The discovery of the relationship between lipids and cardiovascular disease was first made in the 1960s. Following this, an urgent need was filled by the founding of lipid lowering medications, with statins being the gold standard of therapy. However, the consequences of lipid disorders and cardiovascular disease remain prevalent despite this knowledge. Patients with familial hypercholesterolemia (FH), especially LDL-C disorders continue to struggle. Goldstein and Brown won the Noble Prize in Medicine for uncovering the role LDL-C receptors play in clearing lipids from the bloodstream. They also discovered that FH is due to mutation in the LDL receptor gene. This paved the way to other discoveries, including that of the creation of new drugs called PCSK9 inhibitors

PCSK9 inhibitors are a recent development in the battle of the lipids.

These medications are injectable and shown to lower LDL-cholesterol by up to 60% when used in combination with a statin medication. These drugs are monoclonal antibodies (MABs) which bind to and inactivate proprotein convertase subtilisin kexin 9 in (PCSK9) in the liver. The inhibition allows more receptors to be available to capture LDL to be metabolized and removed from the blood.

It has been estimated that over 71 million adults age 20 years or older in the US have LDL-c that are elevated. However, only 34 million are being treated and only 23 million were controlled. Elevated LDL-C has been demonstrated to increase the risk of cardiovascular events. Furthermore, predictive modeling suggests that every 10% increase in the number treated, approximately 8,000 deaths can be prevented.

Studies and clinical trials on PCSK9 inhibitors.

While PCSK9 inhibitors can drastically reduce LDL-C, studies show that when used along with statins, the benefit is complementary. An article in the New England Journal of Medicine tells us that both these classes of medication accelerate apolipoprotein B production. In the Osler-1 and Osler-2 trials, two human monoclonal antibodies (evolocumab and alirocmab) were studied extensively in open label randomized trials. Compared to standard therapy alone, there was an observed 61% reduction in the LDL-C over a period of 11 months. In the ODYSSEY LONG TERM trial, which studied patients at high risk of developing cardiovascular disease, there was a 61% reduction over 78 weeks with the use of alirocumab as compared to a 0.8% increase with statin therapy alone.

Two recent meta-analyses evaluated the use of PCKS9 inhibitors in more than 10,000 patients and included data from most available studies with evolocumab and alirocumab. All trials showed these agents lowered LDL-C substantially with a mean of 50%. The results appeared to hold true despite socioeconomic factors and lasted through-out follow-up. Additionally, there appeared to be no significant difference compared to placebo in terms of adverse events.

The DESCARTES study was a 52-week long study evaluating the efficacy and safety of evolocumab. The scientists found that a monthly injection of 420 mg led to mean reductions of 50% more reduction in LDL-C compared to placebo. This reduction persisted for the year of the clinical trial and the safety appeared to be equivalent compared to placebo.

It was suggested that LDL receptor is cleaved and degraded by PCSK by the fact that PCSK reduces hepatic LDL receptors. This hypothesis was disapproved by Dr. Jay Horton who developed a system for expressing a catalytic inactive type of PCSK9 and showed that it retained its ability to decrease LDL receptor numbers. The mechanism of how LDL receptors is lowered is now ell defined. Once PCSK9 reached the endosome and its acidic environment, the affinity for the PCSK9 and LDL receptor is increased 150-fold and it then binds to the epidermal growth factor-like repeat A of the LDL receptor. This binding causes the redistribution of the LDL receptors from the surface of the cell to the lysosome.

In another study, it was shown that two lipid lowering agents (statins and fibrates) also altered PCSK9 levels. Fibrates act on the PPARalpha pathway and upregulate genes that encode proteins lowering very low density lipoprotein trigylcerides and increasing the level of HDL-C. Their effect on LDL-C has been variable yet, their mean LDL-C reduction has been 17%. Using atorvastatin, researchers concluded that statins increase PCSK9 levels by an average of 7.4% in one study and 34% in another.

In the US, the only FDA-approved medications in this class are evolocumab and alirocumab.  A third medication, bococizumab, is cuurently in Phase 3 trials. They are indicated as an add-on to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH) and clinical ASVD. In the FDA indication, there is no indictation for using them in statin intolerant patients. The only safety concern raised to date is that of cognitive side effects with extensive lipid lowering. The ODYSSEY COMBO II study noted neurocognitive events in 0.8% of patients taking alirocumab, 1.2 % of patients taking ezetimibe and less than 2% of those taking evolocumab. The FDA has ordered further monitoring for neurocognitive events.

While these medications are not meant to be mainstream for lowering lipids, the cost is out-of-reach for those who may benefit. It carries a price tag of almost $15,000 annually. They further estimated that if these drugs were used in all eligible patients, cardiovascular care costs could be reduced by $29 billion over 5 years, but drug costs would increase by $592 billion.

The future of these medications is still uncertain.

While the results currently appear promising, there is still a lack of hard end points, namely reduction in cardiovascular events. Clinical trials are currently ongoing, with perhaps the ODYSSEY OUTCOMES and the FOURIER trials being the largest looking at cardiovascular end points. These medications appear to be safe at this point. However, they have only been investigated for 78 months which is a relatively short time to establish safety. In comparison, statins were investigated for 16 years and looked at millions of treated patients. While it was thought that the injection route may prove to be an obstacle, this has not proven to be evident in clinical trials. Another big barrier is cost as noted above. Unless the cost comes down, likely these agents will not be used commonly. As more evidence pours in, we must wait to know the role these medications will play in the future.

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About the Author

Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.