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Abstract

Background:

Hyperlipidemia or dyslipidemia has been a concern for a long time, with various guidelines emphasizing the importance of managing the lipid profile to prevent cardiac incidences. Although statins have been found to be highly effective, resistance and intolerability to side effects will continue to be a stumbling block for certain patients. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors tackle lipid profile via a novel mechanism and therefore provide an additional effective option for managing lipid profile. The overarching aim of this systematic review was to evaluate the efficacy of evolocumab among various populations with hypercholesterolemia.

Methods:

A comprehensive search was conducted in ProQuest Health & Medical Complete, Google Scholar, ScienceDirect, and PubMed to identify potential records; then titles, abstracts, and full texts were screened using the inclusion criteria to filter out irrelevant studies. Data extraction and quality assessment were undertaken using standardized tools and the results were narratively synthesized and presented in tables.

Results:

Eight studies were included in this systematic review after screening 1191 records. All studies demonstrated a statistically significant reduction in low-density lipoprotein cholesterol (LDL-C) values in the groups that received evolocumab compared with the comparator groups (p < 0.05). The decline in LDL-C levels from baseline in the majority of studies ranged from 40% to 80%, whether used alone or in combination with other agents. Also, high-density lipoprotein cholesterol, lipoprotein (a) and apolipoprotein B were improved with the use of evolocumab.

Conclusions:

This study helped to collate evidence from studies that tested the effectiveness of evolocumab in the management of hyperlipidemia. Evolocumab seems to be highly effective in reducing LDL-C and other lipid parameters. Hence, it provides an excellent alternative for patients with refractory disease or patients who develop intolerable side effects, therefore helping to overcome the stumbling block to achieving optimal lipid management.

Keywords

dyslipidemia evolocumab hyperlipidemia proprotein convertase subtilisin/kexin type 9 inhibitors

Background

Over the last decade, tremendous studies have confirmed the importance of lowering cholesterol, specifically low-density lipoprotein cholesterol (LDL-C) in patients with established cardiovascular risk.^1–4 Hence, lipid-lowering agents, and especially statins, are one of the most commonly prescribed medications for the treatment and prevention of cardiovascular diseases (CVDs).⁵ However, statin intolerance might militate against achieving optimal lipid control.^6–8 In fact, having limited effective alternatives for this substantial population continues to be an insurmountable challenge.

Statin resistance arises when the lipid profile is not reducing successfully to achieve optimal levels, despite the implementation of optimal regimens ⁹. Indeed, statin resistance is not uncommon, as observational studies suggest that it might be seen in up to 10–15% of people.^3,6,10 However, statin intolerance might arise as a result of musculoskeletal adverse events, mainly myopathy, which inevitably might result in stopping or holding the medication.⁹ Furthermore, some studies unraveled the plausibility of the impact of genetic composition on the lack of efficacy of statins.¹¹ To illustrate, numerous candidate genes (>50) and dozens of single-nucleotide polymorphisms were found to be related to pharmacokinetics and pharmacodynamics of statins, therefore impinging upon the observed responses.⁹ Hence, the need for an alternative has been established.¹²

The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for managing lipids and preventing CVD.¹³ Before delving deep into the mechanism of PCSK9, it is important to bring to light the impact of statins on PCSK9. Statins are known to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which in return inhibits the synthesis of cholesterol.^14,15 Blocking the synthesis of cholesterol results in increasing the activity of Sterol regulatory element - binding protein (SREBP) transcription factor, and this in return increases LDL receptor (LDLR) and therefore increase the uptake of LDL from plasma.^14,15 However, the activation of SREBP transcription factor also upregulates the transcription of PCSK9, which then binds to LDLRs, resulting in accelerated degradation of LDLR, hence partially impinging upon the overall activity of LDLR.^14,15 Recently, studies found that the use of a monoclonal antibody (REGN727) can block PCSK9, therefore providing a more potent reduction in LDL-C levels.^14,15 The reduction in LDL-C is considered to be more potent due to the employment of two distinct mechanisms, which are increasing LDLR and reducing PCSK9.^14,15

In 2015, the US Food and Drug Administration (FDA) approved the first PCSK9 inhibitor to be added as an adjunct to diet, and to a maximum tolerated dose of statins in adults with heterozygous familial hyperlipidemia or clinical atherosclerotic CVD.^12,16 Alirocumab (Praluent; Sanofi/Regeneron, Bridgewater, NJ, USA) and evolocumab (Repatha; Amgen, Thousand Oaks, CA, UDA) are currently available and approved for use in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, and clinical atherosclerotic CVD.^12,16 In fact, alirocumab was approved by the FDA even before the completion of its cardiovascular outcome trial, which is expected to be concluded by December 2017. Therefore, this systematic review sought to evaluate the efficacy of evolocumab among various populations with hypercholesterolemia.

