Journal of Clinical Lipidology (2015) -, -–-
Original Contribution
Efficacy and safety of mipomersen in treatment of dyslipidemia: A meta-analysis of randomized controlled trials Raju Panta, MD, MS*, Khagendra Dahal, MD, Sumit Kunwar, MD Department of Hospital Medicine, LRGHealthcare, Laconia, NH, USA KEYWORDS: Mipomersen; Apolipoprotein B synthesis inhibitor; Hyperlipidemia; Familial dyslipidemia; LDL cholesterol; HDL cholesterol; Total cholesterol; Non-HDL cholesterol; Apolipoprotein B; Hepatic steatosis
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipidlowering therapy in people at risk for cardiovascular diseases. Mipomersen inhibits apolipoprotein B-100 (apoB) synthesis and causes reduction in LDL-C by reducing apoB. OBJECTIVE: We aimed to perform a meta-analysis of all published randomized controlled trials comparing safety and efficacy of mipomersen with placebo in adults with dyslipidemia. METHODS: We searched PUBMED, CENTRAL, and EMBASE from inception through March 2014 and used random-effects model to compute the effect size. RESULTS: We identified 8 randomized controlled trials (n 5 462). Mipomersen compared with placebo significantly reduced LDL-C by 32.37% (95% confidence interval, 25.55–39.18; P , .00001), total cholesterol by 24.18% (18.54–29.83; P , .00001), very low–density lipoprotein cholesterol by 21.59% (9.16–34.02; P 5 .0007), non–high-density lipoprotein cholesterol (HDL-C) by 30.83% (23.92–37.74; P , .00001), and triglycerides by 36.26% (22–50.54; P , .00001). It also significantly reduced apoB, lipoprotein(a), and apolipoprotein A1. However, mipomersen did not significantly change HDL-C levels. In safety analysis, mipomersen compared with placebo increased the risks of injection-site reaction (risk ratio, 2.05; 95% confidence interval, 1.39–3.04; P 5 .0003), flu-like symptoms (1.63; 1.22–2.17; P 5 .0008), alanine aminotransferase $3X upper limit of normal (4.44; 1.67–11.86; P 5 .003), and hepatic steatosis (3.85, 1.39–10.67; P 5 .01). The risks of alanine aminotransferase $10X upper limit of normal did not reach statistical significance (1.57; 0.32–7.6, P 5 .58). CONCLUSION: Mipomersen resulted in a significant improvement in lipid parameters except for HDL-C and increased the risks of injection-site reactions, flu-like symptoms, and hepatic steatosis compared with placebo. Ó 2015 National Lipid Association. All rights reserved.
Author contributions: R.P. and K.D. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. R.P. and K.D. contributed to the study concept and design; acquisition, analysis, or interpretation of data; drafting of the article; critical revision of the article for important intellectual content; statistical analysis; and study supervision. S.K. contributed to acquisition, analysis, or interpretation of data; critical revision of the article for important intellectual content; and study supervision.
1933-2874/Ó 2015 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.12.006
Conflict of interest disclosures: None. Funding/support: This research was self-funded. * Corresponding author. Department of Hospital Medicine, LRGHealthcare, 80 Highland Street, Laconia, NH 03246. E-mail address: [email protected] Submitted May 29, 2014. Accepted for publication December 4, 2014.
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Journal of Clinical Lipidology, Vol -, No -, - 2015
Introduction
Study selection
The serum level of low-density lipoprotein cholesterol (LDL-C) is directly linked to the rate of new onset of coronary heart disease (CHD) and progression of an established CHD.1–4 On the other hand, high-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with risk of CHD.5 LDL-C is the primary target of lipidlowering therapy in people at risk for cardiovascular disease, which is the leading cause of death in the industrialized countries.6 According to Centers for Disease Control and Prevention, 71 million American adults (33.5%) have high LDL-C less than half of which get treatment to reduce its levels and 1 of every 3 who get treatment have this condition under control.7 Despite the advent of potent statins and use of combination lipid-lowering therapy, a substantial proportion of patients at high risk of CHD remain unable to achieve optimal LDL-C.8 Mipomersen, an antisense oligonucleotide designed to enhance destruction of the messenger RNA for apolipoprotein B-100 (apoB) provides a means of reducing the synthesis of this major apolipoprotein and therefore the number of very low–density lipoprotein (VLDL) and possibly LDL molecules leaving the liver. This produces a reduction of these apoB-containing lipoproteins in the plasma.9 Statins and other LDL-lowering drugs such as ezetimibe and bile acid sequestrants act through increasing LDL receptors and thereby enhancing clearance. By providing a totally new mechanism of action, mipomersen may be useful in patients with defective or absent LDL receptors or who do not respond fully to existing drugs. In randomized controlled trials, a significant reduction in LDL-C has been observed in patients with familial hypercholesterolemia10–12 and in patients with dyslipidemia on statin therapy13,14 or statin intolerance.15 To better define its efficacy and safety, we performed a meta-analysis of current randomized trials of mipomersen in adults ($18 years) with dyslipidemia.
