Will Evolocumab Help With Coronary Heart Disease?

The jury is out on the therapeutic benefit of evolocumab.

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Until recently, many physicians ascribed to the cholesterol-diet-CHD hypothesis. First, elevated levels of cholesterol in the blood or hypercholesterolemia cause coronary heart disease (CHD). Second, diets rich in animal fat and cholesterol increase cholesterol levels in the blood. Third, lowering cholesterol levels in the blood lowers the risk for coronary heart disease. 

At face value,  the cholesterol-diet-CHD hypothesis seems to make sense.

After all, "we are what we eat," and if we eat diets rich in cholesterol and saturated (animal) fats, then our blood cholesterol levels would likely go up. Furthermore, because plaques—which clog arteries and cause CHD and stroke—are in part made up of cholesterol, increased levels of cholesterol in the blood secondary to diet would increase risk for CHD and stroke. And, if you were to lower cholesterol levels in your blood using medications, then you decrease your risk for CHD and stroke, right? Well, with respect to all these assumptions, unlikely ...

Most recently, there's been a sea change in the principles that govern the management of CHD. We're unsure whether a diet rich in cholesterol and saturated fats is directly responsible for increased levels of cholesterol in the blood. Furthermore, we're unsure whether lowering blood cholesterol levels in those at risk for heart disease helps prevent stroke, unstable angina, heart attack and more.

All we do know is that lifestyle modification (for example, weight loss, exercise and smoking cessation) as well as statins, or drugs like Zocor and Crestor, which stabilize plaques and happen to lower low-density lipoprotein cholesterol (LDL-C) or "bad" cholesterol, probably help prevent death and other adverse cardiovascular events,    

Evolocumab belongs to a new class of drug.  In clinical trials it has been shown to quickly decrease LDL-C levels in various participant populations—most notably in those with a genetic disorder called familial hypercholesterolemia that causes cyclopean (really, really high) levels of cholesterol in the blood. Now whether evolocumab will confer any benefit in the majority of people at risk for death and adverse events caused by coronary heart disease remains to be seen, and likely depends on results of long-term or prospective studies which observe participants during years of evolocumab (Repatha) therapy. In other words, only time will tell whether evolocumab works.

What Is Evolocumab?

Evolocumab is fully human monoclonal antibody that binds and thus inhibits the protein PCSK9. This protein interferes with the receptor that picks up LDL-C for degradation by the liver and also interferes with this receptor's ability to recycle. (Interestingly, research suggest that statins may somehow upregulate PCSK9; however, when used together, statins and evolocumab don't exactly synergize or potentiate.)

Currently, Amgen, evolocumab's maker, is conducting several large-scale clinical trials in diverse patient populations across the globe. Results of these trials are promising with respect to evolocumab's ability to lower LDL-C levels. For example, in one Phase 3 trial, participants with the worst form of familial hypercholesterolemia (homozygous familial hypercholesterolemia) who were on statin therapy (some were also on another cholesterol drug called Zetia) experienced a 31 percent decrease in LDL-C levels at 12 weeks compared with folks who didn't receive the drug. (Participants also experienced a 23 percent decrease in apolipoprotein B.) Importantly, evolocumab worked faster than two other new drugs coming down the pipeline: lomitapide and mipomersen. To boot, in terms of adverse effects, evolocumab is better tolerated than lomitapide and mipomersen.

In another Phase 3 trial, participants who were intolerant of at least two statins and were treated with only evolocumab and Zetia saw a 53 to 56 percent decrease in LDL-C as compared with a 37 to 39 percent decrease in participants receiving Zetia alone. Furthermore, evolocumab elicited fewer adverse events than Zetia.

Finally, in Phase 2 studies, in participants with hypercholesterolemia and already on medium- to high-intensity statin therapy, evolocumab reduced LDL-C levels by  66 to 75 percent when administered twice a month.

What Does Evolocumab Mean to You?

At this point, the jury is still out as to whether evolocumab will be able to confer any health benefit in people at risk for stroke and heart attack. Simply lowering cholesterol levels probably means little in most people, a point driven home by the new ACC/AHA guidelines which have effectively abolished "target" levels of serum cholesterol. Furthermore, these guidelines suggest that statins, the only drugs that really show any benefit in reducing cardiovascular morbidity and mortality, should be prescribed in people who already have cardiovascular disease (stroke or heart attack), people with LDL-C levels more than 190 (very high levels of "bad" cholesterol), people aged 40 to 75 years with type 2 diabetes, and people aged 40 to 75 years with a 7.5 percent risk of cardiovascular disease during the next 10 years. 

If during long-term clinical trials which follow participants for years, evolocumab proves effective at mitigating repercussions of cardiovascular disease like stroke and heart attack, then we're looking at a pharmaceutical success that can only be compared with the statins. We're also facing affirmation of the cholesterol-diet-CHD hypothesis which has so far proven unlikely based on years of scientific scrutiny. Ultimately, evolocumab's ability to dramatically lower LDL-C levels in diverse participant populations brings to mind the blockbuster drug Zetia, which has proven to be ineffective (or even slightly detrimental) at preventing plaque buildup in study participants. In other words, Zetia was an epic fail and so could be evolocumab

Sources

“Anti-PCSK9 Antibody Effectively Lowers Cholesterol in Patients with Statin Intolerance” by Erik Stroes and colleagues published on 11/23/2014 (e-pub ahead of print) in the Journal of the American College of Cardiology. 

Bersot TP. Chapter 31. Drug Therapy for Hypercholesterolemia and Dyslipidemia. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011.

“Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial” by JG Robinson and colleagues published in JAMA on 5/14/2014. 

 “Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolemia (TESLA Part B): a randomised, double-bline, placebo-controlled trial” by FJ Raal and colleagues published in The Lancet on 10/2/2014. 

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