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, MDCollege 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.

Disclosure

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

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)

Characteristic Mean or % CharacteristicMean or

%Age (yrs) 62 Total Cholesterol

(mg/dl)175

Women % 31 LDL-C (mg/dl) 101Race / 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 % 60A1c (%) * 8.3 On another LLA % 8BMI (kg/m2) 32 On Insulin % 33

Baseline Characteristics

* Median values

140

150

160

170

180

190

200

0 1 2 3 4 5 6 7

mg/

dl

Years Post-Randomization

Mean Total Cholesterol

Feno

Placebo

N = 5483 5180 4988 4783 5250 3377 1668 491

60

70

80

90

100

110

120

0 1 2 3 4 5 6 7

mg/

dl

Years Post-Randomization

Mean LDL-C

FenoPlacebo

N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491

37

38

39

40

41

42

0 1 2 3 4 5 6 7

mg/

dl

Years Post-Randomization

Mean HDL-C

FenoPlacebo

N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491

110

120

130

140

150

160

170

0 1 2 3 4 5 6 7

mg/

dl

Years Post-Randomization

Median Triglycerides

FenoPlacebo

N = 5432 5180 4988 4783 5250 3377 1668 491

Adverse Experiences During Follow-upFenofibrate 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%) 0.81plus 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/ 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-upFenofibrate Placebo

Laboratory Measures (no. (%)) (N=2765) (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

Lab Measures During Follow-upFenofibrate Placebo

Laboratory Measures (no. (%)) (N=2765) (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

Serum creatinine elevation235 (27.9%) 157 (18.7%) <0.001698 (36.7%) 350 (18.5%) <0.001

Post-randomization incidence ofmicroalbuminuria (> 30 to < 300 mg/g*) 1050 (38.2%) 1137 (41.6%) 0.01

Post-randomization incidence ofmacroalbuminuria (> 300 mg/g*) 289 (10.5%) 337 (12.3%) 0.03

Primary Outcome

Rate(%/yr)

Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event

310 2.41

Placebo(N=2753)

N of Events

Primary Outcome

Rate Rate(%/yr) (%/yr)

Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event

291 2.24 310 2.41

Fenofibrate Placebo(N=2765) (N=2753)

N of Events

N of Events

Primary Outcome

Rate Rate(%/yr) (%/yr) HR (95% CI) P Value

Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event

291 2.24 310 2.41 0.92 (0.79 - 1.08)

0.32

Fenofibrate Placebo(N=2765) (N=2753)

N of Events

N of Events

Prespecified Secondary Outcomes

Rate Rate(%/yr) (%/yr) HR (95% CI) P Value

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

Fenofibrate Placebo

Outcome

(N=2765) (N=2753)N of

EventsN of

Events

Primary Outcome By Treatment Group and Baseline Subgroups

Primary Outcome By Treatment Group and Baseline Subgroups

Comparison of ACCORD subgroup results with those from prior fibrate studies

Trial(Drug)

Primary Endpoint: Entire Cohort (P-value)

Lipid Subgroup Criterion

Primary Endpoint: Subgroup

HHS (Gemfibrozil) -34% (0.02)

TG > 200 mg/dlLDL-C/HDL-C > 5.0

-71%

BIP (Bezafibrate) -7.3% (0.24)

TG > 200 mg/dl -39.5%

FIELD(Fenofibrate) -11% (0.16)

TG > 204 mg/dlHDL-C < 42 mg/dl

-27%

ACCORD(Fenofibrate) -8% (0.32)

TG > 204 mg/dlHDL-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 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