Statins are the first-line lipid modifier for reducing cardiovascular morbidity and mortality (Ray et al., 2019; Michos et al., 2019). Statins have revolutionized the prevention and treatment of cardiovascular disease, and inspired the development of a range of effective interventions targeting the reduction of low-density lipoprotein (LDL)-cholesterol. Statins have long been suspected of having additional beneficial effects beyond lipid modulation (Schonbeck and Libby, 2004), such as on inflammation (Schonbeck and Libby, 2004), another potential target for reducing cardiovascular disease (Aday and Ridker, 2018). Meta-analysis of randomized controlled trials (RCTs) suggests statins are more effective at reducing mortality than proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or ezetimibe (Schmidt et al., 2017; Khan et al., 2018). However, these findings may be more apparent than real, stemming from differences in trial design, such as shorter duration of the PCSK9 inhibitor trials (Khan et al., 2018), the predominance of industry funded statin trials (Hobbs et al., 2016) or the difficulty of interpreting trials of ‘soft’ events when the treatment affects diagnostically relevant criteria, that is lipid levels (Schooling and Zhao, 2019). To investigate this anomaly, a previous study conducted a systematic agnostic scan of metabolic profile in a trial of statins compared to a PCSK9 inhibitor, which found few differences (Sliz et al., 2018). While characterization of the metabolic effects of statins suggested extensive effects on lipids and fatty acids (Würtz et al., 2016); these investigations were not able to include a factor which has previously been proposed as contributing to statin’s effectiveness, that is effects on male hormones (Schooling et al., 2013), although questions have been raised as to whether statins are as effective in women as men (Plakogiannis and Arif, 2016). However, meta-analysis of the available trial evidence suggests similar relative benefits of LDL-cholesterol reduction by statins for men and women (Fulcher et al., 2015), although the trials mainly concern men (73.2%) which may preclude detection of important sex differences. Men are also at substantially higher risk than women (Ezzati et al., 2015) giving larger absolute benefits in men than women at the same reduction in relative risk.

RCTs are not usually designed or powered to test mediating mechanisms. In addition, trials of statins on cardiovascular disease outcomes designed to be sex-specific are lacking. To assess a potential pathway by which statins might additionally operate, we used Mendelian randomization (MR), an observational study design that avoids confounding by taking advantage of the random allocation of genetic material at conception (Smith and Ebrahim, 2003), here specifically genetic variants mimicking effects of lipid modifiers. This random allocation at conception also avoids selection bias as long as few deaths have occurred between randomization and recruitment due to exposure, outcome, or other causes, that is competing risk, of the outcome (Schooling et al., 2020). So, here we focused on ischemic heart disease (IHD) (Kesteloot and Decramer, 2008), using the UK Biobank (Collins, 2012) to investigate whether testosterone mediated any of the effects of statins, PCSK9 inhibitors or ezetimibe on IHD in men or women using univariable and multivariable MR. As a further test, given some anti-inflammatories have also been shown to have opposite effects on male hormones compared to statins, specifically the interleukin one receptor antagonist (IL-1Ra), anakinra (Ebrahimi et al., 2018), we assessed whether the genetic variants mimicking effects of anakinra or tocilizumab targeting the interleukin six receptor (IL-6r) had opposite patterns of effects on testosterone and IHD (Aday and Ridker, 2018; Swerdlow et al., 2012; Interleukin 1 Genetics Consortium, 2015) to statins. Figure 1 illustrates the possible additional effects of statins, anakinra or tocilizumab on IHD via male hormones in the context of the well-established benefits of statins, PCSK9 inhibitors and ezetimibe acting via LDL-cholesterol and of anti-inflammatories in IHD.

