Hyperlipidemia: Management with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

Role of PCSK9 in Cholesterol Metabolism

Multiple studies demonstrating a linear relationship between lowering serum LDL-C levels and improving outcomes in cardiovascular disease⁵, along with inadequacy of statin with or without concomitant other lipid-lowering strategies to reduce LDL-C to desired levels, have sparked interest in developing novel therapies for LDL-C reduction. PCSK9 is a protein belonging to a family of proteases called proprotein convertases, which is secreted mostly by the liver, with small amounts secreted from the small intestines and the kidneys. It is encoded by the PCSK9 gene located on chromosome 1p32.3.⁶ Under normal conditions, PCSK9 promotes hypercholesterolemia by binding to LDL receptors on the surface of hepatocytes, following which, the LDL receptor is internalized and transported to lysosomes for degradation. This leads to a decrease in the number of LDL receptors on the hepatocyte surface and, therefore, resulting in reduced clearance of LDL-C from the blood⁷, resulting in elevated serum LDL-C levels. There is also supporting data that suggests the low-density lipoprotein receptor and apolipoprotein E2 receptor are partly regulated by PCSK9.⁶

PCSK9 was first recognized as a potential target for LCL-C-lowering therapy in 2003.^8,9 Since then, genetic studies of patients have confirmed the role of PCSK9 in LDL-C regulation. A gain of function mutation in the PCSK9 gene has been recognized as a cause of a rare but severe form of autosomal dominant hypercholesterolemia.⁹ Conversely, a loss of function mutation in the PCSK9 gene has been associated with significantly reduced levels of LDL-C and lower risk of coronary heart disease.¹⁰ These observations have led to PCSK9 being recognized as a potential target for modulating cholesterol metabolism.

PCSK9 Inhibitors

The goal of PCSK9 inhibitor therapy is to reduce serum LDL-C levels by curtailing PCSK9 activity. Suppressing PCSK9 activity leads to decreased LDL receptor degradation, therefore, increasing LDL receptor expression on the hepatocyte surface and resulting in increased clearance of LDL-C from the blood stream (Table 1). Although other therapeutic approaches to inhibit PCSK9 by using compact proteins called adnectins and short interfering RNA targeting PCSK9 synthesis in hepatocyte have been developed, as of now, anti-PCSK9 monoclonal antibodies remain the mainstay PCSK9 inhibitor therapy. The Food and Drug Administration in 2015 approved evolocumab (Repatha) and alirocumab (Praluent) for use in patients with familial hypercholesterolemia and patients with cardiovascular disease who require further reduction in LDL-C. Both of these agents are fully humanized monoclonal antibodies that need to be administered via subcutaneous injections.¹¹ Both evolocumab and alirocumab are approved for administration once a month or every 2 weeks. The drug is stored in a refrigerator and warmed to room temperature before administration.¹¹ Before administration, both evolocumab and alirocumab should be allowed to warm for at least 30 minutes at room temperature. Refrigeration can be avoided if the drug can be stored in original carton at 77°F (or 25°C) and used within 30 days.

Efficacy of Monoclonal Antibodies to PCSK9 and Their Impact on Cardiovascular Outcomes

Monoclonal antibodies have been very effective in lowering serum LDL-C. A well-powered meta-analysis by Zhang XL et al¹² including 25 randomized controlled trials encompassing 12,200 patients evaluated the efficacy and safety profile of monoclonal antibodies to PCSK9. Monthly treatment with 420 mg of evolocumab reduced LDL-C by 55% compared with placebo and by 36% compared with ezetimibe. Furthermore, it increased high-density lipoprotein cholesterol (HDL-C) by 7.6% compared with placebo and by 6.4% versus ezetimibe. Similarly, biweekly treatment with alirocumab decreased LDL-C by 53% and 30% versus placebo and ezetimibe, respectively, while increasing HDL-C by 8% compared with placebo (Table 2).

