Dr. Ahmed Evolocumab and Alirocumab are novel lipid-lowering drugs. They belong to the class of medicines called PCSK-9 Inhibitors (proprotein convertase subtilisin/ Kexin type 9).
PCSK-9 inhibitors are very specific and very potent in lowering lipid levels, however, compared to statins they are very costly.
Evolocumab and Alirocumab may be used alone as monotherapy, in combination with a statin, or combined with ezetimibe.
PCSK-9 Inhibitors are specifically indicated for the treatment of familial hypercholesterolemia and in those patients who do not achieve their target LDL-C levels despite the use of a high-potency statin.
It is also important to note that HMG-COA reductase inhibitors, also called statins should be used as a first of treatment in the management of hypercholesterolemia.
Statins have been proven to have multiple benefits. They are specially indicated to lower cardiovascular mortality.
When patients do not respond adequately or are intolerant to statins because of the side effects of statins (like myopathy and liver dysfunction), PCSK-9 Inhibitors may be used.
The two PCSK9 Inhibitors that have been approved are:
- Evolocumab, and
- Alirocumab
More PCSK-9 inhibitors are being studied and discovered.
Indications of Evolocumab Vs Alirocumab:
Alirocumab is indicated for the treatment of:
- Familial heterozygous hypercholesterolemia, and
- Patients with clinical atherosclerotic cardiovascular disease who have elevated LDL-C despite the maximal dose of a high-potency statin.
Evolocumab is indicated in:
- Familial heterozygouss hypercholesterolemia
- Familial Homozygous hypercholesterolemia, and
- Patients with clinical atherosclerotic cardiovascular disease who require additional treatment to lower LDL-C despite the maximal dose of a statin.
General Pharmacological differences: Evolocumab Vs Alirocumab:
There are minor differences between the Evolocumab (Repatha) and Alirocumab (Praluent) in terms of their bioavailability, half-lives, and duration of action.
These differences are summarized in Table 1 below:
Evolocumab [Ref] | Alirocumab [Ref] | |
| Brand Names | Repatha | Praluent |
| What is it? | It is a human monoclonal IgG2 (immunoglobulin G2) that targets human proprotein convertase subtilisin Kexin type 9 (PCSK9). | It is a human monoclonal IgG1 (Immunoglobulin G1 isotype) that is directed against proprotein convertase subtilisin Kexin type 9 (PCSK9). |
| Target | PCSK9 (proprotein convertase subtilisin Kexin type 9). | PCSK9 (proprotein convertase subtilisin Kexin type 9). |
| Dose | 140 mg every two weeks or 420 mg once a month | 75 mg every two weeks or 300 mg every four weeks |
| Dosage Forms | 140 mg/mL solution in a single-dose prefilled syringe140 mg/mL solution in a single-dose prefilled SureClick® autoinjector420 mg/3.5 mL solution in a single-dose Pushtronex® system (on-body infusor with prefilled cartridge) | Single-dose pre-filled pen of 75 mg/mL and 150 mg/mLSingle-dose pre-filled syringe of 75 mg/mL and 150 mg/mL |
| Bioavailability | 72% | 85% |
| Maximal PCSK9 suppression | 4 hours | 4 to 8 hours after administration |
| Maximum Peak Serum Concentration after administration | 3 to 4 days | 3 to 7 days |
| Half-life | 11 to 17 days | 17 to 20 days |
Table 1: Summary of the pharmacological differences between Repatha and Praluent.
Evolocumab (Repatha) vs Alirocumab (Praluent) in patients with Primary hyperlipidemia:
PCSK-9 Inhibitors are potent lipid-lowering drugs. Both Evolocumab and Alirocumab significantly lowered cholesterol levels compared to placebo in clinical trials.
Effect of Repatha vs Praluent on LDL-C:
LDL is bad cholesterol. LDL-C is primarily responsible for most atherosclerotic cardiovascular conditions such as stroke, myocardial infarction, and peripheral arterial diseases.