Figure 1

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The six single neucleotide polymorphisms (SNPs) mimicking effects of statin (rs12916, rs5909, rs10066707, rs17238484, rs2006760 and rs2303152 from HMGCR) (Ference et al., 2019) were all correlated (r² >0.13). In the main analysis we used only the lead SNP, rs12916. Of the 7 SNPs mimicking effects of PCSK9 inhibitors (rs11206510, rs2149041, rs7552841, rs10888897, rs2479394, rs2479409 and rs562556 from PCSK9) (Ference et al., 2019), the three independently (r² <0.05) and most strongly associated with LDL-cholesterol (rs11206510, rs2149041 and rs7552841) were used in the main analysis. Of the 5 SNPs mimicking effects of ezetimibe (rs10260606 (proxy of rs2073547, r² = 0.99), rs2300414, rs10234070, rs7791240, rs217386 from NCP1L1) (Ference et al., 2019), two SNPs (rs2300414 and rs10234070) were discarded because their F-statistic for LDL-cholesterol was <10. The remaining three SNPs were all correlated at r² >0.05. rs2073547 was used in the main analysis because it had the strongest association with LDL-cholesterol. Supplementary file 1a shows the associations with LDL-cholesterol by sex for the independent SNPs used to mimic effects of statins, PCSK9 inhibitors and ezetimibe. Supplementary file 1b shows the associations of the two SNPs mimicking effects of the anti-inflammatory, anakinra, (rs6743376 and rs1542176 (r² <0.001)) with IL-1Ra and the associations of the SNP (rs7529229), mimicking effects of tocilizumab use, with IL-6r.

There were 179,918 men with 25,410 cases of IHD and 212,080 women with 12,511 cases of IHD in the UK Biobank.

Consistent with meta-analysis of RCTs this study provides genetic evidence that statins reduce testosterone in men (Schooling et al., 2013), and adds by showing that statins could partially operate on IHD, in men only, by reducing testosterone, as previously hypothesized (Schooling et al., 2013; Schooling et al., 2014) while having similar protective effects in men and women independent of testosterone. Previous Mendelian randomization studies have shown lower testosterone associated with lower risk of IHD, particularly in men (Schooling et al., 2018a; Luo et al., 2019; Mohammadi-Shemirani et al., 2019). Conversely, consistent with an RCT (Ebrahimi et al., 2018), this study also provides genetic validation that the anti-inflammatory anakinra, targeting IL-1Ra, increases testosterone in men, and is consistent with a previous Mendelian randomization study showing anakinra increases IHD (Interleukin 1 Genetics Consortium, 2015), but adds by showing why these associations might occur and that they may be specific to men.

A more marked association of testosterone with IHD in men than women (Table 2) is consistent with sex differences in biology, where testosterone is the main sex hormone in men and is much higher in men than in women. The associations of genetically mimicked effects of statins, PCSK9 inhibitors or ezetimibe on testosterone is consistent with the evidence available (Schooling et al., 2013; Ooi et al., 2015; Krysiak et al., 2015) and their mechanisms of action. Specifically, statins inhibit cholesterol synthesis, while PCSK9 inhibitors enable greater clearance of cholesterol, through increasing LDL-receptors, while ezetimibe reduces uptake of dietary cholesterol (Ray et al., 2019; Michos et al., 2019). However, some cells, such as Leydig cells, use de novo cholesterol synthesis to generate steroids, which can be reduced by statins (Shimizu-Albergine et al., 2016). Concerns about statins compromising androgen production pre-date the marketing of statins (Farnsworth et al., 1987; MacDonald et al., 1988). Beneficial immunosuppressive effects of androgens in rheumatoid arthritis have long been known (Cutolo et al., 1991), making androgen reduction a plausible mode of action for therapies, such as anakinra, whose primary indication is rheumatoid arthritis.

