PCSK9 Inhibitors: A 5-Question Quiz


The PCSK9 inhibitor class is here to stay. Find out what you know about the enzyme and how its inhibition is revolutionizing CHD prevention.

The debut of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi-Regeneron) in mid-2015 has completely changed the landscape of primary and secondary prevention of coronary heart disease (CHD). If ever there were a “Cinderella” story in science, it would be this one which embodies a true “bench to bedside” tale. The drug target for inhibition of PCSK9 was discovered with the identification of both gain of function (GOF) and loss of function (LOF) mutations in this enzyme. The GOF mutation resulted in heterozygous familial hypercholesterolemia (HeFH) and high levels of CHD while LOF mutations resulted in a significantly lower LDL-cholesterol and risk of CHD.

Here is a typical patient with FH you might see in clinical practice (case adapted from Yuan et al1): A 34-year-old man of Irish ancestry was referred for dyslipidemia management. He had been in good general health until the age of 29 years, when routine blood tests returned a plasma total cholesterol (TC) result of 387 mg/dL and an LDL-C concentration of 309 mg/dL. His family history included premature CAD: his father and 2 paternal uncles each had elevated plasma levels of LDL-C and died of MI before 50 years of age.

Question 1:


Answer B. A heterogeneous group of disorders resulting in elevated serum cholesterol and triglyceride concentrations. (NOT consistent with FH) 

Familial hypercholesterolemia is transmitted via autosomal dominant inheritance and results mainly in isolated elevated total cholesterol (due to elevated LDL-C) and is less likely to cause elevations in triglyceride (TG) concentration. TGs are more commonly elevated in related disorders of cholesterol homeostasis, such as familial hypertriglyceridemia, familial combined hyperlipidemia and familial dysbetalipoproteinemia. In homozygous familial hypercholesterolemia (HoFH), diagnostic criteria can include genetic analyses and/or clinical scoring systems. Because of its autosomal dominant transmission, a through family history is important. Clinical manifestations include premature CHD, cutaneous manifestations such as tendon xanthomas, widespread atherosclerosis, and early mortality. HeFH, whose prevalence is higher than was previously appreciated, can also result in clinical characteristics such as tendon thickening, xanthelasmas, xanthomas, and corneal arcus. There are three currently accepted resources for diagnosis of FH: the Simon Broom Criteria, the Med Ped Criteria, and the FH Dutch Lipid Clinic Criteria. Although molecular diagnosis is helpful, it is not essential to diagnosis of this condition and early identification and treatment can have a considerable impact on the natural history of the disease.

Going back to our case…. At age 33, the patient experienced an acute MI. Angiography showed widespread CAD that required the placement of 3 stents. Daily oral drug therapy was initiated for secondary CAD prevention: atorvastatin (80 mg), ezetimibe (10 mg), ramipril (5 mg), clopidogrel (75 mg), bisoprolol (5 mg) and ASA (81 mg). At 6 months after his MI, his serum TC and LDL-C concentrations were 207 and 145 mg/dL, respectively; trial of rosuvastatin 40 mg resulted in slight improvement of his serum TC to 180 mg/dL and LDL-C to 125 mg/dL.

Is this patient a candidate for PCSK9 inhibitor therapy?  The answer will follow later. First, how much do you know about PCSK9 and inhibition of this enzyme? Test your knowledge below.

Question 2.


Answer: C. Regulation of LDL receptor glycoprotein on hepatic membrane.

PCSK9, is a part of a family of proprotein convertase enzymes that work to maintain homeostasis. PCSK9 directly regulates the cell-surface expression and degradation of low-density lipoprotein receptors (LDL-R) in the liver. When this enzyme is inhibited with a monoclonal antibody or siRNA (a PCSK9 inhibitor), the LDL-R does not bind PCSK9 and so can be recycled back to the cell surface to scavenge more circulating LDL-C. Hence, PCSK9 inhibition (or LOF mutations in PCSK9) leads to clinically lower levels of circulating cholesterol. Additional physiologic effects of PCSK9 have not yet been identified although animal studies have suggested a role in non-hepatic tissue, such as intestinal and adipocyte lipid metabolism, atherosclerotic plaque, apoptotic cell death, and regulation of glycemic control.