The flow diagram for study selection is shown in Figure 1. We included randomized controlled trials comparing mipomersen vs placebo in adult patients ($18 years) with dyslipidemia in the meta-analysis. We excluded studies with nonrandomized designs, healthy volunteers, pediatric patients, animals, and abstracts without full-text publications.
Methods Data sources and search strategy We wrote a study protocol in accordance with the PRISMA statement.16 We searched MEDLINE, EMBASE, and Cochrane CENTRAL Register of Controlled Trials for publications since inception through March 2014 without language restriction. The search terms were ‘‘mipomersen’’ OR ‘‘apolipoprotein B synthesis inhibitor’’ with restriction to randomized design (‘‘randomized controlled trials’’ OR ‘‘controlled clinical trials’’ OR ‘‘comparative study’’). Two authors (R.P. and K.D.) independently performed the database search, and disagreement was resolved by consensus. A hand search was performed for all relevant references from the selected articles.
Data extraction Two authors (R.P. and K.D.) extracted data from the selected studies in duplicate using standardized dataextraction form. We obtained data on study and patient characteristics, indication(s) of mipomersen use, dosages of mipomersen, duration of follow-up, and major safety and efficacy outcomes as described in the following. In intervention arm, data were only extracted for mipomersen dose of 200 mg if the studies used variable doses,10,13,17 whereas all patients in the control arm were included in the analysis. Disagreement was resolved by consensus.
Major outcomes Efficacy outcomes were percentage change in LDL-C, HDL-C, triglycerides, non–HDL-C, VLDL cholesterol (VLDL-C), total cholesterol, and lipoprotein(a), apolipoprotein A1, and apolipoprotein B. The safety outcomes were risks of elevated alanine aminotransferase (ALT) .3X upper limit of normal (ULN) and .10X ULN, hepatic steatosis, flu-like symptoms, and injection-site reaction.
Statistical analysis We pooled the continuous variables as the difference in percentage change in mean and the categorical variables as risk ratio (RR), both with 95% confidence interval (CI). We used crude events from each study to compute RR with 95% CI. DerSimonian–Laird random-effects model was used for meta-analysis of effect size. The P , .05 (2 tailed) was considered statistically significant for computed effects. We examined the publication bias at the outcome level with Begg funnel plot. We used Jadad scale18 to assess the quality of studies. Jadad scale has a score of 0 to 5 based on the basis of randomization, blinding, and attrition of participants. Study heterogeneity was evaluated with Cochran Q and I2 index with P , .10 and I2 of .60% considered significant heterogeneity, which was explored with sensitivity analysis. Statistical analyses were performed with Comprehensive Meta-Analysis (CMA 2.2; Biostat, Englewood, NJ, USA) and Review Manager (RevMan 5.2; Cochrane Collaboration, Nordic Cochrane Center, Copenhagen, Denmark).
Panta et al
Mipomersen in treatment of dyslipidemia Records identified through database searching (MEDLINE, EMBASE, Cochrane) (n = 397)
3 Additional records identified through other sources (n = 11)
Records after duplicates removed (n = 389)
Records screened (n = 389)
Full-text articles assessed for eligibility (n = 22)
Studies included in qualitative synthesis (n = 8)
Records excluded (n = 367)
Full-text articles excluded (n=14) Duplicates 2 Includes pediatric patients 1 Healthy volunteer 2 Post-hoc analysis 3 Review articles 3 Ongoing open label 1 Unrelated 2
Studies included in quantitative synthesis (meta-analysis) (n = 8)
Figure 1
Flow diagram for study selection.
Results Description of included studies Initial search resulted in 397 citations (Fig. 1). After removal of duplicates, we assessed 389 records for eligibility and extracted 22 citations for full-text review. We included 8 full-text publications in this meta-analysis with 462 patients total (294 mipomersen and 168 placebo) for efficacy analysis and 461 (293 mipomersen and 168 placebo) for the safety analysis. The dose of mipomersen was 50 to 400 mg subcutaneous weekly in 3 studies10,13,17 and 200 mg in 5 studies.11,14,15,19,20 The studies were performed in Europe and the United States and consisted of 45% females. The duration of follow-up was 5 to 26 weeks. Table 1 shows the baseline patient characteristics, study design, duration of treatment, and other parameters of the various studies included in the meta-analysis.
