Lower is Better - No Evidence for Treating

to Specific lipid Targets

&
Use of Statins
Dr.
ACC/AHA Guidelines
ESC Guideline
NPL Guideline
Diabetes & CKD
Indian Perspective
Our Perpective
Conclusion
Statins, lower cholesterol levels by
inhibiting the enzyme HMG-CoA
reductase, which plays a central role
in the production of cholesterol in
the liver, that accounts about 70
percent of total cholesterol of the
body.
 acetyl CoA
HMG-CoA synthase
HMG-CoA
HMG-CoA reductase X Statins
mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

ubiquinones farnesyl pyrophosphate dolichols

Squalene synthase squalene

cholesterol
 Aspergillus terreus The oyster mushroom, naturally contains lovastatin.
In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical
company Sankyo, began the search for a cholesterol-lowering drug. Research
had already shown cholesterol is mostly manufactured by the body in the liver
using the enzyme.

Joseph Goldstein, who won the Nobel Prize for related work on cholesterol,
said of Endo: "The millions of people whose lives will be extended through
statin therapy owe it all to Akira Endo.
High level of evidence was found that statins reduce total mortality in
individuals with a history of prior ASCVD events (e.g., secondary
prevention settings).

In individuals with no prior history of ASCVD events (e.g., primary

prevention setting), there is moderate evidence that statins reduce
total mortality in individuals at increased ASCVD risk.

It should be noted, 2 meta-analyses published after the completion

of the Expert Panel’s systematic review provide strong evidence that
statins reduce total mortality in primary prevention.

2013 ACC/AHA Blood Cholesterol Guideline

 ACC/AHA 2013- Guideline on the Treatment of Blood Cholesterol to
Reduce Atherosclerotic Cardiovascular Risk in Adults.

ESC/EAS 2011 Guidelines for the management of dyslipidaemias.

NLA 2015
National Lipid Association Recommendations forPatient-Centered
Management of Dyslipidemia Terry A. Jacobson and others published in
Journal of Clinical Lipidology

ADA 2014
American Diabetes Association. Standards of medical care in
diabetes.

KDIGO 2015
Kidney Disease Outcomes Quality Initiative
NCEP NCEP NCEP
ATP I ATPIII ATP IV
1988 2001 2013??

NCEP ACC/AHA
NCEP ATP III 2013
ATP II REVISED
1993 2004
 Individuals with
Individuals ≥ 21 years of age
clinical Atherosclerotic
with primary LDL-C ≥ 190 mg/dl
Cardiovascular Disease (ASCVD)

Individuals of Individuals of 40-75 years of age with

40-75 years of age with Diabetes 10-year ASCVD risk ≥ 7.5% or higher
Even if they have LDL-C 70-189 mg/dl without ASCVD or Diabetes
ASCVD Risk Estimator
http://tools.acc.org/ASCVD-Risk-Estimator/
ACS, h/o MI, angina, revascularization, TIA, stroke,
peripheral arterial disease

No RCTs identified that titrated drug therapy to specific

LDL goals to improve ASCVD outcomes
 LDL-C
Age>21 years
>190mg/dl

Evaluate for cause primary secondary

High Maximum LDL-C Evaluate

Management dose tolerated
dose
reduction of
atleast 50%
and treat
accordingly
statin

IIa
IB IB
B
 LDLcholesterol
Diabetes 70-189 mg/dl

<40 yrs,
Age 40-75 yrs >75yrs

Moderate High intensity Balance between

Statins intensity
statins
statins
with risk >7.5%
ASCVDbenefits and
adverse effects

IA IIa B IIa C
Patients without LDLcholesterol
diabetes,primary 70-189 mg/dl
prevention
10 yr ASCVD >7.5
risk estimate % 5-7.5%

