The Food and Drug Administration and Over‐the‐Counter Statins: An Opportunity Lost?

The treatment of hyperlipidemia may seem to be outside the purview of Reflections in Hypertension, but the realization that the majority of hypertensive patients also have elevated lipid levels, and the increasing emphasis on the treatment of global risk rather than simply treating blood pressure, more than justifies its consideration. This and other hypertension journals have often paid attention to the low rates of control of hypertension throughout the world, but the rates of lipid control are even lower. A recent report from the Minnesota Heart Survey reported that the percentage of persons with hyperlipidemia who were successfully controlled (total cholesterol, <200 mg/dL) was 6% in women and 13% in men. ¹ This is paradoxical because, unlike hypertension, there is basically only a single drug class—the statins—that is needed to successfully treat the vast majority of patients. With the experience of 20 years of use and the demonstration of consistent and potent reductions in cardiovascular events, coupled with an excellent safety profile, there has been a move to get statins approved for over‐the‐counter (OTC) use. This was first approved for the Zocor Heart‐Pro program ² in the United Kingdom, which has made the drug available for “behind‐the‐counter” sales. This means that it can only be bought from the pharmacist, as opposed to having it available on the open shelves along with OTC drugs. This category is not currently available in the United States.

In 2000, a Food and Drug Administration (FDA) Advisory Committee reviewed and rejected 2 proposals for the OTC sales of statins (pravastatin and lovastatin). There was concern about whether the persons who bought it were the ones for whom it would be most appropriate. The target population for whom OTC lovastatin was thought to be appropriate were persons who have a risk of a coronary heart disease event over the next 10 years between 5% and 20% based on the Framingham Risk Score. Merck & Co, Inc (the makers of a brand of lovastatin), wanted to pursue the issue, and the FDA proposed a study of lovastatin use in OTC form in a 20‐mg dose, with the dual purpose of seeing whether it would actually be used and lower blood lipids and also whether the patients who would most benefit from it would be the ones who chose to buy it. Of particular concern was the use by women younger than 45 years, who would be mostly at low risk (<5%) and also of child‐bearing age (lovastatin is classified by the FDA as an “X” drug, which is absolutely contraindicated in pregnancy). This was duly performed in the Consumer Use of Over‐the‐Counter Lovastatin (CUSTOM) study, ³ the results of which were presented at a meeting of an FDA advisory committee in 2005. The main findings were that about 20% of persons who bought lovastatin were at low risk (including many women younger than 55 years) but, in those who did buy it, there was a reduction in low‐density lipoprotein (LDL) cholesterol of about 20% (blood was taken before and after starting the lovastatin). The proposal was rejected by the FDA committee on the grounds that the persons who said they would use it included some whose 10‐year risk was low (<5%) and others whose risk was very high (>20%), in whom larger doses would almost certainly be needed. A second study was proposed (the Self‐Evaluation of Lovastatin to Enhance Cholesterol Treatment [SELECT] trial), which was designed to optimize the selection of lovastatin by the public.

THE 2007 FDA MEETING

Findings from the SELECT trial were recently (December 2007) reviewed at another FDA advisory committee meeting, in which I participated. The main focus of the meeting was the issue of whether patients can successfully self‐select if OTC lovastatin would be appropriate for them and to review analyses of the SELECT study, which has not yet been published. Participants in the study were asked to read the box in which the lovastatin was contained; this had a number of questions and warnings. There was much discussion of the extent to which the moderate risk (5%–20%) target population had successfully identified themselves. Not surprisingly, the selection was less than perfect, although a much smaller number of women younger than 45 years said they would buy it (12% vs 23% in the CUSTOM study). There was also concern that people at high risk, some of whom were already taking a statin, would also take it. Another issue was the proposed “muscle pain labeling,” warning patients of muscle pain that could occur while taking lovastatin. The final vote was 10 to 2 against approving lovastatin for OTC use.

WHAT IS THE POTENTIAL BENEFIT OF OTC STATINS?