PCSK-9 inhibitors are especially effective in lowering LDL-C. These drugs are even effective in statin-resistant cases.
The LDL-C lowering effects of Repatha and Praluent are given here in table 2.
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 150 mg every two weeks |
| Effect on LDL-C | -63 | -58 |
| Difference vs Placebo | -71 | -58 |
Table 2: The effect of the two PCSK-9 inhibitors on LDL-C
Effect of Repatha vs Praluent on non-HDL-C:
Non-HDL-C or non-HDL cholesterol is the cholesterol that is derived when the good cholesterol (HDL-C) is subtracted from total cholesterol.
Total Cholesterol – HDL-C = Non-HDL Cholesterol
Non-HDL-C, like LDL-C, are the primary targets of most lipid-lowering drugs including Evolocumab and Alirocumab.
Table 3 summarizes the effects of Evolocumab and Alirocumab on Non-HDL-C.
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 150 mg every two weeks |
| Effect on non-HDL-C | -53 | -49 |
| Difference vs Placebo | -59 | -50 |
Table 3: Non-HDL-C lowering effect of the two PCSK-9 Inhibitors.
Effect of Repatha vs Praluent on Total Cholesterol:
Total cholesterol is the sum of bad and good cholesterol levels. It is a less commonly used efficacy marker when statins or PCSK-9 Inhibitors are studied.
However, estimation of total cholesterol is indirectly related to atherosclerotic cardiovascular conditions.
Table 4 here summarizes the effect of Evolocumab and Alirocumab on total cholesterol levels:
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 150 mg every two weeks |
| Effect on Total Cholesterol | -36 | -36 |
| Difference vs Placebo | -40 | -36 |
Table 4: Summary of the “Total Cholesterol” lowering effects of Repatha and Praluent.
Effect of Repatha vs Praluent on Apo-B levels:
Apo-B or Apolipoprotein B is a protein. It is a component of LDL cholesterol. It was found in one study that Apo-B levels more closely correlate with insulin resistance and atherogenic risk profile compared to LDL-C.
Apo-B is considered a better marker than LDL-C to estimated cardiovascular risk profile in patients at high cardiometabolic risk [Ref].
Table 5 here summarizes the effects of Evolocumab and Alirocumab on Apo-B levels.
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 150 mg every two weeks |
| Effect on Apo-B | -49 | -50 |
| Difference vs Placebo | -55 | -51 |
Table 5: Summary of effects of Repatha and Praluent on Apo-B levels.
Evolocumab (Repatha) vs Alirocumab (Praluent) in patients with Heterozygous Familial Hypercholesterolemia (HeFH):
Heterozygous Familial Hypercholesterolemia is a genetic condition characterized by markedly elevated LDL-C.
It is usually diagnosed when the LDL-C levels are above the 95th percentile for the age along with raised LDL-C levels in first, second, or third-degree relatives.
Patients are at risk of developing myocardial infarction and other atherosclerotic conditions at an early age. Therefore, diagnosis and early treatment to lower the LDL-C are important.
Effect of Evolocumab Vs Alirocumab on LDL-C in patients with heterozygous familial hypercholesterolemia:
The effect of Evolocumab and Alirocumab on plasma LDL-C was studied in patients with familial heterozygous hypercholesterolemia (HeFH).
LDL-C is bad cholesterol. It is the primary cholesterol associated with atherosclerotic cardiovascular conditions. Lowering LDL-C is one of the primary targets of most lipid-lowering drugs.