Methods

Search strategy

A systematic review of the literature was performed based on the Preferred Reporting Items for Systematic review (PRISMA) guidelines.¹⁷ Four electronic databases including ProQuest Health & Medical Complete, Google Scholar, ScienceDirect, and PubMed were searched to retrieve relevant studies, using terms such as (evolocumab AND hyperlipidemia) OR (evolocumab AND dyslipidemia) OR (evolocumab for hyperlipidemia) OR (evolocumab for dyslipidemia) OR (AMG 145 AND hyperlipidemia) OR (AMG 145 AND dyslipidemia) OR (AMG 145 for hyperlipidemia) OR (AMG 145 for dyslipidemia).

Study selection

We reviewed papers of studies that met the following inclusion criteria and were available as full text:

(1) Study population: patients diagnosed with hyperlipidemia.

(2) Study design: randomized controlled trial.

(3) Study aim: to evaluate the efficacy of evolocumab for hyperlipidemia.

(4) Intervention: evolocumab to be prescribed for the management of hyperlipidemia.

(5) Comparator: other antidyslipidemic agents to be prescribed for the management of hyperlipidemia.

(6) Publication language, data, and status: published in English, between the year 2012 and 2016, and is available as full text.

We excluded papers according to the following:

(1) Study design was not randomized controlled trial.

(2) The study aim was not to evaluate the efficacy of evolocumab in hyperlipidemia.

(3) Evolocumab and the comparator were not prescribed for hyperlipidemia.

(4) An agent other than evolocumab was given to the treatment group for the management of dyslipidemia.

(5) Articles for which we were not able to source the full text.

Quality assessment

The quality of the included studies was assessed using the Jadad scale.^18,19 A score of up to 2 indicates a low-quality design, while a score of at least 3 indicates a high-quality design.^18,19 These scores were calculated initially by four researchers, which then were validated by the fifth researcher to ensure reliability.

Review procedure

Four researchers were involved in the process of data extraction, and all extracted data were later reviewed by the fifth researcher.

Data extraction and synthesis

Data were extracted from studies using a standardized document; the document was designed to obtain information such as author, year of publication, published or not, country, aims, number of patients, study design, duration of intervention, type of intervention, type of comparators and main findings, in a systematic fashion. Moreover, the results of the studies were synthesized narratively with all results presented in a tabulation format as well as descriptive graphs.

Results

Identification of studies

The searching process went through a series of phases, as displayed in Figure 1. In the first phase, specific key terms were utilized to identify studies, and this resulted in identifying 1191 hits from ProQuest Health & Medical Complete, Google Scholar, ScienceDirect, and PubMed. In the second phase, the aim was to screen titles and then use the inclusion criteria to filter out irrelevant studies either by exploring abstracts or full texts. This resulted in identifying eight studies to be included in this systematic review, as shown in Figure 1.

Figure 1.

Preferred Reporting Items for Systematic review (PRISMA) flow chart.

All studies included in this systematic review explored the efficacy of evolocumab in the management of dyslipidemia among patients with an established diagnosis of dyslipidemia.^20–27 The primary efficacy parameter explored in this systematic review across all studies is LDL-C.^20–27 Some of these studies used various doses and frequencies of evolocumab, while others investigated one dose only.^20–27 Also, some studies compared evolocumab with other lipid-lowering agents, while others used placebo as a comparator.^20–27 Besides, the Jadad score of the studies included in this systematic review fell within the range of 3–5, indicating the high quality of the included randomized controlled trials.^20–27 Key data and findings are summarized in Table 1.^20–27

Table 1.

Results gleaned from RCTs.