40-75 yrs >75 40-75 >75

Age of the patient yrs
yrs yrs
Assess
Moderate to Moderate risks
high intensity Assess intensity benefits
therapy risk, therapy
benefits
IIa B
IA
Clinical application by Statin dose
HIGH INTENSITY MODERATE LOW INTENSITY
THERAPY INTENSITY THERAPY THERAPY
Daily dose lowers LDL-C Daily dose lowers LDL –C Daily dose lowers LDL –C
on average,by on average,by <30%
approximately ≥50% approximately 30-50%
Atorvastatin (40) 80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg
Rosuvastatin 20 mg Rosuvastatin (5) 10 mg Pravastatin 10-20 mg
Simvastatin 20-40 mg Lovastatin 20 mg
Pravastatin 40 (80) mg Fluvastatin 20-40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Statins modestly increase the excess risk of type 2 diabetes in
individuals with risk factors for diadetes
Potential for an ASCVD risk-reduction benefit outweighs the excess
risk for diabetes
Continue statin therapy to reduce the risk of ASCVD event
Muscle symptoms –
- severe - ? Rhabdomyolysis -- discontinue statins
- mild to moderate - ? Statin related – lower dose/different statin
When 2 consecutive values of LDL –C are
<40mg/dl : decrease dose

No data suggesting adverse events when LDL-C

below this level

Pregnancy X : not be used in women of

childbearing potential
 Adhering to a healthy heart diet,
 Regular exercise habits
 Avoidance of tobacco products
 Maintenance of healthy weight

Remains critical component both prior to and in concert with the use of cholesterol
lowering drug therapies
 Statins
Mechanism
Inhibit HMG CoA reductase which is the rate-limiting step
in cholesterol biosynthesis.
Pharmacodynamics
Most effective class of drugs at lowering LDL-C levels
-  LDL-C by 18-55%
-  HDL-C by 5-15%
-  TG by 7-30%
Adverse reactions
myopathy, rhabdomyolysis, elevations of serum
aminotransferase activity
 Mechanism of Action of Statins
Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA synthase
HMG-CoA
HMG-CoA reductase X Statins
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate

geranyl pyrophosphate

ubiquinones farnesyl pyrophosphate dolichols

Squalene synthase squalene

cholesterol
 Fluvastatin
Atorvastatin Rosuvastatin
Pravastatin
BM Y

1991 1996 2000

1987 1993 1997 2003

Lovastatin
Cerivastatin
Simvastatin
 Rosuvastatin:
A new hydrophilic statin – single enantiomer
Statin Pharmacophore
Relative lipophilicity *

O Ca 2.0
(3R, 5S) HO cerivastatin
O simvastatin
1.5
OH fluvastatin
1.0 atorvastatin
F
CH3 0.5

CH3 0.0

N N rosuvastatin
-0.5

H3C N pravastatin
-1.0
S CH3
O O * log D at pH 7.4

Buckett et al., (2000); Mc

 Rosuvastatin: Hepatoselective
Cholesterol synthesis inhibited in hepatocytes at
1000-fold lower concentrations than fibroblasts
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts

140

120
% of Control Fibroblasts IC50= 331 nM
Mean Hepatocytes IC50= 0.2 nM
100

80

60

40

20

0
0 0.1 1 10 100 1000 10000 100000
Concentration (nM)
Buckett et al., (2000)
 Cerivastatin: Non hepatoselective
Cholesterol synthesis inhibited in fibroblasts
and hepatocytes at similar concentrations
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts
140

120
% of Control Fibroblasts IC 50= 1.3 nM
Mean Hepatocytes IC50= 2.4 nM
100

80

60

40

20

0
0 0.01 0.1 1 10 100 1000 10000 100000
Concentration (nM)
Buckett et al., (2000)
Rosuvastatin: X-Ray crystallography provides
molecular rationale for potent enzyme inhibition

The rosuvastatin:
HMG-CoA reductase
complex has more
bonding interactions
than any other statin

binding interaction
Arg568 and sulphone

Istvan and Deisenhofer (2001)

 Rosuvastatin: Potent inhibitor of
HMG-CoA reductase in human catalytic domain
Three determinations, IC 50 (nM) with 95% confidence limits

Rosuva
5.4
Atorva
8.2 Ceriva *Simva *
10.0
11.2
IC50(nM)
(log scale)
10 Fluva ***
27.6

Prava ***
44.1

100
*P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin
McTaggart et al., (2001)
Pharmacologic properties of Statins
Property Rosuva Atorva Fluva Lova Prava Simva

Prodrug No No No Yes No Yes

Salt form Ca Ca Na None Na None

Single Yes Yes Yes Yes Yes Yes

isormer

Lipophilicity
-0.3 +4.1 +3.2 +4.3 -0.2 +4.7
(log P)

