149

p. 125

p. 126

EFFICACY

Consumption of foods rich in omega-3 fatty acids (e.g., fish) several times a week

has been associated with a reduced risk of heart disease and is recommended as part

of a low-fat diet. Supplements of fish oils demonstrated a reduction in CHD in

patients with a recent MI

151 as well as patients taking statins.

152 Recently, however,

other trials have failed to demonstrate the benefits of omega-3 fatty acids in addition

to standard cardiovascular drugs, such as statins, angiotensin-converting enzyme

(ACE) inhibitors, β-blockers, and antiplatelet agents.

153 Commercial sources of fish

oils vary in their content. The omega-3 fatty acids used in the GISSI study, which

demonstrated a CHD risk reduction, contained 850 mg of combined EPA and DHA.

Currently two trials, the Reduction of Cardiovascular Events with EPA-Intervention

trial (REDUCE-IT) and Outcome Study to Assess Statin Residual Risk Reduction

with Epanova in Hypertriglyceridemia (STRENGTH), are underway to evaluate

cardiovascular outcomes in patients with CHD or at high risk for CHD (REDUCEIT) or high risk for CHD (STRENGTH) already taking statin therapy. The results of

these trials will help to carve out the role of these agents in this patient

population.

154,155

PHARMACOKINETICS/PHARMACODYNAMICS

There is limited pharmacokinetic or pharmacodynamic data available for these

agents. The combined EPA and DHA ethyl ester formulation (Lovaza

R

, Omtryg

R

) is

well absorbed following oral administration. The EPA and DHA carboxylic acid

preparation (Epanova

R

) is directly absorbed in the small intestines subsequently

entering the systemic circulation mainly via the thoracic duct lymphatic system.

150

Steady-state concentrations of EPA and DHA in plasma are achieved within 2 weeks

following repeat daily dosing. The omega-3 fatty acids in carboxylic acid form may

be administered without regard to meals. They are mainly oxidized in the liver and

do not undergo renal elimination.

Following oral administration, the EPA ethyl ester preparation (Vasepa

R

) is deesterified during process and the active metabolite EPA is absorbed in the small

intestine and enters the systemic circulation mainly via the thoracic duct lymphatic

system.

149 Peak plasma concentrations of EPA are reached in approximately 5 hours.

No studies on the effect of food on this product have been conducted. However, the

recommendation is for it to be taken with or following a meal. The EPA ethyl ester is

mainly metabolized by the liver via β-oxidation. This beta oxidation splits the long

carbon chain of EPA into acetyl coenzyme A which is then converted into energy via

the Krebs cycle. EPA ethyl ester does not undergo renal elimination.

ADVERSE EFFECTS

The most common adverse effects associated with Lovaza are eructation, dyspepsia,

and taste perversion. In addition to eructation, Epanova has also been reported to

cause diarrhea, nausea, and abdominal pain. The most common adverse effect

reported with Vasepa is arthralgia.

PLACE IN THERAPY

Fish oils predominantly contain long-chain polyunsaturated (omega-3) fatty acids,

EPA and DHA, which lower TG levels significantly (30%–60%) but have variable

effects on cholesterol levels. They do not provide LDL-C reduction. All of the

available prescription products may be used as an adjunct to diet to treat

hypertriglyceridemia. The recommended dose of Lovaza is 4 g/day in either a single

or divided dose. The dose for Vasepa is 2 g twice daily with food and Epanova is 2

to 4 g daily.

DRUG INTERACTIONS

No significant drug interactions have been reported with any of the prescription

products. However, some studies suggest that the use of omega-3 fatty acids may

prolong bleeding time. However, there have been no thorough clinical trials

conducted to determine the magnitude of this interaction. Therefore, patients taking

these along with other anticoagulants should be evaluated more closely for any signs

of increased bleeding.

CLINICAL PEARLS

Omega-3 fatty acid capsules should be swallowed whole. Do not break open, crush,

dissolve, or chew.

Administering fish oil before meals may decrease the fishy taste.

EPA has negligible effect on LDL-C Both EPA and DHA lower triglycerides but

DHA as well as the combination of EPA/DHA is more effective than EPA-only

preparations DHA-containing preparations may increase LDL-C, mechanism likely

due to increase in apoC-III production.

