins represent the cornerstone for the treatment of hypercholesterolemia, although muscle-related side
effects and dysregulation of glucose metabolism have strongly limited their adherence and compliance especially in primary
prevention therapy. The purpose of the present review is to provide the most recent evidence of the efficacy and safety of statins
in monotherapy or combination with new lipid-lowering drugs.
Recent Findings Recent “life-long” analysis conducted on young familial hypercholesterolemia patients, elderly
hypocholesterolemic subjects, and from a 20-year follow-up of randomized controlled trial (RCT) have been published
confirming that the cardiovascular benefits of statin therapy, in patients for whom it is recommended by current guidelines,
greatly outweigh the risks of side effects. In addition, recent therapies to be used in combination with statins have shown to
increase the percentage of patients at goal for low-density lipoprotein - cholesterol (LDL-C) with a good safety profile. The
cardiovascular (CV) benefits of monoclonal antibodies anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) and
ezetimibe, in patients under statin therapy, have been proven by specific RCT, while we are still waiting for the results of
bempedoic acid and the small-interfering RNA (si-RNA) anti-PCSK9 inclisiran.
Summary Taken together, the approval of new pharmacological agents to be used in combination with statins represents the
future for a tailored therapy of cardiovascular disease patients.

Keywords Statins . PCSK9 . Ezetimibe . Bempedoic acid . Evolocumab . Alirocumab . Inclisiran

Introduction By lowering LDL-C, statins have shown to decrease car-

Statins reduce the synthesis of cholesterol in the liver by com-
petitively inhibiting the enzyme 3-hydroxy-3-methylglutaryl
coenzyme-A (HMG-CoA) reductase, the rate-limiting step in
cholesterol biosynthesis. The reduction in intracellular choles-
terol induces the expression of the low-density lipoprotein
receptor (LDLR) and increased the uptake of LDL from the
blood, with a concomitant decreased of plasma concentrations
of LDL-cholesterol (LDL-C) (Fig. 1).
This article is part Topical Collection on Statin Drugs
* Nicola Ferri
nicola.ferri@unipd.it
diovascular (CV) events in both primary and secondary pre-
vention trials. For each mmol/L reduction in LDL-C, statins
reduced major vascular events (myocardial infarction, coro-
nary artery disease death, coronary revascularization, or
stroke) by 22% over 5 years [1, 2]. The inhibition of HMG-
CoA reductase may also result in pleiotropic effects, such as
anti-inflammatory and antioxidant (Fig. 1), although their
clinical relevance remains unclear [3].
The effects of statins have been analyzed in different pop-
ulations and subgroups, demonstrating a similar relative effi-
cacy on major CV events in all subgroups examined which
was proportional to the absolute baseline risk.

1
Department of Pharmaceutical and Pharmacological Sciences, Clinical Evidence of Long-term Efficacy
University of Padova, Largo Egidio Meneghetti 2, of Statins
35131 Padova, Italy
2
Department of Pharmacological and Biomolecular Sciences, Although lowering of LDL-C is accepted as a key objective in
University of Milan, Milan, Italy the prevention of CV disease, there are still concerns on long-
3
IRCCS Multimedica, Milan, Italy term safety, impact on all-cause mortality, and cost-
26 Page 2 of 9
Fig. 1 Mechanism of action of statins and additional
hypocholesterolemic agents used in combination. Statins, by inhibiting
the HMG-CoA reductase and thus the cholesterol biosynthesis, induces
an intracellular depletion of sterols in hepatocytes. In response to such
effect, the SREBP2 transcription factor is activated and induces the
expression of the LDLR and the reduction of the LDL-C. Statins may
also affect the intracellular pool of isoprenoids (farnesyl-PP and
geranylgeranyl-PP) and protein prenylation thus providing additional
pleiotropic effects, such as anti-inflammatory and antioxidant activity.
Sterol regulatory element-binding protein 2 (SREBP2) transcribes also
effectiveness of statins even after 25 years since the publica-
tion of the first successful primary prevention trial [4] follow-
ed by additional studies [5–7] and meta-analyses [2, 8, 9], all
confirming the benefits of LDL-C reduction.
A better understanding of the efficacy and safety of statins
derived from the examination of the long-term (lifetime) conse-
quencesofloweringLDL-C.In2016,datafrom 20-yearfollow-up
of the WOSCOPS trial came out with the intent to examine a range
of mortality and morbidity outcomes as a first event and as a total
burden of disease [10•]. Given a mean age at randomization of
55 years, the 20-year observation period reached a mean of
75 years (range, 65–84 years), which gave a reasonable approxi-
mation of the lifetime effect of this pharmacological intervention.
