Statins_Slides (1).pptx

Introduction
▶ It is a member of the drug class known as statins.
▶ It is used primarily for lowering blood cholesterol and for
prevention of events associated with cardiovascular disease.
▶ It works by inhibiting HMG-CoAreductase, an enzyme found in
liver tissue that plays a key role in production of cholesterol in the
body.

Administration
▶ Atorvastatin may be used in combination with aspirin and clopidogrel
▶ It is not recommended to combine statin drug treatment with certain other
cholesterol-lowering drugs.
▶ While many statin medications should be administered at bedtime for optimal
effect, atorvastatin can be dosed at any time of day, as long as it is continually
dosed once daily at the same time.
▶ In patients with chronic alcoholic liver disease, levels of atorvastatin may be
significantly increased depending upon the extent of liver disease
▶ Plasma concentrations of atorvastatin in healthy elderly subjects are higher than
those in young adults

Mechanism of action
▶ As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA
reductase. It is a completely synthetic compound.
▶ HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-
coenzymeA (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic
cholesterol biosynthesis.
▶ Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing
expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes.
▶ This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-
cholesterol in the blood.
▶ Atorvastatin also reduces blood levels of triglycerides and slightly increases levels of
HDL-cholesterol.

Pharmacokinetics
Absorption
▶ Atorvastatin undergoes rapid absorption when taken orally, with an approximate time
to maximum plasma concentration of 1–2 h. The absolute bioavailability of the drug is
about 14%, but the systemic availability for HMG-CoA reductase activity is
approximately 30%.
Distribution
▶ The mean volume of distribution of atorvastatin is approximately 381 L. It is highly
protein bound (≥98%), and studies have shown it is likely secreted into human breast
milk.
Metabolism
▶ Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to
form active ortho- and parahydroxylated metabolites. The ortho- and parahydroxylated
metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The
ortho-hydroxy metabolite undergoes further metabolism via glucuronidation.
Excretion
▶ Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2%
recovered in the urine. Bile elimination follows hepatic and/or extrahepatic
metabolism. Atorvastatin has an approximate elimination half-life of 14 h.

Pharmacodynamics
▶ The liver is the primary site of action of atorvastatin, as this is the principal
site of both cholesterol synthesis and LDL clearance.
▶ It is the dosage of atorvastatin, rather than systemic drug concentration,
which
correlates with extent of LDL-C reduction.
Pharmacogenetics
▶ Several genetic polymorphisms have been found to be associated with a
higher incidence of undesirable side effects of atorvastatin.
▶ It is suspected to be related to increased plasma levels of pharmacologically
active metabolites, such as atorvastatin lactone and p-hydroxyatorvastatin.
▶ Atorvastatin and its active metabolites may be monitored in
potentially susceptible patients using specific chromatographic
techniques
6

Interactions
▶ Grapefruit juice can increase the blood levels of atorvastatin. This can increase
the risk of side effects such as liver damage and a rare but serious condition
called rhabdomyolysis that involves the breakdown of skeletal muscle tissue.
▶ Interactions with clofibrate, fenofibrate, gemfibrozil, usually in combination
with statins, increase the risk of myopathy and rhabdomyolysis.
▶ Co-administration of atorvastatin with one of CYP3A4 inhibitors such as
itraconazole, telithromycin, and voriconazole, may increase serum
concentrations of atorvastatin, which may lead to adverse reactions.
▶ Often, bosentan, fosphenytoin, and phenytoin, which are CYP3A4 inducers,
can decrease the plasma concentrations of atorvastatin.
▶ Barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin,
and rifamycin, which are also CYP3A4 inducers, can decrease the plasma
concentrations of atorvastatin.
7

USES
• ▶ Hypercholesterolemia and mixed dyslipidemia to reduce total cholesterol, LDL-C, apo-B,
triglycerides levels, and CRP as well as increase HDL levels.
• ▶ Heterozygous and Homozygous familial hypercholesterolemia
• ▶ Hypertriglyceridemia (Fredrickson Type IV)
• ▶ Primary dysbetalipoproteinemia (Fredrickson Type III) and Combined hyperlipidemia
• ▶ Primary prevention of heart attack, stroke, and need for revascularization procedures in
patients.
▶ Secondary prevention of myocardial infarction, stroke, unstable angina and
revascularization in people with established coronary heart disease.
• ▶ Myocardial infarction and stroke prophylaxis in patients with type II diabetes
▶ There have been recent studies suggesting that high-dose statin therapy plays a plaque-
stabilizing role in patients suffering from acute coronary syndrome and thrombotic stroke.