Bile Acid Resins

MECHANISM OF ACTION

Bile acids are secreted into the intestines and are responsible for emulsifying fat and

lipid particles in food. Most of the bile acids that are secreted are reabsorbed and

returned to the liver by enterohepatic circulation. The BASs are anion-exchange

resins that bind bile acids in the intestinal lumen and cause them to be eliminated in

the stool.

156–159 By disrupting the normal enterohepatic recirculation of bile acids

from the intestinal lumen to the liver, the liver is stimulated to convert hepatocellular

cholesterol into bile acids. This results in a reduction in the concentration of

cholesterol in the hepatocyte, prompting upregulation of LDL receptor synthesis.

Finally, circulating LDL-C levels are lowered by binding to the newly formed LDL

receptors on the liver surface (Fig. 8-14).

Figure 8-14 Mechanism of action of bile acid sequestrants. HMG-CoA, 3 hydroxy-3 methyl-glutaryl coenzyme A;

LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; VLDL, very low-density lipoprotein.

p. 126

p. 127

EFFICACY

The BAS agents have demonstrated the ability to reduce CHD events in the Lipid

Research Clinics Coronary Primary Prevention Trial (LRC-CCPT).

160 This was a

randomized, multicenter trial evaluating the efficacy of cholesterol lowering in

reducing coronary artery disease (CAD) risk in 3,806 men with primary

hypercholesterolemia. In conjunction with diet, patients were randomized to

cholestyramine 24 g/day or placebo. The mean follow-up was 7.4 years. The primary

endpoint of combined CAD death and non-fatal MI was reduced by 19% in the

patients treated with cholestyramine compared to placebo-treated patients (p < 0.05).

This study also supports the “lower is better” hypothesis of LDL-C.

160,161 These

agents reduce LDL-C between 12% and 27%, total cholesterol by 8% and 27%.

HDL-C is increased minimally by around 3% to 10%. All of the BAS also may raise

TG levels by 3% to 10% or more, especially in patients with high TG levels.

PHARMACOKINETICS/PHARMACODYNAMICS

Colesevelam is a nonabsorbable polymeric compound that binds to bile acids more

strongly and more specifically than the other available BAS.

159 Colestipol and

cholestyramine are nonabsorbable hydrophilic basic anion exchange resins. All of

these agents are insoluble in water.

157,158

ADVERSE EFFECTS

The most common adverse effect associated with these agents is constipation.

Additional adverse effects include abdominal bloating, epigastric fullness, nausea,

vomiting, steatorrhea, and flatulence.

157–160 The incidence of these GI symptoms is

less with colesevelam.

PLACE IN THERAPY

BAS are indicated as an adjunct to diet and exercise to lower LDL-C. These agents

may be used alone or in combination with statins. The BAS have appeal in the

management of hypercholesterolemia because they have a strong safety record and

they effectively lower LDL-C. They are not absorbed from the gastrointestinal (GI)

tract and thus lack systemic toxicity. Older BAS (cholestyramine, colestipol) are not

well tolerated due to numerous GI side effects and the unpleasant granular texture of

the powder. Therefore, colesevelam is currently the preferred agent. Colesevelam is

indicated as monotherapy or in combination with a statin to reduce LDL-C levels in

boys and postmenarchal girls, 10 to 17 years of age, with HeFH. Therapy may be

initiated following adequate trial of diet if LDL-C remains ≥190 mg/dL or LDL-C

remains ≥160 mg/dL and there is a positive family history of premature ASVD or

two or more other CVD risk factors. Colesevelam is also approved by the US FDA

for use in type 2 diabetes to improve glycemic control.

159

DRUG INTERACTIONS

Reduction in the absorption of fat-soluble vitamins and folic acid has been reported

with high dosages of BAS, but this is rarely a problem in otherwise healthy patients

consuming a nutritionally balanced diet. Cholestyramine and colestipol may reduce

or delay the absorption of medications when co-administered.

