Vytorin receives FDA approval amid controversy over its role

July 26, 2004

Mon, 26 Jul 2004 14:45:00

Whitehouse Station and Kenilworth, NJ - Late last Friday afternoon it became official: FDA approval had finally arrived for VytorinTM, the highly anticipated simvastatin/ezetimibe combination from Merck/Schering-Plough. Although both components of the drug combination are available separately, the combined pill is expected to play a significant, though somewhat controversial, role in the enormously successful cholesterol-lowering marketplace.

Vytorin will sell for $2.34 at all doses and has been approved at the following doses: 10 mg/10 mg, 10 mg/20 mg, 10 mg /40 mg and 10 mg /80 mg. Across the dosing range, the ezetimibe component of Vytorin is held constant at 10 mg, while the simvastatin component ranges from 10 mg to 80 mg.

Ezetimibe is already available as a separate tablet, but a combination tablet with simvastatin will be much more convenient and popular with patients. Ezetimibe has a complementary action to the statins, preventing the intestinal absorption of cholesterol, and generally adds an extra 20% LDL reduction to that seen with simvastatin alone. This means the combination can achieve large LDL reductions without the need to use maximum doses of statins, and it thus reduces the risk of statin-induced side effects such as myopathy.

Because of this, the combination pill, which will have the brand name Inegy in Europe, is seen as a key product for Merck and Schering-Plough, with analysts predicting blockbuster sales.

The timing of the Vytorin launch is perfect for the companies, in that it follows new recommendations to lower LDL down to 70 mg/dL in certain patients and enables simvastatin to achieve LDL reductions similar to the more potent statins such as atorvastatin (Lipitor®, Pfizer) and rosuvastatin (Crestor®, AstraZeneca). It also allows Merck to continue generating revenues from simvastatin just as its patent is about to expire.

Cardiologists contacted by heartwire before the FDA approval have had a mixed response to the new combination. Some are welcoming the product as a convenient way of achieving a large LDL lowering without too much worry about side effects, but others are concerned that there are no long-term outcome data available for ezetimibe. They point out that it is not known whether the LDL reduction seen with Vytorin will bring about the same reduction in clinical events as that seen with a statin alone. For this reason, they say Vytorin should not be used as a mainstream drug but should be given only when a patient has not reached target LDL levels with maximum statin doses or if they cannot tolerate high doses of statins.

Nissen the most outspoken critic

Dr Steven Nissen

Probably the most outspoken critic of Vytorin is Dr Steven Nissen (Cleveland Clinic, OH). He told heartwire that he would be reluctant to use the new combination pill because there is no scientific evidence that it reduces clinical events. "Yes, it lowers LDL, but it has not been shown to do any more than that. Statins are complex drugsthey have many other effects, and it is likely that these other effects contribute to their benefit."

Nissen comments: "We've just learned from REVERSAL and PROVE-IT that intensive statin treatment is better than moderate statin treatment, and now we are considering a strategy that advocates a little bit of a statin amplified by ezetimibe. But we don't know whether that is equivalent to high-dose statins. If we give ezetimibe and back off on the statin dose we may lose some benefit of the statinthat is a step backward. There is not enough evidence to justify putting millions of Americans on a statin-sparing medicine. Ezetimibe and Vytorin are just marketing toolsa way to evergreen the patent on Zocor."


Although it is highly likely that most of the effects of statins are related to LDL lowering, statins have pleiotropic effects that may relate to their effects on clinical outcomes.


Dr Harvey White (Green Lane Hospital, Auckland, New Zealand) has similar thoughts. "Ezetimibe is a terrific drug, achieving substantial reductions in LDL without important side effects. It will be really useful to achieve goal LDL levels and for patients intolerant of statins. However, we have no evidence-based medicine to show that the effects are equivalent to statins," he notes. "Although it is highly likely that most of the effects of statins are related to LDL lowering, statins have pleiotropic effects that may relate to their effects on clinical outcomes. These biological effects that occur independent of lipid lowering include improved endothelial function, antithrombotic effects, and anti-inflammatory effects," White adds.

White does not believe that lower doses of statins should be used in combination with ezetimibe to achieve the same degree of lipid lowering as high-dose statins. "Patients should be treated with the appropriate dose of statin that achieves an LDL of 62 mg/dL or less based on the extraordinary results of the PROVE-IT study. If they can't do this, ezetimibe should be added," he says.

