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Can Fibrates Improve
CVD Reduction
with Statins? Yes!
PLA/SWLA Chapter Meeting
Grand Wailea Resort, Maui, HI
March 16, 2014
Eliot A. Brinton, MD, FAHA, FNLA
President, American Board of Clinical Lipidology
Director, Atherometabolic Research
Utah Foundation for Biomedical Research
President, Utah Lipid Center
Salt Lake City
[email protected]
Speaker Disclosures
Dr. Brinton has received:
• Research funding: Amarin, Health Diagnostic
Laboratory, Merck, Roche; Aurora Foundation;
NIH
• Honoraria as consultant/advisor: Aegerion,
Amarin, Arisaph, AstraZeneca, Atherotech,
Daiichi-Sankyo, Essentialis, Genzyme,
Janssen, Kowa, Merck, Novartis, Regeneron,
Sanofi-Aventis, Takeda
• Honoraria as speaker: Amarin, Daiichi-Sankyo,
Janssen, Kowa, Merck, Takeda
Talk Outline
• CVD risk residual w/ statin monoRx
– Scope, predictors and mediators of risk
• TG vs Atherosclerosis and CVD Events
– Meta analyses
– Causation (genetic and biologic evidence)
• Fibrates vs Atherosclerosis and CVD
– Fibrate monotherapy
– Fibrates as statin adjuncts
– Meta-analyses
• Fibrates vs Microvascular Disease in
DM2
Statins do NOT Prevent All CHD Events
(Residual Risk ~50-70%)
40
Patients Experiencing
Major CHD Events, %
CHD events occur frequently in patients taking statins
30
20
28.0
Placebo
Statin
19.4
15.9
12.3
13.2
10
0
N
10.2
4S1
LIPID2
CARE3
4444
9014
4159
Secondary
14S
Group. Lancet. 1994;344:1383-9.
2LIPID Study Group. N Engl J Med. 1998;339:1349-57.
3Sacks FM et al. N Engl J Med. 1996;335:1001-9.
11.8
8.7
HPS4
20,536
High Risk
4HPS
7.9
10.9
6.8
5.5
WOSCOPS5 AFCAPS/ 6
TexCAPS
6595
6605
Primary
Collaborative Group. Lancet. 2002;360:7-22.
J et al. N Engl J Med. 1995;333:1301-7.
6 Downs JR et al. JAMA. 1998;279:1615-22.
5Shepherd
What are Key Predictors
(and Possible Mediators) of
Residual CVD Risk
during Statin MonoRx?
TG Levels Predict CHD Risk
(Meta-analysis of 29 Studies, N=262,525*)
Groups
CHD Cases
Duration of Follow-up
≥10 years
5902
<10 years
4256
Sex
Male
Female
7728
1994
Fasting Status
Fasting
Nonfasting
7484
2674
Adjusted for HDL-C
Yes
No
4469
5689
CHD Risk Ratio* (95% CI)
1.72 (95% CI, 1.56-1.90)
Overall CHD Risk Ratio*
Decreased
Risk
1
Increased
Risk
2
*3rd vs 1st tertile, adjusted for at least age, sex, smoking, other lipids & BP.
Sarwar N et al. Circulation. 2007;115:450-8.
22% ↑CVD/ 88 mg/dL ↑TG (61 studies N=330,566).
Liu, J. Lipids in Health and Disease 2013, 12:159.
↑Residual CHD Risk in HTG
Despite LDL-C <70 w/ Statin Rx
Increased death, MI, or
recurrent ACS (% at 30d)
(67%↑ coronary events* if TG ≥200 mg/dL
despite LDL-C <70 mg/dL with a high-dose statin)
25
20
15
+67%
20.3%
†
P=0.001
13.2%
10
5
0
≥200 mg/dL
(n=603)
<200 mg/dL
(n=2796)
*Death, myocardial infarction, or recurrent acute coronary syndrome
†From adjusted hazard ratio of TG <200 mg/dL (95% CI) = 0.60 (0.45-0.81)
Miller M et al. J Am Coll Cardiol. 2008;51:724-30.
HTG As a Cause of
Atherosclerosis & CVD
Biological mechanisms (selected)
• TGRLp Remnants → senescence of endothelial
precursors 1
• ppTG →↑endothelial microparticles,2
inflammatory cytokines,3 apoptosis4
• TG lipolysis → FFA → ↑endothelial cell
inflammation5
• Apo C-III → vascular endothelial activation &
monocyte adhesion6
• Apo C-III deficiency →↓athero & ↑longevity7
1.
2.
3.
4.
5.
6.
7.
Liu L, Atherosclerosis. 2009;202:405– 414.
Ferreira AC. Circulation. 2004;110: 3599–3603.
Norata GD. Atherosclerosis. 2007;193:321–327.
Shin HK. Circulation. 2004;109:1022–1028.
Wang L. J Lipid Res. 2009;50:204–213.
Zheng C. Eur Heart J 2013;34:615-24.
Pollin TI. Science 2008;322:1702–1705.
HTG As a Cause of
Atherosclerosis & CVD (cont.)
Genetic Evidence
• Mendelian randomization studies strongly
suggest HTG causes CVD1-3
Conclusion: “In mild-to moderate [HTG],
intervention can be indicated to prevent
cardiovascular disease, dependent on
triglyceride concentration, concomitant
lipoprotein disturbances, and overall
cardiovascular risk.”2
1.