157–159 This can be

minimized by administering other medications 1 hour before or 4 hours after the resin

dose. The resins may also reduce the absorption of warfarin, levothyroxine, thiazide

diuretics, β-blockers, and presumably other anionic drugs. Colesevelam has been

shown to reduce levels of glimepiride, glipizide, glyburide, levothyroxine,

cyclosporine, olmesartan, and oral contraceptives containing esthynyl estradiol and

norethindrone. To avoid these interactions, these agents should be administered 4

hours prior to colesevelam. Colesevelam has also been shown to increase metformin

levels and patients should be monitored for clinical response. Post marketing reports

have also shown an interaction with phenytoin. As with the other drug interactions,

phenytoin should be administered 4 hours prior to colesevelam.

CLINICAL PEARLS

Use of BAS should be avoided in patients with complete biliary obstruction.

BAS are contraindicated if TGs are >500 mg/dL and in patients with a history of

hypertriglyceridemia-induced pancreatitis.

Colesevelam for oral suspension should be mixed with 4 to 8 ounces of water, fruit

juice, or diet soft drinks.

These agents should be initiated only when TG levels are <300 mg/dL.

Microsomal Triglyceride Protein Inhibitors

(Lomitapide)

MECHANISM OF ACTION

Lomitapide is the first in a new class of antihyperlipidemic agents to improve

lipoprotein profiles in patients with HoFH. Microsomal triglyceride protein (MTP)

resides in the lumen of the endoplasmic reticulum. Inhibiting MTP production

prevents the assembly of apoB-containing lipoproteins in enterocytes and

hepatocytes. This subsequently inhibits the production and subsequent secretion of

chylomicrons and VLDL, and subsequent production of LDL-C.

162

EFFICACY

There is one pivotal phase III study that ultimately led to the approval of lomitapide.

This was a multinational, single-arm, open-label, 78-week trial in 29 patients with

HoFH.

163 Following a 6-week run in phase, patients were initiated on lomitapide 5

mg daily and titrated to doses of 10, 20, 40 mg, up to 60 mg, based on tolerability and

liver enzymes levels.

163 Patients were also instructed to follow a low-fat diet (<20%

of calories from fat) as well as to take dietary supplements to replace fat-soluble

nutrients.

Initial efficacy was assessed after 26 weeks and then patients were continued on

the study medication for an additional 52 weeks to assess for long-term safety. The

primary endpoint was change in LDL-C from baseline at 26 weeks. The results

showed that lomitapide, when added to the existing lipid-lowering therapy,

significantly reduced LDL-C by an average of 40% from baseline at week 26.

163

PHARMACOKINETICS/PHARMACODYNAMICS

Lomitapide undergoes extensive hepatic metabolism. Metabolic pathways include

oxidative-N-dealkylation, glucuronide conjugation, oxidation, and piperidine ring

opening. The CYP3A4 isoenzyme metabolizes lomitapide to its major metabolites.

Lomitapide is highly bound to plasma proteins (99.8%) and has a mean terminal

elimination half-life of 39.7 hours. Approximately 59.5% and 33.4% of the dose is

excreted in the urine and feces, respectively.

162

PLACE IN THERAPY

Lomitapide is approved as an adjunct to a low-fat diet and other lipid-lowering

therapies, including LDLapheresis, to reduce LDL-C, TC, apo B, and non–HDL-C in

patients with HoFH. Due to the concern for liver injury the drug is only available thru

a Risk Evaluation and Mitigation Strategies (REMS) program. Given the risk of

adverse effects, unknown effects on cardiovascular morbidity and mortality, as well

as the absence of data in the non-HoFH population, lomitapide treatment should be

restricted to patients with HoFH.

ADVERSE EFFECTS

The primary adverse effects associated with lomitapide include GI symptoms,

elevated transaminases, and hepatic steatosis. The

p. 127

p. 128

most common GI symptom report was diarrhea which occurred in 79% of patients,

followed by nausea (65%), dyspepsia (38%), and vomiting (34%). Additional GI

symptoms that have been reported include abdominal pain and discomfort,

constipation, and flatulence. To minimize the risk of these adverse effects, patients

should adhere to a diet that is low in fat (<20% of daily energy). Elevations in

hepatic transaminases occurred in 34% of patients. The degree of elevation ranged

from an ALT or AST of ≥3× the ULN to 5× the ULN. However, no patients in the

clinical trial had to discontinue therapy due to elevated transaminases.