In this study, the authors observed a substantial and signif-
icant benefit of the pravastatin treatment with 18% lower cu-
mulative event rates for CV disease and 24% lower for myo-
cardial infarction. A clear and continuing divergence of the
cumulative event curves for heart failure hospitalization over
Curr Atheroscler Rep (2020) 22: 26
for PCSK9 which partially counteract the effect of statins on LDL-C by
inducing the degradation of the LDLR. The combination of statins and
monoclonal antibodies (mAbs) anti-PCSK9 may provide an additive
lipid-lowering action. Bempedoic acid inhibits the ATP citrate lyase
(ACL) and thus the triglyceride and cholesterol biosynthesis inducing
the expression of LDL receptor with an additional hypocholesterolemic
effect on top of statins. Ezetimibe acts by inhibiting the gastrointestinal
cholesterol absorption through the Niemann-Pick C1-Like 1 (NPC1L1)
transporter. Its action has an additive effect with statins on LDL-C plasma
levels
20 years (− 35% in the pravastatin arm) was also observed
[10•]. The reduced incidence of heart failure confirmed previ-
ous evidence obtained in a randomized controlled trial (RCT)
in patients with coronary artery disease (CAD) without previ-
ous heart failure [11, 12]. On these bases, routine administra-
tion of statins in patients with heart failure without other indi-
cations for their use (e.g., CAD) is not recommended [13].
In the original trial and at 20-year follow-up of the
WOSCOPS study, it was not found a significant impact of
statin therapy on stroke [4, 10]. However, this study was a
primary prevention trial in relatively young subjects compared
with the majority of trials in the Cholesterol Treatment
Trialists' (CTT) analysis. Indeed, lipid-lowering therapy has
shown a protective effect on stroke in numerous studies and a
meta-analysis of RCTs; an effect was mainly driven by the
extent of LDL-C reduction [14].
In the assessment of the long-term impact of statin therapy in
primary prevention, it is essential the determination of a positive
Curr Atheroscler Rep (2020) 22: 26
clinical benefit which results from a reduction in CV events and
the potential for adverse clinical events. Statins do cause a rare
side effect known as myositis, defined as muscle symptoms in
association with a substantially elevated serum creatine kinase
(CK) concentration [15]. The onset of muscle pain usually occurs
in the first year of therapy with a median time to onset of one
month or after a dose increase or the addition of an interacting
drug [16, 17]. While the myositis are observed in < 1 in 1000
patients treated with maximum recommended doses, and with an
even lower risk at lower doses [18], the risk of more severe
rhabdomyolysis is ≈ 0.01% [1] (Table 1).
In RCTs, adverse event rates (including complaints of muscle
pain) are similar in statin and placebo groups [6, 19, 20], while
in patient registries it has been reported an incidence of 7–29%
of statin-associated muscle symptoms (SAMS) [15]. SAMS
cover a broader range of clinical presentations, usually with
normal or minimally elevated CK levels and contribute signifi-
cantly to the discontinuation of statin therapy, which has a rate
up to 75% within 2 years of treatment [21]. An internet survey of
10.138 US patients prescribed statins, muscle symptoms were
the most common reason for statin discontinuation (60%), statin
non-adherence (52%), and statin switching (33%) [22].
Such non-adherence/discontinuation from treatment may
have an important impact on CV disease benefit, as suggested
by the higher mortality in elderly secondary prevention pa-
tients with low vs high adherence to statin therapy [23] and
lower CV disease risk in patients compared with those not
adherent to statins [24, 25].
Statin therapy is associated to increase the propensity to
develop type 2 diabetes mellitus (DM) [26, 27], with an hazard
ratio (HR) of ≈ 1.09 (9%) compared with placebo, which rep-
resents one additional case of DM per 1000 patients per year of
exposure (Table 1). A similar increase (12%) in diabetes risk is
associated with the use of high- vs low-dose statin therapy [27].
This side effect represents one of the most critical issues raised
by those concerned about the more widespread use of statins in
the primary prevention in lower risk subjects.