IC50(nm)
5 8 28 NA NA 11
Potency

Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004)

Pharmacokinetic properties of Statins
Parameter Rosuva Atorva Fluva Lova Prava Simva

Absolute bioavailability,% 20 12 10-35 <5 18 >5

Food effect on bioavailability None 13% 15-25% 50%  30% None

Protein binding, % 90 >98 >99 95 48 95

Hepatic extraction, % dose 90 >70 68 >70 50 78-87

Metabolic enzyme Sulfation

(none)
3A4(S) 2C9(I) 3A4(S) 3A4(S)
2C9,2C19 (none)
(S, substrate; I, inhibitor)

Half-life, h 20 14 <1 3-4 1.8 3

Urine %
Elimination,
10 2 5 10 20 13
90 96 95 70 70 80
Feces
 Statin Dose Required to Achieve
45–50% LDL-C Reduction

10 20 40 80 mg

Rosuvastatin

Atorvastatin

Simvastatin

Not achieved with max.

Pravastatin
authorised dose

Not achieved with max.

Fluvastatin authorised dose

Adapted from Jones P.H. 2003

 Rosuvastatin versus Comparators:
LDL-C efficacy at 10mg Dose
Change in LDL-C from baseline (%)
0 –5 –10 –15 –20 –25 –30 –35 –40 –45 –50 –55 –60

10 20 40
mg mg mg
* † ‡

10 20 40 80
mg mg mg mg
Rosuvastatin
Atorvastatin
10 20 40 80 Simvastatin
mg mg mg mg Pravastatin

10 20 40
mg mg mg Rosuvastatin 10 mg (–46%)

*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg
†p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg
‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160 The STELLAR Study

 Rosuvastatin:
10 mg gets more patients to their LDL-C goal
than the start doses of the most commonly used
statins1,2,3,4 Percentage of patients at LDL-C goal at week 6 1, 2

100%
P-values
***p<0.002
90% CRESTOR 10 mg
vs. atorvastatin
% patients reaching LDL-C goal*

10 mg pravastatin
10, 20 & 49 mg and
80% * simvastatin 10, 20,
80 mg & 40 mg
70%
40 mg
10 mg
80 mg
60% Usual start doses
20 mg

50%
40 mg
10 mg
40%
20 mg
30%

20% 40 mg
10 mg
n=160

10% n= n= n= 20 mg
156 158 158
10 mg
CRESTOR atorvastatin simvastatin pravastatin

References: 1. STELLAR 2. Schuster MERCURY I Am Heart J 2004; 147: 705-12. 3.

Krithiades Eur Heart J Suppl 2004; 6(suppl A): A12-A18.4. Shepherd Am J Cardiol
2003; 92(suppl): 11C-19C. *2003 European goals
Rosuvastatin 10 mg gets more patients to
NCEP ATP- III LDL-C Goals
100
P<0.01
90 p<0.0001
Patients achieving LDL-C goal

80 OMNITOR
80 atorvastatin
70 74
60 63
50
40 Baseline mean LDL-C values (mg/dL)
OMNITOR 10 mg: 165.1 (4.28 mmol/L)

30 atorvastatin 10 mg: 162.6 (4.21)

atorvastatin 20 mg: 167.1 (4.33)

20
10
(%)

n=535 n=528 n=923

0
10 10 20
Dose (mg/day)
•high risk (with CHD or CHD risk equivalent) - Target LDL-C: <100mg/dL (2.59mmol/L)

MERCURY I study; Am Heart J 2004; 147: 705-12

 Rosuvastatin: 10mg enables more patients with
hypercholesterolemia to reach their Joint European
Societies LDL-C goals, than atorvastatin 10mg
Patients reaching European LDL-C goals by risk category at week 12
(Pooled Data)
100 rosuvastatin 10mg
atorvastatin 10mg
**
Patients achieving goal (%)

*** ***
80 85
81 82

60 64

51
40 49

20

n=66 n=327 n=393

0 n=75 n=314 n=389
10-yr CHD risk < 20% High CHD risk All Categories

Joint European Societies Cholesterol Categories

**P<0.01 vs atorvastatin; ***P<0.001 vs atorvastatin

Shepherd et al., (2003)
 Rosuvastatin 10 mg gets more patients to
European LDL-C Goals

