Are CETP inhibitors kaput?

Was torcetrapib’s crash and burn fatal for this class of drug?

At the 2007 American Heart Association meetings in Orlando, Florida, Dr. Philip Barter of Sydney, Australia, presented an update of the ILLUMINATE drug trial for the once-promising drug, torcetrapib, the billion-dollar bet that Pfizer made on its first entry into the new drug class.

You may recall that the crash and burn of 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 (heads flew!) 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's® $13 billion annual sales.

Torcetrapib is the first among the “cholesteryl-ester transfer protein inhibitors,” or CETP-inhibitors, drugs that block the exchange of cholesterol and triglycerides between HDL and VLDL particles and prevent formation of the unwanted small LDL particles. Preliminary efforts suggested that effects were positively enormous.

However, the 15,000-participant trial was abruptly terminated after 550 days 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 torcetrapib group, numbering 373 compared to 464 in the no-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.

Why the divergence: enormous improvements in cholesterol values, yet increase in adverse effects including more heart attack? Deeper digging by the principal investigators 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 experienced 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 blocked by blood pressure drugs like ACE inhibitors lisinopril and enalapril, ARBs like losartan.)

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

Spokesman Daniel Bloomfield, M.D., of 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."

However, the data reported only an 8 week expereince. 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.

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.

Strategies that raise HDL and are available today 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. Often a huge effect.
• 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. In fact, supplementing vitamin D has made my life much easier.

And, last I checked, none of these HDL-raising strategies are ever fatal.

Comments (9) -

  • Anonymous

    11/6/2007 5:44:00 PM |

    Dr. Davis,

    Thanks for providing yet another wonderful summary of ongoing research and trials.

    I think there may be a minor error in this post though.  You state: In addition, cardiovascular events were 24% greater in the control group, numbering 373 compared to 464 in the torcetrapib group, including a substantially greater number of heart attacks and hospitalizations.  I think you perhaps meant that the CV events were 24% greater in the trial group, not the control group, yes? Or have I misunderstood?

    Also, I've recently (about 10 weeks ago) started niacin (Niaspan) to try to raise my low HDL level.  Based on reading your postings, I'd also been taking D3 over the past several months.  Interestingly, when I went in a couple weeks ago to have my lipid numbers retested (and ALT), the NP reviewing my data remarked that they usually don't see such a marked change from only .5 g of niacin (though it still wasn't enough).  Her remark was that they usually don't see any change for only .5 g.  I suspected this was maybe the D3 in concert with the niacin.  Comment?

  • Dr. Davis

    11/6/2007 7:17:00 PM |

    Oops! Fixed! Thanks for catching it.

    Yes, I've now seen unexpected rises in HDL when vitamin D replacement in numerous patients. An unexpected bonus!

  • Anonymous

    11/6/2007 7:41:00 PM |

    I wonder how the Apo A-I Milano drug tests are coming along, and if they are even following up with it. I remember one very promising test, a while ago, then nothing. I hope they aren't dropping it entirely, just because they can't create an oral version.

    I too have recently started Niaspan, like your previous poster. I have been on D for several months as well. Unfortunately, D alone didn't help my HDL much at all, but I'm hoping perhaps with niacin it'll start rising.

    A bit off subject, but when taking high-dose niacin, are we supposed to also take higher doses of other B vitamins? I read somewhere that if one B is higher than others, it can throw off the balance, hence why homocysteine occasionally rises. Perhaps TMG-Betaine should be taken when on high-dose niacin?

  • Anonymous

    11/6/2007 8:36:00 PM |

    Dr. Davis,

    You forgot to mention the drugs in development that improve HDL function without necessarily raising HDL. There is a large body of evidence starting to accumulate that says that HDL function may be as important as HDL levels if not more important.

  • russb324

    11/6/2007 9:08:00 PM |

    Great and timely post.  Interesting article on the state of CETP inhibitors in the NY Times today:

    I guess Merck and Roche have not given up on this class of drug but that they are a decade away from the market, if they ever get there.

    I wonder what the immune system issue is all about and why there would be an increase in cancers.  Any thoughts?

  • Dr. Davis

    11/6/2007 9:54:00 PM |

    No, sorry, I was surprised by that, also. I wonder if some inflamatory component was unleashed by CETP inhibition.

  • Dr. Davis

    11/6/2007 9:56:00 PM |

    No, not necessarily. However, niacin does raise homocysteine modestly. Taking more folic acid, B6, B12, and betaine can often block this effect.

  • Anonymous

    11/7/2007 4:57:00 PM |

    Dr. Davis,

    You mentioned good hydration as a way to minimize the niacin flush.  Do you use a specific hydration protocol with your patients, or just tell them to drink more water?  Also, do you have any other pearls for reducing the flush effect?

  • Dr. Davis

    11/7/2007 8:13:00 PM |

    Drinking 2 8-12 oz glasses of water works like a charm when you have the hot flush.

    Other strategies include using an adult uncoated aspirin if the hot flush does not respond to water. I also advise everyone to take niacin with a major meal like dinner, not at bedtime.