The maximal reduction in LDL-C reaches a plateau once all the PCSK9 is bound, with additional dosing only prolonging duration of action.¹¹ In addition to having a positive effect on the LDL-C and HDL-C profile, a pooled analysis of data from 3 12-week trials found evolucumab reduced non-HDL-C by 58%, total cholesterol by 40%, triglycerides by 17%, and lipoprotein(a) by 29%.¹³ Efficacy of evolucumab was comparable in both diabetics and nondiabetics.¹³ In a separate prospective trial, alirocumab was found to have similar effects on the overall lipid profile in both diabetics and nondiabetics.¹¹ The lipoprotein(a)-reducing effect of PCK9 monoclonal antibodies^11,14 seems to be an additional benefit over statins. Lipoprotein(a) has been recognized as an independent risk factor for cardiovascular disease in epidemiologic studies.¹⁵

There is accumulating evidence that PCSK9 monoclonal antibodies are very effective at reducing LDL-C levels.^11,16 OSLER 1 and OSLER 2 were 2 open-labeled randomized trials that looked at the safety and efficacy of evolocumab. These trials showed that evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P value < .001).¹⁷ After 1 year of treatment, adverse event rates were similar in both groups, although the evolocumab group had more neurocognitive events reported.¹⁷ Recently, the FOURIER trial showed a 59% reduction in LDL-C levels that was found at 4 weeks and persisted throughout the mean follow-up of 2.2 years when evolocumab was added to statin therapy. It also showed that evolocumab treatment, in comparison to standard medical therapy, significantly reduced the risk of the primary end point (composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) by 1.5% (9.8% versus11.3%), with a hazard ratio of 0.85 (95% CI, 0.79–0.92; P < .001).¹⁸ There was also reduction in the key secondary end point of composite of cardiovascular death, myocardial infarction, or stroke by 1.5% (5.9% versus 7.4%), with a hazard ratio of 0.80 (95% CI, 0.73–0.88; P < .001).¹⁸ With the exception of injection site reactions, evolocumab did not increase the rate of serious adverse events, including new-onset diabetes and neurocognitive events. Similarly, the trial Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound demonstrated an improvement in coronary plaque volume in patients given evolocumab in addition to statin therapy.¹⁹

We await the ODYSSEY OUTCOMES²⁰ trial, which evaluates the effect of adding alirocumab in cardiovascular outcomes in patients after an acute coronary event. In a post hoc analysis of a 78-week trial comparing alirocumab with placebo in 2341 patients at high risk for cardiovascular events (ODYSSEY LONG TERM trial), in addition to significant reduction of LDL-C levels, the rate of major cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was found to be lower (1.7% versus 3.3%; hazard ratio, 0.52; 95% CI, 0.31–0.90; nominal P = .02) among patients who received alirocumab in addition to statin.¹⁶

Safety Profile of the Monoclonal Antibodies to PCSK9

With their profound LDL-C-lowering effects, PCSK9 inhibitors offer both patients and clinicians a potent alternative or adjunct to current therapy, and their safety profile is as impressive. When comparing emergent adverse events, the overall incidence of these events is not significantly different in placebo, ezetimibe, or PCSK9 inhibitor patient populations.¹² Tolerability is quite high, with low rates of discontinuation in long-term studies of the fully human monoclonal antibodies, alirocumab and evolocumab (Table 3). There are no known drug interactions for either of the medications.

Alirocumab was associated with an increased rate of injection-site reactions (relative risk 1.48, 6%) and with a lower risk of death when compared with placebo at 52 weeks.^12,20 Patients receiving evolocumab had injection-site reactions occurring in 2.1% compared with 1.6% in the placebo arm, with 90% of these reactions classified as mild.²¹ Rates of allergic reactions did not differ significantly between placebo and evolocumab patients.²¹ No difference in reported adverse events was found between the month and bimonthly administration of evolocumab at 12 weeks.

There has been no significantly identifiable trend in the incidence of musculoskeletal or connective tissue disorders, creatine kinase elevation, influenza, nasopharyngitis or autoantibody development reported with the fully human monoclonal antibodies.^12,20

There has been some concern with respect to adverse neurocognitive events; however, they seem unlikely given the size and inability of these agents to cross the blood-brain barrier. Nonetheless, in the EBBINGHAUS substudy of the recently concluded FOURIER study, neurocognitive function (to include memory, attention, and reaction time) was assessed and evolocumab was found to be no different from placebo by noninferiority analysis.²²

Clinical Implications

Increased serum LDL-C concentration has always been considered a major risk factor associated with ASCVD. Although lifestyle modification has an important role in lowering LDL-C levels, pharmacotherapy is often needed to further reduce LDL-C levels, particularly in patients with ASCVD. Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are the most commonly prescribed pharmacologic agents for patients with ASCVD. Although role of statin therapy has been established in both primary prevention as well as progression of ASCVD²³, it is associated with clinically significant side effects that include increased risk of diabetes, muscle pain, and damage to hepatocytes.²⁴ Although their frequency is low, these side effects are often the reason why statin therapy is not tolerated by some patients. Moreover, a subset of patients, whose genomic profile predisposes them to very high levels of LDL-C due to alteration in LDL-C metabolism, will not achieve the desired therapeutic effect from statin therapy alone or in combination with other lipid-lowering agents.

