Accepted Manuscript Tibolone Decreases Lipoprotein(a) levels in Postmenopausal Women: A Systematic Review and Meta-Analysis of 12 studies with 1009 patients Kazuhiko Kotani, Amirhossein Sahebkar, Corina Serban, Florina Andrica, Peter P. Toth, Steven R. Jones, Karam Kostner, Michael J. Blaha, Seth Martin, Jacek Rysz, Stephen Glasser, Kausik K. Ray, Gerald F. Watts, Dimitri P. Mikhailidis, Prof. Maciej Banach, MD, PhD, FNLA, FAHA, FESC; FASA, Head PII: S0021-9150(15)30017-4 DOI: 10.1016/j.atherosclerosis.2015.06.056 Reference: ATH 14168 To appear in: Atherosclerosis Received Date: 28 May 2015 Revised Date: 28 June 2015 Accepted Date: 29 June 2015 Please cite this article as: Kotani K, Sahebkar A, Serban C, Andrica F, Toth PP, Jones SR, Kostner K, Blaha MJ, Martin S, Rysz J, Glasser S, Ray KK, Watts GF, Mikhailidis DP, Banach M, Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group, Tibolone Decreases Lipoprotein(a) levels in Postmenopausal Women: A Systematic Review and Meta-Analysis of 12 studies with 1009 patients, Atherosclerosis (2015), doi: 10.1016/j.atherosclerosis.2015.06.056. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Accepted Manuscript
Tibolone Decreases Lipoprotein(a) levels in Postmenopausal Women: A SystematicReview and Meta-Analysis of 12 studies with 1009 patients
Kazuhiko Kotani, Amirhossein Sahebkar, Corina Serban, Florina Andrica, Peter P.Toth, Steven R. Jones, Karam Kostner, Michael J. Blaha, Seth Martin, Jacek Rysz,Stephen Glasser, Kausik K. Ray, Gerald F. Watts, Dimitri P. Mikhailidis, Prof. MaciejBanach, MD, PhD, FNLA, FAHA, FESC; FASA, Head
PII: S0021-9150(15)30017-4
DOI: 10.1016/j.atherosclerosis.2015.06.056
Reference: ATH 14168
To appear in: Atherosclerosis
Received Date: 28 May 2015
Revised Date: 28 June 2015
Accepted Date: 29 June 2015
Please cite this article as: Kotani K, Sahebkar A, Serban C, Andrica F, Toth PP, Jones SR, Kostner K,Blaha MJ, Martin S, Rysz J, Glasser S, Ray KK, Watts GF, Mikhailidis DP, Banach M, Lipid and BloodPressure Meta-analysis Collaboration (LBPMC) Group, Tibolone Decreases Lipoprotein(a) levels inPostmenopausal Women: A Systematic Review and Meta-Analysis of 12 studies with 1009 patients,Atherosclerosis (2015), doi: 10.1016/j.atherosclerosis.2015.06.056.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.
These results are of high importance because Lp(a) is an independent risk factor for CVD, there
are no effective and safe treatments for high Lp(a) levels, and postmenopausal women are at
higher CVD risk 3-5.
Tibolone treatment can reduce circulating Lp(a) levels by 25% (42-44). More recently,
significant reductions of Lp(a) have been shown with a range of new therapies, including
cholesteryl ester transfer protein (CETP) inhibitors, sequence-specific antisense oligonucleotides
against apoB, inhibitory monoclonal antibodies to proprotein convertase subtilisin/kexin type-9
(PCSK9), thyroid hormone analogues, and synthetic inhibitors of microsomal triglyceride
transfer protein 46-51. The magnitude of reductions of Lp(a) by these drugs appears to be similar
to the ones with tibolone, while the overall magnitude of these recent drugs is still not
established 46-48, 52. The magnitude of reduction of Lp(a) with tibolone is similar to that of niacin.
The influences of the dose and duration of used drugs on Lp(a) is also of concern 25. Niacin can
reduce Lp(a) in a dose-dependent manner 53. Whereas, the present meta-analysis did not find a
dose- or duration-dependent manner of tibolone treatment on Lp(a). This may be an advantage in
using tibolone to decrease Lp(a) levels.
The reduction of circulating Lp(a) by tibolone is still incompletely explained. The estrogenic
property of tibolone is a possible explanation of the reduction of Lp(a) 25; however, the details in
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the involvement of estrogens in the Lp(a) regulation still remain to be fully clarified 54. One of
the mechanism potentially responsible might be the fact that Lp(a) gene has an estrogen response
element and tibolone may active this and reduce hepatic output of Apo(a) 55. Lp(a) is also
decreased by testosterone and the androgenic component of tibolone may have a dual effect 56.
However, further studies of the mechanism of action of tibolone on Lp(a) metabolism are still
required.
The present meta-analysis has limitations. First, the studies included in the present meta-
analysis were not always interventional studies focused on the Lp(a) levels, as a main endpoint,
therefore well-designed interventional trials specific for Lp(a) are still necessary. Next, the
included studies did not evaluate the long-term CVD outcomes associated with Lp(a) reduction.