Efficacy outcomes Lipid parameters The meta-analysis of lipid parameters is shown in Figure 2. Mipomersen compared with placebo significantly
reduced LDL-C by 32.37% (95% CI, 25.55–39.18; P , .00001; I2 5 53%), total cholesterol by 24.18% (18.54–29.83; P , .00001; I2 5 64%), VLDL-C by 21.59% (9.16–34.02; P 5 .0007; I2 5 47%), non–HDL-C by 30.83% (23.92–37.74; P , .00001; I2 5 60%), and triglycerides by 36.26% (22–50.54; P , .00001; I2 5 0%). However, mipomersen did not result in significant change in HDL-C (0.37; 24.24 to 4.99; P 5 .87; I2 5 31%). Because of significant heterogeneity observed on LDL-C, total cholesterol, and non–HDL-C, we performed sensitivity analyses by excluding the study by Visser et al15 that included patients with statin intolerance. The pooled estimates remained statistically significant with reduction in heterogeneity: LDL-C (30.12; 25.35–34.94; P , .00001; I2 5 0%), total cholesterol (21.98; 17.72– 26.25; P , .00001; I2 5 25%), and non–HDL-C (28.37; 23.08–33.65; P , .00001; I2 5 20%). Apolipoprotein and lipoprotein(a) Figure 3 shows meta-analysis of apolipoproteins and lipoprotein(a). Mipomersen significantly reduced lipoprotein(a) by 25.87% (18.24–33.49; P , .00001; I2 5 0%), apolipoprotein A1 by 4.32% (1.98–6.67; P 5 .0003; I2 5 0%) and apolipoprotein B by 32.54% (27–38.07; P , .00001; I2 5 46%).
4
Table 1
Baseline characteristics of individual studies Total patients, n (P/M)
Thomas, 201314
P: 52; M: 105
Stein, 201219
P: 41; M: 83
Visser, 201215
P: 12; M: 21
McGowan, 201220
P: 19; M: 39
Akdim, 201117
P: 10; M: 8
Akdim, 201010
P: 8; M: 11
Visser, 201011
P: 11; M: 10
Akdim, 201013
P: 15; M: 16
Indication(s) Patients with baseline LDL-C $100 mg/dL with or at high risk of CHD who were receiving maximally tolerated lipid-lowering therapy Patients with heterozygous familial hypercholesterolemia and CAD on maximally tolerated statin and LDL-C $100 mg/dL Hypercholesterolemic patients who were at high risk for CVD and statin intolerant Adult patients with CHD on maximally tolerated lipid-lowering therapy that excluded apheresis Adult patients with mild–moderate hyperlipidemia with untreated LDL-C level of $130 mg/dL Adult patients with diagnosis of heterozygous familial hypercholesterolemia Adult patients with diagnosis of heterozygous familial hypercholesterolemia Hypercholesterolemic subjects taking stable statin therapy
Treatment duration (wk)
Patient characteristics Study design
Age in y (mean 6 SD)
Male, n (P/M)
White, n (P/M)
Jadad score
26
Randomized, double blind, multicenter
P: 59.3 6 9.5; M: 59.3 6 10
P: 29; M: 52
P: 40; M: 83
3
26
Randomized, double blind, multicenter
P: 55.9 6 9.3; M: 56.2 6 9.7
P: 28; M: 50
P: 38; M: 81
4
26
Randomized, double blind
P: 52; M: 55
P: 4; M: 11
26
Randomized, double blind, multicenter
P: 47.9 6 13.5; M: 51.8 6 14.3
P: 7; M: 18
13
Randomized, double blind, dose escalation Randomized, double blind, multicenter, dose escalation Randomized, double blind
P: 52.3 6 7.4; M: 49.6 6 8.5
P: 8; M: 7
4
P: 54 6 10; M: 56 6 13
P: 6; M: 4
4
P: 46 6 1; M: 49 6 12
P: 3; M: 6
5
Randomized, double blind, dose escalation
P: 60.8 6 3.3; M: 8.3 6 3.8
P: 8; M: 11
4
6
13
5
5
P: 16; M: 33
CAD, coronary artery disease; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; P/M, placebo/mipomersen; RCT, randomized controlled trial; SD, standard deviation.
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Journal of Clinical Lipidology, Vol -, No -, - 2015
First author, year (reference)
Panta et al
Mipomersen in treatment of dyslipidemia
5
Figure 2 Meta-analysis of mipomersen vs placebo on lipid parameters. CI, confidence interval; df, degrees of freedom; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; VLDL, very low–density lipoprotein.
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Journal of Clinical Lipidology, Vol -, No -, - 2015
Figure 3 Meta-analysis of mipomersen vs placebo on lipoprotein(a) and apolipoproteins. CI, confidence interval; df, degrees of freedom; SD, standard deviation.