Author	Jadad scale	Treatment groups	Comparator/s ‘control’ groups	Sample size	Design	Duration of intervention	Main efficacy endpoint	Main outcomes of the efficacy parameter ‘LDL-C’
Raal et al.^20,22 (2015)	5	Group 1: evolocumab 140 mg SC every 2 weeks Group 2: evolocumab 420 mg SC monthly	Group 3: placebo every 2 weeks Group 4: placebo monthly	Total number of patients who have completed the study was 325: Group 1, n = 110 Group 2, n = 108 Group 3, n = 53 Group 4, n = 54	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): In group 1, the reduction from baseline was approximately 61% (p < 0.05). While in group 2 the LDL-C dropped by around 56% from baseline (p < 0.05). On the other hand, group 3 and 4 showed slight changes from baseline, where the LDL-C in group 3 reduced by 2% only, while in group 4 the LDL-C increased by 6%. The difference between the treatment groups and the comparator/s groups was found to be statistically significant (p < 0.05).
Stroes et al.²¹ (2014)	5	Group 1: evolocumab 140 mg SC every 2 weeks with daily oral placebo Group 2: evolocumab 420 mg SC monthly with daily oral placebo	Group 3: placebo every 2 weeks with daily 10 mg of oral ezetimibe Group 4: placebo monthly with daily 10 mg of oral ezetimibe	Total number of patients who completed the study was 307: Group 1, n = 103 Group 2, n = 102 Group 3, n = 51 Group 4, n = 51	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): In group 1, the reduction in LDL-C from baseline was around 56% (p < 0.05), and in group 2 the reduction was about 53% (p < 0.05). LDL-C in group 3 and group 4 reduced as well by approximately 18% and 15%, respectively. The difference between the treatment groups and the comparator/s groups was found to be statistically significant (p < 0.05).
Raal et al.^20,22 (2015)	5	Group 1: evolocumab 420 mg every 4 weeks	Group 2: placebo every 4 weeks	Total number of patients who completed the analysis was 49: Group 1, n = 33 group 2, n = 16	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): The reduction in the evolocumab group was around 23%, while in the placebo group LDL-C increased from baseline by 8%. The difference between the treatment group and the comparator group was found to be statistically significant (p < 0.05).
Robinson et al.²³ (2014) Section A ‘Atorvastatin 80 mg’	3	Group 1: atrovastatin 80 mg with evolocumab 140 mg SC every 2 weeks with daily oral placebo Group 2: atrovastatin 80 mg with evolocumab 420 mg SC monthly with daily oral placebo	Group 3: atrovastatin 80 mg with placebo every 2 weeks with daily oral ezetimibe (10 mg per day) Group 4: atrovastatin 80 mg with placebo monthly with daily oral ezetimibe (10 mg per day) Group 5: atrovastatin 80 mg with placebo SC every 2 weeks with placebo once daily Group 6: atrovastatin 80 mg with placebo SC monthly with placebo once daily	Total number of patients who completed the analysis was 439: Group 1, n = 109 Group 2, n = 110 Group 3, n = 56 Group 4, n = 54 Group 5, n = 55 Group 6, n = 55	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1 and 2 declined from baseline by about 59% and 60%, respectively. The reduction from baseline was found to be statistically significant (p < 0.05). LDL-C values in group 3 and 4 reduced from baseline by about 13% and 21%, respectively. These changes were found to be statistically significant (p < 0.05). However, in group 5 and 6, LDL-C values increased from baseline by around 11% and 6%, respectively. The changes in group 5 were found to be statistically significant, while the changes in group 6 were found not to be statistically insignificant.
Robinson et al.²³ (2014) Section B ‘Atorvastatin 10 mg’	3	Group 1: atrovastatin 10 mg with evolocumab 140 mg SC every 2 weeks with daily oral placebo Group 2: atrovastatin 10 mg with evolocumab 420 mg SC monthly with daily oral placebo	Group 3: atrovastatin 10 mg with placebo every 2 weeks with daily oral ezetimibe (10 mg per day) Group 4: atrovastatin 10 mg with placebo monthly with daily oral ezetimibe (10 mg per day) Group 5: Atrovastatin 10 mg with placebo SC every 2 weeks with placebo once daily. Group 6: Atrovastatin 10 mg with placebo SC monthly with placebo once daily.	Total number of patients who completed the analysis was 442: Group 1, n = 110 Group 2, n = 110 Group 3, n = 56 Group 4, n = 55 Group 5, n = 56 Group 6, n = 55	Randomized double blind controlled study	Treatment duration was 12 weeks.	LDL-C	LDL-C (in percentage): LDL-C values in group 1 and 2 reduced significantly from baseline by approximately 77% and 80%, respectively (p < 0.05). Group 3 and 4 produced a smaller reduction in LDL-C compared to the treatment groups, where LDL-C in group 3 and 4 reduced by about 25% and 32%, respectively. These changes were found to be statistically significant (p < 0.05). However, in group 5, the LDL-C increased by 7%, while group 6 showed a slight reduction by around 0.4%. These changes in group 5 and 6 were not found to be statistically significant (p > 0.05).
Robinson et al.²³ (2014) Section C ‘Rosuvastatin 5 mg’	3	Group 1: rosuvastatin 5 mg with evolocumab 140 mg SC every 2 weeks Group 2: rosuvastatin 5 mg with evolocumab 420 mg SC monthly	Group 3: rosuvastatin 5 mg with placebo SC every 2 weeks with placebo once daily Group 4: rosuvastatin 5 mg with placebo SC monthly with placebo once daily	Total number of patients who completed the analysis was 343: Group 1, n = 113 Group 2, n = 115 Group 3, n = 58 Group 4, n = 57	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1 and 2 reduced significantly from baseline by approximately 69% and 78%, respectively (p < 0.05). However, LDL-C values in group 3 and 4 increased by about 7% and 0.1%, respectively. Yet, the differences were not found to be statistically insignificant (p > 0.05).