DRUG INTERACTIONS

The use of lomitapide in combination with strong inhibitors of CYP3A4 (boceprevir,

clarithromycin, conivaptan, indivavir, itraconazole, ketoconazole,

lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir,

saquinavir, telaprevir, voriconazole, telithromycin), moderate inhibitors of CYP3A4

(amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, imatinib,

verapamil, crizotinib, atazanavir, diltiazem, darunavir/ritonavir) as well as

grapefruit juice is contraindicated. Strong CYP3A4 inhibitors in combination with

lomitapide can result in an approximately 27-fold increase in exposure of lomitapide.

Moderate CYP3A4 inhibitors in combination with lomitapide have not been fully

evaluated but are expected to increase lomitapide levels. Even weak CYP3A4

inhibitors can increase lomitapide exposure by approximately twofold. When

lomitapide is used in combination with warfarin, the INR may increase by as much as

22%. Lomitapide in combination with simvastatin leads to doubling of simvastatin

exposure. When used in combination with statin therapy, the dose of statin should be

reduced by 50% and the dose of simvastatin should be limited to 20 mg daily. A dose

of simvastatin of 40 mg daily may be used if patients have previously tolerated

simvastatin for at least a year at a dose of 80 mg daily. While specific drug

interactions between lomitapide and lovastatin have not been studied, given that the

metabolizing enzymes and transporters responsible for the disposition of these two

agents are similar, a reduced dose of lovastatin should be considered. Lomitapide is

also an inhibitor of P-glycoprotein (P-gp). The use of lomitapide in combination with

P-gp substrates (aliskiren, fexofenadine, topotecan, sitagliptin, saxagliptin, imatinib,

maraviroc, digoxin, dabigatran, ambrisentan, colchicine, everolimus, lapatinib,

nilotinib, posaconazole, sirolimus, talinolol, tolvaptan, sirolimus, tolvaptan,

talinolol) may lead to increased absorption of these agents and dose reduction should

be considered. Although not tested, it is recommended that BAS be administered at

least 4 hours apart from lomitapide. This is to avoid potential interference with

absorption of lomitapide.

160

CLINICAL PEARLS

The initial dose of lomitapide is 5 mg once daily with a full glass of water, and at

least 2 hours following the evening meal.

Patients should adhere to a low-fat diet consisting of <20% of their dietary intake

when prescribed lomitapide.

Patients should also consume supplements (provided by pharmacy with lomitapide

prescription) that contain vitamin E (400 IU), linoleic acid (200 mg), alphalinolenic acid (210 mg), EPA (110 mg), and DHA (80 mg).

The dose of lomitapide can be increased after 2 weeks to 10 mg once daily and then

titrated upwards as follows: at 6 weeks increase the dose to 20 mg once daily, at

10 weeks increase to 40 mg once daily, and after 14 weeks the dose may be

increased to the maximum dose of 60 mg.

The maximum dose in patients with ESRD on hemodialysis or mild hepatic

impairment is 40 mg once daily.

The use of lomitapide is contraindicated in patients with active liver disease

(unexplained persistent elevations of serum transaminases), moderate to severe

hepatic impairment, pregnancy, as well in combination with moderate or strong

CYP3A4 inhibitors as outlined above.

Patients on warfarin along with lomitapide should have their INR closely monitored

and warfarin dosage adjusted as needed.

Obtain ALT, AST, and total bilirubin prior to initiation of therapy, prior to each dose

increase, or monthly, whichever comes first.

After the first year of therapy, ALT, AST, and total bilirubin should be monitored at

least every 3 months and prior to any dose increase. If the LFTs are >3× the ULN

and <5× the ULN, repeat labs in 1 week to confirm the elevation. If the elevation is

confirmed, reduce the dose and obtain additional liver-related tests. Repeat labs

weekly and discontinue therapy if LFTs increase >5× the ULN and do not decrease

to <3× the ULN within approximately 4 weeks.

Apo B Antisense Oligonucleotides

MECHANISM OF ACTION

Mipomersen is an antisense oligonucleotide targeted to human messenger ribonucleic

acid (mRNA) for apo B-100. Mipomersen is complementary to the coding region of

the mRNA for apo B-100 and binds by Watson and Crick (guanine–cytosine and

adenine–thymine) base pairing. The hybridization of this agent to the cognate mRNA

results in RNase H-mediated degradation of the cognate mRNA thereby inhibiting

translation of the apo B-100 protein. This action leads to reduced apo B synthesis,

the structural core for all atherogenic lipids, including LDL-C.

