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.
Highlights
We used the following minimal important difference (MID) values when interpreting the importance of differences between the groups: for injection site reaction, we considered 25% increase in the number of patients with injection site reactions in the mipomersen group than the baseline risk, for increased in serum alanine transaminase (ALT) level we considered even one more patient in 100 patients with increased at least 3 times more than upper limit of normal (ULN) as MID, and for the decrease in serum low density lipoprotein (LDL), we considered the MID as at least 25% decrease in LDL cholesterol after injection of mipomersen
We considered that a sufficient number of patients provided data for this outcome, and all studies were in favor of using mipomersen; as we considered the MID as at least 25% decrease in LDL after injection of mipomersen compared with placebo, the point estimate of the mean percent of the decrease in serum LDL, and the confidence intervals (CIs) around it cross the line of MID
As we considered MID as 25% increase in the number of patients with injection site reactions in the mipomersen group than the baseline risk as unacceptable (25% multiply by 21 = almost 5 patients) because clinical judgment dictates that even 5 more patients with injection site reaction would be important as it can affect the tolerability of patients in receiving mipomersen injection, so looking at the risk ratios (RRs) and its CI, it is evident that even the lower end of CI (31 patients) is more than the margin of 21 + 5 = 26
Summary
The function of the receptor is catching and removing low-density lipoproteins (LDL) from plasma. Different levels of mutations in the gene will lead to different severity of disturbances in LDL removal from the body [1]. Increased level of serum LDL (hypercholesterolemia) leads to major adverse effects in the cardiovascular system, including the coronary arteries as well as other organs [2]. 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. 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
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