Robinson et al.²³ (2014) Section D ‘Rosuvastatin 40 mg’	3	Group 1: rosuvastatin 40 mg with evolocumab 140 mg SC every 2 weeks Group 2: rosuvastatin 40 mg with evolocumab 420 mg SC monthly	Group 3: rosuvastatin 40 mg with placebo SC every 2 weeks with placebo once daily Group 4: rosuvastatin 40 mg with placebo SC monthly with placebo once daily	Total number of patients who completed the analysis was 334: Group 1, n = 111 Group 2, n = 112 Group 3, n = 56 Group 4, n = 55	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1 and 2 reduced significantly by around 52% and 55%, respectively (p < 0.05). However, LDL-C in group 3 increased by 3%, while LDL-C in group 4 reduced slightly by about 5%. These differences in group 3 and 4 were not found to be statistically significant (p > 0.05).
Robinson et al.²³ (2014) ‘Simvastatin 40 mg’	3	Group 1: simvastatin 40 mg with evolocumab 140 mg SC every 2 weeks Group 2: simvastatin 40 mg with evolocumab 420 mg SC monthly	Group 3: simvastatin 40 mg with placebo SC every 2 weeks with placebo once daily Group 4: simvastatin 40 mg with placebo SC monthly with placebo once daily	Total number of patients who have completed the analysis was 338: Group 1, n = 112 Group 2, n = 115 Group 3, n = 55 Group 4, n = 56	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1 and 2 declined significantly from baseline by around 84% and 78%, respectively (p < 0.05). However, LDL-C in group 3 reduced slightly by approximately 6%, while LDL-C in group 4 increased from baseline by 2%. These differences were not found to be statistically significant (p > 0.05).
Giugliano et al.²⁴ (2012)	5	Group 1: evolocumab 70 mg every 2 weeks Group 2: evolocumab 105 mg every 2 weeks Group 3: evolocumab 140 mg every 2 weeks Group 4: 250 mg every 4 weeks Group 5: evolocumab 350 mg every 4 weeks Group 6: evolocumab 420 mg 4 weeks	Group 7: placebo every 2 weeks Group 8: placebo every 4 weeks	Total number of patients who completed the analysis was 629: Group 1, n = 79 Group 2, n = 79 Group 3, n = 78 Group 4, n = 79 Group 5, n = 79 Group 6, n = 80 Group 7, n = 78 Group 8, n = 77	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1, 2, 3, 4, 5, and 6 reduced significantly by about 42%, 60%, 66%, 42%, 50% and 50%, respectively (p < 0.05). On the other hand, LDL-C values in group 7 and 8 almost showed no changes compared to baseline.
Blom et al.²⁵ (2014)	5	Group 1: dietary modification with evolocumab 420 mg once a month Group 2: dietary modification with atorvastatin 10 mg once daily and evolocumab 420 mg once a month Group 3: dietary modification with atorvastatin 80 mg once a day and evolocumab 420 mg once a month Group 4: dietary modification with atorvastatin 80 mg once daily, ezetimibe 10 mg once daily and evolocumab 420 mg monthly	Group 5: dietary modification with monthly placebo Group 6: dietary modification with atorvastatin 10 mg once a day and monthly placebo Group 7: dietary modification with atorvastatin 80 mg once a day and monthly placebo Group 8: dietary modification with atorvastatin 80 mg once a day, ezetimibe 10 mg once a day and monthly placebo	Total number of patients ‘per protocol set’ is 901: Group 1, n = 74 Group 2, n = 254 Group 3, n = 145 Group 4, n = 126 Group 5, n = 37 Group 6, n = 129 Group 7, n = 73 Group 8, n = 63	Randomized double blind controlled study	Treatment duration was 52 weeks	LDL-C	LDL-C (in percentage): LDL-C in group 1, 2, 3 and 4, declined significantly from baseline by around 48%, 45%, 53%, and 55%, respectively (p < 0.05). While, the reduction in group 5, 6, 7, and 8 from baseline was found to be less compared to the groups that used evolocumab (4–8%).
Koren et al.²⁶ (2012)	5	Group 1: evolocumab 70 mg every 2 weeks Group 2: evolocumab 105 mg every 2 weeks Group 3: evolocumab 140 mg every 2 weeks Group 4: 250 mg every 4 weeks Group 5: evolocumab 350 mg every 4 weeks Group 6: evolocumab 420 mg 4 weeks	Group 7: ezetimibe once daily Group 8: placebo every 2 weeks Group 9: placebo every 4 weeks	Total number of patients who have completed the analysis was 406: Group 1, n = 45 Group 2, n = 46 Group 3, n = 45 Group 4, n = 45 Group 5, n = 45 Group 6, n = 45 Group 7, n = 45 Group 8, n = 45 Group 9, n = 45	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1, 2, 3, 4, 5, and 6 reduced significantly from baseline by approximately 41%, 44%, 51%, 39%, 43%, and 48%, respectively (p < 0.05). In group 7, the reduction in LDL-C from baseline was around 15%. In group 8, the LDL-C reduced by approximately 4%, while and increase by 5% in group 9. Overall, the reduction in LDL-C was found to be the largest among the groups which used evolocumab compared to the other groups. The difference between the treatment groups and the comparator/s groups was found to be statistically significant (p < 0.05).
Kiyosue et al.²⁷ (2016) Part A ‘Atorvastatin 20 mg’	3	Group 1: atrovastatin 20 mg with evolocumab 140 mg SC every 2 weeks Group 2: atrovastatin 20 mg with evolocumab 420 mg SC monthly	Group 3: atrovastatin 20 mg with placebo every 2 weeks Group 4: atrovastatin 20 mg with placebo monthly	Total number of patients who have completed the analysis was 199: Group 1, n = 49 Group 2, n = 51 Group 3, n = 48 Group 4, n = 51	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1 and 2 declined significantly by approximately 75% and 70%, respectively (p < 0.05).
Kiyosue et al.²⁷ (2016) Part B ‘Atorvastatin 5 mg’	3	Group 1: atrovastatin 5 mg with evolocumab 140 mg SC every 2 weeks Group 2: atrovastatin 5 mg with evolocumab 420 mg SC monthly	Group 3: atrovastatin 5 mg with placebo every 2 weeks Group 4: atrovastatin 5 mg with placebo monthly	Total number of patients who have completed the analysis was 198: Group 1, n = 50 Group 2, n = 50 Group 3, n = 49 Group 4, n = 49	Randomized double blind controlled study	Treatment duration was 12 weeks	LDL-C	LDL-C (in percentage): LDL-C values in group 1 and 2 reduced significantly from baseline by around 76% and 67%, respectively (p < 0.05). While in the placebo groups, there was a minor difference from baseline.

