The efficacy of statins as otoprotective agents: A systematic review

This systematic review examined current literature, summarised research findings and identified research gaps regarding the efficacy of statins on audiological outcomes.


| INTRODUC TI ON
Inner ear impairment can be characterised by cochlear dysfunction or vestibular dysfunction or both. 1 Sensorineural hearing loss (SNHL) has a high prevalence and can cause significant adverse impact on an affected individual's quality of life. 2 The pathophysiological mechanisms involved in SNHL include vascular ischaemia, oxidative stress and inflammation. 3 Hyperlipidaemia has been reported to be associated with sudden sensorineural hearing loss (SSNHL) 4 and noise-induced hearing loss (NIHL). 5 One possible explanation regarding the mechanism of hearing damage by dyslipidaemia involves vascular ischaemia of the inner ear artery. Hyperlipidaemia increases plasma viscosity 6 which can trigger the stenosis of the cochlear artery leading to cochlear ischaemia and subsequent SNHL; therefore, vascular compromise is regarded as playing a vital role in SNHL. 7 Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, commonly known as statins, are widely used as cholesterol-lowering drugs. 8 Due to the strong evidence supporting cardiovascular benefits of its usage, statin therapy to reduce high cholesterol is recommended for people with cardiovascular risk factors. The overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol reduction such as improved endothelial function and microcirculation, reduced oxidative stress and decreased inflammation. 9 The effect of statins, including the cholesterol lowering, antioxidative and anti-inflammatory properties, could be beneficial as an otoprotective agent involving both haemodynamic and metabolic mechanisms. This is of interest because hearing loss associated with hyperlipidaemia would be thereby potentially treatable. There has so far been little evidence to support their use in the treatment or prevention of inner ear dysfunction; hence, statins are not routinely used for this purpose. This systematic review examined current literature on the efficacy of statins on audiological outcomes.

| Identify relevant studies
The following databases were searched: Medline, EMBASE, IPA (International Pharmaceutical Abstracts) and ClinicalTrials.gov. Grey literature was also sought through the conference abstracts searching on Google Scholar. The steps followed the PRISMA guideline. 10 Standardised terms and keywords were merged in the search for concepts of statin drugs and otoprotection. Study details were registered on PROSPERO (CRD42019133701). The search was limited to the English language because of resource constraints. The search strategies are reported in Appendix 1.

| Study selection
Eligibility criteria for records to be included were the study of a statin with reporting of audiological outcomes such as hearing, tinnitus or balance in either human or animal studies. All study types were eligible except review articles and in vitro studies. Two screening steps were undertaken independently by two authors. The first step checked that each title and abstract was within the scope of research question. The second step considered the eligibility criteria.
Discrepancies were resolved through discussion.

| Data extraction
Data from each included study were extracted independently by two clinical experts on the team (PP, an otorhinolaryngologist and DB, an audiologist) using a data extraction form. Pre-specified data items included study design, participant demographics, sample size, drug type and dosage, and outcome evaluation. Discrepancies were identified and resolved through discussion.

| Quality assessment
The reviewers independently assessed the methodological quality of the articles by applying the National Institutes of Health (NIH) Quality Assessment Tool. If the ratings were different, then reviewers discussed the article in an effort to reach consensus. The score was assigned for each item: "Yes" was scored 1, and "No" or "Cannot determine" or "Nor reported" was scored 0. The summary score of each study was calculated, expressed as a percentage and could range from 0% to 100%. These were categorised into four categories: poor (0%-25%), fair (26%-50%), good (51%-75%) or excellent (76%-100%). The quality score was not used as the criteria for eligibility because of the limited literature on this topic.

| Data synthesis
A narrative synthesis was implemented for the present systematic review, as there were high heterogeneities of studies included. The characteristics of the study and research findings were collated and summarised.

| RE SULTS
A summary of the study selection processes with the reasons for exclusion is represented in Figure 1. Seventeen individual studies were included for data extraction. The results are presented in a narrative summary and review. We did not perform a meta-analysis as the studies were heterogeneous, and several of them were observational designs.

| Quality assessment
The mean score on the NIH Quality Assessment Tool was 38% (range 7%-79%). There were eight studies (47%) with fair quality; five studies (29%) with poor quality; three studies (18%) with good quality; and one study (6%) with excellent quality (See Table 1).