Safety outcomes All 8 studies reported on most safety outcomes, whereas only 4 studies reported on hepatic steatosis (Fig. 4). Mipomersen compared with placebo increased the risks of injection-site reaction (RR, 2.05; 95% CI, 1.39–3.04; P 5 .0003; I2 5 80%), flu-like symptoms (1.63; 1.22– 2.17; P 5 .0008; I2 5 0%), ALT $3X ULN (4.44; 1.67– 11.86; P 5 .003; I2 5 0%) and hepatic steatosis (3.85; 1.39–10.67; P 5 .01; I2 5 0%). The risk of ALT $10X ULN was statistically nonsignificant (1.57; 0.32–7.6; P 5 .58; I2 5 0%). Because of significant heterogeneity on injection-site reaction, we performed sensitivity analysis by excluding the Visser et al study15 with new estimates (2.20; 1.59–3.05; P , .00001; I2 5 58%).
Study quality and publication bias Quality of the studies was assessed by Jadad scale that ranged from 3 to 5 as shown in Table 1. Jadad score was 3 for 1 study,14 4 for 4 studies,10,13,17,19 and 5 for 3
studies.11,15,20 Visual examination of funnel plot did not reveal publication bias.
Discussion The current meta-analysis showed that mipomersen significantly improves most of the lipid parameters excluding the HDL-C compared with placebo and increased immediate adverse effects. It reduced the levels of LDL-C, total cholesterol, VLDL-C, non–HDL-C, and triglycerides. It also reduced the levels of apo B, apo A1, and lipoprotein(a). On the other hand, it increased the risks of injection-site reaction, flu-like symptoms, elevated ALT $3X ULN, and hepatic steatosis. It however did not reach statistical significance on ALT $10X ULN. The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) identifies LDL-C below 100 mg/dL being optimal and recommends lifestyle modifications and pharmacologic interventions on
Panta et al
Mipomersen in treatment of dyslipidemia
7
Figure 4 Meta-analysis of adverse events. ALT, alanine aminotransferase; CI, confidence interval; df, degrees of freedom; ULN, upper limit of normal.
8 the basis of CHD risk factors and LDL-C levels.6 Recently published American College of Cardiology/American Heart Association guidelines for risk reduction in atherosclerotic cardiovascular disease focuses on 4 statin benefit groups and recommends adding nonstatin therapy to patients without anticipated therapeutic response in 3 to 12 months.21 The Centers for Disease Control and Prevention data also confirm not only the lack of treatment among significant number of patients with dyslipidemia but also inadequate LDL-C goals among patients who are on current treatment necessitating for a development of a more effective therapy for dyslipidemia.7 Mipomersen was approved by the US Food and Drug Administration as an adjunct to diet and lipid-lowering medications for patients with homozygous familial hypercholesterolemia on the basis of data from randomized trials.12,22 Although, the US Food and Drug Administration approval was given only for treatment of homozygous familial hypercholesterolemia, it has been studied in patients with risk of CHD on maximal statin or lipid-lowering therapy14,19,20 and statin intolerance.15 Such trials showed significant improvement in lipid parameters. However, on the basis of increased adverse events, the Committee for Medicinal Products for Human Use of the European Medicines Agency did not approve mipomersen for use.23 Our metaanalysis found significant increases in adverse events of flu-like symptoms, injection-site reactions, elevated ALT, and hepatic steatosis with mipomersen use (Fig. 4). To date, a limited number of hepatic biopsies have been obtained in patients with steatosis, and no evidence of significant fibrosis has been found.24 Despite the efficacy of mipomersen in lowering LDL-C along with other lipid parameters, its effects on cardiovascular outcomes or mortality as well as long-term adverse events are unknown.
Study limitations Our meta-analysis has several limitations. Small number of studies with small number of patients in most of the studies is a major limitation. Besides, these studies only report on the short-term efficacy and safety outcomes of mipomersen. We could not perform analysis at the patient level data, which is a potential limitation. Significant heterogeneity was observed in some of the outcomes although we tried to overcome it by performing sensitivity analyses.
Conclusions The current meta-analysis showed that mipomersen is an effective therapy in improving several lipid parameters in patients with dyslipidemia with increase in immediate adverse events. Data on long-term adverse events and the cardiovascular outcomes and mortality are needed to guide us on the use of this parenteral therapy in patients with dyslipidemia with risks of CHD, or statin intolerance.
Journal of Clinical Lipidology, Vol -, No -, - 2015
References 1. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–1847. 2. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986; 256:2823–2828. 3. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251: 351–364. 4. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251:365–374. 5. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15. 6. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497. 7. Vital signs: prevalence, treatment, and control of high levels of lowdensity lipoprotein cholesterol–United States, 1999-2002 and 2005200. MMWR Morb Mortal Wkly Rep. 2011;60:109–114. 8. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44: 720–732. 9. Bell DA, Hooper AJ, Watts GF, Burnett JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia. Vasc Health Risk Manag. 2012;8:651–659. 10. Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol. 2010;105:1413–1419. 11. Visser ME, Akdim F, Tribble DL, et al. Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. J Lipid Res. 2010;51:1057–1062. 12. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375: 998–1006. 13. Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010;55:1611–1618. 14. Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013;62:2178–2184. 15. Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012;33:1142–1149. 16. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. 17. Akdim F, Tribble DL, Flaim JD, et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J. 2011;32:2650–2659. 18. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.