164–166

EFFICACY

Mipomersen has been evaluated in two phase III studies. The first was a randomized,

double-blind, placebo-controlled multicenter trial in 58 patients with FH. Patients

were included if their LDL-C was ≥140 mg/dL or LDL-C ≥92 mg/dL plus CAD, on

maximally tolerated lipid-lowering therapy. Patients were administered subcutaneous

dose of 200 mg of mipomersen weekly for 26 weeks or placebo.

167 The results

showed a 36% reduction in LDL-C versus a 13% increase with placebo (p < 0.001).

Additionally, apo B and lipoprotein(a) were also significantly reduced (p < 0.001).

ALT and AST were increased in 21% and 13% of patients, respectively. Hepatic

steatosis was observed with an incidence of 13%. The second phase III study was

also a randomized, double-blind, multicenter study evaluating 158 patients with

baseline LDL-C ≥100 mg/dL with or at high risk for CAD and on maximum tolerated

lipid-lowering therapy.

168 As with the previous study, mipomersen 200 mg was

administered subcutaneously once a week for 26 weeks. The results revealed a

36.9% reduction in LDL-C compared to a 4.5% reduction with placebo (p < 0.001).

Apo B was significantly reduced by 38% as was lipoprotein(a) by 24% (p < 0.001).

Additionally, half of the patients achieved LDL-C levels of <70 mg/dL in the

mipomersen group. Elevations in ALTs observed were similar to other studies and

ALT > 3× the ULN occurred in 10% of patients.

PHARMACOKINETICS/PHARMACODYNAMICS

Mipomersen is administered via subcutaneous injection. The drug has a

bioavailability ranging from 54% to 78%. Peak plasma concentrations are generally

obtained within 3 to 4 hours. With weekly administration, steady state is reached

within approximately 6 months. It is highly bound to human plasma (≥90%) and has

an elimination half-life of 1 to 2 months following subcutaneous administration.

Mipomersen is metabolized in tissues by endonucleases to form shorter

oligonucleotides that are then substrates for additional metabolism by exonucleases.

Mipomersen is not a substrate for the CYP450 enzyme system. Elimination occurs

via metabolism in the tissues and urinary excretion.

164

p. 128

p. 129

ADVERSE EFFECTS

The most common adverse effects associated with mipomersen with an incidence of

≥10% include injection site reactions, flu-like symptoms, nausea, headache, and

elevated hepatic transaminases, specifically ALT. Injection site reactions occur in

84% of patients and consist of pain, tenderness, erythema, pruritus, and local

swelling. Flu-like symptoms occur in 30% of patients and are usually noticed within

2 days after the injection. These symptoms include pyrexia, myalgia, chills,

arthralgia, fatigue, and malaise. Elevations in hepatic transaminases occurred in

approximately 12% of patients, with 9% having an ALT ≥ 3× the ULN. Hepatic

steatosis has also been reported.

PLACE IN THERAPY

Mipomersen is indicated as an adjunct therapy to a low-fat diet and other lipidlowering agents to reduce LDL-C, ApoB, TC, and non-HDL in patients with

HoFH.

164 Due to concern for hepatotoxicity, mipomersen is also available only

through a REMS program. Although mipomersen has only been studied in

combination with simvastatin and ezetimibe therapies, its use with other non-statin

lipid-lowering agents as well as in patients undergoing LDL-C apheresis is not

recommended. The effect of mipomersen on cardiovascular morbidity and mortality

is unknown. Additionally, the safety and efficacy of mipomersen has not been

established in patients with hypercholesterolemia not secondary to HoFH. Maximum

LDL-C reduction is usually seen after approximately 6 months of therapy.

DRUG INTERACTIONS

Secondary to the unique metabolism of mipomersen, there are no known clinically

significant drug interactions. However, caution should be exercised when used with

other medications known to have potential for hepatotoxicity, (e.g., isotretinoin,

amiodarone, acetaminophen [>4 g/day for ≥3 days/week]), methotrexate,

tetracyclines, and tamoxifen. If used in combination, more frequent monitoring of

liver-related tests may be necessary.