These findings may seem counter-intuitive given the essential role of testosterone in masculinity and reproduction. However, in 2015 the Food and Drug Administration in the United States required labelling changes for all testosterone prescriptions to warn of the risk of heart attacks and stroke on testosterone, although no sufficiently large RCT of testosterone administration has been conducted to confirm these effects (Onasanya et al., 2016). The Endocrine Society has also recommended caution in the use of testosterone (Bhasin et al., 2018). Meta-analysis of RCTs suggests androgen deprivation therapy reduces all-cause mortality, but is too small to quantify effects on specific diseases beyond prostate cancer (Nguyen et al., 2011). As such, our Mendelian randomization findings of the effects of testosterone have some consistency with the limited experimental evidence. In addition, our findings are consistent with well-established evolutionary biology theory, that is reproductive success may be at the expense of longevity, possibly in a sex-specific manner, impling that central drivers of the reproductive axis, as well as androgen production and catabolism, and their environmental cues may be relevant to IHD (Schooling, 2016; Schooling and Ng, 2019; Figure 2) encompassing the relations tested here (Figure 1). Notably, upregulation of indicators of plentiful living conditions, such as insulin, appear to cause IHD, particularly in men (Zhao et al., 2019), likely via gonadotropin releasing hormone (GnRH) (Schooling and Ng, 2019). Similarly, fatty acids may affect GnRH (Tran et al., 2016; Matsuyama and Kimura, 2015). In contrast, indicators of adversity, such as endotoxins promote an inflammatory response, involving interleukins, which suppresses the reproductive axis (Kalra et al., 1998) and thereby testosterone (Tremellen et al., 2018), which may be reversed by anakinra possibly outweighing the benefits for IHD of suppressing inflammation (Tardif et al., 2019). Statins, in contrast reduce androgen production, while agents that suppress androgen catabolism, such as rofecoxib, have also had unexpectedly adverse effects on IHD (Schooling, 2016). Mechanisms by which androgens might cause IHD have not been extensively investigated, but likely involve coagulation and red blood cell attributes. Several haemostatic and thrombotic factors, such as thromboxane A₂ (Pignatelli et al., 2012; Ajayi and Halushka, 2005), endothelin-1 (Polderman et al., 1993; van Kesteren et al., 1998; Sahebkar et al., 2015), nitric oxide (Pignatelli et al., 2012; Rosselli et al., 1998) and possibly thrombin (Orsi et al., 2019; Ferenchick et al., 1995), may be driven by androgens and likely play a role in IHD (Schooling et al., 2018b; Zhao, 2018; Nikpay et al., 2015). Von Willebrand factor (Sahebkar et al., 2016) and asymmetric dimethylarginine (Serban et al., 2015) are also modulated by statins and may cause IHD (Aday and Ridker, 2018; Au Yeung et al., 2016), whether they are driven by testosterone is unknown. Several red blood cell attributes are affected by androgens, from reticulocytes to hematocrit (Fernández-Balsells et al., 2010; Kanias et al., 2016), but exactly which causes IHD is unclear, although reticulocytes are a possibility (Astle et al., 2016). Currently, comprehensive genetic validation of these pathways is hampered by the lack of availability of large sex-specific genome wide association studies (GWAS) of cytokines and coagulation factors.

Figure 2

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Despite providing information that may be relevant to the performance of statins, and to the development of other therapies to protect against cardiovascular disease (Schooling, 2017), some limitations of this study exist. First, valid instruments should fulfill three assumptions, that is relate strongly to the exposure, not be associated with potential confounders and satisfy the exclusion restriction assumption. The F-statistics were >10. Despite high conditional F-statistics for testosterone the conditional F-statistics for the genetic mimics of statins were quite low and the Q-statistics for instrument validity were high suggesting pleiotropy, which we addressed by using multivariable MR-Egger. The associations with testosterone in women were not adjusted for factors, such as menopausal status, hormone use and history of oophorectomy, which could result in imprecision and weaker instruments. The SNPs used to mimic effects of statins, PCSK9 inhibitors and ezetimibe are well established (Ference et al., 2019), and in genes that harbor the target of each lipid modifier (HMGCR, PCSK9 and NCP1L1 respectively). We did not include body mass index (BMI) as a risk factor explaining the effect of statins on IHD, because statins increase BMI (Swerdlow et al., 2015) and decrease the risk of IHD, so including them in the multivariable analysis may inflate the effect of mimicking statins on IHD, rather than explaining part of their effect on IHD. The SNPs mimicking effects of the anti-inflammatory anakinra have been validated as increasing IL-1Ra (Interleukin 1 Genetics Consortium, 2015), and the SNP used to mimic effects of tocilizumab is well-established as affecting IL-6r (Swerdlow et al., 2012). Testosterone’s effects on IHD in men could be via adiposity, insulin or LDL-cholesterol rather than via testosterone. However, consistent with a previous MR study, we found testosterone did not affect BMI in men (Eriksson et al., 2017), we also found little evidence that testosterone in men affected LDL-cholesterol (data not shown). We could not test whether testosterone in men affects insulin because of the lack of an insulin GWAS including the X chromosome. Sex-specific genetic associations were used throughout with exception of the genetic mimics of effects of anakinra and tocilizumab on IL1Ra and IL-6r respectively. However, inflammation operating on the reproductive axis would be expected to have sex-specific effects not sex-specific drivers. We selected between correlated SNPs based on p-values which is relatively arbitrary, and the estimates could be sensitive to the choice of SNPs. Repeating the analysis using a larger number of correlated SNPs, where possible, taking into account their correlation, gave a similar interpretation. MR studies can be confounded by population stratification. However, we used genetic associations from GWAS mainly comprising people of white British ancestry with genomic control. Functions of each SNP predicting the exposures are not all fully understood, so we cannot rule out the possibility that the SNPs are linked with IHD through other pathways although we used sensitivity analysis.

