This document discusses the benefits of statin drugs beyond their lipid-lowering effects. It summarizes several key studies that show statins reduce cardiovascular events in patients with diabetes or chronic kidney disease, even when baseline lipid levels are normal. The document highlights that atorvastatin and simvastatin have evidence from primary prevention trials of reducing cardiovascular outcomes in diabetes, whereas other statins do not. It also notes that atorvastatin seems to have greater renoprotective effects compared to rosuvastatin in diabetes patients with kidney disease and proteinuria.
Atorvastatin: Statins in CVD management. Is just lipid lowering enough
1. Statins in CVD management : Is just
lipid lowering enough?
Dr Vivek Baliga
Consultant Internal Medicine
Director, HeartSenseTM
www.heartsense.in
2. 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
3. Primary Prevention of CVD
• As per AHA 2013, guidelines all T2DM patients of age 40-75
require either moderate or high dose statin therapy
4. 2016 ADA guidelines for statins in DM
Diabetes Care 2016;39(supple 1): S1-S112
5. 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?
6. MI Risk in Diabetics Without Prior MI Equivalent to
Nondiabetic With MI
Haffner SM et al. N Engl J Med. 1998;339:229-234.
Numbers in bars represent number of persons in category at baseline.
Finnish population study (7-year follow-up)
3.5
20.218.8
45
0
10
20
30
40
50
60
Patients without diabetes Patients with diabetes
Incidenceoffatal/nonfatalMI
during7-yearfollow-up(%)
No prior MI
Prior MI
P<0.001
P<0.001
P<0.001 for diabetes vs no diabetes
8901304
69 169
8. RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12
85.5%
Dyslipidemia
97.8 %
Dyslipidemia
85.5 %
Prevalence of Dyslipidemia (%) in
Male T2 DM
Prevalence of Dyslipidemia (%)
in Female T2DM
In India, 90% diabetics have dyslipidemia
9. Study Patients Follow up Results
ASCOT LLA * 2532 Atorvastatin 10
mg
3.3 yrs 23% risk reduction
CARDS 2838 Atorvastatin 10
mg
3.9 yrs 37% risk reduction
HPS * 2912 Simvastatin 40
mg
5 yrs 33% risk reduction
Major Statin Primary Prevention Trials In
DM
* sub-analysis
Only Atorvastatin and Simvastatin have evidence
that statin reduce CV events in Primary prevention.
OTHERS DO NOT HAVE SUCH EVIDENCE!
10. 4-year follow-up
CARDS: primary prevention in T2DM
Atorvastatin 10 mg/day
(n=1428)
Placebo
(n=1410)
2838 patients
Primary end point:
Incidence of major cardiovascular events:
– Cardiovascular-related death
– Nonfatal MI
– Stroke
– Resuscitated cardiac arrest
– Unstable angina
– Coronary revascularization procedures
Patient population:
Age: 40-75 years
LDL-C 160 mg/dL
Triglycerides 600 mg/dL
Type 2 diabetes
No prior MI or CHD
1+ CHD risk factor
C o l h o u n H M e t a l . L a n c e t . 2 0 0 4 ; 3 6 4 : 6 8 5 - 6 9 6 .
CARDS: Collaborative Atorvastatin Diabetes Study
At Baseline,
LDL-C: 120 mg/dl
HDL-C: 54.5 mg/dl
Non-HDL-C: 153 mg/dl
12. 0
1
2
3
4
5
6
0 1 2 3 4 5 6
CARDS: Atorvastatin Reduces Stroke by
48% in T2DM
Newman C et al. American Heart Association 78th Scientific Sessions, 2005.
RRR= 48% (95% CI: 31%-89%)
P=0.016
Cumulativeincidence
ofevents(%ofpatients)
39 events
21 events
Time (years)
Atorvastatin 10 mg (n=1428)
Placebo (n=1410)
Median follow-up 3.9 years
Stroke was a component of the primary endpoint,
evaluated individually as a secondary survival
analysis.
13. AHA and ADA guidelines for statin therapy in
T2DM for primary prevention are based on
Atorvastatin’s CARDS trial
14. 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
15. Atorvastatin 10 mg Number of events 89
Placebo Number of events 121
0
1
2
3
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
CumulativeIncidence(%)
HR = 0.73 (0.56-0.96)
P = .0236
27%
reduction
ASCOT-LLA
Primary Endpoint:
Nonfatal MI and Fatal CHD
Secondary Endpoint:
Fatal and Nonfatal Stroke
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
CumulativeIncidence(%)
Atorvastatin 10 mg Number of events 100
Placebo Number of events 154
36%
reduction
HR = 0.64 (0.50-0.83)
P = .0005
Sever PS, et al. Lancet. 2003;361:1149-1158.
16. ASCOT-LLA: Primary prevention– DM Sub-
analysis (yellow cells)
Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm.
-blocker ± diuretic CCB ± ACE inhibitor
TC >250 mg/dL
(>6.5 mmol/L)
2532 TC 250 mg/dL
(6.5 mmol/L)
TC >250 mg/dL
(>6.5 mmol/L)
Open lipid lowering
1258
Atorvastatin 10 mg
1274
Placebo
Open lipid lowering
19,342 patients
Randomized
Randomized
Primary end point: Composite of fatal CHD and nonfatal MI
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
17. ASCOT-LLA :23% RRR for total CV events in DM
patients with atorvastatin
Sever PS et al. Diabetes Care. 2005;28:1151-1157.