The need for a more potent LDL-C-lowering therapy, called for more extensive research geared toward mechanisms of LDL-C clearance from the serum. PCSK9 proteins were recognized as important modulators in lipid metabolism. Over the past decade, considerable effort has been made to target PCSK9 to lower serum LDL-C levels.²⁵ In 2015, the Food and Drug Administration approved 2 new humanized monoclonal antibodies, evolocumab (Repatha) and alirocumab (Praluent). These 2 new agents are attractive therapeutic modalities for practitioners treating difficult dyslipidemia, who otherwise have limited options. Moreover, infrequent subcutaneous administration (once every 2 weeks to 4 weeks) guarantees improved compliance and steady blood levels in comparison to medications taken orally.

Although PCSK9 inhibitors seem to take the battle against hyperlipidemia to a whole new level, these novel therapeutic options have a long way to go to gain popularity among health care practitioners. Limited by their annual costs of $14,000 to $15,000, PCSK9 inhibitors add extra costs to the health care system. When compared with the annual costs of statin therapy (assumed at $485 based on low-cost generic therapy), PCSK9 inhibitors are clearly much more expensive. It is not clear if this extra cost is justified by additional long-term benefits, both at individual and health care system levels. With promising clinical outcome benefits, it may add economic value. However, the scale of these outcome benefits needs to be evaluated in large randomized trials. With the currently available outcomes data, it has been suggested that the price should be reduced to $4250. (around 70% of its current value) for PCSK9 inhibitors to be cost-effective.²⁵

Despite the promising potential advantages of PCSK9 that have been addressed so far, there is one important limitation identified. The clinical response among patients with familial hypercholesterolemia varies widely and depends mainly on if patient is heterozygous or homozygous for the disease.²⁶ Patients with a homozygous mutation for familiar hypercholesterolemia had a substantially reduced response to PCSK9, compared with patients who were heterozygous.²⁶

One of the main drawbacks regarding literature supporting PCSK9 inhibitors is the paucity of long-term and large-scale clinical outcomes data. Large-scale trials with long-term follow-up that are adequately powered are needed to address actual impact on clinical outcomes. Until then, its exact role for addressing residual ASCVD risk remains unclear.²⁷

The expert panel of National Lipid Association has recently published a guideline document with recommendations on suggested indications for PCSK9 inhibitors.²⁸ National Lipid Association recommends the use of PCSK-9 inhibitors to reduce the level of LDL-C in following conditions (Table 4):

1. Atherosclerotic Cardiovascular Disease

   1. Stable ASCVD patients with additional risk factors and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL, despite maximum tolerated statin dose with or without ezetimibe,

   2. Progressive ASCVD patients with LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL, despite maximum tolerated statin dose with or without ezetimibe.

2. Phenotypic Familial Hypercholestrolemia (FH)

   1. Phenotypic FH patients aged 40 years to 79 years with baseline LDL-C ≥190 mg/dL and with other ASCVD risk factors that are controlled and with no additional high-risk markers, but with LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL, despite maximum tolerated statin dose with or without ezetimibe,

   2. Phenotypic FH patients aged 40 years to 79 years with baseline LDL-C ≥190 mg/dL and with other uncontrolled ASCVD risk factors or with additional high-risk markers or genetic confirmation of FH and with LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL, despite maximum tolerated statin dose with or without ezetimibe,

   3. Phenotypic FH patients aged 18 years to 39 years with baseline LDL-C ≥190 mg/dL and with other uncontrolled ASCVD risk factors or with additional high-risk markers or genetic confirmation of FH and with LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL, despite maximum tolerated statin dose with or without ezetimibe,

   4. Homozygous FH patients with either of unknown genotype or those known to be LDL-C receptor defective and with LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL, despite maximum tolerated statin dose with or without ezetimibe.

3. Statin Intolerance

   1. High-risk patients who require additional cholesterol-lowering therapies despite using adequate doses of other nonstatin lipid-lowering drugs.

Summary

PCSK-9 offers an option for additional LDL-C reduction beyond that that could be achieved by conventional lipid-lowering strategies to achieve recommended LDL-C goals in patients with high risk of ASCVD events. It is also recommended in patients for primary and secondary prevention of ASCVD in selected group of patients. PCSK-9 inhibitors are fairly well tolerated. The cost of medication is currently an issue and would require third party insurance support for a wider acceptance of this medication.