No large outcome trials in heart-disease patients

Nissen claims that Merck/Schering Plough are not conducting any large-scale trials that will prove the benefit of Vytorin over a statin alone in a heart-disease population and that they have backed out of an intravascular ultrasound (IVUS) study that he was going to conduct. "I have reason to believe that it may not produce an incremental benefit over statins alone and that they are scared of doing the study in case this is the result. I have proposed several IVUS and outcome trials to Merck and they have rejected the idea. We were ready to go with an IVUS study and then the company canceled it. Why would you do this unless you thought you might lose?"


We were ready to go with an IVUS study and then the company canceled it. Why would you do this unless you thought you might lose?


Merck told heartwire that it is conducting three major outcome trials of Vytorin. These are: SEAS in 1400 patients with aortic stenosis, which will be focusing on the progression of aortic stenosis; SHARP, a trial in 9000 renal-disease patients (who have been excluded from previous statin studies) comparing Vytorin with placebo, with a small group on simvastatin alone; and ENHANCE, which is testing whether Vytorin will enhance atherosclerosis regression in 725 patients with familial hypercholesterolemia.

Nissen is not impressed with this portfolio. "None of these trials will give enough comparative data between Vytorin and simvastatin alone, and a trial in renal-failure patients is not really representative of the population that it will be used in," he commented. "If they want to position their drug as a mainstream player in the cholesterol market, they should do some studies in the mainstream population who would take that drug. Where's the beef? I don't see it. We are never going to know if Vytorin is any better than cheap generic simvastatin." He adds: "I am prepared to accept a hypothesis that ezetimibe may produce an incremental benefit in terms of clinical outcome over a statin alone, but I demand a trial to prove this."

A warmer welcome from others

But several other cardiologists think Nissen is being too hard on Vytorin. These include Drs Scott Grundy (UT Southwestern, Dallas, TX), Christie Ballantyne (Baylor College of Medicine, Houston, TX), Rory Collins (Oxford University, UK), and Virgil Brown (Emory University, Atlanta, GA).

Dr Scott Grundy (Source: UT Southwestern)

Grundy says he thinks the combination of simvastatin and ezetimibe is a good idea. "Until we have any evidence to the contrary, I believe that we can use either a high-dose statin or statin plus ezetimibe to get a further lowering of LDL-C with benefit. However, it is always nice to have confirmation through clinical trials," he commented to heartwire . "The very fact that the FDA allowed atorvastatin first and then ezetimibe on the market without clinical-trial data indicates that the FDA has the same belief I do," he added.

Ballantyne also welcomes Vytorin, describing it as a "valuable new option to help achieve more aggressive LDL goals." He believes the most attractive dosing options will be simvastatin 20 mg/ezetimibe 10 mg and simvastatin 40 mg/ezetimibe 10 mg because these are the doses of simvastatin that have proven event reductions, and these doses will give LDL reductions of 50% and 55%, respectively.

Dr Christie Ballantyne

Ballantyne said he is not concerned about the lack of outcome data with Vytorin. "I used statins long before we had outcome studies. Obviously we need outcome studies with ezetimibe plus statin, but they are in progress." He adds: "We still do not have data that the maximum dose of a statin is superior to a lower dose of the same statin. We will not have that until TNT and SEARCH are completed. At the current time, the guidelines remain focused on lowering LDL."


A combination of a moderate dose of a statin and ezetimibe gives almost no myopathy and can achieve even better LDL lowering than high-dose statins.


Collins, who is part of the team conducting the SHARP trial with Vytorin, is another who believes the combination makes sense. "There is concern about myopathy at high doses of statins, but a combination of a moderate dose of a statin and ezetimibe gives almost no myopathy and can achieve even better LDL lowering than high-dose statins," he says. "Doubling the statin dose gives just a 6% LDL reduction and increases the risk of myopathy, whereas adding ezetimibe gives about a 20% reductionequivalent of three doublings of the statin dose, without any increase in risk of myopathy. I think this is a better result."

Dr Rory Collins

On the issue of outcome data he also subscribes to the school of thought that it is chiefly LDL lowering that produces the benefits of statins. "Other drugs that lower LDL also show risk reductions in outcomes, and the proportional reduction in events in the statin trials has clearly been shown to be related to the degree of LDL reductionwith a 25% reduction in risk with each mmol/L reduction in LDL," he commented to heartwire .

Economic advantages of one pill

Dr Virgil Brown

Brown also has no objections to Vytorin. "I use a lot of ezetimibe, as add-on therapy to statins where further LDL lowering is necessary. I find it very safe and very useful. It makes Zocor equivalent to Crestor, but using a statin that has a huge amount of safety data," he commented to heartwire . "But at present, using the combination means giving two drugs, and under current payment-plan rules patients have to pay twice, so the combination will be good as it will be just one drug payment. This is a significant economic advantage for patients."