High-intensity statins and inhibition of inflammation
Liu, Hui MM, et al. Medicine 2018; 97:e12687. Taguchi I, et al. Am J Cardiol. 2013 May 1; 111(9):1246-52. Hwang DS, et
al. Yonsei Med J. 2013 Mar 1; 54(2):336-44. Takata K, et al. Cardiovasc Diagn Ther. 2016 Aug; 6(4):304-21. Khurana S, et
Statins:
Pleiotrop
ic effect
Reducing low grade
inflammation
Suppression of
plaque vulnerability
Reduction of necrotic
core in plaques
Reduction of lipid
accumulation
Improving
endothelial
function
Inhibition of
inflammatory
activity

SideEffects
▶ Cough
▶ Difficulty with swallowing
▶ Fast heartbeat
▶ Fever and dizziness
▶ Itching
▶ Muscle cramps, pain, stiffness, swelling, or weakness
▶ Puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
▶ Skin rash
▶ Tightness in the chest
▶ Unusual tiredness or weakness

Precautions to be taken Before
taking this medicine
▶ Liver disease; or
▶ If you are pregnant or breast-feeding.
▶ Muscle pain or weakness;
▶ History of liver disease;
▶ History of kidney disease;
▶ History of stroke ;
▶ Thyroid disorder; or
▶ If you drink more than 2 alcoholic beverages daily.

Factors associated with poor adherence
Umarje S, et al. Indian J Endocr Metab 2021;25:206-10.
Poor knowledge, high cost of statins, and refill issues
were the leading causes for poor adherence.

Adherence to statin therapy and inhibition of
inflammation
Indian J Endocrinol Metab. 2021 May-Jun; 25(3): 206–210
Around 42.31% had good adherence, 23.07% had moderate
adherence,
and 34.62% had poor adherence

Adherence pattern in various clinical conditions
Good adherence was observed in patients with a
history of coronary heart disease and atorvastatin as
mono-therapy and fixed dose combination.

Outcomes of the patients based on the adherence to
statins
Good adherence was significantly observed in Atorvastatin therapy. Lipid
reduction was dependent on type of adherence. Individuals with moderate
or poor adherence showed significantly higher lipoprotein levels.

Adherence to statin
Study shows that there continues to be underutilization of LMTs(lipid-
modifying therapy) among patients with high or very-high CV risk (1)
Many patients filling high-intensity statins following a myocardial infarction
do not continue taking this medication with high adherence for 2 years post
discharge.(2)
1. Atherosclerosis 271 (2018) 120e127, https://doi.org/10.1016/j.atherosclerosis.2018.02.024
2. JAMA Cardiol. 2017;2(8):890-895. doi:10.1001/jamacardio.2017.0911

Barriers to optimal dyslipidaemia management in ACS
Reda A, et al. Adv Ther. 2020;37(5):1754-1777.
• Dyslipidemia control in ACS is suboptimal
• High prevalence of ASCVD risk factors confers a higher risk
of CVD.
• ACS onset is often earlier in these patients, and they may
be more challenging to treat
• Low awareness of the value of intensive lipid lowering
• Patients non-adherence to given medication
• Fear of side effect
• Lack of follow-up of patients with ACS
• Poor access to intensive medications
• Economical factors

High Intensity statin Vs Low Intensity
Statin
The patients in the more intensive statin group had lower incidence compared with patients in the less
intensive statin group.
 Coronary revascularization by PCI (7.3% vs. 4.1%, p=0.039);
 Target-vessel revascularization (4.6% vs. 2.0%, p=0.029);
 Cardiac death, MI, PCI, OR CABG (8.6% vs. 5.0%, p=0.027);
 MACE (11.6% vs. 6.8%, p=0.010)
J Lipid Atheroscler. 2019 Sep;8(2):208-220,
https://doi.org/10.12997/jla.2019.8.2.208

High Intensity statin Vs Low Intensity
Statin
• A large body of evidence suggests that statins limit myocardial damage and improve outcome in
patients undergoing PCI.
• High-dose statin therapy confers an additional beneficial effect over a low-dose regimen in patients
with stable CAD as well as in those with ACS
• Most of the benefit associated with intensive statin therapy appears to be independent of the lipid-
lowering effect and has been attributed to multiple effects of statins on the vascular bed.
 Preventing thrombus formation and endothelial dysfunction
 Inducing changes in plaque composition,
 Modulating inflammation
Am J Cardiovasc Drugs (2013) 13:189–197, DOI 10.1007/s40256-013-0012-9