100 *
90 *
88
84 *
80
76
70
69
Patients 62
at goal 60
(%) 50
40
30
20
10
0
R10 A10 A20 S20 P40

*p<0.0001 (R10 vs A10, S20 & P40) 1998 European goal <3.0 mmol/l (116 mg/dl)

MERCURY I study; Am Heart J 2004; 147: 705-12

 Rosuvastatin 10 mg
Patients (%) achieving European LDL-C goal
100 † ‡
* 90 ‡
88 86 88
90 86 84 86
80
80 72
70 66

Patients 60
at goal
50
(%)
40
30
20
10
0
AD1o0seA(m10g) A20 A20 A20 S20 S20 P40 P40
R10 A10 R10 R20 A20 R10 S20 R10 P40

vs A10/A10;
vs A20/A20;
10 vs S20/S20 and P40/R10 vs P40/P40)
al <3.0 mmol/l (116 mg/dl)
MERCURY I study; Am Heart
 Pleiotropic Effects of Rosuvastatin
in Animal Models of Vascular Disease

  eNOS, NO availability
  leukocyte-endothelial interactions
  superoxide, oxidative stress
 Preservation of vascular function in
hypertension and insulin-resistance
 Protection against ischaemia-reperfusion
injury
 Protection of kidney function and inhibition
of renal fibrosis and glomerulosclerosis
 Statins – Therapeutic Ratio

Adverse Effects

Therapeutic
Effects

Muscle
Liver
Cardiovascular
protection Drug interactions
 Rosuvastatin Tolerability and Safety –
Withdrawals due to Adverse Events
10
Percentage of patients with an adverse event
9 leading to withdrawal
8

7
6
Percentage of

5
4
patients

2.9% 3.2%
3 2.5% 2.5%
2
10-80 mg
10-40 mg 10-80 mg 10-40 mg
1
0
rosuvastatin atorvastatin simvastatin pravastatin
(n=3074) (n=2899) (n=1457) (n=1278)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K-29K

 Rosuvastatin Tolerability and Safety
- Muscle Effects
 As with other statins, effects on skeletal muscle, e.g.
uncomplicated myalgia, myopathy and, rarely,
rhabdomyolysis have been reported in patients treated
with rosuvastatin
 Incidence of treatment-related myopathy* in clinical
trials was low in patients treated with rosuvastatin up to
40 mg (<0.1%) which is similar to that seen with other
currently marketed statins1
 Frequency of rhabdomyolysis with rosuvastatin is very
rare (<0.01%) which is in line with that reported for
other marketed statins2

*defined as CK >10 ULN plus muscle symptoms

1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

2. Data on File
Please refer to local Prescribing Information
 Rosuvastatin - Muscle Effects
CK >10 x ULN: Frequency by
LDL-C Reduction
3.0 Rosuvastatin (10–40 mg)
Atorvastatin (10–80 mg)
2.5 Simvastatin (40–80 mg)
CK >10 × ULN (%)

Pravastatin (40–80 mg)

2.0 Cerivastatin (0.2–0.8 mg)

1.5

1.0

0.5

0.0
20 30 40 50 60 70
LDL-C reduction (%)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

 Reported Cases of Fatal Rhabdomyolysis and
Numbers for All Statins Dispensed in the US Since
These Products Were Launched
Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Cerivasta Rosuvastati
tin n
Variable
*

Date approved 8/87 10/91 12/91 12/93 12/96 6/97 11/02#

Fatal cases of 19 3 14 0 6 31 0
rhabdomyolysis

No. of
prescriptions 99,197 81,364 116,145 37,392 140,360 9,815 10,100
dispensed since
marketing began
(in thousands)

Reporting rate 0.19 0.04 0.12 0 0.04 3.16 0

(per 1 million
prescriptions)

*worldwide prescriptions
#Netherlands (MR ref state)
Adapted from: Steffa JA, et al. N Engl J Med. 2002;346:539-540.
 Rosuvastatin Tolerability and Safety
- Liver Effects

