Henry C. Ginsberg, MD
College of Physicians & Surgeons , Columbia University, New York
For The ACCORD Study Group
Dr. Ginsberg reports receiving
◦ Consulting fees from Merck, Merck Schering Plough,
Bristol-Myers Squibb, AstraZeneca, Abbott, Roche,
Isis/Genzyme, GlaxoSmithKline, Novartis, Pfizer, and
Regeneron/ SanofiAventis.
◦ Grant support from Merck, ISIS/Genzyme, Roche, and
AstraZeneca.
ACCORD Study Design
• Designed to independently test three medical strategies to reduce
cardiovascular disease in diabetic patients
• Lipid Trial question: whether combination therapy with a
statin plus a fibrate would reduce cardiovascular disease
compared to statin monotherapy in people with type 2
diabetes mellitus at high risk for cardiovascular disease.
• Randomized, placebo-controlled, double-blind clinical trial
conducted in 77 clinical sites in the U.S. and Canada
ACCORD Study Design
• Overall ACCORD Glycemia Trial: 10,251 participants
• Lipid Trial: 5,518 in Lipid Trial
• 2765 randomized to fenofibrate
• 2753 randomized to placebo
• Primary Outcome: First occurrence of a major cardiovascular event
(nonfatal MI, nonfatal stroke, cardiovascular death)
• 87% power to detect a 20% reduction in event rate, assuming
placebo rate of 2.4%/yr and 5.6 yrs follow-up in participants
without events.
ACCORD Lipid Trial Eligibility
• Stable Type 2 Diabetes >3 months
• HbA1c 7.5% to 11%
• High risk of CVD events = clinical or subclinical disease or
2+ risk factors
• Age (limited to <80 years after Vanguard)
•
•
≥ 40 yrs with history of clinical CVD (secondary prevention)
≥ 55 yrs otherwise
• Lipids
•
•
•
60 < LDL-C < 180 mg/dl
HDL-C < 55 mg/dl for women/Blacks; < 50 mg/dl otherwise
Triglycerides < 750 mg/dl if on no therapy; < 400 mg/dl otherwise
• No contraindication to either fenofibrate or simvastatin

All participants on open-labeled simvastatin, 20 to 40 mg/day
◦ Simvastatin dose complied with lipid guidelines

Patients randomized to double-blind placebo or fenofibrate, 54 to
160mg/day
◦ Dosing based upon eGFR level