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Mipomersen in treatment of dyslipidemia
19. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126:2283–2292. 20. McGowan MP, Tardif JC, Ceska R, et al. Randomized, placebocontrolled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7:e49006. 21. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of
9 Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889–2934. 22. FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder. Available at: http://www.fda.gov/newsevents/newsroom/ pressannouncements/ucm337195.htm. Accessed May 16, 2014. 23. Scientific conclusions and grounds for refusal presented by the European Medicines Agency. Available at: http://www.ema.europa.eu/ docs/en_GB/document_library/Other/human/002429/WC500147552. pdf. Accessed May 16, 2014. 24. Hashemi N, Odze RD, MdGowan MP, et al. Liver histology during Mipomersen therapy for severe hypercholesterolemia. J Clin Lipidol. 2014;8:606–611.
Original Contribution
Efficacy and safety of mipomersen in treatment of dyslipidemia: A meta-analysis of randomized controlled trials Raju Panta, MD, MS*, Khagendra Dahal, MD, Sumit Kunwar, MD Department of Hospital Medicine, LRGHealthcare, Laconia, NH, USA KEYWORDS: Mipomersen; Apolipoprotein B synthesis inhibitor; Hyperlipidemia; Familial dyslipidemia; LDL cholesterol; HDL cholesterol; Total cholesterol; Non-HDL cholesterol; Apolipoprotein B; Hepatic steatosis
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipidlowering therapy in people at risk for cardiovascular diseases. Mipomersen inhibits apolipoprotein B-100 (apoB) synthesis and causes reduction in LDL-C by reducing apoB. OBJECTIVE: We aimed to perform a meta-analysis of all published randomized controlled trials comparing safety and efficacy of mipomersen with placebo in adults with dyslipidemia. METHODS: We searched PUBMED, CENTRAL, and EMBASE from inception through March 2014 and used random-effects model to compute the effect size. RESULTS: We identified 8 randomized controlled trials (n 5 462). Mipomersen compared with placebo significantly reduced LDL-C by 32.37% (95% confidence interval, 25.55–39.18; P , .00001), total cholesterol by 24.18% (18.54–29.83; P , .00001), very low–density lipoprotein cholesterol by 21.59% (9.16–34.02; P 5 .0007), non–high-density lipoprotein cholesterol (HDL-C) by 30.83% (23.92–37.74; P , .00001), and triglycerides by 36.26% (22–50.54; P , .00001). It also significantly reduced apoB, lipoprotein(a), and apolipoprotein A1. However, mipomersen did not significantly change HDL-C levels. In safety analysis, mipomersen compared with placebo increased the risks of injection-site reaction (risk ratio, 2.05; 95% confidence interval, 1.39–3.04; P 5 .0003), flu-like symptoms (1.63; 1.22–2.17; P 5 .0008), alanine aminotransferase $3X upper limit of normal (4.44; 1.67–11.86; P 5 .003), and hepatic steatosis (3.85, 1.39–10.67; P 5 .01). The risks of alanine aminotransferase $10X upper limit of normal did not reach statistical significance (1.57; 0.32–7.6, P 5 .58). CONCLUSION: Mipomersen resulted in a significant improvement in lipid parameters except for HDL-C and increased the risks of injection-site reactions, flu-like symptoms, and hepatic steatosis compared with placebo. Ó 2015 National Lipid Association. All rights reserved.
Author contributions: R.P. and K.D. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. R.P. and K.D. contributed to the study concept and design; acquisition, analysis, or interpretation of data; drafting of the article; critical revision of the article for important intellectual content; statistical analysis; and study supervision. S.K. contributed to acquisition, analysis, or interpretation of data; critical revision of the article for important intellectual content; and study supervision.
1933-2874/Ó 2015 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.12.006
Conflict of interest disclosures: None. Funding/support: This research was self-funded. * Corresponding author. Department of Hospital Medicine, LRGHealthcare, 80 Highland Street, Laconia, NH 03246. E-mail address: [email protected] Submitted May 29, 2014. Accepted for publication December 4, 2014.