Brown says he isn't too worried about the lack of outcome data on Vytorin. "I suppose, strictly speaking, we do not know the impact of ezetimibe on the cardiovascular systemis that extra 25% reduction in LDL really the same as if we had brought about all the reduction just with a statin? We don't know for sure, but I haven't seen any evidence that tells me this isn't the case." He believes LDL is the correct target. "There are lots of studies now linking LDL reduction with cardiovascular benefit, and all the national guidelines have focused on LDL reduction. Where is the evidence that it is anything else other than LDL reduction that is responsible for the benefits of statins?"


Where is the evidence that it is anything else other than LDL reduction that is responsible for the benefits of statins?


He suggests it will all come down to the comfort level of the physician and that physicians are comfortable with both simvastatin and ezetimibe. "I think the comfort level may be greater with this combination than with higher doses of a statin alone. There is a fear of pushing statins to their limit."

Brown says he will use Vytorin but exactly how it will fit in to his practice will depend on several issues and will be different for each patient. "A lot will depend on a patient's response to the initial treatment. If they are just 10% away from goal LDL on rosuvastatin 20 mg, I would probably just double the dose and then they would be pretty certain to reach goal. But if they are 30% away, I can be pretty sure that doubling the dose won't get me there, so then I would think about adding in ezetimibe." Brown says he often adds ezetimibe to rosuvastatin at present and is happy with the results, but when Vytorin becomes available, he may use it for patients who are worried about costs. "If patients' economics are such that they just want to pay for one tablet, I would consider Vytorin."

Vytorin likely to be popular in primary care

Dr Michael Miller (Source: University of Maryland Medicine)

One expert who takes more of the middle ground is Dr Michael Miller (University of Maryland Medicine, Baltimore). He believes primary-care doctors will be more likely to take up Vytorin as they use lower doses of statins than specialists and are more frightened of side effects, whereas specialists are now becoming more comfortable with higher doses of statins. "I will discuss the various options with each patient and let them decide. I would tell them that the data are with high doses of statins, but I wouldn't hesitate to use combination therapy if that is what they preferred," Miller told heartwire . "Whichever agents get LDL down safely will do well, and Vytorin is in a good position, but I think a lot will also depend on how Vytorin is priced," he added.

Nissen still not convinced

But Nissen is not convinced by these arguments. "Yes, guidelines just say lower LDL and don't stipulate how, but they are under political pressure not to favor any one particular therapy over another," he comments. He believes that the guidelines should recommend that ezetimibe is used only once a patient is already on the highest possible dose of the most effective statin and still has not reached goal LDL or cannot tolerate any higher doses of statins.


What doctors should be more worried about are deaths from CHD in patients not on maximal doses of statins.


"I don't think ezetimibe or Vytorin should be a mainstream therapy. We will end up with lots of patients on small doses of statins plus ezetimibe. Is this really smart? Obviously not. I will probably not use Vytorin at all, because if a patient fails to get to goal on 80-mg simvastatin, I would switch to a more potent statin such as atorvastatin or rosuvastatin and increase its dose to maximum and then add in ezetimibe. So I can see no use for the simvastatin/ezetimibe single tablet."

Nissen admits that doctors are wary of side effects with maximum doses of statins, but he says they shouldn't be. "We have had two trials showing this is the right way forward, and there are more in progress. What doctors should be more worried about are deaths from CHD in patients not on maximal doses of statins."

New marketing battle ahead

One thing is for certain: the introduction of Vytorin will trigger a new marketing battle in the cholesterol field. Brown points out: "Rosuvastatin hasn't any outcome data either, but AstraZeneca will say that statins have worked in every trial tested, and ours is a statin. The main party using the how-do-you-know-it's-just-LDL argument will be Pfizer, which now has data on atorvastatin. This is a $25-billion market. There will be lots of imaginative marketing, to be sure."

Related links

1. [HeartWire > Atherosclerosis; Jul 12, 2004]

2. [HeartWire > Atherosclerosis; Apr 20, 2004]

3. [HeartWire > Atherosclerosis; Mar 11, 2004]

4. [HeartWire > Atherosclerosis; Mar 8, 2004]

5. [HeartWire > News; Nov 12, 2003]

6. [HeartWire > News; Oct 28, 2002]


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