Table 1 Perspective on benefit/
risk of statin therapy in 10,000 Benefit refers to first events
patients on statins for 5 years,
achieving 77 mg/dL LDL-C
levels Major vascular events prevented (secondary prevention)
Major vascular events prevented (primary prevention)
Risk
Newly diagnosed DM
Muscle symptoms without significant creatine kinase increase
Hemorrhagic stroke
Muscle symptoms in association with a substantially elevated
serum creatine kinase (CK) concentration (myositis)
Rhabdomyolysis
Severe liver injury
Modified from Newman et al. [18]
Page 3 of 9 26
The risk of DM with statin treatment increases with the
severity of the metabolic syndrome especially with the highest
fasting blood glucose levels [28–31]. It has been estimated that
the use of statins will prevent 5 incidences of myocardial in-
farction for every new case of DM. Statin treatment is also
associated, over a 20-year follow-up, with significantly fewer
hospital admissions associated with non-cardiovascular com-
plications of DM. This raises the possibility that, although stat-
in use may affect blood glucose levels, this does not necessarily
translate into deleterious non-cardiovascular pathologies [10•].
Indeed, patients who developed DM, while receiving a statin,
not only had a lower rate of macrovascular disease but also had
a lower rate of microvascular disease complications [32].
Analysis from the JUPITER, the TNT, and IDEAL trials dem-
onstrated that statins reduce the risk of CV disease events in high-
risk patients who developed new-onset DM, thus supporting the
notion that the benefits of LDL-C reduction overcomes those of
potential adverse effects of hyperglycemia [28, 33].
Taken together, although the data from RCTs indicates that
statins affect glucose homeostasis and are associated with a
small risk of incident DM, it might be important to consider
that generally, the studies did not include glucose tolerance
test, the gold standard for the diagnosis of diabetes, before and
after statin treatment. Moreover, while this effect has been
thought to be a drug class effect, recent insights suggest both
pravastatin and pitavastatin seem neutral on glycemic param-
eters in patients with and without DM [34].
Statins have been evaluated on a number of other clinical
conditions considered relevant for long-term therapy. A meta-
analysis of individual participant data from randomized trials
has shown that statins do not have any significant effect on
cancer, at least over a period of ~ 5 years [35]. This evidence
was further confirm in the analysis of the WOSCOPS trial
after 20 years of follow-up [10•].
Statin treatment might induce a mild elevation of liver trans-
aminases in 0.5–2.0% of patients producing approximately a
50% higher risk of transaminase elevation compared with
Estimated number of patients
with benefit or adverse effect
1000
500
100
< 100
10
10
1
<1
26 Page 4 of 9
control or placebo [36]. These elevations were transient and
usually normalized with continuing therapy. The reported inci-
dence of elevations in hepatic transaminases (> 3 × upper limit
of normal (ULN)) is approximately 0.1%, 0.6%, and 0.2% for
atorvastatin 10 mg, atorvastatin 80 mg, and placebo, respective-
ly [37]. In patients with mild ALT elevation due to steatosis or
nonalcoholic fatty liver disease, statin therapy does not result in
worsening of liver disease [38], although caution may be need-
ed in patients with pre-existing primary biliary cirrhosis [39].
Statins should not be prescribed, however, in patients with ac-
tive hepatitis B virus infection until serum levels of AST, ALT,
GGT, total bilirubin, and ALP have normalized [40].
Idiosyncratic liver injury associated with statins is rare but can
be severe. In a real-world setting, moderate to severe hepatotox-
icity was reported in 0.09% patients on atorvastatin vs 0.06% on
simvastatin with rates higher at higher doses of statin used [41].
Data from the Swedish registry [42], reported that 1.2 per
100,000 patients had drug-induced liver injury on statin therapy
(transaminase > 5 × ULN and/or ALP > 2 × ULN) (Table 1).
Taken together, the data on the adverse effects of statins are
largely derived from RCTs. The exceptions are myopathy/
rhabdomyolysis, and severe liver toxicity, where in general,
the incidence is too low to be evaluated in clinical trials, but
the population incidence of these adverse events without an
identifiable cause is very low, such that observational data are
useful. The cardiovascular benefits of statin therapy in patients
for whom it is recommended by current guidelines greatly
outweigh the risks (Table 1).
Efficacy and Safety of Statins in Elderly
Even among patients with established CV disease, rates of use
of statin therapy have been shown to decline with increasing
age and are substantially lower in people older than 75 years
[43]. This decline is even more prominent among older pa-
tients with no evidence of occlusive vascular disease [44].