2
Journal of Clinical Lipidology, Vol -, No -, - 2015
Introduction
Study selection
The serum level of low-density lipoprotein cholesterol (LDL-C) is directly linked to the rate of new onset of coronary heart disease (CHD) and progression of an established CHD.1–4 On the other hand, high-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with risk of CHD.5 LDL-C is the primary target of lipidlowering therapy in people at risk for cardiovascular disease, which is the leading cause of death in the industrialized countries.6 According to Centers for Disease Control and Prevention, 71 million American adults (33.5%) have high LDL-C less than half of which get treatment to reduce its levels and 1 of every 3 who get treatment have this condition under control.7 Despite the advent of potent statins and use of combination lipid-lowering therapy, a substantial proportion of patients at high risk of CHD remain unable to achieve optimal LDL-C.8 Mipomersen, an antisense oligonucleotide designed to enhance destruction of the messenger RNA for apolipoprotein B-100 (apoB) provides a means of reducing the synthesis of this major apolipoprotein and therefore the number of very low–density lipoprotein (VLDL) and possibly LDL molecules leaving the liver. This produces a reduction of these apoB-containing lipoproteins in the plasma.9 Statins and other LDL-lowering drugs such as ezetimibe and bile acid sequestrants act through increasing LDL receptors and thereby enhancing clearance. By providing a totally new mechanism of action, mipomersen may be useful in patients with defective or absent LDL receptors or who do not respond fully to existing drugs. In randomized controlled trials, a significant reduction in LDL-C has been observed in patients with familial hypercholesterolemia10–12 and in patients with dyslipidemia on statin therapy13,14 or statin intolerance.15 To better define its efficacy and safety, we performed a meta-analysis of current randomized trials of mipomersen in adults ($18 years) with dyslipidemia.
The flow diagram for study selection is shown in Figure 1. We included randomized controlled trials comparing mipomersen vs placebo in adult patients ($18 years) with dyslipidemia in the meta-analysis. We excluded studies with nonrandomized designs, healthy volunteers, pediatric patients, animals, and abstracts without full-text publications.
Methods Data sources and search strategy We wrote a study protocol in accordance with the PRISMA statement.16 We searched MEDLINE, EMBASE, and Cochrane CENTRAL Register of Controlled Trials for publications since inception through March 2014 without language restriction. The search terms were ‘‘mipomersen’’ OR ‘‘apolipoprotein B synthesis inhibitor’’ with restriction to randomized design (‘‘randomized controlled trials’’ OR ‘‘controlled clinical trials’’ OR ‘‘comparative study’’). Two authors (R.P. and K.D.) independently performed the database search, and disagreement was resolved by consensus. A hand search was performed for all relevant references from the selected articles.
Data extraction Two authors (R.P. and K.D.) extracted data from the selected studies in duplicate using standardized dataextraction form. We obtained data on study and patient characteristics, indication(s) of mipomersen use, dosages of mipomersen, duration of follow-up, and major safety and efficacy outcomes as described in the following. In intervention arm, data were only extracted for mipomersen dose of 200 mg if the studies used variable doses,10,13,17 whereas all patients in the control arm were included in the analysis. Disagreement was resolved by consensus.
Major outcomes Efficacy outcomes were percentage change in LDL-C, HDL-C, triglycerides, non–HDL-C, VLDL cholesterol (VLDL-C), total cholesterol, and lipoprotein(a), apolipoprotein A1, and apolipoprotein B. The safety outcomes were risks of elevated alanine aminotransferase (ALT) .3X upper limit of normal (ULN) and .10X ULN, hepatic steatosis, flu-like symptoms, and injection-site reaction.
Statistical analysis We pooled the continuous variables as the difference in percentage change in mean and the categorical variables as risk ratio (RR), both with 95% confidence interval (CI). We used crude events from each study to compute RR with 95% CI. DerSimonian–Laird random-effects model was used for meta-analysis of effect size. The P , .05 (2 tailed) was considered statistically significant for computed effects. We examined the publication bias at the outcome level with Begg funnel plot. We used Jadad scale18 to assess the quality of studies. Jadad scale has a score of 0 to 5 based on the basis of randomization, blinding, and attrition of participants. Study heterogeneity was evaluated with Cochran Q and I2 index with P , .10 and I2 of .60% considered significant heterogeneity, which was explored with sensitivity analysis. Statistical analyses were performed with Comprehensive Meta-Analysis (CMA 2.2; Biostat, Englewood, NJ, USA) and Review Manager (RevMan 5.2; Cochrane Collaboration, Nordic Cochrane Center, Copenhagen, Denmark).
Panta et al
Mipomersen in treatment of dyslipidemia Records identified through database searching (MEDLINE, EMBASE, Cochrane) (n = 397)
3 Additional records identified through other sources (n = 11)
Records after duplicates removed (n = 389)
Records screened (n = 389)
Full-text articles assessed for eligibility (n = 22)
Studies included in qualitative synthesis (n = 8)
Records excluded (n = 367)
Full-text articles excluded (n=14) Duplicates 2 Includes pediatric patients 1 Healthy volunteer 2 Post-hoc analysis 3 Review articles 3 Ongoing open label 1 Unrelated 2
Studies included in quantitative synthesis (meta-analysis) (n = 8)
Figure 1
Flow diagram for study selection.
