There is no doubt that statins, drugs like Lipitor and Zocor that lower LDL-cholesterol, reduce the occurrence of heart attacks and strokes in those with cardiovascular disease (CVD). For a long time people have debated whether statins are unique or whether any drug that lowers LDL would also benefit those with CVD. As revealed in a study reported this week at the American Heart Association meeting in Chicago, statins are not unique.
The study, known as IMPROVE-IT, showed that adding Zetia (ezetimibe), an inhibitor of dietary cholesterol absorption, on top of the statin Zocor (simvastatin) in patients who had recently suffered an acute coronary event, resulted in a 6% drop in heart attacks and strokes when compared to those on Zocor alone. This trial, as ably reported by fellow Forbes contributor Larry Husten, enforced the view that, when it comes to LDL cholesterol, “lower is better”. The patients who were on the combination of Zetia and Zocor (sold as Vytorin by Merck), had an average LDL of 53mg/dL whereas those just on Zocor had an average LDL of 70mg/dL. These results reinforce prescribing practices for those physicians who have already been recommending that their high risk patients take Vytorin and that statin intolerant patients be given Zetia to reduce CVD risk.
The question is now whether the IMPROVE-IT results will impact the behaviors and policies of the FDA and also of payers.
The next big breakthrough in lowering LDL is a class of compounds known as PCSK-9 inhibitors. Feverishly being developed by Amgen, Sanofi, and Pfizer, these agents lower LDL far more profoundly than statins, with LDL levels being reported as low as 25mg/dL. Given that “lower is better", one would think that these agents would be a lock for rapid FDA approval based on their profound LDL lowering properties. Maybe, maybe not. There are still some unknowns with which the FDA must struggle. First, in IMPROVE-IT, the drop in LDL from 70 to 53 is pretty substantial. Yet, the reduction in cardiovascular events was relatively modest. Are we reaching a point where further LDL lowering will not provide added benefit? Second, how low is too low? Could unanticipated toxicities result from sustained LDL levels at levels below 40mg/dL?
To answer these questions, the FDA might require an IMPROVE-IT type outcome study for each PCSK-9 inhibitor before approving these drugs in order to demonstrate the long-term benefits and safety of such unprecedented LDL lowering. In fact, the companies developing these drugs already have such studies underway in anticipation of such a requirement. Why wouldn’t the FDA await the results of these studies before approving these drugs? IMPROVE-IT shows that Vytorin can get LDL levels to the 50s and Zetia can provide protection for those who are statin intolerant. This isn’t a situation where patients are currently without viable treatments. Thus, there isn’t a critical medical need requiring rapid approval of these drugs. Furthermore, cardiovascular guru Dr. Steven Nissen of the Cleveland Clinic thinks such outcome studies are absolutely required.
“If ezetimibe can produce benefits with modest LDL lowering, then these drugs with more powerful LDL-lowering effects will likely be better. But we cannot take this for granted without outcome studies. These are essential and are underway. Before the outcome results are available, I think the PCSK-9 drugs should be used only in the sickest populations with few options…”
Nissen’s comments are likely to be music to the ears of payers. Because these drugs are biologics, they are likely to be very expensive and far more costly than generic statins like atorvastatin (generic form of Lipitor) or generic versions of Vytorin which will be available in 2016. Even if PCSK-9 inhibitors are approved by the FDA in advance of the results of any outcome studies, my guess is that payers will severely limit those for whom these drugs will be reimbursed. After all, if heart disease patients already have their LDL levels down to the low 50s with existing (and cheap!) therapies, why pay thousands of dollars to get LDLs down to 40 if there is no proof that any benefit will ensue?
There is tremendous social pressure to get health care costs under control. New drugs to lower LDL – not just PCSK-9 inhibitors but other experimental medicines - might well benefit heart disease patients. But such benefits may need to be defined before these drugs are approved and reimbursed.