LDL-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial; SC, subcutaneous.

Efficacy on LDL-C

Raal and colleagues conducted a randomized, double-blind controlled trial on 325 participants, for a duration of 12 weeks,²⁰ with participants randomly assigned to one of the following four groups (two treatment groups and two comparator groups): evolocumab 140 mg every 2 weeks (treatment group 1), evolocumab 420 mg every month (treatment group 2), placebo every 2 weeks (comparator group 3) or placebo every month (comparator group 4).²⁰ After 12 weeks, it was found that participants who received evolocumab either 140 mg every 2 weeks or 420 mg every month showed a statistically significant reduction in their LDL-C levels (56–61%) in comparison to baseline (p < 0.05).²⁰ However, in the placebo groups, the LDL-C levels showed a slight increase from baseline.²⁰ The difference between the treatment and placebo groups was statistically significant (p < 0.05).²⁰

Stroes and colleagues conducted a study on 307 participants who were randomly assigned to one of the following four groups: evolocumab 140 mg every 2 weeks with daily placebo (treatment group 1), evolocumab 420 mg every month with daily placebo (treatment group 2), ezetimibe 10 mg per day with placebo every 2 weeks (comparator group 3), or ezetimibe 10 mg per day with placebo every month (comparator group 4).²¹ The duration of the intervention was 12 weeks.²¹ The findings of this study were found to be consistent with Raal and colleagues, with LDL-C showing a statistically significant reduction from baseline among the treatment groups (53–56%) in comparison to the reduction seen among the comparator groups (15–18%).²¹ Indeed, the difference between the treatment groups and the comparator groups was found to be statistically significant (p < 0.05).²¹ In the same vein, another study that was conducted by Raal and colleagues on a smaller population captured a similar trend.²²

Robinson and colleagues conducted a randomized, double-blind, controlled study.²³ This study was divided into five sections, A, B, C, D and E, by the authors of this review to help understand the results, as seen in Table 1.²³ The difference between these sections is in the standardized medication (atorvastatin 10 mg and 80 mg, rosuvastatin 5 mg and 40 mg, and simvastatin 40 mg) used across all groups.²³ In sections A and B, there were six groups: evolocumab 140 mg every 2 weeks with daily placebo, evolocumab 420 mg once a month with daily placebo, placebo every 2 weeks with daily ezetimibe, placebo once a month with daily ezetimibe, placebo every 2 weeks with daily placebo, and placebo once a month with daily placebo.²³ While, in sections C, D and E, there were only four groups: evolocumab 140 mg every 2 weeks with daily placebo, evolocumab 420 mg once a month with daily placebo, placebo twice a month with daily placebo, and placebo once a month with daily placebo.²³

In section A, atorvastatin 80 mg once a day was the standardized medication used across all six groups.²³ The results showed that participants who received evolocumab had the highest reduction (59–60%) in LDL-C levels, and this reduction was found to be statistically significant (p < 0.05), as seen in Table 1.²³ However, in the groups that did not receive evolocumab, the LDL-C levels reduced mildly (6–21%), with the least reduction seen among participants who received placebo only.²³ In section B, atorvastatin 10 mg was used as the standardized medication, and findings for this section were found to be in parallel with section A.²³ The most potent and significant reduction from baseline was seen among participants who received evolocumab (77–80%) (p < 0.05).²³ The ezetimibe groups showed a statistically significant reduction (25–32%) in LDL-C from baseline (p < 0.05), yet this reduction was found to be less extensive compared with the evolocumab groups.²³ In section C, rosuvastatin 5 mg per day was the standardized medication used across all four groups.²³ The findings for this section do not deviate from the previous ones, where evolocumab groups showed a statistically significant reduction (69–78%) in LDL-C (p < 0.05), in comparison to the placebo groups which showed a statistically insignificant (p > 0.05) slight elevation in LDL-C.²³ Rosuvastatin 40 mg once daily was the standardized medication used in section D.²³ Findings within this section confirmed the previous ones, with LDL-C levels declining significantly (by 52–55%) among the treatment groups (p < 0.05).²³ In section E, simvastatin 40 mg once daily was the standardized medication, with findings showing a statistically significant (p < 0.05) reduction from baseline in the evolocumab groups (78–84%) compared with the placebo groups (2–6%), as seen in Table 1.²³

