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Inclisiran vs Repatha (Leqvio vs Evolocumab) for HeFH

Inclisiran vs Repatha

inclisiran vs repatha leqvio vs evolocumab

Inclisiran (Leqvio), Evolocumab (Repatha), and Alirocumab (Praluent) are drugs approved to lower plasma lipids in patients with HeFH (heterozygous familial hypercholesterolemia). A comparison of Inclisiran vs Repatha is discussed here.

Heterozygous Familial Hypercholesterolemia (HeFH) or Heterozygous Familial Hyperlipidemia is a medical condition characterized by very high levels of LDL-C (low-density lipoprotein cholesterol).

It is an inherited disorder with multiple genetic defects. The three main genetic mutations that result in high LDL-C levels in patients with HeFH are:

  • Defects in LDL receptors
  • Apolipoprotein B (Apo-B), and
  • Proprotein convertase subtilisin/Kexin type 9 (PCSK9)

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What are Inclisiran and Repatha?

Both Inclisiran and Repatha are lipid-lowering drugs that act directly or indirectly on PCSK-9 (proprotein convertase subtilisin/ Kexin type 9).

Repatha (evolocumab) targets PCSK-9 directly while Inclisiran indirectly acts on PCSK-9.

PCSK-9 is a protein that binds to the LDL receptors present on the surface of liver cells. After binding to the LDL receptors, PCSK-9 promotes the internalization and degradation of LDL receptors.

Evolocumab (Repatha) 140 mg & 420 mg; a PCSK9 Inhibitor

Mechanism of action of Repatha (evolocumab) [Ref]:

Repatha (Evolocumab) is a human immunoglobulin (IgG2) that inhibits the binding of PCSK-9 enzymes to the LDL receptors. Thus, more LDL receptors are present to bring down the circulating LDL (bad cholesterol) in the plasma.

Mechanism of action of Inclisiran (Leqvio) [Ref]:

Inclisiran is a novel class of drugs. It is a small interfering RNA (Ribonucleic Acid). It is linked with triantennary N-Acetylgalactosamine (GalNAc) so that it can be easily taken up by the liver cells.

Via the interfering mechanism, it causes the breakdown of mRNA that is responsible for coding for PCSK-9.

When the levels of PCSK-9 drop as they are not synthesized, more LDL receptors are available to lower the circulating LDL from the plasma into the liver cells.

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Indications of Inclisiran (Leqvio) vs Repatha (Evolocumab):

Inclisiran and Repatha are both indicated to lower LDL levels in the blood.

Inclisiran (Leqvio) Indications:

Inclisiran is indicated in patients who are intolerant to statins or those patients who require additional lipid-lowering therapy despite diet and maximum doses of high-potency statins.

It is indicated in patients with either heterozygous familial hypercholesterolemia (HeFH) or those with clinical atherosclerotic cardiovascular disease.

It is of note that the long-term effects of Inclisiran (Leqvio) on cardiovascular mortality and morbidity are not known.

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Repatha (Evolocumab) Indications:

Evolocumab (Repatha) is a PCSK-9 Inhibitor. It is indicated in the following groups of patients:

  • Patients with clinical atherosclerotic cardiovascular diseases who require additional lipid-lowering drugs despite on high doses of a high-potency statin
  • Patients with HeFH (heterozygous familial hypercholesterolemia)
  • Patients with HoFH (Homozygous Familial Hypercholesterolemia)

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General Pharmacological differences between Inclisiran VS Repatha:

General Pharmacological differences between Inclisiran and Repatha are presented here in the table below:

Inclisiran [Ref]

Evolocumab [Ref]

Brand Names Leqvio Repatha
What is it? It is a small interfering mRNA that interferes or causes the breakdown of mRNA responsible for coding PCSK-9. It is a human monoclonal IgG2 (immunoglobulin G2) that targets human proprotein convertase subtilisin Kexin type 9 (PCSK9).
Target mRNA that codes for PCSK-9 PCSK9 (proprotein convertase subtilisin Kexin type 9).
Dose 284 mg administered subQ, then after 3 months, and then every 6-monthly 140 mg every two weeks or 420 mg once a month
Dosage Forms 284 mg/1.5 mL (189 mg/mL) available in a single prefilled syringe. 140 mg/mL solution in a single-dose prefilled syringe

140 mg/mL solution in a single-dose prefilled SureClick® autoinjector

420 mg/3.5 mL solution in a single-dose Pushtronex® system (on-body infusor with prefilled cartridge)

Maximal effects Maximal LDL-C reduction occurs at Day 120 (75% Maximal PCSK-9 suppression occurs after 4 hours of administration
Maximum Peak Serum Concentration after administration 4 hours after administration 3 to 4 days
Half-life 9 hours 11 to 17 days

Table 1: General Pharmacological differences between Inclisiran and Repatha.