One explanation for this observation might relate to uncertain-
ty about the transferability of the efficacy and safety results
obtained in the RCTs to an older population, often excluded in
these studies. Within this contest, the CTT Collaboration has
recently performed a meta-analysis of data from 28 large statin
trials to compare the effects of statin therapy at different ages
and explore their effects on older individuals [45•]. This anal-
ysis included 186,854 subjects (with 14,483 [8%] older than
75 years at randomization) and found slightly smaller propor-
tional risk reductions in major vascular events and vascular
deaths with increasing age [45•]. However, after excluding the
trials that enrolled patients with moderate to severe heart fail-
ure and end-stage renal disease requiring dialysis, statins show
the same benefit with increasing age on major vascular events
or on vascular death [45•]. In the same analysis, the authors
found a trend towards smaller proportional reductions in ma-
jor coronary events with increasing age. The reasons
Curr Atheroscler Rep (2020) 22: 26
potentially involve age-related factors such as altered pharma-
cokinetics and pharmacodynamics, and an increased risk of
drug interactions in the setting of polypharmacy [46].
Alternatively, this trend might reflect a reduced capacity for
statins to impact on advanced atherosclerotic plaques, greater
diagnostic uncertainty at older ages, and poorer long-term
adherence to the assigned study treatment.
Regarding the safety profile, a meta-analysis of published
data for participants older than 65 years at randomization in
statin trials reported no increased risk of less severe muscle-
related adverse events [47]. Similarly, the risk of DM associ-
ated to statins seems higher in trials with older participants
[26], indicating that surveillance for dysglycemia might be
useful for older people receiving statin therapy.
Taken together, statin therapy produces significant reduc-
tions in major vascular events, irrespective of age. There is less
definitive direct evidence of benefit in the primary prevention
setting among patients older than 75 years, but evidence sup-
ports that the use of statin therapy in older people considered to
have a sufficiently high risk of occlusive vascular events.
Efficacy and Safety of Statins in Children
Treatment of children with familial hypercholesterolemia
(FH) includes a healthy lifestyle and statin treatment.
Current EAS/ESC guidelines recommend to consider statin
treatment at 6–10 years of age [13]. A 20-year follow-up study
involving children with genetically defined FH who started
statin therapy at an age of 8 to 18 years was recently per-
formed [48••]. The incidence of CV disease among these FH
patients was compared with that among their parents with FH
for whom statins were only available much later in life [48••].
The study observed a positive effect of lipid-lowering treat-
ment on both surrogate (carotid intima–media thickness) and
hard CV disease outcomes, even if a modest percentage of
patients with FH achieved their LDL-C target (20%).
In terms of safety, four patients discontinued the therapy
because of side effects, and no episodes of noted rhabdomy-
olysis or other serious adverse events were reported. There
were no significant differences in the results of liver function
tests or CK levels between patients with FH and their unaf-
fected siblings.
Statins in Combination with Lipid-Lowering
Drugs
Ezetimibe
The average adult body contains approximately 140 g of ste-
rols, mainly in the form of cholesterol. This pool of cholesterol
is derived from the synthesis by the liver (500–1000 mg/day)
and absorption by the intestines (up to 500 mg/day) [49].
Curr Atheroscler Rep (2020) 22: 26
A key protein involved in cholesterol absorption is
Niemann-Pick type C1 protein (NPC1) [49], which has been
found to be abundantly expressed in the small intestine and
liver [50]. Ezetimibe is the first in a class of cholesterol-
lowering agents acting by inhibiting NPC1L1 and thus intes-
tinal cholesterol absorption (Fig. 1). In response to this activ-
ity, the liver reacts by upregulating LDL receptors, which in
turn leads to increased clearance of cholesterol from the blood
[51]. Following oral administration, ezetimibe is rapidly
glucuronidated in the intestines, and the glucuronide un-
dergoes enterohepatic recirculation which explains the long
duration of action (22 h) [52]. More importantly, ezetimibe
does not interact with statins.
Adding ezetimibe to ongoing statin therapy led to a sub-
stantial additional reduction in LDL-C levels, facilitating at-
tainment of EAS/ESC goals [13]. For instance, in patients
with hypercholesterolemia, ezetimibe (10 mg) determined an
additional 25% reduction of LDL-C levels, compared with the
usual 6% attained by doubling the statin dose [53]. The com-
bination improved LDL-C goal attainment from 20% on statin
monotherapy to 71% [54]. The benefits were consistent across
the type of statin and dose subgroups [53].
The clinical significance of ezetimibe as an add-on to statin
therapy was first tested in the SHARP trial conducted in 9270
patients with chronic kidney disease treated with the combi-
nation of ezetimibe 10 mg plus simvastatin 20 mg [55]. The
results of the trial demonstrated that the drug combination
reduced LDL-C by 33 mg/dL (0.85 mmol/L) which yielded
a significant 17% reduction in major atherosclerotic events,
thus similarly to the effects seen in the CTT.
