Atorvastatin for Secondary Prevention of ASCVD

DrVivek Baliga
Consultant Internal Medicine
Director, HeartSenseTM
Dyslipidemia Management:
An Evidence Based Approach

2013 ACC/AHA Guidelines:
Statins without any lipid “goals”
Circulation 2014; 129: S1-S45
• Clinical ASCVD*
• LDL-C ≥190 mg/dL, Age ≥21 years
• Primary prevention – Diabetes: Age 40-75 years, LDL-
C 70-189 mg/dL
• Primary prevention - No Diabetes†: ≥7.5%‡ 10-year
ASCVD risk, Age 40-75 years, LDL-C 70-189 mg/dL
*Atherosclerotic cardiovascular disease
†
Requires risk discussion between clinician and patient before statin initiation
‡
Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator
Circulation. 2014;129[suppl 2]:S1-S45

LAI 2016 Statement: Both LDL-C/Non-
HDL-C goals are important in Indian
context
Journal of The Association of Physicians of India March
2016 supplement

Clinical Conditions where Lipid
Lowering therapy required
A. Patients with ASCVD
B. Patients undergoing PCI
C. Primary prevention of CVD for DM
D. Patients with low HDL-C
E. For patients with CKD
F. For patients with very high LDL-C (> 190 mg/dl)
G. Patients with IGT and High CV risk
H. Patients with statin intolerance
I. Residual risk with statin therapy:
a.Atherogenic (Mixed) Dyslipidemia withT2DM
b.Atherogenic (Mixed) Dyslipidemia withoutT2DM

Statin For Secondary Prevention
Current guidelines recommend moderate to high dose of statins for
secondary prevention.
Atorvastatin has multiple landmark trials for secondary prevention
Amongst all statins, Atorvastatin has robust evidence for
secondary prevention of ASCVD
Amongst all statins, Atorvastatin has robust evidence for
secondary prevention of ASCVD
Higher dose atorvastatin has shown incremental benefits over and
above those expected with lower dose statins
Higher dose atorvastatin has shown incremental benefits over and
above those expected with lower dose statins

TNT: High Vs Low Dose statin in Stable
CAD
22% risk reduction by 80 mg Vs 10 mg atorvastatin
p<0.001
Waters DD et al. N Engl J Med 2005;352:1425-35
Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD),
nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke
High dose statin is more effective for CV
protection in stable IHD patients

CV events in PROVE IT study
Cannon et al. NEJM 2004 Ray et al. Am J Cardiol 2006
Death/MACEDeath/MI/Urg. Revascu.
↓33%
↓16%
Intensive statin Rx provides more benefits
than moderate statin Rx
PROVE IT trial randomly assigned 4,162 patients who had been hospitalized within the
previous 10 days for ACS to receive pravastatin 40 mg vs intensive regimen of 80 mg
atorvastatin.

NAME: REAL-CAD (Randomized Evaluation of Aggressive or
Moderate Lipid Lowering With Pitavastatin in CAD)
Objective To evaluate CVD prevention by moderate cholesterol lowering (pitavastatin
1mg/day) or aggressive cholesterol lowering pitavastatin 4mg/day in
patients with stable CAD
Design Randomized, multicentric, Intervention, Parallel, Open Label, Prevention
No of Patients/
follow up
12,600 (3-6 years)
Inclusion criteria Age: 20-80 years, Stable CAD (with/without ACS, PCI, CABG in past)
Intervention Pitavastatin 1 mg daily Vs Pitavastatin 4 mg daily
Primary
Outcome
Composite of: CV death, Non-fatal MI, Non-fatal Cerebral Infarction (CI),
Unstable angina requiring urgent hospitalization)
Expected Time
of completion
March 2017
Pitavastatin in Secondary Prevention
: Ongoing Study

Loading High dose statin before PCI in ACS
reduces CV events: ARMYDA-ACS
%
5
17
P=0.01
JACC 2007:49:1272-78
171 NSTEACS patients randomized to atorvastatin (80 mg 12 h before PCI, with a further 40-mg pre-PCI or
placebo. All patients received long-term atorvastatin thereafter (40 mg/day). Primary end point : 30-day
incidence of MACE(death, myocardial infarction, or unplanned revascularization)
Among patients with ACS undergoing PCI, pretreatment with atorvastatin 80
mg improves clinical outcomes, driven mainly by reduction in periprocedural
MI
Among patients with ACS undergoing PCI, pretreatment with atorvastatin 80
mg improves clinical outcomes, driven mainly by reduction in periprocedural
MI

