Was Torcetrapib’s Crash and Burn Fatal for this Class of Drug?

Dr. William Davis Health Pro
  • Dr. Philip Barter of the Heart Research Institute of Sydney, Australia, presented an update of the disappointing ILLUMINATE clinical drug trial for the once-promising drug, torcetrapib, at the 2007 American Heart Association meetings in Orlando, Florida.


    The crash and burn of drug manufacturer Pfizer's torcetrapib in December 2006 made headlines and prompted enormous disappointment for many patients and doctors who had hoped for a new drug choice to raise HDL cholesterol. Pfizer executives and investors were also disappointed, anticipating release of a drug that might have become the number one biggest selling drug in the world-ever, surpassing even Lipitor®.

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    Torcetrapib is the first among a new class of drugs given the tongue-twisting name of "cholesteryl-ester transfer protein inhibitors," or CETP-inhibitors, drugs that block the release of cholesterol from HDL particles and prevent formation of the unwanted small LDL particles. Preliminary efforts had suggested that, not only did the drug do the job, but the effects were positively enormous.


    However, in the first large trial of efficacy and safety, a Data Safety Monitoring Board, charged with monitoring ongoing trial safety, terminated the 15,000-participant trial after 550 days into the effort when an excess of deaths were identified among the group taking the experimental drug (59 deaths in control group; 93 deaths in the torcetrapib group). In addition, cardiovascular events were 24% greater in the control group numbered 373 compared to 464 in the torcetrapib group, including a substantially greater number of heart attacks and hospitalizations. Another surprise came in the way of cause of death among some of the torcetrapib patients, with an excess of deaths due to cancers (twice as many in the torcetrapib group), strokes, and infections.


    Hopes at first were high for the success of the drug, since interim analysis of the data showed a 72% rise in HDL, ordinarily a notoriously difficult value to increase, along with a further 25% decrease in LDL cholesterol when added to atorvastatin (Lipitor®). Despite these favorable changes, the dangers of the drug were undeniable.


    Why the discrepancy: enormous improvements in cholesterol values, yet a serious increase in an array of adverse effects including more heart attack? Some detective work by the principal investigators of the trial uncovered unexpected distortions of electrolytes like sodium and potassium. They then re-analyzed blood samples from participants on both sides of the trial and discovered that participants taking torcetrapib experience a significant rise in the blood pressure hormone, aldosterone. This, they surmised, also likely accounted for the 4 mmHg average rise in blood pressure among those taking the experimental drug. (This is the same pathway that is blocked by blood pressure drugs like ACE inhibitors lisinopril and enalapril.)



    Anacetrapib to the rescue?


    Simultaneously with the torcetrapib data, investigators at competing drug manufacturer, Merck, reported encouraging data with their version of CETP inhibitor, anacetrapib. In their trial of 589 patients, anacetrapib reduced LDL-C levels by up to 40% and increased HDL-C up to 139%.


    Daniel Bloomfield, M.D., Clinical Research, Merck Research Laboratories reported that "The favorable lipid effects seen in this study with multiple doses of anacetrapib were significant, and confirm the continued evaluation of the clinical benefits of CETP inhibitors in the treatment of dyslipidemia." Quick to distinguish this drug from torcetrapib's track record of dangerous effects on blood pressure, he added that "the decreased LDL-C concentrations, increased HDL-C concentrations and no demonstrable increase in blood pressure seen with anacetrapib are particularly encouraging results of this study."

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    However, the data reported have only proceeded 8 weeks. Given the experience with torcetrapib, longer term data will obviously be required to assess safety. After Pfizer spent over $1 billion and sacrificed lives to obtain this experience, Merck will need to tread carefully.



    All is lost if you have low HDL?


    It will clearly be many years before we have a confident answer on whether the CETP-inhibitor class of drugs will be a safe choice for correction of cholesterol abnormalities, especially low HDL. Are we helpless until then?


    Though CETP inhibitors offer the potential for a one-stop opportunity to raise HDL substantially, there are still many strategies available to raise HDL. But you and your doctor will likely have to employ more than one strategy to effectively and substantially raise HDL.


    Strategies that can raise HDL and are available today-and are safe-include:

    • Weight loss-to your ideal weight. A very effective strategy.
    • Reduction in processed carbohydrates-like breads, pasta, cookies, pretzels, etc. Note that very low-fat diets reduce HDL.
    • Fish oil-A small effect, more dramatic when triglycerides are high.
    • Niacin-Vitamin B3, the best we have at present. Doses of 500-1500 mg per day raise HDL 20-50%; work with your doctor if you are contemplating niacin. We use this agent everyday and have had great success; good hydration is key to minimize the annoying "hot-flush" effect.
    • Dark chocolate-40 grams, or about 2 inches square, a delicious way to squeeze out a little rise in HDL.
    • Alcoholic beverages-Red wines are almost certainly the preferred route, rich in flavonoids.
    • Exercise-HDL-raising effects vary, but can sometimes be as much as 10-20 mg.
    • Other drugs-Though not commonly used for this effect, drugs like pioglitazone (for diabetes and pre-diabetes); fibrates (Tricor® or fenofibrate; Lopid® or gemfibrozil); and Pletal® or cilostazol are occasionally prescribed.
    • Vitamin D-You won't find validation of this effect in any scientific study, but our emerging experience in our heart disease reversal program is suggesting that this neglected nutrient can exert powerful HDL-raising effects.


    Related Information:


    Vitamin D: The Newest Coronary Risk Factor? 


    Lowering Cholesterol with Some TLC: Therapeutic Lifestyle Changes


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    Six Basic Steps to a Healthier Heart 


Published On: November 06, 2007