Melissa Walton-Shirley

Disclosures

December 12, 2013

My patient had obviously been preparing for her February 2013 office visit. We talked about how many medications she was taking. Financial concerns and pill fatigue had set in. She asked if there was anything she could stop.

"Hmm . . . let's see," I said aloud as I perused her long medication list. "You can stop vitamin C and vitamin E because they have no proven cardiovascular benefit. We're not sure vitamin-D supplementation does anything good for you either. . . . Sure, it's the latest 'miniskirt' in pharmaceuticals, and it's fun to find a low level and relish the satisfaction of making something normal on paper, but there is no real proof it's going to save your life. As for Zetia [ezetimibe, Merck], though we know it makes your LDL cholesterol look fantastic, we don't know that it makes you safer from heart attack or stroke."

My patient brightened at the prospect of stopping just three or four pills daily.

"I'll surely learn something about Zetia at the AHA meeting in November in Dallas," I said reassuringly as she exited the exam room. She was obviously listening because when she bounced in the door two weeks ago, it was the first question out of her mouth. "Can I stop my Zetia?" she asked. "Did they talk about that trial at the meeting you went to?" she queried enthusiastically. I obviously disappointed her in that I really didn't have an answer. I hadn't seen her since the big announcement in March.

Since around 2005, we've looked forward to 2013, which marked the first real expectation for IMPROVE-IT trial results to be published. Practitioners are thirsty for detailed information about the impact of the combination of simvastatin and ezetimibe on vascular health. Unfortunately, in March of this year, the company announced that the release of the IMPROVE-IT trial results would be delayed until September 2014. This announcement came shortly after Merck settled two lawsuits brought by investors alleging the drug maker delayed releasing the ENHANCE results (Merck admitted no wrongdoing).

Regardless of the motivation, practitioners wait . . . and wait . . . and wait, along with our patients who pass daily through our doors with 11-year-old prescriptions. I don't know if I'm practicing benign neglect or malignant engagement by allowing them to remain on it. I truly don't know if I'm decreasing the risk of vascular events or aiding and abetting plaque progression. I have not prescribed ezetimibe since the ENHANCE trial, but I've rarely stopped it in patients who were already taking it, and even then mostly due to financial concerns. I hate to break the hearts of patients and their healthcare providers who celebrate those beautiful LDL-C levels that were pinned like wrestlers to the mat and in short order with a simple prescription of the well-tolerated Zetia.

What about the ENHANCE trial? This two-year-long study published in 2008 compared carotid plaque burden in patients treated with simvastatin alone (80 mg) to patients treated with simvastatin (80 mg) and ezetimibe (10 mg). The lesson learned here was more about the philosophy of "going for broke" in clinical trials. Sometimes, getting greedy for results hangs you. The lyrics Kenny Roger's song "The Gambler" clearly advise, "You gotta know when to hold 'em and know when to fold 'em, know when to walk away and know when to run." Trialists should have "run" from this particular set of familial-dyslipidemia cohorts, who have the meanest, nastiest, highest, and most stubborn LDL-C levels on the planet. Although, in the combination group, the LDL-C level decreased by 16.5%, triglycerides improved by 6%, and C-reactive protein levels improved by 25%, the stubborn carotid intima media thickness didn't budge (and in some cases it progressed). It was the largest hint at that time in lipidology that it really is the journey toward cholesterol lowering that counts and that ezetimibe likely lacks the "magic" of statins despite biomarker improvements.

There is no argument that Zetia, prescribed for 11 years in global markets, lowers LDL and total serum cholesterol by around 15% to 20%. But will the results from IMPROVE-IT affirm the hard lesson from AIM-HIGH : that "beauty is as beauty does," and the lack of impact on mortality is pretty ugly for any compound? It's uglier yet when you can't even claim that a drug improves quality of life. Take nitro, for instance. There's hardly a speck of mortality data, but where would our patients be without it? We can't say the same for Zetia, whose only attribute is to help us champion the paper chase of LDL-C lowering.

In the year 2013, as stated in our recent updated guidelines of lipid lowering, we've come to the conclusion that patients are no longer viewed as living or dying by absolute numbers of LDL and total serum cholesterol. We've come to realize that patients really live or die based on whether or not they rupture plaque and clot their vessels for a cold time of 20 minutes or more. They live or die based on whether or not they can recruit their own clot-busting tPA. They survive or not based on the presence or absence of collateral flow and whether they reach for a bottle of Tums or the phone to dial 911. They survive if their systems can get them to a PCI facility within that golden 90 to 120 minutes. Those are the cold hard facts, and I don't think ezetimibe is going to fit into that formula—but we'll see.

I hope I'm wrong about ezetimibe. I hope and pray that it's really one of the magic silver bullets that cut down plaque in usual individuals despite its failure in familial dyslipidemics. In September 2014, if ezetimibe is found guilty of impersonating a vascular health aid—what's the punishment? Probably nothing for prescribers, but you know the class-action boys and girls are literally licking their chops. It will be the latest fodder for the "have you been harmed by" commercials if there is any hint of a marginal increase in negative outcomes. Never mind if patients aren't exercising, are smoking, or are 30 pounds overweight, if ezetimibe fails with any harm, it will get the blame.

Perhaps the lesson to be learned is that starting in 2014, let's not put compounds on the market for human ingestion without knowing if they help or hurt. Let's make it unacceptable for a company to make tens of billion dollars from the sale of a compound without knowing if it lowers mortality or improves quality of life. Let's run a big trial powered for hard outcomes instead of doing lots of costly little trials that look at surrogate end points of blood levels or plaque burden. Let's focus on prescribing a healthy diet that's never killed or harmed anyone. Let's make 2014 a year of truth and accountability and make the findings of the IMPROVE-IT trial about much more than ezetimibe.

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