ARMYDA-RECAPTURE: loading 80 mg atorvastatin
pre-PCI in those on statin already also reduces CV events
0
3
6
9
12
3.4
9.1
P=0.045
MACE(%)
PlaceboAtorvastatin
JACC 2009:54:558-65
383 patients with stable angina (53%) or NSTMI(47%) and chronic statin therapy undergoing PCI were
randomized to atorvastatin reload (80 mg 12 h before PCI , + 40-mg pre-PCI) or placebo. All patients
received long-term atorvastatin thereafter (40 mg/day). Primary end point : 30-day MACE (cardiac death,
myocardial infarction, or unplanned revascularization)
Reloading with high-dose atorvastatin resulted in 50%
reduced risk of MACE at 30 days versus placebo
Reloading with high-dose atorvastatin resulted in 50%
reduced risk of MACE at 30 days versus placebo
These findings support strategy of routine reload with high-
dose atorvastatin early before intervention even in the
background of chronic therapy.
These findings support strategy of routine reload with high-
dose atorvastatin early before intervention even in the
background of chronic therapy.

Clinical Conditions where Lipid Lowering
therapy required
A. Patients with ASCVD
B. Patients undergoing PCI
C. Primary prevention of CVD for DM
D. Patients with low HDL-C
E. For patients with CKD
F. For patients with very high LDL-C (> 190 mg/dl)
G. Patients with IGT and High CV risk
H. Patients with statin intolerance
I. Residual risk with statin therapy:
a. Atherogenic (Mixed) Dyslipidemia with T2DM
b. Atherogenic (Mixed) Dyslipidemia without T2DM

Major Statin Primary Prevention
Trials
Study Patients Cohort Follow up Results
ASCOT LLA
*
2532 HT Atorvastatin
10 mg
3.3 yrs 23% risk reduction
CARDS 2838 DM Atorvastatin
10 mg
3.9 yrs 37% risk reduction
HPS * 2912 DM Simvastatin 40
mg
5 yrs 33% risk reduction
* sub-analysis

CARDS: Statin For Primary Prevention In
T2DM (2838 patients)
*Acute CHD event, coronary revascularization, stroke.
RRR: Relative risk reduction
Colhoun HM et al. Lancet. 2004;364:685-696.
0
5
10
15
0 1 2 3 4 5 6
RRR=37%RRR=37% pp=0.001=0.001RRR=37%RRR=37% pp=0.001=0.001
CumulativeincidenceCumulativeincidence
ofevents(%ofpatients)ofevents(%ofpatients)
127 events
83 events
Time (years)Time (years)
Atorvastatin 10 mg (LDL 119) (n=1428)Atorvastatin 10 mg (LDL 119) (n=1428)
Placebo (LDL 118) (n=1410)Placebo (LDL 118) (n=1410)
median follow-up 3.9 yearsmedian follow-up 3.9 years
Atorvastatin 10 mg daily is safe and efficacious in reducing
risk of first cardiovascular disease events, including stroke,
in patients with T2DM without high LDL-C. The level of LDL
should not dictate statin use.
Atorvastatin 10 mg daily is safe and efficacious in reducing
risk of first cardiovascular disease events, including stroke,
in patients with T2DM without high LDL-C. The level of LDL
should not dictate statin use.
Collaborative Atorvastatin Diabetes Study – Performed in patients without CVD

 28th Feb 2012:
 FDA Drug Safety Communication:
Important safety label changes to
cholesterol-lowering statin drugs
 Increases in HbA1c and fasting serum glucose levels
have been reported with statin use
www.fda.gov
EFFECT ON BLOOD GLUCOSE LEVELS
A 2016 analysis estimated that high-dose statin therapy
(eg, atorvastatin 40 mg daily) would lead to 50 to 100
new cases of diabetes in 10,000 treated individuals.

