1. Effects of Combination Lipid Therapy on
Cardiovascular Events in Type 2 Diabetes
Mellitus: The Action to Control
Cardiovascular Risk in Diabetes
(ACCORD) Lipid Trial
Henry C. Ginsberg, MD
College of Physicians & Surgeons , Columbia University, New York
For The ACCORD Study Group
3/14/10

2. ◦ Consulting fees from Merck, Merck Schering Plough,
Bristol-Myers Squibb, AstraZeneca, Abbott, Roche,
Isis/Genzyme, GlaxoSmithKline, Novartis, Pfizer, and
Regeneron/ SanofiAventis.
Dr. Ginsberg reports Merck, ISIS/Genzyme, Roche, and
◦ Grant support from receiving
AstraZeneca.
◦
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.
3/14/10

3. 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
3/14/10

4. 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.
3/14/10

5. 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
• 3/14/10
No contraindication to either fenofibrate or simvastatin

6. ACCORD Lipid Protocol
 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)
3/14/10

7. Baseline Characteristics
Characteristic Mean or % Characteristic Mean or %
Age (yrs) 62 Total Cholesterol (mg/dl) 175
Women % 31 LDL-C (mg/dl) 101
Race / Ethnicity HDL-C (mg/dl) 38
White % 68 Triglyceride (mg/dl)* 162
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
3/14/10

8. Mean Total Cholesterol Mean LDL-C
200 120
190 110
180 100
Feno Feno
170 90
Placebo
m
Placebo
m
d
g
d
g
l
/
l
/
160 80
150 70
140 60 Years Post-
Years Post-
0 1 2 3 4 5 6 7 Randomization 0 1 2 3 4 5 6 7 Randomization
N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491
Mean HDL-C Median Triglycerides
42 170
41 160
150
40 Feno Feno
140
Placebo Placebo
m
m
39
d
g
d
g
l
/
l
/
130
38
120
37 Years Post- 110
Years Post-
0 1 2 3 4 5 6 7 Randomization 0 1 2 3 4 5 6 7 Randomization
N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5432 5180 4988 4783 5250 3377 1668 491
3/14/10

9. Adverse Experiences During Follow-up
Fenofibrate Placebo
Adverse events (no. (%)) (N=2765) (N=2753) P value
Out of the ordinary severe muscle
aches/pains:
regardless of CK 1110 (40.1%) 1115 (40.5%) 0.81
plus CK > 5 X ULN 7 (0.3%) 8 (0.3%) 0.79
plus CK > 10 X ULN 1 (0.04%) 2 (0.07%) 0.56
Any nonhypoglycemic SAE 54 (2.0%) 43 (1.6%) 0.27
Any Myopathy/Myositis/
4 (0.1%) 4 (0.1%) 1.00
Rhabdomyolysis SAE
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
3/14/10

10. Lab Measures During Follow-up
Fenofibrate Placeb
Laboratory Measures (no. (%)) (N=2765) o
(N=2753) P
value
ALT ever > 3X ULN 52 40 0.2
(1.9%) (1.5%) 1
ALT ever > 5X ULN 16 6 0.0
(0.6%) (0.2%) 3
CK ever > 5X ULN 51 59 0.4
(1.9%) (2.2%) 3
CK ever > 10X ULN 10 9 0.8
(0.4%) (0.3%) 3
3/14/10

11. Lab Measures During Follow-up
Fenofibrate Placeb
Laboratory Measures (no. (%)) (N=2765) o
(N=2753) P
value
ALT ever > 3X ULN 52 40 0.2
(1.9%) (1.5%) 1
ALT ever > 5X ULN 16 6 0.0
(0.6%) (0.2%) 3
CK ever > 5X ULN 51 59 0.4
(1.9%) (2.2%) 3
CK ever > 10X ULN 10 9 0.8
(0.4%) (0.3%) 3
Serum creatinine elevation
235 (27.9%) 157 (18.7%) <0.00
698 (36.7%) 350 (18.5%) 1
<0.00
1
Post-randomization incidence of
microalbuminuria ( > 30 to < 300 mg/g*) 1050 (38.2%) 1137 (41.6%) 0.0
1
Post-randomization incidence of
macroalbuminuria ( > 300 mg/g*) 289 (10.5%) 337 (12.3%) 0.0
3
3/14/10

12. Primary Outcome
Placeb
(N=275
o
N 3) Rat
of
Even (%/y
e
Primary Outcome: ts r)
Major Fatal or
Nonfatal
Cardiovascular
3 2.
Event 1 41
0
3/14/10

13. Primary Outcome
Fenofibra Placeb
te(N=276 (N=275
o
N 5) Rat N 3) Rat
of
Even (%/y
e of
Even (%/y
e
Primary Outcome: ts r) ts r)
Major Fatal or
Nonfatal
Cardiovascular
2 2. 3 2.
Event 9 24 1 41
1 0
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14. Primary Outcome
Fenofibra Placeb
te(N=276 (N=275
o
N 5) Rat N 3) Rat
of
Even (%/y
e of
Even (%/y
e HR (95% P
Primary Outcome: ts r) ts r) CI) Value
Major Fatal or
Nonfatal
Cardiovascular
2 2. 3 2. 0.92 0.
Event 9 24 1 41 (0.79 - 32
1 0 1.08)
3/14/10

15. Prespecified Secondary Outcomes
Fenofibrate Placebo
(N=2765) (N=2753)
N of Rate N of Rate
Events (%/yr) Events (%/yr) HR (95% CI) P Value
Outcome
Primary + Revasc +
641 5.35 667 5.64 0.94 (0.85-1.05) 0.30
hospitalized CHF
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
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16. 3/14/10

17. Primary Outcome By Treatment Group and Baseline Subgroups
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18. Primary Outcome By Treatment Group and Baseline Subgroups
3/14/10

19. Comparison of ACCORD subgroup results with
those from prior fibrate studies
Trial Primary Endpoint: Lipid Primary
(Drug) Entire Cohort Subgroup Endpoint:
(P-value) Criterion Subgroup
HHS TG > 200 mg/dl
(Gemfibrozil) LDL-C/HDL-C
-34% (0.02) > 5.0 -71%
BIP TG > 200 mg/dl
(Bezafibrate) -39.5%
-7.3% (0.24)
FIELD TG > 204 mg/dl
(Fenofibrate) HDL-C < 42
-11% (0.16) mg/dl -27%
ACCORD TG > 204 mg/dl
(Fenofibrate) HDL-C < 34
-8% (0.32) mg/dl -31%
3/14/10

20. 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 HDL-C and
TG levels that are close to the normal range
3/14/10

21. Conclusion (2)
•
Subgroup analyses suggesting heterogeneity in
response to combination therapy by gender and by
the presence of significant dyslipidemia require
further investigation
3/14/10