What Went Wrong with Torcetrapib? The Complex World of HDL-C

Dr Myerson is Director of Preventive Cardiology, St. Luke’s-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY.

The abrupt halt to the clinical testing of Pfizer’s drug torcetrapib was striking for several reasons. Pfizer lost millions, if not billions, of dollars, not only in money already spent to develop this drug but also in the loss of sales from a potential blockbuster drug. In addition, physicians had anticipated a valuable addition to their armamentarium for dyslipidemia. Last, the failure highlighted a fact many physicians may not appreciate: lipids are not that simple. What you see in terms of the “basic” lipid profile of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides is not really what you get. In fact, lipid physiology is complex. Each particle is made up of many subfractions, including cholesterol, lipoproteins, and enzymes. There is considerable interindividual heterogeneity in these particles in terms of size, density, apolipoproteins, and core lipid content. Each may have an important role in determining the composition and function of LDL, HDL, and triglycerides and their effect on atherosclerosis.

When we talk about HDL, we are really talking about what is commonly measured—the cholesterol content of the HDL particle, or HDL cholesterol (HDL-C). Because measuring lipoprotein particles directly was more costly and complicated, a surrogate measure was adopted. Epidemiologic studies were also carried out using this surrogate measure. Studies found an inverse association with HDL-C levels and risk for coronary artery disease (CAD), and guidelines were developed using the surrogate measurement of HDL-C. Although this has seemingly served us well over the years, it is important to remember that it may not be the whole story, and it may explain why torcetrapib did not live up to its promise. Indeed, we may have raised HDL-C levels, but we may not have raised what was really needed.

Evidence for HDL’s Beneficial Role

The role HDL-C plays in atherosclerosis was first realized in the 1950s.¹ In the 1970s, the Framingham Heart Study reported the inverse relationship between HDL and CAD in men and in women. ² Many other large epidemiologic studies have confirmed this relationship, and HDL became recognized as an important and independent risk factor for CAD. The benefits extended to even small increases in HDL-C: for each 1-mg/dL increase in HDL-C, there was a 2% to 4% increase in protection.

Following the epidemiologic evidence came prospective clinical trials evaluating ways to raise HDL-C levels. One of the first was the Helsinki Heart Study, which showed that treatment with gemfibrozil (Lopid) in asymptomatic middle-aged men increased HDL-C levels by 11% and reduced the risk of CAD by 34% compared with placebo.³ The Air Force/Texas Coronary Atherosclerosis Prevention Study found that lovastatin (Mevacor) resulted in a 37% decrease in first major coronary events in men and women with average LDL-C levels; a finding attributed in part to the reduction in HDL-C.⁴ The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial also used gemfibrozil to treat men with known CAD and low HDL-C levels. HDL-C increased by 6%, and there was a 22% reduction in death or nonfatal myocardiac infarction. ⁵

Current Treatment of Low HDL-C

Based on this research, HDL-C has become an independent target for therapy. The National Cholesterol Education Program Adult Treatment Panel III guidelines state that levels should be >40 mg/dL. Most of our medications used to treat dyslipidemia also raise HDL-C, with nicotinic acid and fibrates offering the most benefit; nicotinic acid raises HDL-C by 15% to 35%. Lifestyle factors also have a modest effect on HDL-C. These include diet (in particular, omega-3 polyunsaturated fatty acids), exercise, smoking cessation, hormone therapy, weight loss, and moderate alcohol consumption. Despite treatment with medication and lifestyle modification, HDL-C levels often remain low, much to the frustration of physicians and their patients.

Potential Targets for Therapy

As a result, increasing attention has been paid to developing alternative medications to raise HDL-C levels. The complex nature of HDL and its metabolism opened many possible avenues for which to develop therapies. These included medications that target apolipoprotein (Apo) A-I, the main protein in HDL. However, it has proven difficult to develop drugs that would lead to upregulation of endogenous ApoA-I expression.

Other approaches have looked at ways to enhance the components of the reverse cholesterol transport mechanism, primary among the actions of HDL. HDL particles promote efflux of cholesterol from peripheral tissues to cholesterol acceptor particles to HDL, where it is then transported to the liver and excreted in the bile. Three proteins are keys to this process. The first, adenosine triphosphate-binding cassette transporter A1, transports free cholesterol and phospholipid to ApoA-I. This transported cholesterol is then esterified by lecithin cholesterol acyltransferase to form a mature HDL particle. Cholesteryl ester transfer protein (CETP) then exchanges the cholesterol ester in HDL for triglyceride in apolipoprotein B containing LDL and very-low-density lipoprotein particles. Inhibition of CETP was thought to be a good way to increase HDL. As described in this issue (page 10), trials of torcetrapib, a CETP inhibitor, were terminated after an increase was seen not only in HDL levels, but also in cardiovascular (CV) events, death, and blood pressure.

What Happened with Torcetrapib?

So why did torcetrapib fail? Perhaps the complex nature of HDL was not fully appreciated. Dr Steven Nissen and coinvestigators of the ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition) study offer several explanations. ⁶ Could the HDL produced by torcetrapib have been dysfunctional? The role of CETP inhibition is still not fully understood and perhaps may not have produced the kind of HDL that was protective. The investigators also discuss how the increase in systolic blood pressure seen in the treatment group may have counterbalanced any benefits derived from the HDL increase. In addition, there may have been a toxic effect specific to this agent that had nothing to do with HDL.

The ILLUSTRATE investigators also ask an important question: Has the failure of torcetrapib precluded the possibility that other CETP inhibitors may be of benefit? It is clear that lipids are crucial in the pathogenesis of atherosclerosis and of CV events. Therefore, efforts to identify and treat the critical component or components of HDL-C should continue. Further dissection of the torcetrapib study may yield helpful information. We may also need to revise our measurement strategies and identify other components of lipid particles that are more specific to the atherogenic process and that may give us better predictive information. For example, instead of measuring LDL-C, we can measure Apo B. The complex nature of lipid particles presents a unique challenge to scientists and clinicians. Perhaps the failure of torcetrapib, while clearly a setback, may help revamp our efforts to treat lipid disorders.

References

1. Nikkila E. Studies on the lipid-protein relationship in normal and pathological sera and the effect of heparin on serum lipoproteins. Scand J Clin Lab Invest. 1953; 5(suppl 8):9-100.

2. Gordon T, Castelli WP, Hjortland MC, et al. High-density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977; 62:707-714.

3. Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA. 1988; 260:641-651.

4. Downs JR, Clearfield M, Tyroler HA, et al. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TECAPS): additional perspectives on tolerability of long-term treatment with lovastatin. Am J Cardiol. 2001; 87:1074-1079.

5. Rubins HB, Robins SJ, Collins D, et al, Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999; 341:410-418.

6. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007; 356:1304-1316.