Effect on Blood Sugar Levels
Statins could have effects on glucose metabolism that
might influence the development of diabetes mellitus in
non-diabetics or affect glycemic control in patients with
existing diabetes.
A 2011 meta-analysis of five randomized trials (N =
32,752) also found an increased risk of incident diabetes
with intensive statin therapy compared with moderate
statin therapy
Consider riskVs benefit

Pitavastatin in T2DM:No glycemic disturbances
T2DM patients were treated by Atorvastatin 10 mg (n=99), pravastatin 10 mg (n=85) and
pitavastatin 2 mg (n=95) for 3 months.
J Atheroscler Thromb. 2008;15(5):269–275
Pitavastatin does not increase FPG and HbA1c in T2DM
patients unlike Atorvastatin

LIVES study: 2 years of Pitavastatin in
T2DM
Expert Opin Pharmacother. 2010;11(5):817–828.
Pitavastatin does not increase FPG and HbA1c in T2DM
patients even in long term therapy (upto 2 years)
Pitavastatin is a good option for long term treatment in
T2DM patients

B. Effect on HDL-C
LIVES : Pitavastatin increases HDL-C upto 32.4%^
Effects of pitavastatin on HDL-cholesterol in the LIVES study according to the previous use of statins. *p < 0.05; **p < 0.01; ***p <
0.001 (vs baseline, one-sample t-test).
^ in patients with low HDL-C
Expert Opin. Pharmacother. 2012;13(6): 859–865
Pitavastatin's ability to significantly and continually
increase HDL-C levels over time suggests a particular
benefit for patients with low baseline levels of HDL-C
and/or those that fail to increase their HDL-C levels
using alternative statins.

Shifting from other statins to Pitavastatin
further increases HDL-C
129 dyslipidemia patients (already on statin for 3 months were crossed over
to other statins for 3 months
↑ 7.7% (p< 0.05)
↓5.5% (p< 0.05)
↑ 7.5% (p< 0.05)
↓2.9.%

Dose of statins in patients with CKD
Atorvastatin: No dose adjustment required
Rosuvastatin: In patients severe CKD with creatinine
clearance < 30 ml/min (not on hemodialysis), Maximum dose: 10
mg/day
Pitavastatin: In patients with moderate/severe CKD (GFR:
15-59 ml/min) Maximum dose: 2 mg/day
GFR: Glomerular Filtration Rate

Atorvastatin Vs Rosuvastatin For Proteinuria: A Meta-
analysis
 A meta-analysis of 5 clinical trials head to head comparing atorvastatin vs
rosuvastatin
Atorvastatin is better than rosuvastatin for reduction
in proteinuria
Atorvastatin is better than rosuvastatin for reduction
in proteinuria
Circ J 2012;76:1259-66

Effect of pitavastatin on eGFR in CKD patients
(eGFR<60 ml/min/1.73m2
)
J Atheroscler Thromb 2010;17:601-609
Pitavastatin 2 mg provides
nephroprotective effects in CKD patients
(eGFR 15-59 ml/min)

Effect of Pitavastatin on proteinuria
* P <0.01 Vs Control Diabetes Care 2005;28:2728–2732
20 T2DM patients were treated with pitavastatin or placebo for 12 months

Even at 1 mg/day dosage, pitavastatin reduces
proteinuria in CKD patients
12-16 week treatment with pitavastatin (n=65) or control (n=40) ** p< 0.01
Am J Cardiol 2011;107:1644 –1649

For patients with very high LDL-C (> 190 mg/dl)
WOSCOPS
31% Risk
Reduction
P=0.0001
Shepherd J, et al, N Engl J Med 1995;333:1301-7
Statin therapy can reduce CV events in those
without CVD and LDL-C > 190 mg/dl

Lipid Lowering with Various statins :
VOYAGER Meta analysis-37 trials, > 32,000
patients
Am J Cardiol 2010;105:69 –76
Rosuvastatin showed higher reduction in LDL-C &
Non-HDL-C compared to other statins

 13 statins trials included, 91140 participants.
 Statins therapy is associated with 9% increase in the risk of
new diabetes (usually in patients predisposed to developing
T2DM).
 Conclusion: Statin therapy is associated with a
slightly increased risk of development of diabetes
Lancet 2010;375:735-42

J PREDICT: Effect of Pitavastatin
on NOD in IGT patients
Only large scale prospective study done to evaluate effect of
statin therapy on new onset DM in IGT (impaired glucose
tolerance) patients
1,269 IGT patients were randomized to lifestyle changes +
pitavastatin or control (lifestyle changes only)
Patients are followed upto > 5 years
Primary End Point: % patients developing New onset DM