For OTC lovastatin, the claim was made that it would reduce cardiovascular events by 37%, based on the results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS‐TexCAPS), ⁴ in which lovastatin 20 to 40 mg was compared against placebo. A recent meta‐analysis of all the major primary prevention trials of statins ⁵ concluded that there was an overall reduction in events of 21%, with a somewhat bigger reduction in men than women. The number of individuals who might benefit from OTC lovastatin has been estimated using the CUSTOM study results, ⁶ where the participants' median 10‐year risk of events was 10%. The conclusion was that the use of 20 mg of lovastatin for 10 years would prevent 33,100 events per million users, which would clearly have a significant public health impact. The other question here is: will people buy OTC statins? Perhaps surprisingly, the answer to this appears to be “yes.” A survey of consumers, physicians, and pharmacists commissioned by the National Lipid Association ⁷ found that more than one‐half (53%) of the consumers said they would buy an OTC statin.

HOW SAFE ARE STATINS?

The big issue with this topic is the safety of statins. The 3 major areas of concern are the effects on liver, muscle, and pregnancy. Abnormal liver test results have gotten a lot of publicity, even though they occur in only about 1% of patients, ⁸ and statins are commonly not prescribed for patients with any type of liver disease. The increase in transaminases, however, is almost always symptomless, and the more important question is whether these changes herald irreversible liver damage. A procedure used by the FDA is the application of “Hy's Rule,” which assesses the frequency of elevated transaminases and bilirubin levels, but normal alkaline phosphatase. ⁹ An analysis of statin use in the Kaiser Permanente database of patients with preexisting abnormalities of liver function described at the FDA meeting found that there were actually fewer persons in the statin group than in the control group who met the Hy's Rule criteria. Another analysis found no hepatotoxocity (defined by the Hy's Rule criteria) in patients who took statins who had abnormal liver function test results at baseline. ⁹ Thus, even in patients with preexisting liver disease, there is no evidence that statins cause major liver damage.

Of potentially greater importance is the effect on the muscles. The problem here is that muscle pain is very common, and in the Heart Protection Study, ¹⁰ which studied simvastatin 40 mg, one‐third of the patients in the statin group experienced muscle pain at some part of the study, but so did the same number of patients in the control group. The vast majority of statin‐related symptoms are benign and the only life‐threatening adverse effect is rhabdomyolysis. This is fortunately rare, however, and is discussed further below.

Finally, although lovastatin is classified as a class X drug by the FDA (ie, it should not be taken during pregnancy), it was apparent during the meeting that despite a considerable exposure to lovastatin by pregnant women, there was no evidence of any increase in fetal abnormalities. ¹¹ , ¹²

COMPARISON WITH ASPIRIN

OTC drugs are generally taken for the acute relief of symptoms. The lovastatin OTC proposal is very different in that people who are feeling well will have to take the drug for a long period of time without any change in symptoms. Perhaps the best comparison is that of aspirin for the prevention of cardiovascular disease. No one questions the wisdom of having aspirin available as an OTC drug; it has been widely recommended for the prevention of heart disease. In this context, it is instructive to compare the efficacy and safety of aspirin with statins. A recent meta‐analysis ¹³ of randomized trials of the use of aspirin for the primary prevention of cardiovascular events identified 6 trials comprising 95,456 patients, with an approximately equal number of men and women. In women, there was a 12% reduction in cardiovascular events and a 17% reduction in stroke but no effect on incidence of myocardial infarction. In men, there was a 14% reduction in events and a 32% reduction in myocardial infarctions but no effect on strokes. In both sexes, aspirin significantly increased the risk of major bleeding, and in men it increased the risk of hemorrhagic strokes by 69%.

