Why Are Patients Not Reaching LDL-C Goal?

Medscape: It appears that a large proportion of patients with high low-density lipoprotein cholesterol (LDL-C) do not achieve a sufficient decrease to reach their LDL-C goal with statin therapy, especially the more aggressive goals now being suggested.^[1] Is this because patients do not adhere to treatment? Do they stop treatment because of side effects, or are the doses of statin that they are taking too low to be effective? Or is it simply that some patients are resistant to statins?

Dr. Sacks: It is documented that unfortunately a large percentage of patients stop taking their statin as the months progress,^[2-6] even though they need to, and there are multiple reasons for that. One reason is the patients' lack of understanding of how important it is for them to keep taking statins. Some patients believe that if they take the statin for a few months then they are cured of their cholesterol problems. So we have insufficient education and misperception. Another reason is the potential side effects. Patients become aware of side effects from statins, real or perceived, by reading product literature or from friends and will sometimes attribute muscle aches and pains to statins when it is really just something else. This happens especially in older people taking statins who will get aches and pains more frequently and unpredictably anyway, and they tend to blame these effects on the statin. Then there are people who really do have muscle aches and weakness caused by the statin, and that of course provokes them to discontinue the medication. There are other reasons, such as cost, of course; if patients have cannot afford the medication then they may not be adherent. True biologic unresponsiveness to statins is unusual and not very well documented. Whether true biologic unresponsiveness exists or whether these are patients who are not adhering to their medication even though they say they are, is not really clear.

Medscape: Is there a problem with statin dosing similar to that with antihypertensive dosing, ie, are physicians negligent about increasing the dose or are they sometimes reluctant to increase the dose to the maximum available for safety reasons?

Dr. Sacks: Physicians as a group are getting better these days than they have been, and more recent studies show that patients are reaching their goal more frequently than they were 5-10 years ago. However, there is certainly still room for improvement.

Medscape: It has been suggested that some individuals may be so-called hyperproducers of LDL-C via the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase pathway, while others may be hyperabsorbers, taking up more cholesterol through the small intestine. Statins would therefore be relatively more effective in the first group, while drugs that inhibit intestinal absorption of dietary and biliary cholesterol such as ezetimibe would be more effective in the second group. Do you agree with this?

Dr. Sacks: There are undoubtedly different metabolic mechanisms underlying high LDL-C levels in various people. In principle, heterogeneity of response to statins and ezetimibe is possible. But it is speculative to assert that some people have a better inherent responsiveness to blocking cholesterol absorption vs increasing LDL-C removal with statins. I have not seen any data to support this.

Medscape: So everyone with high LDL-cholesterol apparently should respond to a good dose of a statin, so why do some not respond effectively? In some clinical trials of statins, a significant percentage of patients did not show a reduction in events.

Dr. Sacks: In big statin trials, trials of more than 2000 people, a statin reduces the incidence of cardiovascular events by up to 40%. That means that during treatment with a statin many people continue to have coronary events. This is known as "residual risk." So the question is: what more can we do for our patients who are at higher risk and already on maximum doses of statins? That is really what we are talking about when we use the term "residual risk," ie, that statins do not reduce the probability of a cardiovascular event to zero. So are any of those people truly statin-unresponsive? That is really hard to say. Maybe they would have had an event 5 years earlier if they were not on a statin; maybe the statin did delay their events. One thing that people agree on is that statins are not a cure and that they do not prevent all the events, or even the majority of the events that a population will experience. That provides a rationale for additional treatments.

Medscape: Maybe in some of these studies patients were not treated for long enough, or they began treatment too late, or the dose was insufficient?

Dr. Sacks: Even at the higher approved doses of statins -- 80 mg for fluvastatin, simvastatin, and atorvastatin, and 40 mg for pravastatin and rosuvastatin in the United States -- I think it is fair to say that 50% to 60% of events would still occur, projecting from combined results from trials of standard and high-dose statins.