ADA 2013, Late breaking abstract No. 61-L
J PREDICT: Effect of Pitavastatin on
NOD in IGT patients
18
%
Pitavastatin significantly reduces the new onset of DM
by 18% in IGT patients

J-PREDICT Sub-analysis based on
BMI: ADA 2015
Abstract No: 1199-P, June 7, 2015
Pitavastatin significantly reduces the new onset of DM
by 39% in IGT patients with BMI < 23.4 kg/m2

Upto 29% of patients on statin
develops muscle related symptoms
LAI estimate – 10 – 15%. 75% of cases in first 3
months, 90% in first 6 months

Re-challenge with different statin is
important if symptoms disappear

Pitavastatin For Statin Intolerant
Patients: Study 1
In Florida, USA, 152 patients intolerant to > 2 previous statins
due to myopathy (average 2.7 statins) were placed on pitavastatin
therapy.
Percentage (%) of patients tolerating pitavastatin and achieving
NCEPATP-III LDL-C goal non-HDL-C goal were measured
104 patients (76%) patients tolerated pitavastatin
therapy and continued it for > 6 months
87% of patients with intermediate CV risk achieved their
NCEP-ATP III LDL-C goals with pitavastatin therapy
Journal of Clinical Lipidology 2012: 6(3) : 274
Pitavastatin is a good option for those who
cannot tolerate other statins

Pitavastatin For Statin Intolerant
Patients: Study 2
In a study, 148 patients who had history of > 2 statin
intolerance were prescribed pitavastatin.
104 patients who tolerated pitavastatin > 6 weeks were
followed up for 1 year to detect long term tolerance of
pitavastatin
Results: 80.1% of the patients were still tolerating
pitavastatin after 1 year use.
79% of patients who tolerated pitavastatin reached
NCEP LDL goal
Journal of Clinical Lipidology 2013;7(3):264
Conclusions
Pitavastatin is well tolerated by majority
of statin intolerant patients

Pitavastatin For Statin Intolerant Patients: Study
3
A study presented in ACC 2013 conference
40 patients (USA) who were intolerant to other statins were treated
with pitavastatin 2 mg
27 (68%) patients could tolerate pitavastatin for > 3 months
LDL-C was reduced by 34% (from 147 mg/dl to 93 mg/dl)
Conclusion: Low dose pitavastatin is an acceptable alternative to
abandoning statin among 2/3rd
of patients documented to be
intolerant to other statins, providing an average LDL-C reduction of
34%.
JACC 2013;61(10):E1465

Minimum rise in CK enzymes with
Pitavastatin
Adverse
events
Pitavastatin Atorvastatin Rosuvastatin
CK elevation 1.41 2.19 2.29
Incidence of adverse effects (%)
Drug Design, Development and Therapy 2011:5 283–297
Pitavastatin-lesser incidence of CK
elevation: Better tolerance?

Pitavastatin: Less change in CoQ10
levels
 An open, randomized, four-phased crossover study using
4 mg of pitavastatin or 20 mg of atorvastatin was
performed to compare their efficacy and safety,
especially regarding plasma levels of coenzyme Q10
(CoQ10).
 Results:
Atorvastatin Pitavastatin
-26.1%
-7.7%
*
* P = 0.0007 vs. baseline
Change in plasma CoQ10 from baseline (%)
Clin Pharmacol Ther. 2008 May;83(5):731-9
Pitavastatin-lesser Change in Co-enzyme-
Q10 : Better tolerance

Residual CV risk: after using High dose statin
RRR=22%
P=0.001
78%
residual
risk
TNT study
N Engl J Med 2005;352:1425-35

Drug therapy for Non-HDL-C
As mentioned, in a patient on optimal statin therapy, TG
lowering therapy is preferred for non-HDL-C reduction
•Saroglitazar (Dual PPAR agonist)- For T2DM
•Fibrates

Diabetes. 2005 Aug;54(8):2460-70
Saroglitazar – Mechanism of action
PPAR α action – reduces TG and non HDL
PPAR γ action – improves insulin sensitivity

Efficacy and Safety of Saroglitazar in
Indian diabetics - 2 year data (ADA-2016)
• Design: Observational, post-marketing surveillance study (phase 4 study).
• Eligibility: As per the approved indication and prescribing information of
saroglitazar
• Medication: Saroglitazar 4mg OD
• Background Tx : Antidiabetics and statin therapy
• Outcome: Safety (adverse event monitoring) and effectiveness (lipid and
glycemic parameters) at baseline and 2 years follow up
• Statistics: Significant differences in the means from baseline to post
baseline were assessed by paired t-tests.

