Update on the use of fibrates: focus on bezafibrate

Figures & data

Table 1 PPARα-mediated gene regulation by fibrates

Target gene	Function of gene product	Gene expression
Lipoprotein lipase	Lipolysis, clearance of triglyceride-rich lipoproteins	Increase
Apolipoprotein CIII	Inhibits VLDL clearance	Decrease
Apolipoprotein AI	HDL-C formation, reverse cholesterol transport	Increase
Apolipoprotein AII	HDL-C formation, reverse cholesterol transport	Increase
Acyl CoA synthetase	Fatty acid activation, acyl CoA esters	Increase
ABCA1	HDL-C formation, cellular cholesterol efflux	Increase
Fatty acid binding protein	Cellular fatty acid uptake	Increase
b-oxidation pathway	Fatty acid oxidation	Increase
Acetyl CoA carboxylase	Fatty acid synthesis	Decrease
Fibrinogen	Blood clotting	Decrease
C-reactive protein	Acute phase reactant	Decrease
Interleukin 6	Acute phase reactant	Decrease
Cyclooxygenase-2	Fatty acid metabolism	Decrease
VCAM-1	Adhesion molecule	Decrease

Abbreviations: ABCA, ATP binding cassette transporter A1; VCAM-1, vascular cell adhesion molecule-1.

Figure 1 Mechanism of action of fibrates.

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; PPAEα, peroxisome proliferator-activated receptor-α; PPRE, peroxisome proliferator response elements; RXR, retinoid X receptor; ↑ indicates increase; ↓ indicates decrease.

Table 2 Summary of major randomized intervention trials involving fibrate therapy

Trial	Drug	No. of patients	Baseline lipids mg/dL			End point	Outcome
			TC	TG	HDL-C
Primary prevention
WHO	Clofibrate	10627	248	NR	NR	Nonfatal MI	25% reduction (p < 0.05)
Helsinki Heart Study	Gemfibrozil	4081	270	176	47	Nonfatal MI/CHD death	34% reduction (p < 0.05)
Secondary prevention
Newcastle	Clofibrate	497	246	NR	NR	Fatal/nonfatal MI	14% reduction (p > 0.10)
Edinburgh	Clofibrate	717	265	NR	NR	CHD events	53% reduction (p < 0.05)
CDP	Clofibrate	3892	250	NR	NR	Nonfatal MI/CHD death	8% reduction (p > 0.10)
Stockholm Ischaemic Heart Disease	Clofibrate	555	249	209	48	Total death	26% reduction (p < 0.05)
VA-HIT	Gemfibrozil	2531	175	161	32	Nonfatal MI/CHD death	22% reduction (p < 0.05)
BIP	Bezafibrate	3090	212	145	35	Fatal/nonfatal MI/sudden death	9% reduction (p > 0.10)
Leader	Bezafibrate	1568	216	189	43	Nonfatal MI/CHD death/stroke	4% reduction (p > 0.10)
Primary/secondary prevention
FIELD	Fenofibrate	2795	195	119	42	Nonfatal MI/CHD death	11% reduction (p > 0.10)

Notes: See text for abbreviations of study names.

Abbreviations: CHD, coronary heart disease; MI, myocardial infarction; NR, not reported.

Figure 2 All-cause and cardiac mortality rates in tertiles of HDL-C change in the bezafibrate group compared to the placebo group.

*p for trend < 0.05

Reprinted with permission from Goldenberg et al (2006).

Figure 3 Kaplan-Meier cumulative probability of outcome the combined endpoint of cardiac death or nonfatal myocardial infarction, and cardiac death separately, during an extended follow-up of the BIP trial.

*p < 0.05.

Figure 4 Outcome of patients with the metabolic syndrome in BIP.

*p < 0.05.

Abbreviation: MI, myocardial infarction.

Figure 5 Two- and five-year Kaplan-Meier cumulative probability of diabetes incidence (in accordance with time of diagnosis after annual fasting blood glucose measurements) in the bezafibrate and placebo groups of the BIP trial.

GoldenbergIGoldbourtUBoycoVRelationship between on-treatment increments in serum HDL levels and cardiac events in patients with coronary heart disease: an extended follow-up of the Bezafibrate Infarction Prevention TrialAm J Cardiol2006974667116461038

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