Statins in CVD management : Is just

lipid lowering enough?

Dr Vivek Baliga
Consultant Internal Medicine
Director, HeartSenseTM
www.heartsense.in
 Preamble
• Statins were originally introduced as lipid lowering drugs, but
today they are recommended in many high risk patient groups
irrespective of baseline lipid levels.
• This suggests that benefits of statins are beyond and
independent of lipid lowering effects.
• So Choice of statin should be based on evidence of CV
benefits rather than lipid lowering
 Primary Prevention of CVD
• As per AHA 2013, guidelines all T2DM patients of age 40-75
require either moderate or high dose statin therapy
 2016 ADA guidelines for statins in DM

Diabetes Care 2016;39(supple 1): S1-S112

 All DM patients with> 1 CV risk factor require
moderate to high dose statin

But what is the evidence that statins reduce CV

events in T2DM patients without high LDL-C?
 MI Risk in Diabetics Without Prior MI Equivalent to
Nondiabetic With MI
Finnish population study (7-year follow-up)
P<0.001 for diabetes vs no diabetes
60
P<0.001
Incidence of fatal/nonfatal MI
during 7-year follow-up (%)

50 No prior MI 45
Prior MI
40

30
P<0.001 20.2
18.8
20

10
3.5
69 890 169
0 1304
Patients without diabetes Patients with diabetes

Numbers in bars represent number of persons in category at baseline.

Haffner SM et al. N Engl J Med. 1998;339:229-234.

Diabetes is CHD equivalent
 In India, 90% diabetics have dyslipidemia

Prevalence of Dyslipidemia (%) in Prevalence of Dyslipidemia (%)

Male T2 DM in Female T2DM

85.5%
85.5 % 97.8 %

Dyslipidemia Dyslipidemia

RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12
 Major Statin Primary Prevention Trials In
DM
Study Patients Follow up Results
ASCOT LLA * 2532 Atorvastatin 10 3.3 yrs 23% risk reduction
mg
CARDS 2838 Atorvastatin 10 3.9 yrs 37% risk reduction
mg
HPS * 2912 Simvastatin 40 5 yrs 33% risk reduction
mg

Only Atorvastatin and Simvastatin have evidence

that statin reduce CV events in Primary prevention.
OTHERS DO NOT HAVE SUCH EVIDENCE!

* sub-analysis
 CARDS: primary prevention in T2DM
Atorvastatin 10 mg/day
Patient population: (n=1428)
 Age: 40-75 years
 LDL-C 160 mg/dL
2838 patients
 Triglycerides 600 mg/dL
 Type 2 diabetes
Placebo
 No prior MI or CHD
(n=1410)
 1+ CHD risk factor
4-year follow-up

Primary end point:

 Incidence of major cardiovascular events: At Baseline,
– Cardiovascular-related death
– Nonfatal MI LDL-C: 120 mg/dl
– Stroke
– Resuscitated cardiac arrest
HDL-C: 54.5 mg/dl
– Unstable angina Non-HDL-C: 153 mg/dl
– Coronary revascularization procedures

Colhoun HM et al. Lancet. 2004;364:685-696.

CARDS: Collaborative Atorvastatin Diabetes Study
 CARDS: Atorvastatin reduces CV events by
37%
15
Atorvastatin 10 mg (n=1428)
Placebo (n=1410)
of events (% of patients)
Cumulative incidence

127 events
10 median follow-up 3.9 years

83 events

RRR=37% p=0.001
0
0 1 2 3 4 5 6

Time (years)

*Acute CHD event, coronary revascularization, stroke. Colhoun HM et al. Lancet. 2004;364:685-696.
RRR: Relative risk reduction
 CARDS: Atorvastatin Reduces Stroke by
48% in T2DM
6 Atorvastatin 10 mg (n=1428)
Placebo (n=1410)
5
Median follow-up 3.9 years
of events (% of patients)
Cumulative incidence

4
RRR= 48% (95% CI: 31%-89%) 39 events
3 P=0.016

2 21 events

0
0 1 2 3 4 5 6

Time (years)
Stroke was a component of the primary endpoint,
evaluated individually as a secondary survival
analysis. Newman C et al. American Heart Association 78th Scientific Sessions, 2005.
AHA and ADA guidelines for statin therapy in
T2DM for primary prevention are based on
Atorvastatin’s CARDS trial
Atorvastatin for Primary Prevention in High
risk patients: ASCOT-LLA

A double-blind, placebo-controlled trial of atorvastatin 10 mg Vs

Placebo in 10305 hypertensive patients studied
Median follow up: 3.3 years
Study end points
Primary: Combined nonfatal MI (including silent MI) and fatal CHD
Secondary: Fatal and nonfatal stroke
Total cardiovascular events and procedures
Total coronary events
 ASCOT-LLA

Primary Endpoint: Secondary Endpoint:

Nonfatal MI and Fatal CHD Fatal and Nonfatal Stroke
4 3
36% 27%
Cumulative Incidence (%)

3 reduction reduction

Cumulative Incidence (%)

2

1
1
HR = 0.64 (0.50-0.83) HR = 0.73 (0.56-0.96)
P = .0005 P = .0236

0 0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years Years

Atorvastatin 10 mg Number of events 100 Atorvastatin 10 mg Number of events 89

Placebo Number of events 154 Placebo Number of events 121

Sever PS, et al. Lancet. 2003;361:1149-1158.

 ASCOT-LLA: Primary prevention– DM Sub-
analysis (yellow cells)
19,342 patients

Randomized

-blocker ± diuretic CCB ± ACE inhibitor

TC >250 mg/dL 2532 TC 250 mg/dL TC >250 mg/dL

(>6.5 mmol/L) (6.5 mmol/L) (>6.5 mmol/L)

Randomized
1258 1274
Open lipid lowering Open lipid lowering
Atorvastatin 10 mg Placebo

Primary end point: Composite of fatal CHD and nonfatal MI

Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm.

ASCOT: LLA: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
Sever PS et al. J Hypertens. 2001;19:1139-1147. CCB: Calcium Channel Blocker
ACE: Angiotension Convertase Inhibitor TC: Total Cholesterol
ASCOT-LLA :23% RRR for total CV events in DM
patients with atorvastatin

15 Atorvastatin 10 mg
Placebo 151 events
of events (% of patients)

116 events
Cumulative incidence

10

median follow-up 3.3 years

RRR=23%
P=0.036
0
0 1 2 3 4 5 6
Time (years)
Sever PS et al. Diabetes Care. 2005;28:1151-1157.
 Statin in CKD patients

Alterations in Lipid Profiles in CKD

Triglycerides
Normal or low LDL

Normal or low TC
HDL
VLDL remnants

Lipoprotein (a)

Clin J Am Soc Nephrol 2007; 2(4):766-85.

 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 in DM+ CKD
PLANET I study
• Patients: 325 DM nephropathy patients urinary protein/creatinine ratios
(UPCR): 500-5000 mg/g, LDL >90 mg/dL, and on ACEIs/ARBs for > 3
months.
• Patients divided in 3 groups: Rosuvastatin 10 mg, Rosuvastatin 40 mg and
Atorvastatin 80 mg for duration of 52 weeks
• Baseline eGFR: 69-72 ml/min Baseline UPCR: 1160-1260 mg/g
• The primary end point: Change in urinary protein/ creatinine ratio
from baseline to week 52

The Lancet Diabetes & Endocrinology 2015;3(3):181-90

 PLANET I: % Change in UPCR and eGFR
p=0.83
4
0
2
2 Change in eGFR
-1
0
UPCR Change (%) -2 -1.61
-2
-3
-4
-4
-6 -4 -3.7
p=0.53

-8 -5
Atorvastatin 80 mg

-10 Rosuvastatin 10 mg
-6
Atorvastatin 80 mg Rosuvastatin 40 mg

Conclusion:
-12 Atorvastatin
Rosuvastatin 10seems
mg -7to have more renoprotective
effects for
-14 -13the studied chronic
Rosuvastatin 40 mg kidney disease population.
-7.29
-8
p=0.033

The Lancet Diabetes & Endocrinology 2015;3(3):181-90

 Atorvastatin vs Rosuvastatin for
renal function PLANET I:

Rosuvastatin Rosuvastatin Atorvastatin

10 mg/day 40 mg/day 80 mg/day
Adverse event (n = 116) (n = 123) (n = 110) p
Any renal 7.8 9.8 4.5 NS
adverse event

Acute renal failure 0.0 4.1 0.9 <0.05

Serum creatinine 0.0 4.9 0.0 <0.01

doubling
Serum creatinine 0.0 7.3 0.9 <0.01
doubling or acute
renal failure

de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27,
2010; Munich, Germany.
Atorvastatin Vs Rosuvastatin For Proteinuria: A
Meta-analysis

• A meta-analysis of 5 clinical trials head to

head comparing atorvastatin vs rosuvastatin

Circ J 2012;76:1259-66
Atorvastatin is safer than Rosuvastatin in DM
patients with proteinuria

Atorvastatin is better than Rosuvastatin for

reduction in proteinuria
 2013 KDIGO Guidelines for dyslipidemia
management in CKD
• In adults aged > 50 years with eGFR< 60 ml/min/1.73
m2 but not treated with chronic dialysis or kidney
transplantation (GFR categories G3a-G5), we
recommend treatment with a statin or
statin/ezetimibe combination. (1A)
• In adults aged > 50 years with CKD and eGFR> 60
ml/min/1.73m2 (GFR categories G1-G2) we
recommend treatment with a statin. (1B)
 Can we consider rosuvastatin for primary
prevention in DM/CKD based on JUPITER?