Efficacy and Safety of Saroglitazar in Indian
diabetics - 2 year data (ADA-2016)
Results
• 41% reduction (P < 0.001) in triglycerides
• 12% reduction in LDL-C
• 16.3% reduction in TC
• 28% reduction in non HDL-C
• Significant absolute reduction of 0.7 % in HbA1C
• Significant improvement in Fasting and PP plasma glucose
• Renal, hepatic and cardiac functions were monitored every 3
months and no serious adverse events were seen
• No edema or weight gain was reported during 2 years follow-up

Efficacy of Saroglitazar in 4 studies
presented at ADA 2016
Follow up
Patients with
dyslipidemia
6 months
(N=40)
Prediabetes
10 months
(N=74)
Diabetes
1 year
(N=106)
Diabetes
2 years
(N=108)
Diabetes
Laboratory Parameters: Absolute reduction(% reduction)
Triglycerides (mg/dL) -131.5(-38.7%) * -193.56* -91.14* (-41%) *
LDL-C (mg/dL)
-31.9(-15%) * -14.48* -55.25* (-12%) *
Non-HDL-C (mg/dL)
-54.5(-19.9%) * -38.48* -57.33* (-28%) *
HbA1C(%)
-0.7* -1.0* -1.4* -0.7*
Abbreviations: N = number of subjects in specified treatment;
* -significant p value

Meta-analysis: in 6632 patients with high TG (> 200 mg/dl),
fibrates reduced CV risk by 28%
Cardiovasc Pharmacol 2011;57:267–272

Choline fenofibrate

Only fenofibrate that do not require activation from the liver

Only fenofibrate with predictable bioavailability (81%)

Dose is 135 mg/day, lower than micronized and nanoparticle
fenofibrate

Can be taken with or without food

As per Indian consensus statement for dyslipidemia 2014, It
is only preparation of fenofibric acid recommended for use
at present.

Long term choline fenofibrate + statin well
tolerated

93% patients completed 116 wks study

The combination resulted in sustained improvement in
HDL-C (+17.4%), TG (−46.4%) and LDL-C (−40.4%).

No deaths/treatment-related serious adverse events

Discontinuation due to adverse events was 2.9%

Rhabdomyolysis was not reported in any group

Conclusion: choline fenofibrate is safe for combination
with statin (moderate dose) for long term use
Clinical Drug Investigation 2010;30(1): 51-61

Primary Prevention – Who To
Treat
• It may be most appropriate to view lipid-lowering
therapy with statins as an intervention that can
reduce relative cardiovascular (CV) risk by
approximately 20 to 30 percent regardless of
baseline low-density lipoprotein cholesterol (LDL-C)
• The absolute benefit of treatment will be
proportional to the underlying absolute risk.
• Use a risk calculator like the Framingham Risk score.
• Moderate intensity best – 20 mg Atorva, 5 – 10 mg
Rosuvastatin

Current LAI Guidelines – Key Points
Enas EA, Dharmarajan T S. The Lipid Association of India Expert Consensus Statement 2016: A sea change for management of
dyslipidemia in Indians. J Clin Prev Cardiol 2016;5:62-6

Take Home Message
Patient’s Profile Preferred
Option
Patients with ASCVD Atorvastatin
Patients undergoing PCI Atorvastatin/Rosuvastatin
Primary prevention of CVD for DM Atorvastatin
Patients with low HDL-C Pitavastatin/Rosuvastatin
For patients with CKD Atorvastatin/Pitavastatin
For patients with very high LDL-C (> 190 mg/dl) Rosuvastatin
Patients with IGT and High CV risk Pitavastatin
Patients with statin intolerance Pitavastatin
Atherogenic (Mixed) Dyslipidemia with T2DM statin+ Saroglitazar
Atherogenic (Mixed) Dyslipidemia without T2DM statin + Fenofibrate

Atorvastatin for Secondary Prevention of ASCVD

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