Option A is the mechanism of action of statins, which competitively inhibit HMG-CoA reductase, which is the first and rate-limiting enzymatic step of the cholesterol biosynthetic pathway. Option B is the mechanism of action of ezetemibe (Zetia) and option D is the mechanism of action of niacin.

In recent years, increasing attention has been turned towards familial lipid disorders, a risk factor that had previously been thought to not be readily modifiable.

Question 3.


Answer: B. As an adjunct to diet and maximally tolerated statin therapy for adults with HeFH or with clinical ASCVD.

 The indications listed in option B are the only currently approved indications for use of alirocumab in the United States. Option A is incorrect as this agent is not recommended as an alternative to statin therapy in patients who have no history of statin intolerance – statins remain the first line therapy for hyperlipidemia.. In Europe, alirocumab is approved for use as a stand-alone agent for adult patients with primary hypercholesterolemia (HeFH and non-familial) or mixed dyslipidemia as an adjunct to diet:

a) in combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach their LDL-C goals with the maximally-tolerated statin, or

b) alone or in combination with other lipid-lowring therapies for patients who are statin intolerant, or for whom a statin is contraindicated.

Alirocumab is not yet approved in primary prevention populations (option C) unless there is clinical ASCVD or FH present.

Question 4.


Answer: A. True (with a caveat).

The ODYSSEY-OUTCOMES trial, a prospective trial of ~18,000 patients after acute coronary syndrome (acute ischemic population) during treatment with alirocumab is expected to report results at the American College of Cardiology Conference in March 2018. However, outcome data are available from the FOURIER trial2 which reported on cardiovascular outcomes with the use of the evolcumab (Repatha, Amgen) in a secondary prevention population (stable CAD). At median follow up of 2.2 years, the results showed that there was a sustained reduction in LDL-C and a resulting reduction in the primary endpoint (composite of CVD, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the secondary endpoint (CVD, MI, stroke) with the benefit being driven primarily by reduction of non-fatal events such as stroke (lower by 0.4%), myocardial infarction (lower by 1.2%), coronary revascularization (lower by 1.5%). There was no mortality benefit. Some suggest that a mortality benefit may emerge with longer follow-up. No apparent safety signals emerged.

Question 5.


Answer: D. A and B

Overall, the two FDA-approved PCSK9 inhibitors are very well tolerated and there have been rare serious side effects. The mechanism of alirocumab and evolocumab is a humanized monoclonal antibody against PCSK9. Common side effects include injection site reactions and cold or flu and flu-like symptoms.  Serious side effect such as severe systemic allergic reactions/hypersesnitivity and hypersensitivity vasculitis, have been reported but are rare. Neurocognitive events were reported in 0.8% of patients treated with alirocumab and 0.7% of patients treated with placebo. Confusion or memory impairment were reported more frequently by those in the alirocumab group (0.2% for each) vs those in the placebo group (<0.1% for each). Liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of alirocuman-treated patients and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with alirocumab vs 1.4% of patients treated with placebo.

To date, despite thousands of patients being treated with monoclonal antibodies against PCSK9, there have been no significant unexpected adverse effects. Notably, no significant neurocognitive effects have emerged (a theoretical concern of achieving very low LDL concentrations) in a post-hoc analysis of the FOURIER randomized trial3 with another evolocumab.

And here's one to keep you on your toes...

Question 6.


Answer: B.

Isn’t it a mouthful?

Finally, to answer the question about the patient introduced earlier: Yes, he is most definitely a candidate for PCSK9 inhibitor therapy.  For this patient, he has already had clinical ASCVD (an MI) and he continues to have elevated LDL-C despite maximal dose of high intensity statin and ezetemibe. It is likely that he has HeFH driving his hyperlipidemia and PCSK9 inhibitors would be the most reasonable next step in optimal secondary prevention therapy.


1. Yuan G, Wang J, Hegele RA. Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. CMAJ : Canadian Medical Association Journal. 2006;174:1124-1129.

2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376:1713-1722. DOI: 10.1056/NEJMoa1615664.

3. Giugliano RP, Pedersen TR, Park J-G, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. The Lancet. 2017;390:1962-1971.

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