The reduction of Lp(a) is theoretically thought to be favorable for the prevention of the events,
but whether the reduction of Lp(a) with Lp(a)-targeted therapies can lead to the favorable
outcomes still needs to be proven, especially that available long-term controlled studies with a
Lp(a)-lowering drug (nicotinic acid plus laropiprant) have failed to find a positive impact of the
Lp(a) reduction on CV events 19. Some studies have also indicated that very low Lp(a) levels
might be harmful 57, 58, however Mendelian randomization studies did not confirm that low Lp(a)
increases the risk of diabetes 59. However, tibolone can improve not only Lp(a) level but also
vascular functions (e.g. vasodilation) with its estrogenic property 21. Additionally, tibolone is
reported to modulate other lipoprotein factors, i.e. the drug with its androgenic properties can
reduce high-density lipoprotein cholesterol (HDL-C) as an unfavorable change 25. However,
there are findings that the change of HDL-C is usually transient 33; on the other hand there are
more and more data that we should not focus on HDL-C as it is not main target of the lipid-
lowering therapy, also due to the lasting debate on HDL functionality in different patients’
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groups 42, 60, 61. It should be emphasized that data on circulating Lp(a) levels were obtained from
studies using different assays for Lp(a). It would be also necessary to look at the tibolone effects
in general, including the influence on inflammatory markers, and other risk factors of CVD (e.g.
blood pressure) 62, in order to finally confirm the possible benefits of its therapy. Finally, the
included studies did not particularly focus on tibolone therapy-related side effects. One should
notice that the side effects after tibolone therapy with doses ≤2.5 mg/day are uncommon 63. In
the Long-Term Intervention on Fractures with Tibolone (LIFT) trial 64 in older postmenopausal
women (aged 60-85 years) tibolone therapy (in comparison to placebo) significantly reduced the
risk of vertebral and nonvertebral fractures, invasive breast cancer and colon cancer, however,
increased of the stroke risk. There were also no significant differences in the risk of either CHD
or venous thromboembolism 64. However the above mentioned stroke risk was not observed in
other studies with younger postmenopausal women 65, 66.
In conclusion, the present meta-analysis revealed that oral tibolone treatment significantly
reduced circulating Lp(a) levels in postmenopausal women. The significance of this metabolic
effect for the prevention of CVD needs to be weighed against other effects of tibolone and
requires further investigations. Large-scale, well-designed studies may then be justified to
explore the value of tibolone treatment in high risk subjects with elevated plasma Lp(a) levels 19.
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DECLARATION OF INTEREST
This meta-analysis was written independently; no company or institution supported it
financially. No authors have any conflict of interest concerning the preparation of this analysis.
Some of the authors have given talks, attended conferences and participated in trials and
advisory boards sponsored by various pharmaceutical companies. No professional writer was
involved in the preparation of this meta-analysis.
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TABLES
Table 1. Demographic characteristics of the included studies
Values are expressed as mean ± SD or median (25–75 percentiles).
ABBREVIATIONS: BMI: body mass index; BP: blood pressure; NS: not stated; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; DM: diabetes mellitus; FSH: serum levels of follicle stimulating hormone; HRT: hormonal replacement therapy; adenotes 1.25 mg/day tibolone; bdenotes 2.5 mg/day tibolone; cdenotes 0.3 mg/day tibolone; ddenotes 0.625 mg/day tibolone; edenotes 20 mg/day oral tamoxifen (Nolvadex-D; Astra-Zeneca) plus either 2.5 mg/ day oral tibolone (Livial; NVOrganon), fdenotes a combined estrogen (0.625 mg/day) – progestin (0.15 mg for 12 days in 28) preparation; g denotes oral medroxyprogesterone acetate (MPA; 10 mg/day for 12 days); hdenotes conjugated ET (Premarin, 0.625 mg/d oral tablets; Wyeth, Istanbul, Turkey); *denotes patients belonging to tibolone group n = 34; ** denotes patients belonging to tibolone group or placebo group n = 29.
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Table 2. Risk of bias assessment in the studies considered for meta-analysis.
Study Ref SEQUENCE GENERATION
ALLOCATION CONCEALMENT
BLINDING OF PARTICIPANTS
AND PERSONNEL
BLINDING OF OUTCOME
ASSESSMENT
INCOMPLETE OUTCOME
DATA
SELECTIVE OUTCOME
REPORTING
OTHER POTENTIAL
THREATS TO VALIDITY
Bjarnason et al. 33 U U L L L L L Gallagher et al. 34 U H L L L L L Kalogeropoulos et al. 35 U U U U L L L Kroiss et al. 36 L L L L L L L Lloyd et al. 37 U U L L L L L Milner et al. 38 L U U U L L L Ostberg et al. 39 U U U U L L L Perrone et al. 40 U U U U L L L von Eckardstein et al. 41 U U L L L L L von Eckardstein et al. 42 U U L L L L L Anedda et al. 43 U U L L L L L Demirol et al. 44 U U L L L L L L: low risk of bias; H: high risk of bias; U: unclear risk of bias
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FIGURE LEGENDS
Figure 1. Flow chart of the number of studies included to the meta-analysis.
Figure 2. Forest plot displaying weighted mean difference and 95% confidence intervals for the
impact of tibolone on circulating Lp(a) levels. Lower plot shows leave-one-out sensitivity analysis.
Figure 3. Forest plot displaying weighted mean difference and 95% confidence intervals for the
impact of tibolone on circulating Lp(a) levels in trials administering doses < 2.5 mg/day (upper
plot) and ≥ 2.5 mg/day (lower plot).
Figure 4. Forest plot displaying weighted mean difference and 95% confidence intervals for the
impact of tibolone on circulating Lp(a) levels in trials lasting < 24 months (upper plot) and ≥ 24
months (lower plot).
Figure 5. Meta-regression plots of the association between mean changes in circulating Lp(a)
levels s and dose and duration of treatment with tibolone. The size of each circle is inversely
proportional to the variance of change.
Figure 6. Funnel plot detailing publication bias in the studies reporting the impact of tibolone on