Giuglian and colleagues conducted a randomized, double-blind, controlled study of 629 participants for a period of 12 weeks.²⁴ Participants were randomly assigned to one of eight groups: evolocumab 70 mg every 2 weeks, evolocumab 105 mg every 2 weeks, evolocumab 140 mg every 2 weeks, evolocumab 250 mg every 4 weeks, evolocumab 350 mg every 4 weeks, evolocumab 420 mg every 4 weeks, placebo every 2 weeks, and placebo every 4 weeks.²⁴ The results of this study unraveled a statistically significant decline in LDL-C from baseline among groups receiving various doses of AMG 145 (p < 0.05), as seen in Table 1.²⁴ Another double-blind, randomized, controlled study that was carried out for a period of 52 weeks by Blom and colleagues found that the evolocumab groups showed a statistically significant reduction in their LDL-C levels (45–63%) in comparison to the other groups which showed a slight elevation in LDL-C (4–9%).²⁵

Koren and colleagues, who conducted a randomized, double-blind, controlled study to test the efficacy of evolocumab on the lipid profile, found a statistically significant reduction (39–51%) in LDL-C among the evolocumab groups (p < 0.05).²⁶ Additionally, Kiyosue and colleagues conducted a study in which participants were randomly assigned to received one of two standardized medications: atorvastatin 5 mg once daily (section A) or atorvastatin 20 mg once daily (section B), alongside the evolocumab or placebo.²⁷ Almost similar findings were observed in both sections, with the groups that received evolocumab showing a statistically significant (p < 0.05) reduction in LDL-C values (67–75%), as seen in Table 1.²⁷

Evolocumab and other lipid parameters

Apolipoprotein B

The results obtained from all the studies that looked into the effect of evolocumab on apolipoprotein B unveiled that evolocumab produces a statistically significant reduction in apolipoprotein B levels from baseline (p < 0.05), as seen in Figure 2.^{20–22,24,26,27}

Figure 2.

The mean reduction from baseline in apolipoprotein B among all evolocumab groups.^{20–22,24,26,27}

High-density lipoprotein cholesterol

Stroes and colleagues mentioned that in the evolocumab groups, there was a slight but statistically significant elevation in high-density lipoprotein cholesterol (HDL-C) ranging from 5% to 7% (p < 0.05).²¹ In the same vein, Giugliano and colleagues reported similar findings, with a slight but statistically significant elevation in HDL-C (2–8%) being observed among participants who received evolocumab (p < 0.05).²⁴ However, the group that received evolocumab 280 mg every 4 weeks did not show a statistically significant elevation in HDL-C.²⁴ In addition, Kiyosue and colleagues found that participants who received evolocumab had significantly increased HDL-C from baseline, by around 10–17% (p < 0.05).²⁷ Additionally, one of the two studies that were conducted by Raal and colleagues confirmed the effectiveness of evolocumab in increasing HDL-C from baseline (p < 0.05).²⁵ However, the other study that was done by Raal and colleagues, although detecting an elevation in the HDL-C, it was not found to be statistically significant (p > 0.05).²² Also, the study that was conducted by Koren and colleagues reported consistent findings with regards to HDL-C, with the groups that received evolocumab having levels increasing from baseline by about 5–12%.²⁶ Yet, the statistical significance of these findings was only demonstrated in groups that received the following doses of evolocumab: 105 mg every 2 weeks, 140 mg every 2 weeks, and 420 mg every 4 weeks.²⁶

Lipoprotein (a)

Figure 3 presents findings of five studies that explored the effect of evolocumab on lipoprotein (a).^{20–22,26,27} All these studies found that the groups that received evolocumab showed a statistically significant reduction in their lipoprotein (a) levels compared with baseline (p < 0.05), as seen in Figure 3.^{20–22,26,27}

Figure 3.

The mean reduction from baseline in lipoprotein (a) among all evolocumab groups.^{20–22,26,27}

Discussion

Having a rudimentary understanding about the burden and the detrimental impact of dyslipidemia is essential.^1,29 As a result, plenty of guidelines such as hypertension, myocardial infarction, and diabetes are recommending that lipid-lowering agents are added as a prophylactic agent to prevent unforeseen consequences.³⁰ Research on dyslipidemia and CVD continues to attract scientists to discover new medications with a better safety and efficacy profile. Evolocumab, as illustrated earlier, lowers lipids via a unique and novel mechanism, which is blocking PCSK9. Consequently, it provides an additional effective choice to be implemented in the management of atherosclerosis, dyslipidemia, or hypercholesterolemia. Furthermore, this therapy could be extremely useful in cases of resistance or when developing intolerable side effects. All studies included in this systematic review confirmed that evolocumab in various doses reduced LDL-C levels in a statistically significant manner (p < 0.05).^20–27 The PCSK9 levels are expected to increase with the use of statins, and this was proven by Blom and colleagues.²⁵ In return, this results in elevating LDL-C, hence by blocking PCSK9, this should be able to reduce LDL-C by counteracting the mechanism.²⁶ Therefore, anti-PCSK9 is expected to be effective when administered alongside the statins, however amalgamated evidence has brought to light that the efficacy of evolocumab in the presence and absence of statins is comparable, and the reduction in LDL-C seems to be dose dependent.²⁶ Indeed, Dias and colleagues confirmed that high doses were associated with a much more sustained effect due to the biological nature of PCSK9 inhibition.³¹ The findings of studies that have tested the efficacy of evolocumab are in line with alirocumab, which was found to be significantly effective in reducing LDL-C.^32–34

