The Effect of Mipomersen in the Management of Patients with Familial Hypercholesterolemia: A Systematic Review and Meta-Analysis of Clinical Trials

Abstract

Background: Familial hypercholesterolemia (FH) lead to significant adverse effects in coronary arteries. Mipomersen is a second-generation antisense oligonucleotide that inhibits the synthesis of apolipoprotein B-100, an essential component of low density lipoprotein (LDL), and thus decreases the production of LDL. We aimed to determine the effect of mipomersen in patients with FH. Methods: We searched Ovid Medline, Ovid EMBASE, WHO ICTRP search portal, ISI database, the reference lists of relevant articles, and also Google Scholar to retrieve articles. All randomized controlled trials (RCTs) comparing patients with FH receiving mipomersen as an add-on and a parallel group receiving a placebo or no intervention were selected. Results: Five studies with more than 500 patients were included. All had low risk of bias. Pooling data showed that mipomersen probably reduces LDL compared with placebo [mean difference: −24.79, 95% CI (−30.15, −19.43)] but with a moderate level of certainty. There was a high level of evidence for injection site reactions [RR = 2.56, CI (1.47–4.44)] and a low level for increased serum alanine transaminase (ALT) > 3 times upper limit of normal (ULN) [RR = 5.19, CI (1.01–26.69)]. Conclusion: A moderate level of evidence in decreasing serum LDL indicates that we are uncertain if this drug provides benefit in any outcome important to patients. Although a low level of evidence for an increase in serum ALT leaves uncertainty about this adverse effect, injection site reactions in 10% or more of patients can be an important concern.

Inflammation and atherosclerosis: signaling pathways and therapeutic intervention

“… 298 A meta-analysis demonstrated that, unlike lomitapide, mipomersen could significantly reduce Lp(a) by 20–40%, non-HDL-C by 28%, LDL by 35–47% without influencing the level of HDL-C. 306 Though numbers of clinical trials have suggested that mipomersen has efficacy in lowering ApoB-related lipoproteins in patients with different hypercholesterolemic phenotype, its approval is currently only available to treat homozygous familial hypercholesterolemia as an adjunctive orphan drug due to adverse effects such as flu-like symptoms and transaminitis. 306 – 308 …”

Mipomersen in Familial Hypercholesterolemia: An Update on Health-Related Quality of Life and Patient-Reported Outcomes

“…A recent meta-analysis by Astaneh et al demonstrated that mipomersen significantly reduced LDL-C levels in patients with FH when compared with placebo [mean difference: −24.79, 95% CI (−30.15, −19.43), overall effect P value <0.00001]. 20 However, its use was associated with an incidence of injection site reactions of approximately 10% of patients. Patients receiving mipomersen were 2.56 (1.47-4.44) times more likely than those receiving the placebo to develop injection site reactions.…”

“…Additional analyses from this study suggest the potential for hepatotoxicity via increased serum alanine transaminase levels >3 times upper limit of normal. 20 These are important considerations when assessing tolerability of mipomersen.…”

Hsp40s play distinct roles during the initial stages of apolipoprotein B biogenesis

“…Based on its central role, in lipoprotein metabolism, ApoB has been directly targeted to treat CAD (Boekholdt et al, 2014;Nandakumar et al, 2018;Reyes-Soffer et al, 2016;Zimmermann et al, 2006). Unfortunately, a second generation ApoB-targeted antisense oligonucleotide-based drug (Mipomersen) is effective yet exhibits severe side-effects (namely, liver damage) (Astaneh et al, 2021). Nevertheless, these data position ApoB as a bona fide therapeutic target.…”

“…, 2018 ). Unfortunately, a second generation ApoB-targeted antisense oligonucleotide-based drug (Mipomersen) is effective yet exhibits severe side effects (namely, liver damage) ( Astaneh et al. , 2021 ).…”