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 Age (yrs) Women % Race / Ethnicity White % Black %

Mean or % 62 31

Characteristic Total Cholesterol (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl)

Mean or % 175 101 38 162 134/74

68 15

Triglyceride (mg/dl)* Blood pressure (mm Hg)

Hispanic %
Secondary prevent % DM duration (yrs)* A1c (%) * BMI (kg/m2)

7
37 9 8.3 32

Serum creatinine (mg/dl)

Current smoking % On a statin % On another LLA % On Insulin %

0.9
15 60 8 33

Median values

Mean Total Cholesterol

200
190 180

Mean LDL-C
120
110 100
mg/dl
Feno Placebo

mg/dl

170 160

90
80 70

Feno
Placebo

150
140
Years PostRandomization

60
0
N = 5483

0
N = 5483

1
5180

2
4988

3
4783

4
5250

5
3377

6
1668

7
491

1
5180

2
4988

3
4783

4
5250

5
3377

6
1668

7
491

Years PostRandomization

Mean HDL-C
42 41
mg/dl
170 160 150

Median Triglycerides

mg/dl

40 39

Feno
Placebo

140

Feno Placebo

130

38 37
0
N = 5483 Years PostRandomization

120

110
0
N = 5432

1
5180

2
4988

3
4783

4
5250

5
3377

6
1668

7
491

1
5180

2
4988

3
4783

4
5250

5
3377

6
1668

7
491

Years PostRandomization

Adverse Experiences During Follow-up

Adverse events (no. (%)) Out of the ordinary severe muscle aches/pains: regardless of CK plus CK > 5 X ULN plus CK > 10 X ULN Any nonhypoglycemic SAE Any Myopathy/Myositis/ Rhabdomyolysis SAE Any Hepatitis SAE Any SAE attributed to lipid meds 1110 (40.1%) 1115 (40.5%) 7 (0.3%) 8 (0.3%) 1 (0.04%) 2 (0.07%) 54 (2.0%) 4 (0.1%) 3 (0.1%) 27 (1.0%) 43 (1.6%) 4 (0.1%) 0 (0.0%) 19 (0.7%) 0.81 0.79 0.56 0.27 1.00 0.18 0.24 Fenofibrate (N=2765) Placebo (N=2753) P value

Lab Measures During Follow-up

Laboratory Measures (no. (%))
ALT ever > 3X ULN ALT ever > 5X ULN CK ever > 5X ULN CK ever > 10X ULN Fenofibrate (N=2765) 52 (1.9%) 16 (0.6%) 51 (1.9%) 10 (0.4%) Placebo (N=2753) 40 (1.5%) 6 (0.2%) 59 (2.2%) 9 (0.3%)

P value
0.21 0.03 0.43 0.83

Lab Measures During Follow-up

Laboratory Measures (no. (%))
ALT ever > 3X ULN ALT ever > 5X ULN CK ever > 5X ULN CK ever > 10X ULN Serum creatinine elevation 235 (27.9%) 698 (36.7%) 157 (18.7%) 350 (18.5%) <0.001 <0.001 Fenofibrate (N=2765) 52 (1.9%) 16 (0.6%) 51 (1.9%) 10 (0.4%) Placebo (N=2753) 40 (1.5%) 6 (0.2%) 59 (2.2%) 9 (0.3%)

P value
0.21 0.03 0.43 0.83

Post-randomization incidence of microalbuminuria ( > 30 to < 300 mg/g*)

Post-randomization incidence of macroalbuminuria ( > 300 mg/g*)

1050 (38.2%) 1137 (41.6%)

0.01

289 (10.5%)

337 (12.3%)

0.03

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 Placebo (N=2753) Rate N of (%/yr) Events

291

2.24

310

2.41

Primary Outcome
Fenofibrate (N=2765) Rate N of (%/yr) Events Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event Placebo (N=2753) Rate N of (%/yr) Events

HR (95% CI)

P Value

291

2.24

310

2.41

0.92 0.32 (0.79 - 1.08)

Prespecified Secondary Outcomes

Fenofibrate (N=2765) N of Rate Events (%/yr) Outcome Primary + Revasc + hospitalized CHF Major Coronary Event Nonfatal MI Total Stroke Nonfatal Stroke Total Mortality Cardiovascular Death Fatal/Nonfatal CHF 641 332 173 51 47 203 99 120 5.35 2.58 1.32 0.38 0.35 1.47 0.72 0.90 667 353 186 48 40 221 114 143 5.64 2.79 1.44 0.36 0.30 1.61 0.83 1.09 0.94 (0.85-1.05) 0.92 (0.79-1.07) 0.91 (0.74 - 1.12) 1.05 (0.71 - 1.56) 1.17 (0.76 - 1.78) 0.91 (0.75 - 1.10) 0.86 (0.66 - 1.12) 0.82 (0.65 - 1.05) 0.30 0.26 0.39 0.80 0.48 0.33 0.26 0.10 Placebo (N=2753) N of Rate Events (%/yr) HR (95% CI) P Value

Primary Outcome By Treatment Group and Baseline Subgroups

Primary Outcome By Treatment Group and Baseline Subgroups

Trial (Drug)

Primary Endpoint: Entire Cohort (P-value)

Lipid Subgroup Criterion

Primary Endpoint: Subgroup

HHS
(Gemfibrozil)

-34% (0.02)

TG > 200 mg/dl LDL-C/HDL-C > 5.0 TG > 200 mg/dl

-71%

BIP
(Bezafibrate)

-7.3% (0.24) TG > 204 mg/dl HDL-C < 42 mg/dl TG > 204 mg/dl HDL-C < 34 mg/dl

-39.5%

FIELD
(Fenofibrate)

-11%

(0.16)

-27%

ACCORD
(Fenofibrate)

-8%

(0.32)

-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 HDL-

C 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