Evolocumab for statins intolerance

Although statins are considered to be well tolerated, adverse drug events were seen in approximately 10–20% of participants, which in return limits their cardioprotective effect.³⁵ Although there are multiple agents available to manage the lipid profile, these have been found to be associated with either intolerable side effects such as nicotinic acid and bile acid sequestrants, or have limited efficacy such as ezetimibe.²¹ Furthermore, other agents with novel mechanisms such as apolipoprotein B synthesis inhibitors are not commonly used due to their safety profile.^36,37

Since statins upregulate PCSK9, adding evolocumab to a statin is theoretically expected to provide an additional benefit; evolocumab is found to inhibit PCSK9, which in return increases the recycling of LDL-C.^34–36 Stroes and colleagues looked specifically into the efficacy of evolocumab in patients with statin intolerance, with findings unraveling that evolocumab reduced LDL-C in a statistically significant manner.²¹ Therefore, this agent provided an alternative option for this substantial population, hence facilitating optimal control over the lipid profile, minimizing patient suffering with intolerable muscle-related side effects, and ensuring that their previous unmet needs can finally be addressed. These findings, in fact, illuminate the ability of these agents to produce a paradigm shift in the upcoming guidelines, specifically in this substantial population.

Evolocumab for heterozygous familial hypercholesterolemia and other patients with dyslipidemia

Heterozygous familial hypercholesterolemia is considered to be the commonest inherited disorder worldwide.^38–41 It occur as a result of mutations in genes that encode proteins involved in LDL-C metabolism, therefore resulting in the reduction of the uptake of LDL-C.^40,42 Consequently, this imposes serious and premature cardiovascular risks.^42,43 Although statins have significantly improved the lipid profile and lowered cardiovascular risks, some patients still do not achieve the desirable LDL-C levels, despite using an intensified treatment regimen and a combination of lipid-lowering agents.^{13,40–42,44} Raal and colleagues, who have conducted a study on patients with heterozygous familial dyslipidemia, found that evolocumab is effective in reducing LDL-C from baseline in a statistically significant manner (p < 0.05).²⁰ These findings are consistent with evidence collated from some smaller studies conducted on similar populations.^14,31,45 Furthermore, patients with heterozygous familial hypercholesterolemia are specifically known to have mutations in PCSK9, which is assumed to be the root cause of the whole dilemma.^46–48 Yet, evidence from the literature showed that the efficacy of evolocumab is not only limited to patients with heterozygous familial dyslipidemia, but rather evolocumab is found to be effective in various populations.^14,31,45 Hence, the use of genetic analysis to guide treatment in patients with heterozygous familial dyslipidemia might not be as useful and as necessary as we thought.²² Additionally, the responses of participants with an identical receptor mutation were diverse, indicating that other factors might play a role.²⁰

Evolocumab for homozygous familial hypercholesterolemia

It has been suggested that obtaining genetic confirmation before using anti-PCSK9 in a patient with homozygous familial dyslipidemia would be highly useful and valuable.^31,49 This indeed has been confirmed by Raal and colleagues, who found that exploring the genetic status of the participant with homozygous familial dyslipidemia would help in predicting the efficacy of the medication among these participants.²² Participants who have two LDLR-defective mutations are expected to respond to a greater extent compared with a patient with a single LDLR-negative mutation.²² Yet, Raal and colleagues found that evolocumab is effective in patients with either one or two defective LDLR mutations.²² Hence, evolocumab provides an additional treatment option for patients with familial homozygous dyslipidemia, who are difficult to treat or show a response. It is noteworthy that even in participants who have identical LDLR mutation, the degree of reduction in LDL-C was diverse, indicating that other factors might have played a role.^22,50,51

Evolocumab effect on other lipid parameters

The importance of HDL-C for cardiovascular health has a long tradition, with low levels of HDL-C known to be associated with increasing cardiovascular risks.⁸ Increasing HDL-C is one of the crucial recommendations and objectives stressed in various guidelines concerned with dyslipidemia management.⁵² Moreover, studies have found that an elevation in lipoprotein (a) is considered to be an independent cardiovascular risk factor,⁵³ because lipoprotein (a) can induce or worsen atherosclerosis and thrombosis.^54–57 Also, apolipoprotein B is another important parameter; evidence brought to light showed that apolipoprotein B is superior to LDL-C and non-HDL-C in predicting cardiovascular risks.^58–62 Therefore, having a medication that could manage all these parameters is highly beneficial and will help to prevent some of the unforeseen consequences. Evolocumab was found to be effective in tackling several lipid subfractions and not only LDL-C.^20–27 Being able to target multiple lipid subfractions to achieve optimal levels is extremely important as it helps to achieve the most stringent targets, therefore adhering to the current guidelines and preventing cardiovascular risks.