Thus, the benefits of statins may be regarded as greater than the benefits of aspirin for the primary prevention of cardiovascular disease. But how does the safety of aspirin and statins compare? Despite all the attention paid to liver damage and myopathy with statins, the only life‐threatening adverse effect to emerge with any consistency is rhabdomyolysis. A recent review concluded that the incidence of rhabdomyolysis was 3.4 events per 100,000 patient‐years. ¹⁴

Rhabdomyolysis associated with a statin may be compared with a major bleed associated with aspirin in terms of severity. A meta‐analysis of the aspirin studies ¹³ reported that about 3 major bleeds would occur in 1000 patients treated for 6.4 years, which translates to 6 bleeds per 100,000 patient‐years. Thus, to the extent that these comparisons are fair, it can be concluded that statins are both more effective and safer than aspirin for primary prevention.

THE ISSUE OF SELF‐SELECTION

A major part of the 2007 FDA meeting was dedicated to the discussion of whether consumers could successfully decide whether they came into the moderate‐risk group for cardiovascular events. Since, by definition, the purchase of an OTC drug does not necessarily involve interaction with a pharmacist, this would have to be achieved by reading the labeling on the box, possibly combined with media advertising.

What appears to have derailed the lovastatin application is the fact that there were substantial numbers of individuals who chose to use it who were either at low risk (<5%) or at high risk (>20%), which was of concern to both the FDA reviewers and most of the committee members. So the issue is: how much does this matter? For low‐risk patients, the benefit of taking lovastatin would be small but still present. For high‐risk patients, there would be a very substantial benefit, but there were 2 concerns expressed at the meeting: first, the 20‐mg dose would not be sufficient to normalize the LDL cholesterol level and, second, some of the high‐risk individuals might already be taking a statin, which would be switched to lovastatin. In the CUSTOM study, only about 16% of patients in the high‐risk group were already taking a statin, so the majority of high‐risk patients would derive some benefit from the lovastatin.

By definition, low‐risk persons who would purchase OTC lovastatin are health‐conscious, and many of these individuals may already take supplements such as “red rice yeast,” which is said to be a natural form of lovastatin and is thus not subject to FDA control. “Natural” medicines are often considered to be safer by the general public than synthetic drugs. Although red rice yeast has been shown to lower total and LDL cholesterol levels, ¹⁵ we know next to nothing about its side effects because long‐term studies on its use have not been performed.

In addition, it is agreed that there is no threshold level below which lowering LDL level fails to produce a benefit. The Heart Protection Study ¹⁰ found no threshold level of LDL below which there was no benefit from the statin. A few years ago, the concept of the “polypill” was introduced, ¹⁶ which included a statin, aspirin, and ≥2 antihypertensive drugs. In theory, this combination would reduce cardiovascular risk in the general population by about 80% if taken by everyone older than 55 years. Needless to say, this has not happened, but the authors made the case that the benefits would probably outweigh the risks.

The approach with the lovastatin OTC program is very different from the polypill recommendation in that the decision to start the treatment would be exclusively made by the patient, as opposed to being an official health recommendation. Thus, it is in keeping with the “self‐management” movement that fosters the greater involvement of patients in their own treatment of chronic disease and risk factors. The concerns of the FDA committee about poor self‐selection seem to me to be overinflated, mainly because the assumption was that there would be no contact between the consumers and their physicians or pharmacists. In the National Lipid Association survey ⁷ mentioned above, 83% of the consumers said that they would talk with their doctor before buying an OTC statin. What their doctor would have said, however, is another matter: only 45% of the physicians in the survey said they would support the consumers' decision to buy, whereas 68.5% of pharmacists were supportive.

CONCLUSIONS

As a class, there is no doubt that the statins are extremely effective in reducing a variety of cardiovascular morbid events, but there is still a large number of Americans who would benefit from taking them who are currently not doing so. From a public health point of view, the gap between what could be done and what is being done is even greater for controlling cholesterol levels than for controlling blood pressure. It is surprising and gratifying that many people who are currently not on a statin are enthusiastic about the availability of an OTC statin. There has been intense scrutiny of the safety of statins but, at the end of the day, they emerge as being remarkably safe. If we are not concerned with the OTC availability of aspirin for the long‐term prevention of cardiovascular disease, why should we not also approve the use of statins, which are effective and just as safe?