Only blinded ACCORD trial

Observed Follow-up: 4 to 8 years (mean 4.7 years)
Characteristic
Mean or %
Characteristic
Mean or %
Age (yrs)
62
Total Cholesterol (mg/dl)
175
Women %
31
LDL-C (mg/dl)
101
HDL-C (mg/dl)
38
162
Race / Ethnicity
White %
68
Triglyceride (mg/dl)*
Black %
15
Blood pressure (mm Hg)
134/74
Hispanic %
7
Serum creatinine (mg/dl)
0.9
Secondary prevent %
37
Current smoking %
15
DM duration (yrs)*
9
On a statin %
60
A1c (%) *
8.3
On another LLA %
8
BMI (kg/m2)
32
On Insulin %
33
*
Median values
Mean LDL-C
200
120
190
110
180
100
Feno
170
Placebo
mg/dl
mg/dl
Mean Total Cholesterol
160
80
150
70
140
0
N = 5483
1
5180
2
3
4
5
6
7
4988
4783
5250
3377
1668
491
Feno
90
Placebo
60
Years PostRandomization
0
1
N = 5483
5180
3
4
5
6
4988
4783
5250
3377
1668
7
Years PostRandomization
491
Median Triglycerides
42
170
41
160
150
40
Feno
Placebo
39
mg/dl
mg/dl
Mean HDL-C
2
Feno
140
Placebo
130
38
120
37
0
N = 5483
1
5180
2
3
4
5
6
4988
4783
5250
3377
1668
7
491
Years PostRandomization
110
0
N = 5432
1
2
3
4
5180
4988
4783
5250
5
3377
6
7
1668
491
Years PostRandomization
Adverse Experiences During Follow-up
Adverse events (no. (%))
Fenofibrate
(N=2765)
Placebo
(N=2753)
P value
Out of the ordinary severe muscle
aches/pains:
regardless of CK
plus CK > 5 X ULN
plus CK > 10 X ULN
1110 (40.1%) 1115 (40.5%)
7 (0.3%)
8 (0.3%)
1 (0.04%)
2 (0.07%)
0.81
0.79
0.56
Any nonhypoglycemic SAE
54 (2.0%)
43 (1.6%)
0.27
Any Myopathy/Myositis/
Rhabdomyolysis SAE
4 (0.1%)
4 (0.1%)
1.00
Any Hepatitis SAE
3 (0.1%)
0 (0.0%)
0.18
Any SAE attributed to lipid meds
27 (1.0%)
19 (0.7%)
0.24
Lab Measures During Follow-up
Fenofibrate
(N=2765)
Placebo
(N=2753)
P value
ALT ever > 3X ULN
52 (1.9%)
40 (1.5%)
0.21
ALT ever > 5X ULN
16 (0.6%)
6 (0.2%)
0.03
CK ever > 5X ULN
51 (1.9%)
59 (2.2%)
0.43
CK ever > 10X ULN
10 (0.4%)
9 (0.3%)
0.83
Laboratory Measures (no. (%))
Lab Measures During Follow-up
Fenofibrate
(N=2765)
Placebo
(N=2753)
P value
ALT ever > 3X ULN
52 (1.9%)
40 (1.5%)
0.21
ALT ever > 5X ULN
16 (0.6%)
6 (0.2%)
0.03
CK ever > 5X ULN
51 (1.9%)
59 (2.2%)
0.43
CK ever > 10X ULN
10 (0.4%)
9 (0.3%)
0.83
235 (27.9%)
698 (36.7%)
157 (18.7%)
350 (18.5%)
<0.001
<0.001
Laboratory Measures (no. (%))
Serum creatinine elevation
Post-randomization incidence of
microalbuminuria ( > 30 to < 300 mg/g*)
1050 (38.2%) 1137 (41.6%)
0.01
Post-randomization incidence of
macroalbuminuria ( > 300 mg/g*)
289 (10.5%)
0.03
337 (12.3%)
Primary Outcome
Placebo
(N=2753)
Rate
N of
(%/yr)
Events
Primary Outcome:
Major Fatal or Nonfatal
Cardiovascular Event
310
2.41
Primary Outcome
Fenofibrate
(N=2765)
Rate
N of
(%/yr)
Events
Primary Outcome:
Major Fatal or Nonfatal
Cardiovascular Event
291
2.24
Placebo
(N=2753)
Rate
N of
(%/yr)
Events
310
2.41
Primary Outcome
Fenofibrate
(N=2765)
Rate
N of
(%/yr)
Events
Primary Outcome:
Major Fatal or Nonfatal
Cardiovascular Event
291
2.24
Placebo
(N=2753)
Rate
N of
(%/yr)
Events
310
2.41
HR (95% CI)
P Value
0.92
0.32
(0.79 - 1.08)
Prespecified Secondary Outcomes
Fenofibrate
(N=2765)
N of
Rate
Events
(%/yr)
Placebo
(N=2753)
N of
Rate
Events
(%/yr)
HR (95% CI)
P Value
Outcome
Primary + Revasc +
hospitalized CHF
641
5.35
667
5.64
0.94 (0.85-1.05)
0.30
Major Coronary Event
332
2.58
353
2.79
0.92 (0.79-1.07)
0.26
Nonfatal MI
173
1.32
186
1.44
0.91 (0.74 - 1.12)
0.39
Total Stroke
51
0.38
48
0.36
1.05 (0.71 - 1.56)
0.80
Nonfatal Stroke
47
0.35
40
0.30
1.17 (0.76 - 1.78)
0.48
Total Mortality
203
1.47
221
1.61
0.91 (0.75 - 1.10)
0.33
Cardiovascular Death
99
0.72
114
0.83
0.86 (0.66 - 1.12)
0.26
Fatal/Nonfatal CHF
120
0.90
143
1.09
0.82 (0.65 - 1.05)
0.10
Primary Outcome By Treatment Group and Baseline Subgroups
Primary Outcome By Treatment Group and Baseline Subgroups
Trial
(Drug)
HHS
(Gemfibrozil)
BIP
(Bezafibrate)
FIELD
(Fenofibrate)
ACCORD
(Fenofibrate)
Primary Endpoint:
Entire Cohort
(P-value)
-34% (0.02)
Lipid Subgroup
Criterion
TG > 200 mg/dl
LDL-C/HDL-C
> 5.0
Primary
Endpoint:
Subgroup
-71%
TG > 200 mg/dl
-7.3% (0.24)
-11%
-8%
(0.16)
(0.32)
-39.5%
TG > 204 mg/dl
HDL-C < 42
mg/dl
-27%
TG > 204 mg/dl
HDL-C < 34
mg/dl
-31%
Conclusion (1)
• ACCORD Lipid does not support use of the
combination of fenofibrate and simvastatin
compared to simvastatin alone to reduce CVD events
in the majority of patients with T2DM who have HDLC and TG levels that are close to the normal range
Conclusion (2)
• Subgroup analyses suggesting heterogeneity in
response to combination therapy by gender and by
the presence of significant dyslipidemia require
further investigation