Safety and drawbacks of the drug

All studies included in this systematic review confirmed that evolocumab is well tolerated and not associated with any serious adverse drug events.^20–27 In fact, the incidences of adverse drug events were found to be similar to the comparator groups.^20–27 The most common adverse event observed among the evolocumab groups was the upper respiratory tract related side effect ‘nasopharyngitis’.^20–27 However, evolocumab is superior to the other lipid-lowering agents in terms of musculoskeletal-related side effects.^20–27 Additionally, the increase in creatine kinase occurred significantly less when using anti-PCSK9 in comparison to not having anti-PCSK9 on board. This finding suggests that PCSK9 antibodies may have a muscle-sparing effect even in statin-treated patients, which may attenuate statin intolerance. Nevertheless, it is important to understand that the results of assessing the adverse drug events might be afflicted by the relatively short-term follow up (12 and 52 weeks for evolocumab and mostly 24 weeks for alirocumab), thus rare events could not be fully revealed.^20–27 Notably, the rates of serious adverse events reported in the studies did not statistically significantly differ with versus without anti-PCSK9 treatment, confirming the overall comparative safety of the drug. On the basis of these findings of reduced mortality and muscle complications in patients at lower risk (for example, those without or with stable coronary artery disease), PCSK9 inhibition may be even more useful in higher-risk patients, such as those with the acute coronary syndrome, in whom a high dosage of statin is conventionally recommended. Moreover, the rate of neurocognitive adverse events was found to be higher among participants who received evolocumab and alirocumab compared with placebo.⁶³ This confirms that cholesterol is an important component of neurons and PCSK9 is imperative for cortical neuron regeneration.⁶⁴

Although one of the advantages of this medication is overcoming the compliance issue with patients, where the frequency of administration is either once every 2 weeks or every month, reaching a conclusion about which one is preferred (statins or anti-PCKS9) is yet to be reached. This is due to the fact that cost and convenience have to be taken into consideration. Evolocumab and other anti-PCKS9 drugs are known to be associated with a high cost in comparison to statins and other antihyperlipidemia drugs.⁶⁵ The route of administration, ‘subcutaneous’ in comparison to oral administration with statins, is perceived to be inconvenient, which is a common perception with injectable drugs.^66–68 Moreover, as this medication has been recently introduced (2015), data on long-term effects are scarce.

Limitations

It is noteworthy that the vast majority of studies included in this review were sponsored by the manufacturer of evolocumab and this might afflict the authenticity of results. Publication bias is another concern in systematic reviews as it might lead to false-positive overall conclusions. In fact, one of the major limitations of this systematic review is having reduced access to certain studies that we were not able to source as full text. Furthermore, some studies might still have been in the publication process and not yet available to be sourced as full text, and so could not be incorporated in this review. With regards to the studies included in this systematic review, a number of limitations were encountered, such as small sample size.²² Hence statistical comparison between groups might not be sufficiently powered.²² Additionally, the majority of participants in studies included in this systematic review were white; therefore, caution should be taken when applying findings to other populations. Furthermore, the results are derived from study-level data rather than patient-level data; individual patient data would have improved the accuracy of the analysis by allowing subgroup comparisons. Heterogeneities in patient profiles (unrelated or familial hypercholesterolemia) and background lipid-lowering therapy (maximum tolerated statin, statin intolerance, or no background antilipid therapy) will afflict the results and this divergence will need to be further analyzed.

Conclusion

In conclusion, the findings of this systematic review decipher the efficacy of evolocumab in dyslipidemia. In fact, the findings brought to light the manifold benefits of the medication for various lipid parameters and subfractions which are receiving more attention lately due to their close association with cardiovascular risks. Furthermore, evolocumab provides an alternative for patients who have refractory disease or develop intolerable side effects, therefore overcoming the stumbling block and helping to achieve optimal lipid management. Finally, the investigated populations represent a broad spectrum of patients (with and without known genetic disorders), hence future studies focusing on substantial populations will provide ample opportunity to learn more about the most responsive population.

Footnotes

Acknowledgements

This work took place in the Higher Colleges of Technology, Dubai Campus. All authors contributed to the study design. All authors were involved in the literature review and data extraction process. All authors participated in the writing and the revision of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

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The efficacy of evolocumab in the management of hyperlipidemia: a systematic review

Abstract

Background:

Methods:

Results:

Conclusions:

Keywords

Background

Methods

Search strategy

Study selection

Quality assessment

Review procedure

Data extraction and synthesis

Results

Identification of studies

Efficacy on LDL-C

Evolocumab and other lipid parameters

Apolipoprotein B

High-density lipoprotein cholesterol

Lipoprotein (a)

Discussion

Evolocumab for statins intolerance

Evolocumab for heterozygous familial hypercholesterolemia and other patients with dyslipidemia

Evolocumab for homozygous familial hypercholesterolemia

Evolocumab effect on other lipid parameters

Safety and drawbacks of the drug

Limitations

Conclusion

Footnotes

Acknowledgements

Funding

Conflict of interest statement

References