2.
3.
Do R. Nature Genetics 2013, e-pub 6 October.
Hegele RA. Lancet, 2013 epub 23 December.
Holmes MV Eur HJ 2014, epub 27 January.
Fibrates Favorably Modify
Essentially All the
HTG-Related MoA for
Atherosclerosis & CVD
Fenofibrate Reduces
Macrovascular Disease
Fibrates Decrease Major CV Outcomes
Jun, M, et al. Lancet 2010;375;1875-84.
Fibrates Reduce Coronary Events (not Stroke or Death)
Jun, M, et al. Lancet 2010;375;1875-84.
Fibrates
Reduce
Coronary
Events
Across Pt
Subgroups
(greater benefit
w/ TG >176)
Jun, M, et al. Lancet
2010;375;1875-84.
ACCORD-Lipid 1o Outcome
by Baseline Subgroups
1st tert.TG + 3rd Tert HDL-C,
Feno → 28% ↓ CVD,
pi = 0 057; NNT = 20
ACCORD-Lipid 1o Outcome
by Baseline Subgroups
1st tert.TG + 3rd Tert HDL-C,
Feno → 28% ↓ CVD,
pi = 0 057; NNT = 20
W
hi
fl k ?
Fibrates Reduce CHD Risk by 35% in Patients with High TG and Low HDL‐C A meta‐analysis of randomized fibrate trials
A Subjects with Dyslipidemia
BB Complementary
Subjects Subgroups
without
Dyslipidemia
Without Dyslipidemia
Similar pattern w/ and w/o background statin Rx—
ACCORD vs others
“With Dyslipidemia” = HTG (~≥204 mg/dL) and low HDL-C (~≤34mg/dL)
Sacks FM et al. N Engl J Med. 2010;363:692-4.
ACCORD-LIPID: TG >204 & HDL-C <34
Major Fatal or Non-Fatal
CV Events, %
(vs. Rest of Cohort)
Entire fenofibrate benefit was
in HTG/Low HDL patients!
28.6%
RRR
P = 0.057
79
456
60
485
HTG (>204 mg/dL &
Low HDL-C (<34 mg/dL)
17.6% (n=941) of Entire Cohort
231
2284
229
2264
Rest of Cohort
82.4% (n=4548) of Entire Cohort
1o Outcome in Pre-specified Subgroup. ACCORD Study Group, 2010; 362:1563-1574
Fenofibrate Reduces
Microvascular Disease in
Diabetes Mellitus-2
Fibrates Decrease Diabetic
Microvascular Disease:
Retinopathy and Albuminuria
FIELD data.
Jun, M, et al. Lancet 2010;375;1875-84.
Fenofibrate Decreased Foot Amputations in DM2
Despite V. Good Background Glycemic Control
FIELD data. Rajamani, K, et al. Lancet 2009;373;1780-8
Patient Types in which to
Consider Fibrate Rx
• HTG/low HDL-C, and/or
• Insulin resistance, and/or
• Diabetes Mellitus
–
–
–
–
Retinopathy
Microalbuminuria
Foot amputation
Peripheral neuropathy?
Patient Types in which to
Consider Fibrate Rx
• HTG/low HDL-C, and/or
• Insulin resistance, and/or
• Diabetes Mellitus
–
–
–
–
Retinopathy
Microalbuminuria
Foot amputation
Peripheral neuropathy?
ASCVD
(Macrovascular
Disease)
Patient Types in which to
Consider Fibrate Rx
• HTG/low HDL-C, and/or
• Insulin resistance, and/or
• Diabetes Mellitus
–
–
–
–
Retinopathy
Microalbuminuria
Foot amputation
Peripheral neuropathy?
ASCVD
(Macrovascular
Disease)
Microvascular
Disease
Fenofibrate Clinical Dilemma:
Suggestive Data w/o Proof
• Concordant data: fibrate →↓CVD among
RCTs in HTG/low HDL-C patients
(ACCORD-Lipid ≈ other fibrate trials), so
• We have reasonable evidence (albeit not
proof) that fenofibrate →↓CVD in pts with
DM-2 and HTG/low HDL-C (even w/
background statin Rx)
• VA-FIT will test this directly, but results are
many years away (not started yet)
• What to do in the meantime?
What level of proof is needed
for clinical practice?
Most providers use a given Rx when:
• Disease risk is moderate-high, and
• Drug risk/benefit is favorable, and
• Drug cost/benefit is favorable (cost to
patient vs system?)
Therefore:
• Preponderance of evidence is usu. enough
• Proof not needed, and unfortunately
• “Evidence-based medicine” (= requiring
proof) can block best care!—“don’t let the
perfect be the enemy of the good”
• Absence of proof ≠ proof of absence
As a HCP my job is to provide all
reasonably beneficial treatment.
If I withhold a treatment,
I am saying that there is
not reasonable evidence
it has net benefit!
(I look for preponderance of evidence
not proof!)
We should use a treatment
when its benefit likely exceeds
both its risk and cost
We should use a treatment
when its benefit likely exceeds
both its risk and cost
For me, the likelihood of ↓CVD
w/ fenofibrate added to a statin
is sufficient to warrant its use
in many patients with DM-2
and/or HTG/Low HDL-C
while we await definitive data!
Mahalo Nui Loa!

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