Key points
• Animal experiments presented promising audiological outcomes, demonstrated by electrophysiological results and inner ear histology.
• Human trials showed no clear effect due to the mixed results, and heterogeneity in research methodology and quality.
• Audiological outcomes were not always correlated with cholesterol levels.
• Statins remain a potential candidate as otoprotective agents which warrant further study.
Two studies classified participants into responsive and unresponsive groups according to cholesterol levels after the treatment and then compared the audiological outcomes. 13,14 The criteria for responsive and non-responsive individuals were substantially different. Cholesterol responsive was defined by a return to normal cholesterol or triglyceride level but normal levels were not specified, 13 or cholesterol level less than 200 mg/dL. 14

| Audiometry
Mixed results were reported with two studies concluding no improvement in hearing threshold, 11,17 and four studies reporting some improvement. 12,13,18,19 Two studies reported a correlation between statin use and a reduced prevalence of hearing loss. 15,18 There was no significant difference in pure-tone thresholds between atorvastatin and placebo groups. 11 Another study reported no significant difference in hearing threshold between simvastatin and ginkgo groups. 17 Nine out of twelve (75%) patients with chronic-phase SSNHL had hearing improvement in at least two frequencies. 12 There was a significant improvement of hearing threshold at higher frequencies in the cholesterol treatment responsive group compared with the unresponsive group. 13 Patients on statins showed reduced severity of hearing loss than did non-statin users. 18 A case report described a substantial hearing improvement after rosuvastatin therapy. 19 Gopinath et al 15 indicated that persons with self-reported statin use had a 48% reduced odds of hearing loss. Another study reported reduced incidence of hearing loss compared with pre-treatment audiograms in statin users relative to individuals who were not on a concurrent statin therapy. 18

| Tinnitus
Studies described varied results of no significant improvement of tinnitus 11,17 and significant improvement. 13,14,19 There was a trend towards relief of tinnitus in the atorvastatin group while tinnitus severity scores were rather stable in the placebo group. 11 In another study, there was no significant difference in tinnitus score between simvastatin and ginkgo groups. 17 There was a significant improvement of tinnitus intensity and selfrated tinnitus in cholesterol responsive group relative to cholesterol non-responsive group. 13 Improvement in THQ score by at least 10 points was seen in 70.5% of patients in cholesterol responsive group compared with 4.2% in cholesterol unresponsive group. 14 A case report described complete relief of tinnitus after statin therapy. 19

| Vertigo
One article reported that 84% of vertiginous patients had complete resolution of vertigo, and total remission in one case of recurrent vertigo after statin treatment. 16

| Cholesterol level and audiological outcomes
Most patients who received statin treatment had elevated cholesterol levels ranging from 100-190 11 to 239-356 14 mg/dL. However, specified criteria of hyperlipidaemia or cholesterol levels were not reported in some studies. 13

| Animal experiments
Outcome measurements were highly variable among studies and include auditory brainstem response (ABR), 20 Table 2.

| ABR
Most of the included studies reported protection of hearing detected by ABR, 20,22,24-27 except in one study. 21 Cai et al 20  which was substantially lower than the 41.7 dB in the noise-only group. 27 Another study reported that fluvastatin given 7 days before noise exposure can protect the inner ear against NIHL in the guinea pigs. 26 Statin treatment prior to acoustic injury appeared to be more effective than when given after noise exposure. 26 Only one study examined statin treatment in cisplatin ototoxicity, reporting that ABR thresholds were significantly protected in cisplatin-treated mice receiving prior lovastatin relative to cisplatin-only treated mice. 24 Furthermore, hearing preservation was observed in diabetic mice treated with atorvastatin but without detailed information. 25 In contrast, there were no significant differences in hearing thresholds between atorvastatin-treated mice and control mice, but all animals had normal hearing threshold. 21

| DPOAE
Three studies reported DPOAE results: all showed positive auditory outcomes of statin usage. 21,23,24 Two of three studies reported both ABR and DPOAE outcomes. 21,24 The results were concordant in one study which demonstrated the preservation of both ABR threshold and DPOAE in the lovastatin-treated group. 24 Conversely, another study demonstrated better results of DPOAE in atorvastatin-treated mice though no significant differences in hearing thresholds detected by ABR. 21