0
5
10
15
0 1 2 3 4 5 6
RRR=23%
P=0.036
151 events
116 events
median follow-up 3.3 years
Cumulativeincidence
ofevents(%ofpatients)
Time (years)
Atorvastatin 10 mg
Placebo
18. Statin in CKD patients
Alterations in Lipid Profiles in CKD
Clin J Am Soc Nephrol 2007; 2(4):766-85.
Triglycerides
HDL
Lipoprotein (a)
Normal or low LDL
Normal or low TC
VLDL remnants
19. 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
20. • 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
Atorvastatin vs Rosuvastatin in DM+ CKD
PLANET I study
The Lancet Diabetes & Endocrinology 2015;3(3):181-90
21. PLANET I: % Change in UPCR and eGFR
-13
2
-4
-14
-12
-10
-8
-6
-4
-2
0
2
4
UPCR Change (%)
Atorvastatin 80 mg
Rosuvastatin 10 mg
Rosuvastatin 40 mg
p=0.033
p=0.83
p=0.53
The Lancet Diabetes & Endocrinology 2015;3(3):181-90
-1.61
-3.7
-7.29
-8
-7
-6
-5
-4
-3
-2
-1
0
Change in eGFR
Atorvastatin 80 mg
Rosuvastatin 10 mg
Rosuvastatin 40 mg
Conclusion: Atorvastatin seems to have more renoprotective
effects for the studied chronic kidney disease population.
22. de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27,
2010; Munich, Germany.
Atorvastatin vs Rosuvastatin for
renal function PLANET I:
Adverse event
Rosuvastatin
10 mg/day
(n = 116)
Rosuvastatin
40 mg/day
(n = 123)
Atorvastatin
80 mg/day
(n = 110) p
Any renal
adverse event
7.8 9.8 4.5 NS
Acute renal failure 0.0 4.1 0.9 <0.05
Serum creatinine
doubling
0.0 4.9 0.0 <0.01
Serum creatinine
doubling or acute
renal failure
0.0 7.3 0.9 <0.01
23. • A meta-analysis of 5 clinical trials head to
head comparing atorvastatin vs rosuvastatin
Atorvastatin Vs Rosuvastatin For Proteinuria: A
Meta-analysis
Circ J 2012;76:1259-66
24. Atorvastatin is safer than Rosuvastatin in DM
patients with proteinuria
Atorvastatin is better than Rosuvastatin for
reduction in proteinuria
25. 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)
26. Rosuvastatin 20 mg (N=8901) MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
4-week
run-in
Ridker PM et al, Circulation 2003;108:2292-2297
No Prior
CVD/CKD/DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
Placebo (N=8901)
Follow up: 1.9 yrs
Can we consider rosuvastatin for primary
prevention in DM/CKD based on JUPITER?
Patients with DM and CKD were excluded from
JUPITER, So there is no evidence for primary CV
prevention with rosuvastatin in DM/CKD!!!
27. Statin for secondary prevention
• Current guidelines recommend moderate to high dose of
statins for secondary prevention.
• Atorvastatin has multiple landmark trials for secondary
prevention
28. 771 pts with
NSTE-ACS
sent to
early coronary
angiography
(<48 hours)
Randomization(N=191)
Atorvastatin 80 mg
12 hrs pre-angio;
further 40 mg
2 hrs before
N=96
Coronary
angiography
Placebo
12 hrs pre-angio;
further
dose 2 hrs
before
N=95
Primary end
point:
30-day
death, MI,
TVR
1st blood sample
(pre-PCI)
CK-MB, troponin-I, myoglobin, CRP
High dose Atorvastatin in ACS
ARMYDA-ACS trial
2nd and 3rd
blood samples
(8 and 24 hrs
post-PCI)
30 days
580 pts excluded for:
- 451 statin therapy
- 41 emergency angiography
- 43 LVEF <30%
- 30 contraindications to statins
- 15 severe renal failure
PCI
atorvastatin
N=86
PCI
placebo
N=85
20 pts excluded for indication to:
- medical therapy (N=8)
- bypass surgery (N=12)
atorvast
29. ARMYDA-ACS: Secondary end point
Post-PCI percent increase of CRP levels from baseline
%
63
147
P=0.01
JACC 2007:49:1272-78
31. • 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).
Loading atorvastatin in patients already
on statin ARMYDA-RECAPTURE
J. Am. Coll. Cardiol. 2009;54;558-565
33. Atorvastatin 80 mg
n=4,995
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.
Atorvastatin for stable CAD
TNT Trial
Presented at ACC 2005
Atorvastatin 10 mg
n=5,006
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
34. TNT Trial: Primary endpoint
Hazard Ratio [HR]=0.78
p<0.001
Presented at ACC 2005
35. 4,162 patients with an Acute Coronary Syndrome < 10 days
ASA + Standard Medical Therapy
“Standard Therapy”
Pravastatin 40 mg
“Intensive Therapy”
Atorvastatin 80 mg
Duration: Mean 2 year follow-up (>925 events)
Atorvastatin in ACS: PROVE IT - TIMI 22
2x2 Factorial: Gatifloxacin vs. placebo
Double-blind
Primary Endpoint: Death, MI, Documented UA requiring hospitalization,
revascularization (> 30 days after randomization), or Stroke
36. 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 therapy provides more benefits than
low/moderate Intensity statin
37. 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