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Effect of Inclisiran Vs Repatha on the lipid parameters in patients with Atherosclerotic Cardiovascular disease:

Both Inclisiran and Repatha are indicated in patients who are using maximally tolerated doses of statins and still do not achieve their lipid goals.

Both drugs are indicated as an add-on therapy to maximally tolerated statins.

The effect of Inclisiran vs Repatha on LDL-C levels:

LDL-C is the primary culprit responsible for most atherosclerotic cardiovascular events. It gets deposited in the blood vessels which get narrowed with time and are blocked.

LDL-C is the target of most lipid-lowering drugs. The effect of Inclisiran and Repatha on LDL-C is given here in Table 2:

Inclisiran (Leqvio) [Ref]

Evolocumab (Repatha) [Ref]

Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin
Effect on LDL-C -51 -63
Difference vs Placebo -52 -71

Table 2: The effect of Inclisiran and Repatha on LDL-C levels.

Both the drugs significantly lower the LDL-C levels compared with placebo in patients who were already using the maximum doses of statins.

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The effect of Inclisiran vs Repatha on non-HDL-C levels:

non-HDL-C or non-HDL cholesterol is calculated by subtracting HDL cholesterol from total cholesterol. As HDL cholesterol is considered good cholesterol, non-HDL-C is a combination of all the bad cholesterol.

non-HDL-C levels are being increasingly used in patients with clinical atherosclerotic cardiovascular conditions to estimate the disease burden.

The effect of Inclisiran and Repatha on non-HDL-C levels is summarized here in Table 3:

Inclisiran (Leqvio)

Evolocumab (Repatha) [Ref]

Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin
Effect on non-HDL-C -47 -53
Difference vs Placebo -47 -59

Table 3: The effect of Inclisiran and Repatha on non-HDL-C in patients with atherosclerotic cardiovascular conditions who require additional lipid-lowering therapies despite maximal doses of statins.

Both Inclisiran (Leqvio) and Repatha (Evolocumab) significantly reduced non-HDL-C levels compared to placebo.

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The effect of Inclisiran vs Repatha on Total Cholesterol levels:

Total cholesterol is rarely used as a direct measure of atherosclerotic cardiovascular disease burden, however, it is one of the indirect clues indicating the efficacy of a lipid-lowering drug.

Total cholesterol was reduced by both Leqvio and Repatha in clinical trials as summarized here in Table 4:

Inclisiran (Leqvio)

Evolocumab (Repatha) [Ref]

Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin
Effect on Total Cholesterol -34 -36
Difference vs Placebo -33 -40

Table 4: The effect of Inclisiran and Repatha on total cholesterol levels compared to placebo.

Both Inclisiran and Repatha significantly lowered total cholesterol levels compared to placebo.

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The effect of Inclisiran vs Repatha on Apo-B levels:

Apo-B levels are being increasingly used as a marker of atherosclerosis. It is a component of LDL cholesterol that has been shown to be associated strongly with atherosclerotic cardiovascular risks, especially in patients with a high-risk metabolic profile.

These may include patients with insulin resistance and metabolic syndrome.

The effect of Inclisiran (Leqvio) and Repatha (Evolocumab) on Apo-B levels is summarized here in table 5:

Inclisiran (Leqvio)

Evolocumab (Repatha) [Ref]

Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin
Effect on Apo-B -45 -49
Difference vs Placebo -43 -55

Table 5: Both Inclisiran and Repatha significantly lowered Apo-B levels compared to placebo.

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Effect of Inclisiran Vs Repatha on the lipid parameters in patients with HeFH (Heterozygous Familial Hypercholesterolemia:

HeFH (Heterozygous Familial Hypercholesterolemia) is a relatively common genetic disorder characterized by very high levels of LDL Cholesterol.

Patients usually have a strong family history of dyslipidemias and early onset of atherosclerotic cardiovascular diseases.

Both Inclisiran and Repatha are indicated in patients with HeFH (heterozygous familial hypercholesterolemia) who are using maximally tolerated doses of statins and still do not achieve their lipid goals.

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Both drugs are indicated as an add-on therapy to maximally tolerated statins.

The effect of Inclisiran vs Repatha on LDL-C levels in patients with HeFH:

The effect of Inclisiran and two different doses of Repatha (evolocumab) on plasma LDL-C levels was evaluated in patients with HeFH.