| Inner ear histology
Three studies reported histological findings of the inner ear in animals. 20,22,25 After statin administration, there was preservation of the numbers and morphology of hair cells and spiral ganglions in hyperlipidaemic mice, 20 and spiral ganglia and stria vascularis in diabetic mice. 25 Conservation of hair cells was also demonstrated after noise exposure. 22

| Cholesterol level and audiological outcomes
Hearing improvements corresponded to the results of cholesterol lowering in two studies, 20,22 but not related to cholesterol level in one study reported. 21 Nonetheless, cholesterol levels were not reported in five studies. [23][24][25][26][27] Normal hearing findings, alongside lower cholesterol levels and much less severe atherosclerotic lesions in simvastatintreated mice, support the role statin drugs play in the protection of hearing loss. 20 Interestingly, the inner ear protection efficacy of statins was also found when cholesterol-lowering effects were absent. 21

| Drug type, dosage and timing of administration
Statin type and dosage varied among studies. While low-dose atorvastatin used before exposure to noise can potentially prevent NIHL in rats, the effect was not observed in higher doses. 23 Animal studies demonstrated a protective effect when the drug was administered before or during noise exposure but showed limited efficacy when given after noise exposure. 22,23,26,27 This could be explained by the pathophysiology of ROS production in that ROS is hard to overcome when it has occurred but prevention by diminishing the inflammatory process is more effective. • Preservation of hair cells and neurons in the spiral ganglion in simvastatin-treated group.

| Outcome measures
• Total cholesterol levels were 131 mg/dL in simvastatintreated group, and 253 mg/ mL in non-treated group.
• LDL-c levels were 133 mg/ dL in simvastatin-treated group, and 198 mg/dL in nontreated group. • DPOAE at 4-40 kHz • All animals had normal hearing thresholds.
• No significant differences in hearing thresholds between atorvastatin-treated group and control group.
• No increased attenuation of threshold shift when pravastatin was further administered after noise exposure, compared with the pre-exposure group.
• Increase hair cells survival rate in statintreated group.
• Cholesterol levels in pravastatin group were lower compared with the control group, although cholesterol levels in both groups were within the reference range. Syka et al 21 can be explained by the different pathways and sensitivities of the tests. 28,29 Tinnitus evaluation varied highly among studies using self-reported symptoms and standard questionnaires which emphasises the difficulty of comparison between studies.

| Inner ear conditions
Tentative evidence was identified to support an otoprotective effect of statin against NIHL caused by acoustic overstimulation 13,22,23,26,27 and cisplatin ototoxicity. 24 Interestingly, one accepted mechanism shared by these conditions is related to overproduction of ROS, 30 supporting the proposal of an antioxidative effect of statin treatment.

| Cholesterol level and audiological outcomes
Six studies showed positive audiological outcomes accompanied by lower cholesterol levels, [12][13][14]19,20,22 indicating cholesterol dependent effects of statin on audiological outcomes. These studies support the pathophysiology of vascular ischaemia associated with hypercholesterolaemia which leads to oxygen reduction, overproduction of ROS and an inflammatory process causing eventually to apoptotic cell death.
In contrast, three studies reported no correlation of inner ear functions and cholesterol-lowering outcomes after statin treatment, 11,17,21 signifying that hearing outcome may not be associated

| Limitations of the study
Some limitations of the current review are that a significant portion of included studies reported limited information, and only publications in the English language were included; thus, language bias may have occurred.

| CON CLUS ION
Included studies had variable methodology and quality. Most animal experiments showed promising results; however, no clear effect was discerned from the results in human trials. Developing therapeutic strategies for the prevention of hearing loss using otoprotective drugs is one of the major goals of current auditory research, and statins remain of interest in this regard.

ACK N OWLED G EM ENT
David Baguley is supported by the UK National Institute of Health Research (NIHR), but the views herein are his own and do not reflect those of the NIHR nor the UK Department of Health and Social Care.

CO N FLI C T S O F I NTE R E S T
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets analysed in this manuscript are not publicly available.
Requests to access the datasets should be directed to the corresponding author.