Table 6 A and 6 B here summarizes the effects of Evolocumab and Alirocumab on plasma LDL-C levels in HeFH patients:
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 75 mg every two weeks |
| Effect on LDL-C | -62 | -43 |
| Difference vs Placebo | -61 | -48 |
Table 6A: Summary of the effects of Evolocumab and Alirocumab on plasma LDL-C levels in HeFH patients:
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 420 mg every four weeks in the background of a statin | Praluent 75 mg every two weeks titrated upwards to 150 mg every two weeks |
| Effect on LDL-C | -56 | -47 |
| Difference vs Placebo | -60 | -54 |
Table 6B: Summary of the effects of Evolocumab and Alirocumab on plasma LDL-C levels in HeFH patients:
Effect of Evolocumab Vs Alirocumab on Non-HDL-C in patients with heterozygous familial hypercholesterolemia:
Non-HDL-C or non-HDL cholesterol is measured by subtracting the good cholesterol from total cholesterol.
Thus, it accounts for all the bad cholesterol in the blood. Like LDL-C, it is a marker of atherosclerotic cardiovascular diseases.
Table 7A and 7B here summarize the effects of Evolocumab and Alirocumab on plasma non-HDL-C levels in patients with Heterozygous familial hypercholesterolemia:
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 75 mg every two weeks |
| Effect on Non-HDL-C | -56 | -38 |
| Difference vs Placebo | -54 | -42 |
Table 7A: Summary of the effects of Evolocumab and Alirocumab on plasma non-HDL-C levels in HeFH patients.
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 420 mg every four weeks in the background of a statin | Praluent 75 mg every two weeks titrated upwards to 150 mg every two weeks |
| Effect on Non-HDL-C | -49 | -42 |
| Difference vs Placebo | -53 | -49 |
Table 7B: Summary of the effects of Evolocumab and Alirocumab on plasma non-HDL-C levels in HeFH patients.
Effect of Evolocumab Vs Alirocumab on Total Cholesterol in patients with heterozygous familial hypercholesterolemia:
Total cholesterol is the sum of all the bad and the good cholesterol in the plasma. It is not commonly used as a direct indicator of atherosclerotic cardiovascular diseases. However, as an indirect indicator of cardiovascular diseases, it may be used.
Table 8A and 8B here summarize the effects of Evolocumab and Alirocumab on plasma Total Cholesterol levels in patients with heterozygous familial hypercholesterolemia:
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 75 mg every two weeks |
| Effect on Total Cholesterol | -42 | -27 |
| Difference vs Placebo | -40 | -31 |
Table 8A: Summary of the effects of Evolocumab and Alirocumab on plasma Total Cholesterol levels in HeFH patients.
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 420 mg every four weeks in the background of a statin | Praluent 75 mg every two weeks titrated upwards to 150 mg every two weeks |
| Effect on Total Cholesterol | -37 | -30 |
| Difference vs Placebo | -39 | -36 |
Table 8B: Summary of the effects of Evolocumab and Alirocumab on plasma Total Cholesterol levels in HeFH patients.
Effect of Evolocumab Vs Alirocumab on Apo-B in patients with heterozygous familial hypercholesterolemia:
Apo-B levels are considered more closely linked with atherosclerotic cardiovascular conditions compared to LDL-C.
It is especially useful in patients with a high-risk cardiometabolic profile such as insulin resistance.
Table 9A and 9B here summarize the effects of Repatha and Praluent on Apo-B levels in patients with HeFH:
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 140 mg every two weeks in the background of a statin | Praluent 75 mg every two weeks |
| Effect on Apo-B | -49 | -34 |
| Difference vs Placebo | -49 | -36 |
Table 9A: Summary of the effects of Evolocumab and Alirocumab on plasma Apo-B levels in HeFH patients.
| Evolocumab (Repatha) [Ref] | Alirocumab (Praluent) [Ref] | |
| Dose | Repatha 420 mg every four weeks in the background of a statin | Praluent 75 mg every two weeks titrated upwards to 150 mg every two weeks |
| Effect on Apo-B | -44 | -40 |
| Difference vs Placebo | -48 | -42 |
Table 9B: Summary of the effects of Evolocumab and Alirocumab on plasma Apo-B levels in HeFH patients.