Results Description of included studies Initial search resulted in 397 citations (Fig. 1). After removal of duplicates, we assessed 389 records for eligibility and extracted 22 citations for full-text review. We included 8 full-text publications in this meta-analysis with 462 patients total (294 mipomersen and 168 placebo) for efficacy analysis and 461 (293 mipomersen and 168 placebo) for the safety analysis. The dose of mipomersen was 50 to 400 mg subcutaneous weekly in 3 studies10,13,17 and 200 mg in 5 studies.11,14,15,19,20 The studies were performed in Europe and the United States and consisted of 45% females. The duration of follow-up was 5 to 26 weeks. Table 1 shows the baseline patient characteristics, study design, duration of treatment, and other parameters of the various studies included in the meta-analysis.
Efficacy outcomes Lipid parameters The meta-analysis of lipid parameters is shown in Figure 2. Mipomersen compared with placebo significantly
reduced LDL-C by 32.37% (95% CI, 25.55–39.18; P , .00001; I2 5 53%), total cholesterol by 24.18% (18.54–29.83; P , .00001; I2 5 64%), VLDL-C by 21.59% (9.16–34.02; P 5 .0007; I2 5 47%), non–HDL-C by 30.83% (23.92–37.74; P , .00001; I2 5 60%), and triglycerides by 36.26% (22–50.54; P , .00001; I2 5 0%). However, mipomersen did not result in significant change in HDL-C (0.37; 24.24 to 4.99; P 5 .87; I2 5 31%). Because of significant heterogeneity observed on LDL-C, total cholesterol, and non–HDL-C, we performed sensitivity analyses by excluding the study by Visser et al15 that included patients with statin intolerance. The pooled estimates remained statistically significant with reduction in heterogeneity: LDL-C (30.12; 25.35–34.94; P , .00001; I2 5 0%), total cholesterol (21.98; 17.72– 26.25; P , .00001; I2 5 25%), and non–HDL-C (28.37; 23.08–33.65; P , .00001; I2 5 20%). Apolipoprotein and lipoprotein(a) Figure 3 shows meta-analysis of apolipoproteins and lipoprotein(a). Mipomersen significantly reduced lipoprotein(a) by 25.87% (18.24–33.49; P , .00001; I2 5 0%), apolipoprotein A1 by 4.32% (1.98–6.67; P 5 .0003; I2 5 0%) and apolipoprotein B by 32.54% (27–38.07; P , .00001; I2 5 46%).
4
Table 1
Baseline characteristics of individual studies Total patients, n (P/M)
Thomas, 201314
P: 52; M: 105
Stein, 201219
P: 41; M: 83
Visser, 201215
P: 12; M: 21
McGowan, 201220
P: 19; M: 39
Akdim, 201117
P: 10; M: 8
Akdim, 201010
P: 8; M: 11
Visser, 201011
P: 11; M: 10
Akdim, 201013
P: 15; M: 16
Indication(s) Patients with baseline LDL-C $100 mg/dL with or at high risk of CHD who were receiving maximally tolerated lipid-lowering therapy Patients with heterozygous familial hypercholesterolemia and CAD on maximally tolerated statin and LDL-C $100 mg/dL Hypercholesterolemic patients who were at high risk for CVD and statin intolerant Adult patients with CHD on maximally tolerated lipid-lowering therapy that excluded apheresis Adult patients with mild–moderate hyperlipidemia with untreated LDL-C level of $130 mg/dL Adult patients with diagnosis of heterozygous familial hypercholesterolemia Adult patients with diagnosis of heterozygous familial hypercholesterolemia Hypercholesterolemic subjects taking stable statin therapy
Treatment duration (wk)
Patient characteristics Study design
Age in y (mean 6 SD)
Male, n (P/M)
White, n (P/M)
Jadad score
26
Randomized, double blind, multicenter
P: 59.3 6 9.5; M: 59.3 6 10
P: 29; M: 52
P: 40; M: 83
3
26
Randomized, double blind, multicenter
P: 55.9 6 9.3; M: 56.2 6 9.7
P: 28; M: 50
P: 38; M: 81
4
26
Randomized, double blind
P: 52; M: 55
P: 4; M: 11
26
Randomized, double blind, multicenter
P: 47.9 6 13.5; M: 51.8 6 14.3
P: 7; M: 18
13
Randomized, double blind, dose escalation Randomized, double blind, multicenter, dose escalation Randomized, double blind
P: 52.3 6 7.4; M: 49.6 6 8.5
P: 8; M: 7
4
P: 54 6 10; M: 56 6 13
P: 6; M: 4
4
P: 46 6 1; M: 49 6 12
P: 3; M: 6
5
Randomized, double blind, dose escalation
P: 60.8 6 3.3; M: 8.3 6 3.8
P: 8; M: 11
4
6
13
5
5
P: 16; M: 33
CAD, coronary artery disease; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; P/M, placebo/mipomersen; RCT, randomized controlled trial; SD, standard deviation.