Both drugs significantly lowered plasma LDL-C levels compared to placebo as summarized in the table below:

Inclisiran (Leqvio) Evolocumab (Repatha) [Ref] Evolocumab (Repatha) [Ref]
Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin Repatha 420 mg every four weeks in the background of a statin
Effect on LDL-C -40 -62 -56
Difference vs Placebo -48 -61 -60

Table 6: Summary of LDL-C lowering effects of Inclisiran and two different doses of Repatha in patients with HeFH.

Both Repatha and Inclisiran significantly lowered LDL cholesterol in patients with HeFH compared to placebo.

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The effect of Inclisiran vs Repatha on non-HDL-C levels:

Non-HDL cholesterol is calculated by subtracting HDL (good cholesterol) from total cholesterol. It is being commonly used as a disease marker of atherosclerotic conditions.

It is an indirect marker of the atherogenic potential of a person. In patients with HeFH, both Inclisiran and Repatha significantly lowered plasma non-HDL-C compared to placebo medicine as summarized in the table below:

Inclisiran (Leqvio) Evolocumab (Repatha) [Ref] Evolocumab (Repatha) [Ref]
Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin Repatha 420 mg every four weeks in the background of a statin
Effect on non-HDL-C -35 -56 -49
Difference vs Placebo -42 -54 -53

Table 7: Summary of non-HDL-C lowering effects of Inclisiran and two different doses of Repatha in patients with HeFH.

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The effect of Inclisiran vs Repatha on Total Cholesterol levels:

Total cholesterol was lowered by Inclisiran and Repatha significantly in patients with HeFH compared to placebo medicine.

Summary of the total cholesterol-lowering effects of Inclisrian and Repatha is given in the table below:

Inclisiran (Leqvio) Evolocumab (Repatha) [Ref] Evolocumab (Repatha) [Ref]
Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin Repatha 420 mg every four weeks in the background of a statin
Effect on Total Cholesterol -25 -42 -37
Difference vs Placebo -32 -40 -39

Table 8: Summary of Total Cholesterol-lowering effects of Inclisiran and two different doses of Repatha in patients with HeFH.

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The effect of Inclisiran vs Repatha on Apo-B levels:

Apo-B is a marker of atherosclerosis. It is considered to be more significantly associated with atherosclerosis compared to LDL levels.

The significance of Apo-B levels as a causative factor in atherosclerosis is even more evident in patients with high metabolic risks such as those with insulin resistance and metabolic syndrome.

Inclisiran and Repatha both effectively lowered plasma Apo-B levels compared to placebo as summarized in the table below:

Inclisiran (Leqvio) Evolocumab (Repatha) [Ref] Evolocumab (Repatha) [Ref]
Dose 284 mg on Day 1, Day 90, Day 270, and Day 450. LDL-C checked at Day 510 Repatha 140 mg every two weeks in the background of a statin Repatha 420 mg every four weeks in the background of a statin
Effect on Apo-B levels -33 -49 -44
Difference vs Placebo -36 -49 -48

Table 9: Summary of Apo-B lowering effects of Inclisiran and two different doses of Repatha in patients with HeFH.

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One main difference between Inclisiran (Leqvio) and Repatha (Evolocumab) is the cardiovascular benefits. Repatha has been proven to lower cardiovascular mortality and morbidity.

Inclisiran has the advantage of twice-yearly dosing with almost similar efficacy as Repatha in lowering LDL-C and Apo-B levels.

However, Inclisiran (Leqvio) has not yet been proven to lower cardiovascular mortality and morbidity. It is being studied in high-risk patients to prevent 3-point major cardiovascular events. The study is being sponsored by Novartis Pharmaceuticals. It is expected to complete by 2027 [Ref].

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In Summary:

Inclisiran and Repatha are novel lipid-lowering drugs. Both drugs target PCSK-9 protein that is responsible for the degradation of LDL receptors present on the surface of liver cells.

Repatha directly inhibits the binding of PCSK-9 with LDL receptors while Inclisiran interferes with the mRNA that decodes PCSK-9.

Both Inclisiran and Repatha significantly lower the LDL levels compared to placebo, however, only Repatha has proven cardiovascular benefits.

Inclisiran has the advantage on twice yealry dosing while Repatha is administered once or twice monthly.

What do you think?

Written by Diabetes Doctor

I am an Internist practicing medicine for the last fifteen years. Over the years, I have learned that medicine is not about prescribing pills. True medical practice is helping people.
I do prescribe pills as well but the best results I get are when I motivate people to overcome their problems with little changes in their lifestyles.
Since most of my patients are obese, have diabetes, hypertension, high cholesterol levels, I am writing at dibesity.com when free.
Dibesity, I know the correct word is diabesity. Ignore this! Be with us.

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