Effect of Evolocumab (Repatha) in patients with homozygous familial hypercholesterolemia (HoFH):
Familial Homozygous Hypercholesterolemia is a rare life-threatening condition characterized by markedly elevated levels of cholesterol levels.
LDL-C levels usually exceed 500 mg/dl. In addition, patients have extensive xanthomas and early-onset cardiovascular diseases.
Evolocumab is especially helpful in these patients as they are usually resistant or intolerant to high doses of statins.
Alirocumab has not been studied in patients with Familial Homozygous Hypercholesterolemia. It is not indicated for use in patients with HoFH because of limited data.
The effect of REPATHA on Lipid Parameters in Patients with HoFH is given in the table below:
| LDL-C | Non-HDL-C | Total Cholesterol | Apo-B levels | |
| Repatha 420 mg every four weeks | -22 | -20 | -17 | -17 |
| Placebo once monthly | 9 | 8 | 8 | 4 |
| Mean Difference vs Placebo | -31 | -28 | -25 | -21 |
Table 10: The effect of Evolocumab on lipid parameters in patients with HoFH.
Evolocumab (Repatha) Vs Alirocumab (Praluent): Comparing Mortality Benefits:
An indirect comparison of Evolocumab and Alirocumab was done in one review article. There were no significant differences between the two PCK9 Inhibitors, however, Alirocumab (Praluent) was associated with a significant reduction in all-cause mortality.
The results of the research article are as follows [Ref]:
All-cause mortality:
- Alirocumab was associated with a significantly lower all-cause mortality (death from any cause) compared to Evolocumab (RR: 0.80; 95%CI: 0.66-0.97, p=0.02).
There was no significant difference between Evolocumab and Alirocumab in the following parameters:
- Stroke: (RR: 0.96; 95%CI: 0.71-1.28, p=0.77)
- Cardiovascular death: (RR: 0.83; 95% CI: 0.65-1.05, p=0.12),
- MI (Myocardial Infarction): (RR: 1.15; 95%CI: 0.99-1.34, p=0.07), or
- Ischemia-driven coronary revascularization: (RR: 1.13; 95%CI: 0.99-1.29, p=0.06).
Evolocumab (Repatha) Vs Alirocumab (Praluent): Comparing Safety Parameters:
An indirect comparison of the two PCSK-9 Inhibitors was done. Compared to placebo medicine, both drugs were associated with a significantly increased risk of injection site reactions.
Compared to Evolocumab (Repatha), Alirocumab (Praluent) was associated with a significantly increased risk of injection-site reactions ((RR: 1.27; 95% CI:1.04-1.55, p=0.02).
There was no significant difference between the two PCSK-9 Inhibitors in the following parameters:
- The difference in adverse drug reactions leading to treatment discontinuation: (RR: 0.98; 95%CI: 0.79-1.22, p=0.89)
- Risk of systemic allergic reactions: (RR: 0.96; 95%CI: 0.82-1.13, p=0.65)
- Neurocognitive dysfunction: (RR: 0.82; 95%CI: 0.62-1.08, p=0.16)
- Eye-related adverse events: (RR: 0.94; 95%CI: 0.71-1.22, p=0.62)
- New-onset diabetes: (RR: 0.85; 95%CI: 0.28-2.60, p=0.78)
In Summary:
Both evolocumab (Repatha) and Alirocumab (Praluent) are potent lipid-lowering drugs. These drugs target the enzyme responsible for degrading LDL-C receptors called PCSK-9.
Both evolocumab (Repatha) and Alirocumab (Praluent) are indicated in patients with hyperlipidemia that is resistant to high doses of statins and in patients with Heterozygous familial hypercholesterolemia.
Until now, only Evolocumab (Repatha) has got FDA approval for the treatment of Homozygous Familial Hypercholesterolemia.
In indirect comparison between the two drugs, Alirocumab (Praluent) reduced all-cause mortality compared to Evolocumab.
In terms of safety parameters, Injection site reactions were seen in a significantly greater number of patients compared to Evolocumab (Repatha).
