A pharmacist's perspective on health and metabolic disease
I’ve just been asked about PCSK9 inhibitors. These “Pesky” medications, which include the agents Alirocumab and Evolocumab, lower LDL cholesterol by inactivating a protein in the liver called called proprotein convertase subtilisin kexin 9 (PCSK9). PCSK9 inactivates liver receptors that transport LDL into the liver for metabolism. So by preventing the inactivating substance from working, more receptors remain available to transport LDL from the blood, which lowers LDL levels.
These medications work very differently to other medications which lower LDL levels, including the statins and ezetimibe. Statins block an enzyme called HMG-CoA reductase which is critical to the manufacture of LDL cholesterol. Ezetimibe prevents cholesterol from being absorbed in the small intestines.
The PCSK9 inhibitors have been shown to significantly reduce LDL cholesterol levels in people who have not responded to statin therapy. But should we use them?
These medications belong to an overall class of medications called monoclonal antibodies, often called “MABs”. We use other MABs to treat diseases such as rheumatoid arthritis or cancer. MABs are designed to specifically target a particular receptor or cellular target within the body. This makes them very expensive. Currently it is estimated that a year’s supply of treatment would cost about $14 500 (USD), or more than 10 times the cost of the most expensive statin in the USA.
This cost might be worth it, IF it gives good outcomes. BUT……….as with all medications, PCSK9 inhibitors have adverse effects.
This is an injection that has to be given every two to four weeks. Over the short-term 70-80% of patients suffered adverse effects including injection site reactions, fatigue or muscle pain. I’m not sure how many people stopped using these medications because of adverse effects or who just suffered through. About 1% of people had neurocognitive issues (again, I’m not sure if these were permanent effects or resolved when the drug was stopped). But we have no long-term side effect data……will these drugs increase the risk of cancer? What else does this enzyme do and will blocking it cause any other adverse effects? There are concerns that too low levels of LDL increase risk of events. But it is not just the long-term side effect profile that we don’t yet know, actually we have very little overall long-term data including whether the drug actually saves lives!
We know this drug lowers LDL cholesterol. But what we really care about (or should care about) is whether this medication lowers the risk of having a heart attack or a stroke. This data isn’t yet available. From what data I could easily access, it seems that the PCSK9 inhibitors can halve your risk of having heart attack over one year. This might sound good, but when you look at actual numbers, not so good. Of the ~4500 people studied, about 2% in the control group had an ‘event’ (heart attack, stroke or other cardiovascular event) compared to about 1% in the treatment group. And the difference between the groups was only about 60 people. The study size just simply isn’t big enough, nor has it run for long enough to really tell if these medications are worth it. A bigger study is in progress, but we won’t get the results before 2017. Even then, we may not have the long-term risk/benefit data. A systematic review on the medications in 2014 concluded that there is currently insufficient data to show benefit.
But why are we still targeting LDL-cholesterol in the first place? We still don’t have enough evidence that it is the reason behind increased cardiovascular events. As for using these “pesky” medications, do you really want to spend all that money, probably suffer some really significant side-effects for potentially very little benefit? Personally – I’d wait for more evidence…….a lot more evidence.
PCSK9 Inhibitors Not Cost-effective at Current Price: ICER Reviewhttp://www.medscape.com/viewarticle/850715
Statins Cost Four Times More in US Than UKhttp://www.medscape.com/viewarticle/756771
A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumabhttp://www.jmcp.org/doi/abs/10.18553/jmcp.2016.22.6.641