Secondly, the IMPROVE-IT trial was designed to evaluate
the efficacy of the combination ezetimibe simvastatin in ACS
patients [56]. The addition of ezetimibe to simvastatin lowered
LDL-C by approximately 24%, an effect associated with 6.4%
reduction in CV events compared with simvastatin alone and an
absolute 2% lower incidence of the primary CV endpoints at a
follow-up of 6-years [56]. No significant differences were seen
in safety endpoints observed between the two study groups,
including the incidence of rhabdomyolysis or myopathy [56].
Bempedoic Acid
Bempedoic acid, a small molecule that is orally administered,
is a prodrug rapidly metabolized by an endogenous liver acyl-
CoA-synthetase (ACSVL1) and converted to a coenzyme-A
derivate. Bempedoic acid is the active metabolite responsible
for the inhibition of ATP citrate lyase (ACL) reducing the
production of cytosolic acetyl-coenzyme-A, a precursor of
the mevalonate pathway of cholesterol biosynthesis [57].
Since ACSVL1 is expressed mainly in the liver, the pharma-
cological activity of bempedoic acid is restricted to this site,
where bempedoic acid suppresses cholesterol synthesis and
induces a compensatory upregulation of LDL receptor
Page 5 of 9 26
(Fig. 1) [58]. Conversely, ACSVL1 is absent in the skeletal
muscle and thus provides a mechanistic basis for bempedoic
acid to potentially avoid the SAMS.
Although bempedoic acid acts on the same pathway of
statins, when it is added to a moderate-intensity or high-
intensity statin regimen, it showed a further reduction of
LDL-C by approximately 15% [59]. The CLEAR Wisdom
trial evaluated the efficacy and safety of bempedoic acid in
patients with pre-existing atherosclerotic cardiovascular dis-
ease (ASCVD) risk and/or HeFH, already at maximally toler-
ated statin doses [60]. Bempedoic acid led to an absolute
17.4% reduction on LDL-C, maintained for 52 weeks [60].
This effect is greater than the 6% reduction expected from
doubling the dose of statins [61].
Concerning clinical endpoints, adjudicated clinical events
occurred in 8.2% of patients (43/522) in the bempedoic acid
group and 10.1% (26/257) in the placebo group [60]. Myalgia
was reported by approximately 3% of patients and muscle
weakness by 0.4% of patients who were receiving either
bempedoic acid or placebo. New-onset or worsening DM oc-
curred in approximately 7% of patients in both treatment
groups [60]. Thus, bempedoic acid, besides efficiently lower-
ing LDL-C, has shown excellent tolerability without occur-
rence of myalgia [62].
The primary route of elimination for bempedoic acid is
through metabolism of the acyl glucuronide [63]. Indeed, both
parental and active drugs are converted to inactive glucuro-
nide conjugates in vitro by UDP-glucuronosyltransferase 2B7
(UGT2B7). Due to its inhibitory activity on the UGT2B7,
bempedoic acid increases simvastatin and pravastatin expo-
sure by approximately 2-fold, while no significant interaction
was seen with atorvastatin and rosuvastatin. Thus, bempedoic
acid cannot be associated with simvastatin at doses greater
than 20 mg and with pravastatin greater than 40 mg [63].
While awaiting the results of the CLEAR Outcomes study,
an important indication of this therapeutic option is provided
by a Mendelian randomization analysis. This study demon-
strated that inherited variants in the ACL locus, which mimic
its pharmacological inhibition, were associated with a signif-
icant reduction in major CV events [64]. The combination of
both ACLY and HMGCR scores were associated with a dose-
dependent decrease in LDL-C and apoB, and major cardio-
vascular events [64].
PCSK9 Inhibitors
Proprotein convertase subtilisin/kexin 9 (PCSK9) induces the
degradation of hepatic LDL receptors, and for this reason
represents a pivotal pharmacological target for the treatment
of hypercholesterolemia [65] (Fig. 1). Two PCSK9 monoclo-
nal antibodies, evolocumab and alirocumab, have been ap-
proved by the FDA and EMA. Alirocumab, in combination
with a maximally tolerated statin therapy determined an
26 Page 6 of 9
additional 62% decrease in LDL-C occasional incidences of
mild, local injection site reactions [66]. The ODYSSEY
OUTCOME trial evaluated alirocumab in 18,924 patients
with ACS on a maximally tolerated statin therapy [67].