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First author, year (reference)
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Mipomersen in treatment of dyslipidemia
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Figure 2 Meta-analysis of mipomersen vs placebo on lipid parameters. CI, confidence interval; df, degrees of freedom; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; VLDL, very low–density lipoprotein.
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Figure 3 Meta-analysis of mipomersen vs placebo on lipoprotein(a) and apolipoproteins. CI, confidence interval; df, degrees of freedom; SD, standard deviation.
Safety outcomes All 8 studies reported on most safety outcomes, whereas only 4 studies reported on hepatic steatosis (Fig. 4). Mipomersen compared with placebo increased the risks of injection-site reaction (RR, 2.05; 95% CI, 1.39–3.04; P 5 .0003; I2 5 80%), flu-like symptoms (1.63; 1.22– 2.17; P 5 .0008; I2 5 0%), ALT $3X ULN (4.44; 1.67– 11.86; P 5 .003; I2 5 0%) and hepatic steatosis (3.85; 1.39–10.67; P 5 .01; I2 5 0%). The risk of ALT $10X ULN was statistically nonsignificant (1.57; 0.32–7.6; P 5 .58; I2 5 0%). Because of significant heterogeneity on injection-site reaction, we performed sensitivity analysis by excluding the Visser et al study15 with new estimates (2.20; 1.59–3.05; P , .00001; I2 5 58%).
Study quality and publication bias Quality of the studies was assessed by Jadad scale that ranged from 3 to 5 as shown in Table 1. Jadad score was 3 for 1 study,14 4 for 4 studies,10,13,17,19 and 5 for 3
studies.11,15,20 Visual examination of funnel plot did not reveal publication bias.
Discussion The current meta-analysis showed that mipomersen significantly improves most of the lipid parameters excluding the HDL-C compared with placebo and increased immediate adverse effects. It reduced the levels of LDL-C, total cholesterol, VLDL-C, non–HDL-C, and triglycerides. It also reduced the levels of apo B, apo A1, and lipoprotein(a). On the other hand, it increased the risks of injection-site reaction, flu-like symptoms, elevated ALT $3X ULN, and hepatic steatosis. It however did not reach statistical significance on ALT $10X ULN. The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) identifies LDL-C below 100 mg/dL being optimal and recommends lifestyle modifications and pharmacologic interventions on
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Mipomersen in treatment of dyslipidemia
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Figure 4 Meta-analysis of adverse events. ALT, alanine aminotransferase; CI, confidence interval; df, degrees of freedom; ULN, upper limit of normal.
8 the basis of CHD risk factors and LDL-C levels.6 Recently published American College of Cardiology/American Heart Association guidelines for risk reduction in atherosclerotic cardiovascular disease focuses on 4 statin benefit groups and recommends adding nonstatin therapy to patients without anticipated therapeutic response in 3 to 12 months.21 The Centers for Disease Control and Prevention data also confirm not only the lack of treatment among significant number of patients with dyslipidemia but also inadequate LDL-C goals among patients who are on current treatment necessitating for a development of a more effective therapy for dyslipidemia.7 Mipomersen was approved by the US Food and Drug Administration as an adjunct to diet and lipid-lowering medications for patients with homozygous familial hypercholesterolemia on the basis of data from randomized trials.12,22 Although, the US Food and Drug Administration approval was given only for treatment of homozygous familial hypercholesterolemia, it has been studied in patients with risk of CHD on maximal statin or lipid-lowering therapy14,19,20 and statin intolerance.15 Such trials showed significant improvement in lipid parameters. However, on the basis of increased adverse events, the Committee for Medicinal Products for Human Use of the European Medicines Agency did not approve mipomersen for use.23 Our metaanalysis found significant increases in adverse events of flu-like symptoms, injection-site reactions, elevated ALT, and hepatic steatosis with mipomersen use (Fig. 4). To date, a limited number of hepatic biopsies have been obtained in patients with steatosis, and no evidence of significant fibrosis has been found.24 Despite the efficacy of mipomersen in lowering LDL-C along with other lipid parameters, its effects on cardiovascular outcomes or mortality as well as long-term adverse events are unknown.
Study limitations Our meta-analysis has several limitations. Small number of studies with small number of patients in most of the studies is a major limitation. Besides, these studies only report on the short-term efficacy and safety outcomes of mipomersen. We could not perform analysis at the patient level data, which is a potential limitation. Significant heterogeneity was observed in some of the outcomes although we tried to overcome it by performing sensitivity analyses.
Conclusions The current meta-analysis showed that mipomersen is an effective therapy in improving several lipid parameters in patients with dyslipidemia with increase in immediate adverse events. Data on long-term adverse events and the cardiovascular outcomes and mortality are needed to guide us on the use of this parenteral therapy in patients with dyslipidemia with risks of CHD, or statin intolerance.
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