We used SNPs predicting testosterone, but not other exposures, obtained from the same study as the genetic effects on IHD. However given the estimates for testosterone were largely obtained from non-cases, the overlap unlikely introduced substantial bias (Burgess et al., 2016). Canalization, that is buffering of genetic factors during development, may occur however; whether it does so is unknown. Our findings, largely in Europeans, may not be applicable to other populations. However, causes are unlikely to act differently in different populations, although the causal mechanisms may not be as relevant in all settings (Lopez et al., 2019). The SNPs mimicking effects of statins, PCSK9 inhibitors and ezetimibe were previously selected for their relations with LDL-cholesterol and on functional grounds (Ference et al., 2019), assuming the lipid modifiers act by action on lipids (Ference et al., 2019), so it is possible that relevant SNPs might have been discarded if they work through other mechanisms independent of lipids. It is also possible that the SNPs mimicking lipid modifiers might act via a different lipid trait, such as apoB (Richardson et al., 2020). The SNPs mimicking effects of anakinra and tocilizumab were similarly selected. Replication based on genetic instruments functionally relevant to all the exposures would be ideal. However, we used the most recent, published genetic instruments for testosterone (Ruth et al., 2020). Replication based on another large sex-specific IHD GWAS where the IHD cases are not from the same study as the testosterone instruments, would be ideal. However, sex-specific summary statistics are not available for large existing IHD GWAS, such as CARDIoGRAM (Nikpay et al., 2015). Moreover, the UK Biobank has the advantage of being very intensively genotyped and including the X chromosome, which is important for testosterone, but is not usually included in publicly available summary statistics. Lack of replication is a limitation of this study. Lastly, Mendelian randomization assesses the lifelong effects of an endogenous exposure rather than short-term effects of an interventions assessed in an RCT. Our estimates give an indication of the role of the exposures rather than the exact effects of the corresponding interventions. Nevertheless our estimates for statins on IHD are comparable with meta-analyses of statin trials considering similar outcomes (Fulcher et al., 2015).

Here, we present a hypothesis driven study examining the role of testosterone in mediating the effect of specifically statins in IHD, particularly in men. Future work could encompass a comprehensive sex-specific multivariable MR to confirm the role of sex hormones and sex hormone binding globulin in IHD as well as any mediation of their effects by key lipids, such as LDL-cholesterol or apoB. This work would be facilitated by the development of published genetic instruments for estrogen in women. Future work could also encompass assessing whether any other drugs that reduce cardiovascular disease, such as canakinumab (Ridker et al., 2017), also impact testosterone.

Taken together these complimentary findings for statins and anakinra raise the possibility that modulating testosterone, by whatever means, is a relevant feature for modulating IHD in men, with potential relevance to the development of new interventions, side-effects of existing interventions, re-purposing and appropriate use. Statins lowering testosterone could also be relevant to the muscle weakness or pain experienced on statins (Collins et al., 2016). Recognition that statins lower testosterone might also provide greater impetus for investigation of their role in other relevant conditions, such as prostate cancer (Alfaqih et al., 2017). Conversely, statins and anakinra did not clearly affect testosterone in women (Table 1) nor did testosterone mediate the effect of statins on IHD in women (Table 3). These differences by sex highlight the need for sex-specific approaches to IHD prevention and management, specifically in terms of the use of statins and investigation more broadly of causes of IHD.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. CM Schooling

   1. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
   2. City University of New York, Graduate School of Public Health and Health Policy, New York, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Validation, Methodology, Writing - original draft, Project administration

   For correspondence

   cms1@hku.hk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9933-5887

2. JV Zhao

   School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

   Contribution

   Data curation, Validation, Writing - review and editing

   Competing interests

   No competing interests declared

3. SL Au Yeung

   School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

   Contribution

   Resources, Data curation, Supervision, Investigation, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

4. GM Leung

   School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

   Contribution

   Conceptualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

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