Alirocumab was titrated to keep LDL-C between 25 and
50 mg/dL. Alirocumab showed a significant reduction in the
primary endpoint (coronary heart disease death, myocardial
infarction, ischemic stroke, or unstable angina requiring hos-
pitalization) of 9.5% compared with 11.1% with placebo. A
reduction in all-cause mortality was seen with alirocumab
(3.5% compared with 4.1% with placebo) [67].
Differently from alirocumab, evolocumab is approved for
the treatment of homozygous familial hypercholesterolemia
(HoFH), as well as HeFH and ASCVD. The FOURIER trial
evaluated the clinical efficacy and safety of evolocumab when
added to a high-intensity or moderate-intensity statin therapy
in patients with ASCVD [68]. Evolocumab reduced by 59%
of the LDL-C levels from a median baseline and by the risk of
the CV primary endpoint compared with placebo (9.8% vs
11.3%). There were no significant differences in adverse
events between the study groups, including new-onset of
DM, myalgia, and neurocognitive events, with the exception
of a higher incidence of injection site reactions seen with
evolocumab (2.1 vs 1.6%) [68].
Finally, an analysis of benefit in total CV events has been
performed from the data of FOURIER trial [69]. The addition
of evolocumab to statin therapy resulted in reductions in total
primary endpoint events (decrease in myocardial infarction,
stroke, and coronary revascularization), over a follow-up of
2.2 years, supporting the long-term use of evolocumab in
preventing recurrent cardiovascular events [69].
Beyond monoclonal antibodies, an N-galactosamine-
conjugated small interfering RNA (siRNA) anti-PCSK9,
inclisiran is under clinical development. In phase I trials, this
agent achieved consistent reductions in LDL-C in patients
with a wide range of renal function, with no dose adjustment
necessary for those with renal impairment [70]. In phase 2,
ORION-1 study, inclisiran was tested in high-risk ASCVD
patients with elevated LDL-C levels, already at maximally
tolerated statin therapy [71]. Inclisiran shoed an efficient
LDL-C reduction (− 52.6%) on top of statins after two doses
of 300-mg. Importantly, the percentage of patients with seri-
ous adverse events did not significantly differed from placebo
(11% vs 8%) although the injection site reactions occurred in
5% of the patients. The long-term cardiovascular outcomes of
inclisiran are currently under investigation in the ORION-4
trial involving approximately 15,000 ASCVD risk patients.
Conclusions
Although the discovery of statins is dated more than 25 years
ago, this class of drugs still represents the cornerstone for the
Curr Atheroscler Rep (2020) 22: 26
treatment of hypercholesterolemia. Nevertheless, there are still
concerns on long-term safety, impact on all-cause mortality,
and cost-effectiveness of their use, especially for primary pre-
vention. Muscle symptoms and the effect on glucose metabo-
lism are the most common reason for statin discontinuation,
statin non-adherence, and statin switching, which has a rate up
to 75% within 2 years of treatment. Such non-adherence/dis-
continuation from treatment may have an important impact on
CV disease benefit. However, recent “life-long” analysis con-
ducted on young FH patients, elderly hypocholesterolemic
subjects, and from 20-year follow-up of RCT have provided
additional evidence on the efficacy of statins in preventing CV
diseases with limited, although, not absent side effects. Above
statins, more recent therapies have been approved for control-
ling the LDL-C levels, such as monoclonal antibodies anti-
PCSK9, ezetimibe, and bempedoic acids. All these therapies
have demonstrated a positive effect on LDL-C levels in com-
bination with statins and represent an important therapeutic
option for increasing the percentage of patients reaching their
LDL-C goal with a substantial improvement or safety profile.
In particular, the CV benefits of monoclonal antibodies anti-
PCSK9 and ezetimibe in patients under statin therapy have
been proven by specific RCT. However, it remains to estab-
lish the clinical efficacy of bempedoic acid, currently under
investigation in the CLEAR Outcomes study, and of the
siRNA anti-PCSK9 inclisiran tested in ORION-4 trial.
Compliance with Ethical Standards
Conflict of Interest Dr. Corsini reports personal fees from Sanofi, per-
sonal fees from Recordati, personal fees from Pfizer, personal fees from
AstraZeneca, personal fees from Mylan, personal fees from DOC, per-
sonal fees from Mediolanum, personal fees from MSD, outside the sub-
mitted work.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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