 Elevations in liver transaminase levels are an infrequent

but recognized complication of treatment with statins
 Incidence of clinically significant increases in serum
transaminases* with rosuvastatin 10–40 mg in clinical
trials was low (0.2%) which is similar to that seen with
other currently marketed statins1,2
 As with other statins:
– liver function tests recommended
– caution in patients who consume excessive quantities of
alcohol and/or have a history of liver disease
– contraindicated in patients with active liver disease

*ALT >3 x ULN on 2 successive occasions

1.Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

2.Shepherd J et al. Am J Cardiol 2004;94:882-888
Please refer to local Prescribing Information
 Rosuvastatin – Liver Effects

Persistent ALT >3 × ULN: Frequency by

LDL-C Reduction Rosuvastatin (10–40 mg)
Atorvastatin (10–80 mg)
3.0 Simvastatin (40–80 mg)
Lovastatin (20–80 mg)
Persistent ALT >3 × ULN (%)

2.5 Fluvastatin (20–80 mg)

2.0

1.5

1.0

0.5

0.0
20 30 40 50 60 70
LDL-C reduction (%)
Persistent elevation is elevation to >3 x ULN on 2 successive occasions

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

 Potential Drug Interactions
3A4 2C9
 Simvastatin • Fluvastatin
• Phenytoin
 Atorvastatin
• Fluconazole
 Lovastatin
• Warfarin
 Diltiazem
• Rosuvastatin
 Clopidogrel
 Amiodarone Low potential for
 Cimetidine cytochrome P450

 Ery/clarithromycin interactions with

rosuvastatin
 Ketoconazole
 Carbamazepine
 St John’s wort
 Grapefruit juice
 Rosuvastatin Safety

Safety profile of rosuvastatin, including

effects on liver enzymes and creatine
kinase, compares favorably to those of
other marketed statins from 10–40 mg
daily in all pre-approval studies
• Hydrophilic properties

• Good selectivity for target organ – liver

• Limited metabolism by cytochrome P450

(2C9‚2C19)
Rosuvastatin: Drug Interactions

Interactions of limited significance:

• Oral contraceptives -  ethinyl oestradiol and norgestrel
• Antacid -  50% rosuvastatin levels
• Erythromycin -  20–30% rosuvastatin plasma levels
• Warfarin – transient  INR in some patients

Not recommended for use with:

• Gemfibrozil – 2x increase in rosuvastatin plasma levels
(Note: Fenofibrate may be co-administered)

Contraindication:
• Cyclosporin – 7x increase in rosuvastatin AUC
• ANY fibrate with rosuvastatin 40 mg
Rosuvastatin: Limited drug-drug interactions
 No clinically significant interactions seen or expected with:
• Fluconazole / Ketoconazole / Itracnoazole
• Fenofibrate
• Digoxin
• Drugs mediated by cytochrome P450 metabolism
 Interactions with limited clinical significance:
• Oral contraceptive pill -  ethinyl oestradiol and norgestrel levels
• Antacid -  50% rosuvastatin levels
• Erythromycin -  20-30% rosuvastatin plasma levels
• Warfarin –  INR
 Interactions resulting in not recommended for use:
• Gemfibrozil – 2x increase in rosuvastatin plasma levels
 Interactions resulting in contraindication to concomitant use:
• Cyclosporin – 7x increase in rosuvastatin plasma levels
Rosuvastatin Summary of Product Characteristics;
Martin PD et al., (2001); Cooper et al., (2001); Kemp et al., (2001)
Statins lower cholesterol . More importantly statins modulate the
atherosclerotic risk factors- both primary and secondary prevention.

Statins are in the centre of managing the both primary and

secondary prevention of ASCVD ( Ischaemic heart disease,
ischamic stroke and peripheral vascular diseases )

Assessment of risk factors for ASCVD is recommended in a group

of patients before initiation of statins, in all major guidelines though
estimation methods differ .
• Statins are recommended at high intensity and moderate intensity doses
depending on risk stratification.
• No target level of LDL-C is stated in ACC/AHA guideline
• Target level assessment , as recommended by ESC guideline may increase
the adherence to therapy
• Non -statins give no additional ASCVD benefit in patients with high intensity
statin therapy.
• New drugs are in pipeline, RCT s required for their incremental benefit in
ASCVD risk reduction when added to statins
• Lifestyle modification remains the foundation of the management of blood
cholesterol.
Thank You