MI
Rosuvastatin 20 mg (N=8901)
No Prior Stroke
Unstable
CVD/CKD/DM Angina
Men >50, Women >60 4-week Placebo (N=8901)
CVD Death
LDL <130 mg/dL run-in CABG/PTCA
hsCRP >2 mg/L Follow up: 1.9 yrs

Patients with DM and CKD were excluded from

JUPITER, So there is no evidence for primary CV
prevention with rosuvastatin in DM/CKD!!!

Ridker PM et al, Circulation 2003;108:2292-2297

 Statin for secondary prevention
• Current guidelines recommend moderate to high dose of
statins for secondary prevention.
• Atorvastatin has multiple landmark trials for secondary
prevention
 580 pts excluded for: High dose Atorvastatin in ACS
- 451 statin therapy
- 41 emergency angiography
- 43 LVEF <30%
ARMYDA-ACS trial
- 30 contraindications to statins
- 15 severe renal failure 20 pts excluded for indication to:
- medical therapy (N=8)
- bypass surgery (N=12)

30 days
Atorvastatin 80 mg
12 hrs pre-angio;
further 40 mg
Randomization (N=191)

PCI
771 pts with 2 hrs before Primary end
atorvastatin
N=96 N=86 point:
NSTE-ACS atorvast
sent to Coronary 30-day
early coronary angiography death, MI,
angiography PCI TVR
Placebo placebo
(<48 hours) 12 hrs pre-angio; N=85
further
dose 2 hrs
before
N=95
1st blood sample 2nd and 3rd
blood samples
(pre-PCI)
(8 and 24 hrs
post-PCI)

CK-MB, troponin-I, myoglobin, CRP

 ARMYDA-ACS: Secondary end point
Post-PCI percent increase of CRP levels from baseline

147
P=0.01
%

63

JACC 2007:49:1272-78
 ARMYDA-ACS trial
Composite primary end-point (30-day death, MI, TVR)

% 17

P=0.01

JACC 2007:49:1272-78
 Loading atorvastatin in patients already
on statin ARMYDA-RECAPTURE

• 383 patients with stable angina (53%) or NST-ACS (47%)

and on chronic statin therapy (55% atorvastatin)
undergoing PCI were randomized to atorvastatin reload
(80 mg 12 h before intervention, 40-mg pre-procedural
dose or placebo (n=191).
• All patients received long-term atorvastatin treatment
thereafter (40 mg/day).
• The primary end point was 30-day incidence of major
adverse cardiac events (cardiac death, myocardial
infarction, or unplanned revascularization).

J. Am. Coll. Cardiol. 2009;54;558-565

 ARMYDA-RECAPTURE:
PRIMARY ENDPOINT

9.1
12

9 P=0.045
Loading of Atorvastatin high dose before
PCI
6
can reduce
3.4 the CV events
3

Atorvastatin Placebo

J. Am. Coll. Cardiol. 2009;54;558-565

 Atorvastatin for stable CAD
TNT Trial
10,003 patients with stable coronary heart disease
Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL
19% female, mean age 60.3 years
All received atorvastatin 10 mg during 8 week open-label run-in period

Atorvastatin 80 mg Atorvastatin 10 mg
n=4,995 n=5,006

Primary Endpoint: Major cardiovascular event defined as coronary

heart death (CHD), nonfatal M, resuscitated cardiac arrest, and fatal or
nonfatal stroke at a mean follow-up of 4.9 years.

Presented at ACC 2005

TNT Trial: Primary endpoint
Hazard Ratio [HR]=0.78
p<0.001

Presented at ACC 2005

 Atorvastatin in ACS: PROVE IT - TIMI 22

4,162 patients with an Acute Coronary Syndrome < 10 days

ASA + Standard Medical Therapy

Double-blind
“Standard Therapy” “Intensive Therapy”
Pravastatin 40 mg Atorvastatin 80 mg

2x2 Factorial: Gatifloxacin vs. placebo

Duration: Mean 2 year follow-up (>925 events)

Primary Endpoint: Death, MI, Documented UA requiring hospitalization,

revascularization (> 30 days after randomization), or Stroke
 CV events in PROVE IT study
Death/MI/Urg. Revascu. Death/MACE

↓33%
↓16%

Intensive statin therapy provides more benefits than

low/moderate Intensity statin
Cannon et al. NEJM 2004 Ray et al. Am J Cardiol 2006
 Take Home Message

• CV protection with statin is not completely dependent on

lipid lowering.
• Though rosuvastatin is slightly more effective than
atorvastatin for lipid lowering, Atorvastatin has stronger
evidence for CV protection
• Atorvastatin is approved in both primary and secondary
prevention, while rosuvastatin is approved only in
primary prevention in patients with hsCRP > 2 mg/L
WITHOUT DM/CKD