CLINICAL PEARLS

Alcohol consumption should be limited to no more than 1 drink/day as it may

increase hepatic fat and induce or exacerbate the risk of liver injury.

The recommended dose of mipomersen is 200 mg by subcutaneous injections once a

week.

If a dose is missed, the injection should be given at least 3 days from when the next

weekly dose is due.

Mipomersen should be stored in the refrigerator but removed from the refrigerator

and allowed to reach room temperature for at least 30 minutes prior to

administration.

Injection sites include the abdomen, thigh area, or outer area of upper arm.

Mipomersen should not be injected into any site that has injury to the skin such as

sunburn, rash, skin infections, inflammation, or active areas of psoriasis, or in

areas with tattoos or scars.

A full liver panel to include ALT, AST, total bilirubin, and alkaline phosphatase

should be obtained prior to therapy initiation.

Mipomersen is contraindicated in patients with moderate or severe hepatic

impairment or active liver disease.

For the first year, liver-related tests at least an ALT and AST should be checked

monthly.

After the first year of therapy, liver tests should be checked at least every 3 months.

Discontinue therapy if persistent or clinically significant elevations occur.

If transaminase elevations are accompanied by clinical symptoms of liver injury,

increases in bilirubin ≥2× the ULN, or active liver disease, therapy should be

discontinued.

Lipid levels should be monitored at least every 3 months for the first year.

Proprotein Convertase Subtilisin/Kexin Type 9

MECHANISM OF ACTION

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a member of the

proprotein convertase family, which consists of nine members. PCSK9 is thought to

play a critical role in modulating the number of LDL receptors on the surface of the

hepatocyte and consequently the amount of LDL-C in the plasma. PCKS9 binds

irreversibly to LDL receptors on the hepatocyte and is internalized into the liver

cells. This prevents the LDL receptor from being recycled back to the cell surface

and the LDL-R/PCSK9 complex is degraded along with the LDL-C. Monoclonal

antibodies to PCKS9, or PCSK9 inhibitors, neutralize PCSK9 and prevent PCSK9-

mediated LDL receptor degradation, allowing more LDL receptors to return back to

the cell surface. An increase in the number of LDL receptors leads to enhanced

clearance of LDL-C and thus lower LDL-C levels (Fig. 8-15).

169,170

EFFICACY

These agents have been evaluated in patients with HeFH and HoFH and in patients

with ASCVD who have been on maximally tolerated statin doses and require further

LDL-C reduction.

The LAPLACE-2 (LDL-C Assessment with PCSK9 Monoclonal Antibody

Inhibition Combined with Statin Therapy) trial was a 12-week trial to evaluate the

safety and efficacy of evolocumab in 2,067 patients with primary

hypercholesterolemia and mixed dyslipidemia.

171 The study included 296 patients

with clinical ASCVD. Patients were randomized to a specific, open-label regimen of

three different statin doses (atorvastatin 80 mg daily, rosuvastatin 40 mg daily, or

simvastatin 40 mg daily) and either fixed dose evolocumab 140 mg every 2 weeks,

evolocumab 240 mg once a month, or placebo. The primary endpoint was change in

baseline LDL-C at 12 weeks with a secondary endpoint of percent of patients

achieving LDL-C of less than 70 mg/day. The results showed that in patients already

on either moderate- or high-intensity statin therapy and clinical ASCVD, evolocumab

demonstrated an additional mean reduction in LDL-C of 71% for the twice-weekly

dose and 63% for the once-monthly dose compared to placebo (p < 0.0001).

Additionally, 90% of evolocumab-treated patients achieved LDL-C < 70 mg/dL. The

Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES),

was a randomized, double-blind, placebo-controlled 52-week trial comparing

evolocumab versus placebo in 901 patients on background lipid-lowering therapy.

172

Background therapy included atorvastatin 80 mg with or without ezetimibe 10 mg

daily. Of the entire study population, 139 patients had ASCVD. Evolocumab was

administered 420 mg SQ once monthly. The results showed that in patients with

ASCVD who received evolocumab, the mean percent LDL-C reduction was 54% (p

< 0.0001). Alirocumab was evaluated in the COMBO study.

