Peter H. Jones, MD Lipid Metabolism and Atherosclerosis Clinic, Baylor College of Medicine, Houston, Tex jones@bcm.tmc.edu
Dr Jones is an advisory board member/consultant for Abbott and AstraZeneca, and is on the speakers bureau for Pfizer, Merck/Schering-Plough, Abbott, and AstraZeneca. He received writing assistance for this article from Ruth Sussman, PhD, and Nancy Hudson, MS, of Landmark Programs. Their assistance was supported by AstraZeneca.
The Journal of Family Practice no longer accepts articles whose authors have received writing assistance from commercially sponsored third parties. This article was accepted prior to implementation of this policy.
Fibrates, alone and combined, with statins By activating the nuclear transcription factor peroxisome proliferator-activated receptor-α, fibrates increase HDL-cholesterol by 8% to 35%.33 The Veterans Affairs HDL Intervention Trial (VA-HIT)34 studied the effects of gemfibrozil in men with CHD and HDL-cholesterol <40 mg/dL. After a median follow-up of 5 years, gemfibrozil raised HDL-cholesterol by 6% more than placebo and lowered triglycerides by 31% more (P<.001 for both), but did not affect levels of LDL-cholesterol. Compared to placebo, gemfibrozil treatment reduced the risk of CHD death and nonfatal myocardial infarction by 22% (P=.006). In post hoc analysis, each 5-mg/dL increase in HDL-cholesterol was associated with an 11% decrease in the risk of these CHD events.34
FAST TRACK
Investigative approaches for increasing HDL-cholesterol levels include IV and oral therapies such as apolipoprotein A1-Milano, apolipoprotein A1-mimetic peptides, and phospholipid-directed therapies.
The Helsinki Heart Study35 reported similar results with gemfibrozil in a population without CHD. Fibrates may be combined with statins: small studies using rosuvastatin and fenofibrate36 and atorvastatin and fenofibrate37 have shown positive effects on dyslipidemia. Gemfibrozil may be associated with increased risks of myositis, whereas fenofibrate combined with statins has not shown this effect.38
High hopes, sobering findings, for torcetrapib The glycoprotein cholesteryl ester transfer protein (CETP) can make HDL particles smaller and more readily removed by the kidneys, with the overall effect of a reduction in HDL-cholesterol.39 Inhibiting this effect, then, should raise HDL levels. Expectations were high for torcetrapib, the first CETP inhibitor, which had been shown to increase HDL-cholesterol by >50% in early clinical trials.40 However, a clinical outcomes trial comparing torcetrapib and atorvastatin with atorvastatin alone was stopped early because the combination therapy was associated with a higher incidence of adverse cardiovascular events, including total mortality.41 Significant increases in average systolic blood pressure with torcetrapib were reported, but it is not clear if this was the cause of the unfavorable outcome. Further, substantial HDL-cholesterol increases of 54% and 61% achieved with torcetrapib in 2 surrogate outcomes trials did not have a beneficial effect on atherosclerosis.42,43
FAST TRACK
In high-risk patients, aggressive therapy with higher dosages of statins is more beneficial than less intensive treatment.
Other CETP inhibitors are currently in development that, investigators hope, will not have the adverse effects associated with torcetrapib.44,45 Additional investigative approaches for increasing HDL-cholesterol levels or increasing reverse cholesterol transport include both intravenous and oral therapies such as apolipoprotein A1-Milano, apolipoprotein A1-mimetic peptides, and phospholipid-directed therapies.46-49
CORRESPONDENCE Peter Jones, MD, 6565 Fannin Street, MSA-601, Suite B157, Houston, TX 77030; jones@bcm.tmc.edu