High Intensity Atorvastatin
Atorvastatin led to a reduction in HS-CRP, IL6, TNFα and improvement in
endothelial function in a dose-dependent manner.
Improvements in lipid profile and simultaneously to vascular direct
effects that are early and dose-dependent.
Higher dose statin therapy in patients with STEMI undergoing primary
percutaneous coronary intervention showed early greater vascular
protective effects compared to moderate dose
Gavazzoni et al , Drug Design, Development and Therapy 2017:11 , http://dx.doi.org/10.21

High Intensity Atorvastatin Vs Low Intensity
Atorvastatin
• The ACS patients with DM can improve the prognosis through long-term therapy of high
intensity atorvastatin compared with moderate intensity atorvastatin. Furthermore, it is
safe for long-term atorvastatin 40 mg/d.
• At the end of one-year, low-density lipoprotein cholesterol level was lower in high intensity
group than in moderate group (1.6±0.6 vs 1.8±0.6, p=0.041).
• MACE in high intensity group decreased 44.5% than moderate group (8.4% vs. 14.6%, p =
0.018).
• The adjusted hazard ratio (HR) for MACE in patients with atorvastatin 40 mg/d was lower
compared to patients with atorvastatin 20 mg/d (HR [95% CI] 0.61 [0.36 to 0.91], p = 0.026).
The rates of adverse events were no significantly different between the two groups.
Z. Liu et al. / International Journal of Cardiology 222 (2016) 22–26, http://dx.doi.org/10.1016/j.ijcard.2016.07.140

2019 ACC/AHA Guideline on the Primary
Prevention of Cardiovascular Disease

Adults with High Blood Cholesterol
Recommendations for Adults with High Blood Cholesterol
COR LOE Recommendations
I A
1. In adults at intermediate risk (≥7.5% to <20% 10-year ASCVD risk),
statin therapy reduces risk of ASCVD, and in the context of a risk
discussion, if a decision is made for statin therapy, a moderate-
intensity statin should be recommended.
I A
2. In intermediate risk (≥7.5% to <20% 10-year ASCVD risk) patients,
LDL-C levels should be reduced by 30% or more, and for optimal
ASCVD risk reduction, especially in patients at high risk (≥20% 10-
year ASCVD risk), levels should be reduced by 50% or more.

Adults with High Blood Cholesterol (cont’d)
I A
3. In adults 40 to 75 years of age with diabetes, regardless of
estimated 10-year ASCVD risk, moderate-intensity statin therapy is
indicated.
I B-R
4. In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL
(≥4.9 mmol/L) or higher, maximally tolerated statin therapy is
recommended.

IIa B-R
5. In adults with diabetes mellitus who have multiple ASCVD risk
factors, it is reasonable to prescribe high-intensity statin therapy
with the aim to reduce LDL-C levels by 50% or more.
IIa B-R
6. In intermediate-risk (≥7.5% to <20% 10-year ASCVD risk) adults,
risk-enhancing factors favor initiation or intensification of statin
therapy.

IIa B-NR
7. In intermediate-risk (≥7.5% to <20% 10-year ASCVD risk) adults or selected
borderline-risk (5% to <7.5% 10-year ASCVD risk) adults in whom a coronary artery
calcium score is measured for the purpose of making a treatment decision, AND
 If the coronary artery calcium score is zero, it is reasonable to withhold statin
therapy and reassess in 5 to 10 years, as long as higher-risk conditions are absent
(e.g., diabetes, family history of premature CHD, cigarette smoking);
 If coronary artery calcium score is 1 to 99, it is reasonable to initiate statin therapy
for patients ≥55 years of age;
 If coronary artery calcium score is 100 or higher or in the 75th percentile or higher,
it is reasonable to initiate statin therapy.

IIb B-R
8. In patients at borderline risk (5% to <7.5% 10-year ASCVD risk), in
risk discussion, the presence of risk-enhancing factors may justify
initiation of moderate-intensity statin therapy.

ESC guidelines 2019 for management of
Dyslipidemia

Foundations of new Guidelines
©ESC
These Guidelines recognize that low density lipoproteins and other apoB-containing
lipoproteins cause ASCVD
These Guidelines therefore make recommendations to reduce the risk of ASCVD by
lowering LDL and other apoB-containing lipoproteins
These Guidelines recognize that benefit of lipid lowering therapies is determined by
both the absolute reduction in LDL and other apoB-containing lipoproteins and
corresponding absolute reduction in ASCVD risk
These Guidelines therefore recommend titrating lipid lowering therapy intensity
based on both baseline lipid levels and baseline risk of ASCVD
These Guidelines prioritize identifying people at High and Very-High 10-year risk of
experiencing a cardiovascular event because they are most likely to derive the
greatest short- term clinical benefit from aggressive lipid lowering therapy

Using baseline LDL-C
and risk of ASCVD to
estimate expected
clinical benefit of low-
density lipoprotein
lowering therapies
©ESC
Intensity of lipid lowering treatment
Treatment Average LDL-C
reduction ≈
30%
≈ 60%
≈ 75%
≈ 85%
Moderate intensity statin High intensity
statin
≈ 50%
High intensity statin plus ezetimibe
≈ 65%
PCSK9 inhibitor
PCSK9 inhibitor plus moderate intensity statin
PCSK9 inhibitor plus high intensity statin plus
ezetimibe
% reduction LDL-C Baseline
LDL-C
Absolute reduction
LDL-C
Relative risk reduction Baseline
risk
Absolute risk
reduction
LDL-C= low-density lipoprotein cholesterol;
PCSK9= proprotein convertase subtilisin/kexin type 9.

Recommendations Class Level
In secondary prevention patients at very-high riskc, an LDL-C
reduction of at least 50% from baselined and an LDL-C goal of
<1.4 mmol/L (<55 mg/dL) are recommended.
I A
In primary prevention, for individuals at very-high risk but
without FHc, an LDL-C reduction of at least 50% from baselined
and an LDL-C goal of
<1.4 mmol/L (<55 mg/dL) are recommended.
I C
In primary prevention, for individuals with FH at very-high risk,
an LDL-C reduction of at least 50% from baseline and an LDL-C
goal of <1.4 mmol/L (<55 mg/dL) should be considered.
IIa C
cFor definitions see Table 1.
dThe term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C lowering medication. In people who are taking LDL-
C-lowering medication(s), the projected baseline (untreated) LDL-C levels should be estimated, based on the average LDL-C-
lowering efficacy of the given medication or combination of medications.
Recommendations for treatment goals
for low-density lipoprotein cholesterol
(1)
©ESC
2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce
cardiovascular risk (European Heart Journal 2019 -doi: 10.1093/eurheartj/ehz455)
www.escardio.org/guidelines

(2)
©ESC
For patients with ASCVD who experience a second vascular
event within 2 years (not necessarily of the same type as the
first event) while taking maximally tolerated statin therapy, an
LDL-C goal of <1.0 mmol/L (<40 mg/dL) may be considered.
IIb B
For patients at high-riskc, an LDL-C reduction of at least 50%
from baselined and an LDL-C goal of <1.8 mmol/L (<70 mg/dL)
are recommended.
I A
c For definitions see Table 1.
d The term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C lowering medication. In people who are taking LDL-C-
lowering medication(s), the projected baseline (untreated) LDL-C levels should be estimated, based on the average LDL-C-lowering
efficacy of the given medication or combination of medications.

(3)
©ESC
For individuals at moderate riskc, an LDL-C goal of <2.6 mmol/L
(<100
mg/dL) should be considered.
IIa A
For individuals at low riskc an LDL-C goal <3.0 mmol/L (<116
mg/dL) may be considered.
IIb A
C For definitions see Table 1.

Treatment goals for low-density lipoprotein
cholesterol (LDL-C) across categories of total
cardiovascular disease risk
©ESC
Low
Moderate
High
Very-
High
3.0
mmol/L
(116mg/d
L)
Treatmentgoa
l forLDL-
C
2.6
mmol/L
(100mg/d
L)
1.8mmol/
L
(70
mg/dL)
1.4mmol/
L (55
mg/dL)
&
≥50%
reduction
from
baseline
Low
Moderat
e
Hig
h
very-
High
CVRis
k
•SCORE<1%
• SCORE ≥1% and <5%
• Youngpatients (T1DM<35 years; T2DM<50 years)
with DM duration <10years withoutother
riskfactors
• SCORE ≥5% and<10%
• Markedlyelevatedsingleriskfactors, in particular TC>8 mmol/L
(310 mg/dL) or LDL-C>4.9 mmol/L (190mg/dL) or
BP≥180/110mmHg
• FH withoutother majorriskfactors
• Moderate CKD(eGFR 30–59mL/min)
• DMw/otarget organdamage, with DM
duration≥10years or otheradditionalriskfactor
•ASCVD(clinical/imaging
)
•SCORE≥10%
•FHwithASCVDorwithanother
majorriskfactor
•SevereCKD(eGFR<30mL/min)
•DM& target organdamage:≥3
majorriskfactors; or earlyonsetof
T1DMof longduration(>20years)

J Am Coll Cardiol 2019;73:e285–350
Secondary Prevention in Patients With Clinical ASCVD

J Am Coll Cardiol 2019;73:e285–350
Recommendations for Statin Therapy Use in Patients
With ASCVD

Focus on Atherosclerotic Cardiovascular Disease

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