173 This was a

multicenter, double-blind, placebo-controlled trial that randomly assigned patients to

alirocumab or placebo in addition to maximally tolerated doses of statins with or

without additional lipid-lowering therapy who required additional LDL-C lowering.

The dose of alirocumab was 75 mg every 2 weeks. If additional LDL-C lowering

was still needed at 12 weeks, the dose of alirocumab was increased to 150 mg every

2 weeks and continued for another 12 weeks. At 24 weeks, the mean reduction in

LDL-C with alirocumab was 44% compared to 2% with placebo (p < 0.0001). A

significant portion (84%) of the study population had ASCVD. After 12 weeks, the

mean reduction in LDL-C from baseline was 45% versus 1% with placebo.

Alirocumab has been evaluated in the Long-Term Safety and Tolerability of

Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not

adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG

TERM) trial in 2,341 patients at high risk for CHD.

174 Patients were randomly

assigned alirocumab 150 mg twice weekly to placebo in addition to maximum

tolerated statin therapy with or without additional lipid-lowering therapy. Patients

with ASCVD comprised 69% of the trial. At 24 weeks, the percent change in LDL-C

reductions with alirocumab compared to placebo was 58% (p < 0.0001). This

reduction in LDL-C was sustained over a 78-week treatment period.

Figure 8-15 Mechanism of action of PCSK9 inhibitors. 1. PCSK9 inhibitors bind to PCSK9 made in the

hepatocyte. 2. By binding to the PCSK9 receptor, PCKS9 inhibitors prevent PCSK9-mediated LDL receptor

degradation. 3. Secondary to reduce degradation, more LDL receptors are recycled back to the cellsurface that

subsequently leads to lower LDL-C levels. Used with permission of Amgen.

p. 129

p. 130

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9

Inhibition in Subjects with Elevated Risk) was the first trial published to demonstrate

reduction in cardiovascular outcomes with the addition of a PCSK9 inhibitor.175

This was a randomized, double-blind, placebo-controlled trial that included 27,564

patients aged 40 to 85 years with clinical ASCVD. Patients were included if they had

ASCVD defined as either MI, nonhemorrhagic stroke, or symptomatic peripheral

arterial disease [PAD]). Study subjects were also required to have at least one major

ASCVD risk factor or two minor risk factors. The minor risk factors were defined as

a history of non-MI-related coronary revascularization, residual CAD with ≥40%

stenosis in ≥2 large vessels, HDL-C <40 mg/dL for men and <50 mg/dL for women,

high-sensitivity C-reactive protein [hs-CRP] >2 mg/L, LDL-C ≥130 mg/dL or non–

high-density-lipoprotein cholesterol [non-HDL-C] ≥160 mg/dL, or metabolic

syndrome). Patients also had to have a fasting LDL-C level >70 mg/dL or a nonHDL-C levels ≥100 mg/dL after ≥4 weeks of stable dose of atorvastatin 20, 40, or

80 mg daily, with or without ezetimibe, and fasting TG ≤400 mg/dL. The median

LDL-C at baseline was 92 mg/dL. Patients were randomized to receive evolocumab

administered subcutaneously at a dose of 140 mg every 2 weeks (or 420 mg monthly)

or matching placebo. The median duration of therapy was 2.2 years. The results

demonstrated that treatment with evolocumab significantly reduced the risk of the

primary endpoint (composite of cardiovascular death, MI, stroke, hospitalization for

unstable angina, or coronary revascularization) (hazard ratio, 0.85; 95% confidence

interval [CI], 0.79 to 0.92, P < 0.001) and the key secondary endpoint

(cardiovascular death, MI, or stroke) (hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P <

0.001). The degree of risk reduction in cardiovascular death, MI, or stroke increased

over time, from 16% in the first year of follow-up to 25% after 1 year. In terms of

LDL-C reduction, at 48 weeks, the mean LDL-C was reduced by 59% (mean 56

mg/dL). Approximately 87% of patients achieved an LDL-C of <70 mg/dL.

Additionally, 67% of patients had LDL-C levels <40 mg/dL, and 42% reached levels

of <25 mg/dL. There was a slightly higher rate of injection-site reactions in the

patients receiving evolocumab compared with placebo (2.1% vs. 1.6%).