FIBRATES














  • Values are average percent change from baseline
  • Data is from pooled results of 4 placebo-controlled trials
  • Reference [1]
Fenofibrate at recommended dosing for 3 - 6 months
Lipid parameter
(average baseline value)		 Fenofibrate
(N=361)		 Placebo
(N=285)
Total
(307 mg/dl)		 -19% 0%
LDL
(214 mg/dl)		 -21% -2%
Triglycerides
(191 mg/dl)		 -29% +8%
HDL
(52 mg/dl)		 +11% +1%

  • Values are average percent change from baseline
  • Reference [1]
Fenofibrate at recommended dosing for 8 weeks
Lipid parameter
(average baseline value)		 Fenofibrate
(N=48)		 Placebo
(N=44)
Total
(267 mg/dl)		 -14% 0%
LDL
(101 mg/dl)		 +45% -4%
Triglycerides
(718 mg/dl)		 -55% +7%
HDL
(28 mg/dl)		 +23% +5%



VA-HIT Trial - Gemfibrozil vs Placebo for Secondary Prevention of CAD, NEJM (1999) [PubMed abstract]
  • The VA-HIT trial enrolled 2531 men with coronary artery disease
Main inclusion criteria
  • Age < 74 years
  • Documented CAD
  • HDL ≤ 40 mg/dl
  • LDL ≤ 140 mg/dl
  • Triglycerides ≤ 300 mg/dl
Main exclusion criteria
  • Serious coexisting medical condition
Baseline characteristics
  • Average age 64 years
  • Diabetes - 25%
  • Previous CABG or PCI - 56%
  • Average LDL - 112 mg/dl
  • Average HDL - 32 mg/dl
  • Average triglycerides - 160 mg/dl
Randomized treatment groups
  • Group 1 (1267 patients) - Placebo twice a day
  • Group 2 (1264 patients) - Gemfibrozil 600 mg twice a day
Primary outcome: Composite of nonfatal myocardial infarction or death from coronary heart disease (defined as sudden death, death due to myocardial infarction, death due to congestive heart failure, and death as a complication of invasive cardiac procedures)
Results

Duration: Median of 5.1 years
Outcome Placebo Gemfibrozil Comparisons
Primary outcome 21.7% 17.3% RR 0.78, 95%CI [0.65 - 0.93], p=0.006
Nonfatal myocardial infarction 14.5% 11.6% RR 0.77, 95%CI [0.62 - 0.96], p=0.02
Death due to heart disease 9.3% 7.4% RR 0.78, 95%CI [0.59 - 1.02], p=0.07
Stroke 6% 4.6% RR 0.75, 95%CI [0.53 - 1.06], p=0.10
Overall mortality 17.4% 15.7% RR 0.89, 95%CI [0.73 - 1.08], p=0.23
Dyspepsia 34% 40% p=0.002
Average HDL at one year 32 mg/dl 34 mg/dl p<0.001
Average triglycerides at one year 166 mg/dl 115 mg/dl p<0.001
Average LDL at one year 113 mg/dl 113 mg/dl p>0.05

Findings: Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.
ACCORD Trial - Fenofibrate vs Placebo Added to Simvastatin for Prevention of CVD in Diabetics, NEJM (2010) [PubMed abstract]
  • The ACCORD trial enrolled 5518 patients with type 2 diabetes
Main inclusion criteria
  • Type 2 diabetes
  • HgA1C ≥ 7.5%
  • Age 40 - 79 years with CVD or age 55 - 79 with 2 risk factors for CVD
  • LDL of 60 - 180 mg/dl
  • HDL < 55 mg/dl (women and blacks), < 50 mg/dl (all others)
  • Triglycerides < 750 mg/dl (no lipid therapy), < 400 mg/dl (lipid therapy)
Main exclusion criteria
  • BMI > 45
  • Serum creatinine > 1.5 mg/dl
  • History of myopathy
  • History of gallbladder disease
Baseline characteristics
  • Average age 62 years
  • Previous CVD event - 37%
  • Taking statin - 60%
  • Average HgA1C - 8.3%
  • Median duration of diabetes - 9 years
  • Average LDL - 100 mg/dl
  • Average HDL - 38 mg/dl
  • Median triglycerides - 162 mg/dl
Randomized treatment groups
  • Group 1 (2765 patients) - Fenofibrate 160 mg + simvastatin once daily
  • Group 2 (2753 patients) - Placebo + simvastatin once daily
  • The protocol for simvastatin and fenofibrate dosing changed over the course of the trial
  • The average dose of simvastatin was 22 mg in both groups
Primary outcome: Composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes
Results

Duration: Average of 4.7 years
Outcome Fenofibrate Placebo Comparisons
Primary outcome 10.5% 11.3% RR 0.92, 95%CI [0.79 - 1.08], p=0.32
Nonfatal myocardial infarction 6.3% 6.8% RR 0.91, 95%CI [0.74 - 1.12], p=0.39
Stroke 1.8% 1.7% RR 1.05, 95%CI [0.71 - 1.56], p=0.80
Overall mortality 7.3% 8% RR 0.91, 95%CI [0.75 - 1.10], p=0.33
ALT ever > 5 X ULN 0.6% 0.2% p=0.03
Serum creatinine > 1.3 mg/dl in women 28% 19% p<0.001
Serum creatinine > 1.5 mg/dl in men 37% 19% p<0.001
Incidence of microalbuminuria 38% 42% p=0.01
Average LDL at end of study 81 mg/dl 80 mg/dl p=0.16
Average HDL at end of study 41.2 mg/dl 40.5 mg/dl p=0.01
Average triglycerides at end of study 147 mg/dl 170 mg/dl p<0.0001
Drug discontinuation 22.7% 18.7% N/A

Findings: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes.