Accepted Article

DR AHMED ABU-ZAID (Orcid ID : 0000-0003-2286-2181)

Article type : Meta-Analysis

Efficacy and Safety of Mirogabalin Treatment in Patients with Diabetic Peripheral

Neuropathic Pain: A Systematic Review and Meta-analysis of Randomized
Controlled Trials

Running title: Mirogabalin in patients with DPNP

Reem Abdullah Alyoubi,1 Aysha Abdulmalek Alshareef,2 Saud Musaab Aldughaither,3 Abeer
Mahdi Aljaroudi,3 Alwaleed Alabdulwahed,3 Faisal Muhammed Alduraibi,3 Ahmed Taher
Masoud,4 Ahmed Abu-Zaid,3,5,*

1 Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi
Arabia
3 Department of Internal Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
4 Faculty of Medicine, Fayoum University, Fayoum, Egypt
5 Department of Pharmacology, College of Graduate Health Sciences, University of Tennessee
Health Science Center, Memphis, Tennessee, United States
* Corresponding author

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/IJCP.13744
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 Correspondence address: Ahmed Abu-Zaid, MBBS, PhD (candidate); Department of
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Pharmacology, College of Graduate Health Sciences, University of Tennessee Health Science
Center, Memphis, Tennessee, USA; Telephone number: +1(901)-283-4596; Fax number: +1(901)-
448-5052; Email address: aabuzaid@live.com; ORCID ID: https://orcid.org/0000-0003-2286-2181.
PubMed: https://pubmed.ncbi.nlm.nih.gov/?term=Abu-Zaid+A&sort=date&size=200

Acknowledgments: None.
Funding: None.
Conflict of Interest Statement: None.
Efficacy and Safety of Mirogabalin Treatment in Patients with Diabetic Peripheral
Neuropathic Pain: A Systematic Review and Meta-analysis of Randomized
Controlled Trials

Abstract
Aim: We aimed to perform a systematic review and meta-analysis to examine the efficacy and
safety of mirogabalin in patients with diabetic peripheral neuropathic pain (DPNP).
Methods: We searched four databases from inception to July 1st, 2020. We included all
randomized controlled trials (RCTs) which assessed the effectiveness and safety of mirogabalin in
patients with DPNP. We evaluated the quality of the included RCTs using the Cochrane risk of
bias assessment tool. We pooled dichotomous outcomes as risk ratios and continuous outcomes
as mean differences with 95% confidence intervals, both under the random- or fixed-effects
model.
Results: Three RCTs matched our inclusion criteria with a total of 1732 patients with DPNP: 1057,
534, and 141 patients received mirogabalin, placebo, and pregabalin, respectively. The quality of
included RCTs was marked as moderate-to-high. Mirogabalin treatment was significantly
associated with a significant reduction in the average daily pain score (ADPS) compared to
placebo over seven weeks. Compared to pregabalin, mirogabalin was significantly associated
with more decrease in ADPS only after three, four, and five weeks. The proportion of patients
with ≥30% and ≥50% reduction in the ADPS was significantly higher in the mirogabalin versus

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 placebo and pregabalin groups. Compared to placebo, mirogabalin was significantly associated
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with more adverse events of dizziness, increased weight, peripheral edema, and somnolence.
The safety profile was comparable between mirogabalin and pregabalin.
Conclusions: Our systematic review and meta-analysis revealed that in patients with DPNP,
mirogabalin treatment was superior to placebo and pregabalin in decreasing the ADPS over time.
Besides, mirogabalin was largely safe and associated with some adverse events that could be
managed conservatively.

Keywords
Diabetic peripheral neuropathic pain; Mirogabalin; Pregabalin; Efficacy; Safety

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 Review Criteria
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 We conducted a systematic review and meta-analysis of all RCTs which examined the efficacy
and safety of mirogabalin versus placebo or pregabalin in patients with DPNP.
 We searched four (Cochrane Central, PubMed, Scopus, and Web of Science) databases from
inception to July 1st, 2020 to look for eligible RCTs using relevant keywords.
 We pooled dichotomous outcomes as risk ratios and continuous outcomes as mean
differences with 95% confidence intervals, both under the random- or fixed-effects model.

Message for the Clinic

 Mirogabalin is a novel, oral selective ligand for the alpha-2/delta subunit of the voltage-
dependent calcium channels implicated in neuropathic pain.
 Mirogabalin is safe and superior to placebo/pregabalin in patients with DPNP.

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 Introduction
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Diabetic peripheral neuropathic pain (DPNP) is a frequent aftermath of diabetes mellitus. It is
estimated to affect nearly one-third of patients with diabetic peripheral neuropathy.1,2 Patients
with DPNP experience various morbidities, including decreased work productivity, sleep
disturbance, anxiety, and depression. Eventually, these morbidities unfavorably influence the
quality of well-being and cause considerable economic encumbrances in patients with DPNP.3–5
The underlying mechanisms behind the etiopathogenesis of DPNP are not fully understood to
date. Nonetheless, voltage-dependent calcium channels (VDCCs) seem to be involved in the
pathogenesis of DPNP. Therefore, over recent years, targeting these VDCCs has been the primary
pharmacological intervention in patients with DPNP.6,7
Some VDCC ligands exert analgesic effects, which are mediated through decreasing calcium influx
into neurons in the central nervous system.6 Such VDCC ligands comprise gabapentin and
pregabalin, both of which are used globally as first-line therapies for DPNP.8,9 Nevertheless, they
do not provide adequate therapeutic value to many DPNP patients. Besides, they exhibit a range
of expected adverse reactions—such as dizziness, somnolence, and weight gain—which largely
limit their wide use for DPNP.10–13 Interestingly, many DPNP patients are not satisfied with their
treatment plan. This may be ascribed to numerous reasons, including insufficient pain relief,
poorly tolerated therapeutics, and low rates of analgesic responses.6 Hence, treatment
effectiveness decreases with time and the need for additional therapy or dose escalation
becomes essential. 14,15 For the aforementioned reasons, DPNP patients require an effective
medication that offers maximal efficacy with minimal well-endured adverse reactions.
Mirogabalin is a novel, oral selective ligand for the alpha-2/delta subunit of VDCCs in the central
nervous system.16 It has been industrialized for the management of DPNP and postherpetic
neuralgia.17 Mechanistically, mirogabalin exerts a superior tendency over pregabalin in its slower
dissociation rate from the alpha-2/delta-1 subunit of VDCCs, which exerts a fundamental
analgesic function in neuropathic pain.18 Three randomized, double-blind, controlled studies
were conducted to gauge the efficacy and tolerability of mirogabalin in DPNP patients.16,19,20
Overall, these studies showed promising results that need to be confirmed in further trials.

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 In this study, we endeavored to perform a systematic review and meta-analysis of all randomized
Accepted Article
controlled trials (RCTs) with regard to the efficacy and safety of mirogabalin in the treatment of
DPNP.

Methods
We implemented this systematic review and meta-analysis while following the principles of the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.21
Additionally, we performed all steps of this study according to the guidelines of the Cochrane
Handbook of systematic reviews and meta-analyses.22

Literature search strategy

From inception to July 1st, 2020, we searched Cochrane Central, PubMed, Scopus, and Web of
Science databases using relevant keywords. For our search strategy, the following keywords were
used: “Mirogabalin OR Mirogabalin besylate OR Tarlige” AND “Diabetic Peripheral Neuropathic
Pain OR Diabetic Peripheral Neuropathy OR Peripheral Neuropathy OR Neuropathic Pain”.

Eligibility criteria and study selection

We included all RCTs which matched the following criteria for PICO research question.
Population: patients with DPNP; Intervention: mirogabalin treatment 10, 15, 20, and 30 mg/day;
Comparator: placebo or pregabalin; and Outcomes: efficacy and safety measures.
We excluded studies with the following criteria: duplicate citations, review articles, animal
studies, studies performed on healthy subjects, published protocols without a journal full-text, in
addition to citations with irrelevant conditions (for example, postherpetic neuralgia and
fibromyalgia) or outcomes.

Screening and study selection

After we searched four medical databases, we advanced to the screening step. Two reviewers
were assigned to screen the retrieved citations on two consecutive steps. The first step was to
screen titles and abstracts, whereas the second step was to scrutinize full-texts against the

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 prespecified inclusion and exclusion criteria. In addition, we manually screened reference lists of
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reviews published about the topic.

Data Extraction
Data were extracted from the eligible studies into a predesigned Excel sheet. Components of this
data extraction included the baseline characteristics of included studies, the risk of bias domains,
and the study outcomes (efficacy and safety).
We examined two primary efficacy outcomes. The first efficacy outcome was the average daily
pain score (ADPS) in relation to the baseline between the treatment (mirogabalin) and control
(placebo or pregabalin) groups. The ADPS was instituted on the 11-point numeric rating scale
(NRS). In this scale, a zero score equals no pain at all, whereas a ten score describes having the
worst possible pain.23 The second efficacy outcome was the proportion of study participants who
achieved ≥30% and ≥50% decrease in the ADPS in relation to the baseline24 between the
treatment (mirogabalin) and control (placebo or pregabalin) groups.
For safety outcomes, we reviewed the most frequently reported adverse reactions (headache,
nasopharyngitis, vomiting, dizziness, weight gain, peripheral edema, and somnolence) between
the treatment (mirogabalin) and control (placebo or pregabalin) groups.

Risk of bias assessment

Two authors independently assessed the risk of bias domains in the included RCTs. We applied
the Cochrane risk of bias assessment tool for the appraisal of bias domains. This tool is
adequately demonstrated in the Cochrane handbook of systematic reviews of interventions
version 5.1.0.22 The Cochrane risk of bias tool is able to detect five types of bias. Those bias
domains are performance bias, selection bias, detection bias, reporting bias, and attrition bias.
Each bias domain is judged to have high, unclear, or low bias.

Data analysis
In this meta-analysis, under the fixed-effect model, we pooled dichotomous outcomes as risk
ratios (RRs) with 95% confidence intervals (95% CIs). To calculate the RRs, the Mantel Haenszel
(M–H) method was utilized. Additionally, under the fixed-effect model, we pooled continuous

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 outcomes as mean differences (MDs) with 95% CIs. To calculate the MDs, the Inverse Variance
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method was utilized. The data were analyzed using the Review Manager (RevMan) software,
version 5.3 for Windows.
The Chi-square test was used to assess the heterogeneity among pooled studies. The degree of
heterogeneity was measured by the I-square (I2) test. The included studies in the meta-analysis
were considered heterogeneous whenever the p-value of the Chi-square test was less than 0.1. If
there was significant heterogeneity among the pooled references, we would switch the fixed-
effect model to the random-effect model. Additionally, in this case, we would perform a
sensitivity analysis test to resolve the heterogeneity problem. This was achieved by excluding one
study at a time and witnessing whether the heterogeneity issue would be resolved. Moreover,
we performed a subgroup analysis to compare the efficacy and safety of the commonly used
doses of mirogabalin treatment, namely 10 mg, 15 mg, 20 mg, and 30 mg per day.
We could not assess the publication bias of the included studies using Egger’s funnel plots. This is
because the number of included studies was less than the minimum required number. This
number is 10 studies according to Egger et al.25

Results
Search results
The search process of four medical databases resulted in the retrieval of 47 unique records after
removal of duplicates (Figure 1). After we performed the screening of titles and abstracts, nine
full-text articles were rigorously screened against the inclusion and exclusion criteria. Finally, we
found three RCTs to be eligible for this systematic review and meta-analysis.16,19,20

Demographics and characteristics

Our study included a total of 1732 patients with DPNP. Specifically, there were 1057, 534, and
141 patients who received mirogabalin, placebo, and pregabalin, respectively. There were two
studies that compared mirogabalin to pregabalin.16,20 In both studies, the dose of pregabalin was
uniform (300 mg/day). Table 1 shows the baseline summary of the included RCTs.

Quality assessment of included studies

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 The quality of included RCTs was estimated to be moderate to high according to the Cochrane
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risk of bias assessment tool. The risk of bias summary and graph for included studies are shown
in Figure 2.

Efficacy outcome: Change from baseline in ADPS between mirogabalin versus placebo
When compared to placebo, the use of mirogabalin was associated with a significant decrease in
the ADPS after one week (MD = -0.18, 95% CI [-0.27, -0.08], p = 0.0002), pooled studies were
homogenous (p = 0.62; I² = 0%); and two weeks (MD = -0.32, 95% CI [-0.42, -0.23], p < 0.00001),
pooled studies were heterogeneous (p = 0.06; I² = 45%) (Figure 3). Similar results were
reproduced in favor of mirogabalin after three weeks (MD = -0.41, 95% CI [-0.51, -0.32], p <
0.00001), pooled studies were heterogeneous (p = 0.008; I² = 60%); and four weeks (MD = -0.41,
95% CI [-0.51, -0.31], p < 0.00001), pooled studies were heterogeneous (p = 0.006; I² = 61%)
(Figure 4).
Homogeneity could be regained in the second week forest plot by omitting the results of Baba et
al. 201919 (p = 0.29; I² = 18%), with the effect estimate being consistent (MD = -0.40, 95% CI [-
0.57, -0.23], p < 0.00001). Moreover, the heterogeneity in the effect estimate of the third week
was resolved by exclusion of the results of Baba et al. 201919 (p = 0.49; I² = 0%), with the effect
estimate being consistent (MD = -0.51, 95% CI [-0.69, -0.33], p < 0.00001). Lastly, we resolved the
heterogeneity among the effect estimate of the fourth week by excluding the results of Baba et
al. 201919 (p = 0.46; I² = 0%), with the effect estimate being consistent (MD = -0.54, 95% CI [-0.72,
-0.36], p < 0.00001).
Additionally, when contrasted to placebo, mirogabalin use was associated with a significant
decrease in the ADPS after five weeks (MD = -0.35, 95% CI [-0.45, -0.25], p < 0.00001), pooled
studies were heterogeneous (p = 0.02; I² = 53%); six weeks (MD = -0.37, 95% CI [-0.50, -0.25], p <
0.00001), pooled studies were heterogeneous (p = 0.02; I² = 68%); and seven weeks (MD = -0.30,
95% CI [-0.43, -0.16], p < 0.00001), pooled studies were heterogeneous (p = 0.01; I² = 73%)
(Figure 5).
Likewise, homogeneity could be regained in the fifth week analysis by excluding the report of
Baba et al. 201919 (p = 0.35; I² = 11%), with the effect estimate being consistent (MD= -0.43, 95%
CI [-0.61, -0.24], p < 0.00001). However, the heterogeneity in the forest plots of the sixth and

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 seventh weeks could not be resolved. This is because there were only two studies pooled in the
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analysis.19,20

Efficacy outcome: Change from baseline in ADPS between mirogabalin versus pregabalin
There was no significant difference between mirogabalin and pregabalin 300 mg/day with
respect to ADPS after one week (MD = -0.04, 95% CI [-0.23, 0.14], p = 0.67), pooled studies were
homogenous (p = 0.76; I² = 0%); and two weeks (MD= -0.17, 95% CI [-0.38, 0.03], p = 0.09),
pooled studies were homogenous (p = 0.76; I² = 0%) (Figure 6).
In contrast to pregabalin 300 mg/day, mirogabalin therapy was associated with a significant
reduction in the ADPS after three weeks (MD = -0.39, 95% CI [-0.60, -0.18], p = 0.0003), pooled
studies were homogenous (p = 0.74; I² = 0%) (Figure 6); four weeks (MD = -0.40, 95% CI [-0.65, -
0.16], p = 0.001), pooled studies were homogenous (p = 0.28; I² = 21%)(Figure 7); and five weeks
(MD = -0.29, 95% CI [-0.50, -0.08], p = 0.007), pooled studies were homogenous (p = 0.30; I² =
18%) (Figure 7).

Efficacy outcome: ≥30% and ≥50% reduction in the ADPS between mirogabalin versus placebo
The proportion of patients with ≥30% reduction in the ADPS was significantly higher in the
mirogabalin versus placebo group (RR = 1.27, 95% CI [1.16, 1.39], p < 0.00001), pooled studies
were homogenous (p = 0.19; I² = 28%) (Figure 8). Similar results were reproduced in favor of the
mirogabalin group with regard to the proportion of patients with ≥50% reduction in the ADPS (RR
= 1.38, 95% CI [1.20, 1.58], p < 0.00001), pooled studies were homogenous (p = 0.49; I² = 0%)
(Figure 9).

Efficacy outcome: ≥30% and ≥50% reduction in the ADPS between mirogabalin versus
pregabalin
The proportion of patients with ≥30% reduction in the ADPS was significantly higher in the
mirogabalin versus pregabalin group (RR = 1.25, 95% CI [1.08, 1.44], p = 0.002), pooled studies
were homogenous (p = 0.40; I² = 3%) (Figure 10). Similar results were reproduced in favor of the
mirogabalin group with regard to the proportion of patients with ≥50% reduction in the ADPS (RR

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 = 1.32, 95% CI [1.05, 1.65], p = 0.02), pooled studies were homogenous (p = 0.85; I² = 0%) (Figure
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11).
Safety outcomes between mirogabalin versus placebo
There was no significant difference between mirogabalin and placebo groups in terms of the
occurrence of headache (RR = 1.56, 95% CI [0.82, 2.96], p = 0.17), pooled studies were
homogenous (p = 0.85; I² = 0%) (Figure 12); nasopharyngitis (RR = 1.35, 95% CI [0.99, 1.82], p =
0.05), pooled studies were homogenous (p = 0.27; I² = 23%) (Figure 13); or vomiting (RR = 1.13,
95% CI [0.50, 2.52], p = 0.77), pooled studies were homogenous (p = 0.84; I² = 0%) (Figure 14).
Conversely, compared to placebo, mirogabalin was significantly associated with more events of
dizziness (RR = 4.12, 95% CI [2.85, 5.95], p < 0.00001), pooled studies were homogenous (p =
0.85; I² = 0%) (Figure 15); increased weight (RR = 5.07, 95% CI [2.61, 9.84], p < 0.00001), pooled
studies were homogenous (p = 0.91; I² = 0%) (Figure 16); peripheral edema (RR = 4.52, 95% CI
[2.67, 7.67], p < 0.00001), pooled studies were homogenous (p = 0.97; I² = 0%) (Figure 17); and
somnolence (RR = 3.14, 95% CI [2.31, 4.27], p < 0.00001), pooled studies were homogenous (p =
0.67; I² = 0%) (Figure 18).

Safety outcomes between mirogabalin versus pregabalin

There was no significant difference between mirogabalin and pregabalin 300 mg/day in terms of
the occurrence of dizziness (RR = 1.32, 95% CI [0.88, 1.98], p = 0.18), pooled studies were
homogenous (p = 0.33; I² = 14%) (Figure 19); headache (RR = 0.86, 95% CI [0.47, 1.58], p = 0.64),
pooled studies were homogenous (p = 0.51; I² = 0%) (Figure 20); increased weight (RR = 1.84,
95% CI [0.77, 4.39], p = 0.17), pooled studies were homogenous (p = 0.73; I² = 0%) (Figure 21);
peripheral edema (RR = 0.85, 95% CI [0.45, 1.60], p = 0.61), pooled studies were homogenous (p
= 0.72; I² = 0%) (Figure 22); somnolence (RR = 1.05, 95% CI [0.73, 1.51], p = 0.81), pooled studies
were homogenous (p = 0.41; I² = 1%) (Figure 23); or vomiting (RR = 0.72, 95% CI [0.35, 1.48], p =
0.37), pooled studies were homogenous (p = 0.30; I² = 18%) (Figure 24).

Subgroup analysis of efficacy and safety outcomes

Table 2 displays a summary of the results of the subgroup analysis of study outcomes (efficacy
and safety). With regard to efficacy outcomes, individual doses of mirogabalin did not show a

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 pattern of consistency with the general effect estimate. We observed that escalating the dose of
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mirogabalin was associated with increased effectiveness and higher risk of adverse events. With
regard to safety outcomes, when compared to pregabalin 300 mg/day, all doses of mirogabalin
showed results consistent with the overall effect estimate. Besides, in comparison to the
placebo, the safety of individual doses of mirogabalin was consistent with the total effect
estimate in the following adverse events: headache, nasopharyngitis, vomiting, and dizziness.
However, other safety outcomes showed different dose-related effects.

Discussion
Summary of main results
In this systematic review and meta-analysis, we reviewed three RCTs which examined
mirogabalin in the treatment of DPNP.16,19,20 This report included a total number of 1732 patients
in the mirogabalin, placebo, and pregabalin treatment groups. We aimed to scrutinize the
therapeutic value and adverse events related to the administration of mirogabalin versus
placebo or pregabalin in DPNP patients.
Based on our results, DPNP patients who received mirogabalin had more reduction in the ADPS
compared to those who received placebo for seven weeks. Compared to pregabalin 300 mg/day,
mirogabalin was associated with more reduction in the ADPS after three, four, and five weeks.
However, there was no significant difference between the two medications in the first two
weeks. With regard to ≥30% and ≥50% reduction in the ADPS, mirogabalin was associated with a
large cohort of treatment responders when compared to both placebo and pregabalin 300
mg/day groups.
Treatment of DPNP using mirogabalin seems to be associated with higher side effects when
contrasted to placebo, particularly for dizziness, increased weight, peripheral edema, and
somnolence. Nonetheless, other side effects of mirogabalin were comparable. Subgroup analysis
for safety measures showed consistency of individual doses with the overall effect estimate, in
comparison to the pregabalin 300 mg/day group. Other study parameters did not show
consistency of individual doses with the general effect estimate.
The optimal dose of mirogabalin would be that dose which generates minimal adverse reactions
while delivering the greatest therapeutic value. A meta-regression computation could predict this

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 particular dose. Nonetheless, we could not perform this computation due to the small number of
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studies included in this meta-analysis. Regardless, the consumption of mirogabalin dose 300
mg/day was associated with maximal effectiveness and comparable adverse reactions in relation
to lower doses.
Results obtained from this systematic review and meta-analysis are clinically significant and
therefore could be utilized to provide a safe and effective treatment for DPNP patients. This is
because the included RCTs in this systematic review and meta-analysis were of moderate to high
quality. Based on the results of this report, mirogabalin treatment could be used effectively in
different populations.
The study of Vinik et al. was the first phase II clinical trial to use mirogabalin 5 to 30 mg/day for
the treatment of DPNP.26 In their study, the authors aimed to identify which mirogabalin dose
would provide considerable improvements with tolerable side effects. They found that the use of
mirogabalin 15, 20, and 30 mg/day was associated with significant reductions in ADPS when
compared to placebo. In addition, the use of mirogabalin 30 mg/day was correlated with a
reduction of at least one point on the pain NRS. The results of Baba et al. were in agreement with
our analysis.19 In their study, they found mirogabalin therapeutic responses were dose-
dependent. Additionally, they found the 30 mg/day dose to exhibit the significant pain relief in
comparison to the placebo. Moreover, all the mirogabalin doses they used in the study were well
tolerated. Another study by Baba et al. was an open-label 52-week extension study of
mirogabalin treatment.27 In this phase III clinical trial, DPNP Asian patients were receiving
mirogabalin initially at 10 mg/day and then upgraded to a flexible maintenance dose of 20 or 30
mg/day. By the end of this study, 20 and 30 mg/day doses of mirogabalin were shown to be safe
and effective for treatment of patients with DPNP.
Recently, Tetsunaga et al. reported their retrospective, single-arm, single-center experience with
mirogabalin in 187 DPNP patients.28 All studied patients had switched from pregabalin to
mirogabalin owing to reasons of absence of therapeutic responses or occurrence of side effects.
Overall, pain NRS scores were substantially reduced after one week of mirogabalin and continued
to reduce even further over the course of therapy. By the end of eight weeks of therapy, nearly
two thirds of patients (n=113, 69%) had improved pain NRS scores of ≥30% from baseline.
Nonetheless, mirogabalin therapy was discontinued by 24 patients owing to adverse side effects,

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 most notably edema (6%), dizziness (12%), and somnolence (27%). The study concluded that
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mirogabalin is largely effective and endurable in patients with DPNP.

Study strengths and limitations

To the best of our knowledge, this is the first systematic review and meta-analysis to compare
different doses of mirogabalin treatment, in terms of efficacy and safety measures. Besides, this
is the first report to compare mirogabalin to placebo or pregabalin using the high-quality meta-
analysis approach. In addition, from a methodological point, whenever heterogeneity existed
during analysis of outcomes, we performed subgroup analysis to solve the heterogeneity.
The limitations of this research include the relatively small number of studies that were included
in the meta-analysis. In addition, the included RCTs reviewed the effect of mirogabalin for only
seven weeks. Hence, we could not analyze the long-term outcomes of mirogabalin treatment.
Additionally, we found significant heterogeneity between pooled references in some of the
efficacy endpoints.

Implications for further research

Future studies should carry out large-sized phase III RCTs with longer follow-up periods. The 30
mg/day dose of mirogabalin seems to be the most efficacious one, with comparable side effects.
Therefore, its long-term effects should be studied in further trials. Moreover, trials of
mirogabalin for DPNP should be expanded globally to other countries of different ethnicities.
Table 3 shows a list of registered but not published clinical trials about mirogabalin in the
management of patients with DPNP.

Conclusions
Our systematic review and meta-analysis revealed that in patients with DPNP, mirogabalin
treatment was superior to placebo and pregabalin 300 mg/day in decreasing ADPS over time.
Besides, mirogabalin was largely safe and associated with some adverse events that could be
managed conservatively. Additional large-sized and powered phase III clinical trials with longer
follow-up periods are needed to consolidate the therapeutic efficacy and safety of mirogabalin
for the treatment of patients with DPNP.

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 11. Boyle J, Eriksson MEV, Gribble L, Gouni R, Johnsen S, Coppini DV, et al. Randomized, Placebo-
Accepted Article
Controlled Comparison of Amitriptyline, Duloxetine, and Pregabalin in Patients with Chronic
Diabetic Peripheral Neuropathic Pain: Impact on pain, polysomnographic sleep, daytime
functioning, and quality of life. Diabetes Care. 2012;35:2451-2458.
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 20. Baba M, Kuroha M, Ohwada S, Murayama E, Matsui N. Results of Mirogabalin Treatment for
Accepted Article
Diabetic Peripheral Neuropathic Pain in Asian Subjects: A Phase 2, Double-Blind,
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 Figure and Table Legends
Accepted Article
Figure 1. PRISMA flow diagram.
Figure 2. Risk of bias graph and summary
Figure 3. Change in the ADPS from baseline between mirogabalin vs placebo after first (A) and
second (B) week.
Figure 4. Change in the ADPS from baseline between mirogabalin vs placebo after third (A) and
fourth (B) week.
Figure 5. Change in the ADPS from baseline between mirogabalin vs placebo after fifth (A), sixth
(B), and seventh (C) week.
Figure 6. Change in the ADPS from baseline between mirogabalin vs pregabalin after first (A),
second (B), and third (C) week.
Figure 7. Change in the ADPS from baseline between mirogabalin vs pregabalin after fourth (A)
and fifth (B) week.
Figure 8. ≥30% reduction in the ADPS from baseline between mirogabalin vs placebo.
Figure 9. ≥50% reduction in the ADPS from baseline between mirogabalin vs placebo.
Figure 10. ≥30% reduction in the ADPS from baseline between mirogabalin vs pregabalin.
Figure 11. ≥50% reduction in the ADPS from baseline between mirogabalin vs pregabalin.
Figure 12. The risk of headache between mirogabalin vs placebo.
Figure 13. The risk of nasopharyngitis between mirogabalin vs placebo.
Figure 14. The risk of vomiting between mirogabalin vs placebo.
Figure 15. The risk of dizziness between mirogabalin vs placebo.
Figure 16. The risk of weight gain between mirogabalin vs placebo.
Figure 17. The risk of peripheral edema between mirogabalin vs placebo.
Figure 18. The risk of somnolence between mirogabalin vs placebo.
Figure 19. The risk of dizziness between mirogabalin vs pregabalin.
Figure 20. The risk of headache between mirogabalin vs pregabalin.
Figure 21. The risk of weight gain between mirogabalin vs pregabalin.
Figure 22. The risk of peripheral edema between mirogabalin vs pregabalin.
Figure 23. The risk of somnolence between mirogabalin vs pregabalin.
Figure 24. The risk of vomiting between mirogabalin vs pregabalin.

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 Table 1. Baseline summary of the included studies.
Accepted Article
Table 2. Subgroup analysis for study outcomes.
Table 3. A list of registered but not published clinical trials about mirogabalin in the management
of patients with DPNP.

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 Table 1. Baseline summary of included randomized controlled trials
Author, Year, Country Treatment Male % Age* Weight* Kg CrCl* (mL/min) ADPS* Type II Duration of Duration of Mean
NCT, phase (years) DM % DPN** painful DPN** HbA1c (%)
(months) (months)
Baba et al. Japan 72.3%, Placebo, n = 334 72.2 61 69.38 100.9 5.6 96.4 43 36 7.57
2019, Korea 15.6%, Mirogabalin 15 mg/day, 68.1 61.9 67.98 97.3 5.6 96.4 36 36 7.45
NCT02318706, Taiwan 8.8%, n = 166
phase III Malaysia Mirogabalin 20 mg/day, 72 61.2 67.88 100.6 5.57 96.4 48 41.5 7.51
3.4% n = 168
Mirogabalin 30 mg/day, 78.3 61.8 70.78 99.3 5.56 95.8 44 36 7.42
n = 166
Baba et al. Japan, South Placebo, n = 88
70.5 58.4 (9.9) 68.4 (13.2) 91.3 (23.5) 6.0 (1.2) 96.6 34.0 (6, 209) 32.0 (6, 209) .
2020, Korea, and
NCT01504412, Taiwan Pregabalin 300 mg/day,
phase II n = 85 70.6 60.2 (8.8) 69.0 (12.5) 91.6 (30.0) 6.1 (1.5) 98.8 43.0 (6, 233) 32.0 (6, 152) .
Mirogabalin 10 mg/day,
n = 90 65.6 60.5 (9.8) 68.0 (10.1) 91.3 (31.2) 5.8 (1.2) 98.9 48.0 (6, 221) 36.0 (6, 165) .
Mirogabalin 20 mg/day,
n = 93 62.4 60.7 (9.3) 66.1 (10.8) 90.2 (27.9) 5.9 (1.4) 96.8 60.0 (6, 332) 41.0 (6, 332) .
Mirogabalin 30 mg/day, 59.0
n = 90 54.4 (10.1) 67.0 (14.8) 92.4 (31.7) 5.9 (1.3) 94.4 41.5 (6, 411) 36.0 (6, 411) .
Vinik et al. USA Placebo, n = 112 50 60.2 96.2 (19.87) . . 88.4 . 70.8 (55.32) 7.3 (1.25)
2014, (9.57)
NCT01496365, Pregabalin 300 mg/day, 57.1 59.5 98.9 (24.87) . . 98.2 . 68.4 (60) 7.5 (1.46)
phase II n = 56 (9.40)
Mirogabalin 5 mg/day, 47.4 58.9 97.3 (23.85) . . 93 . 57.6 (48.6) 7.1 (1.23)
n = 57 (9.85)
Mirogabalin 10 mg/day, 50.9 60.9 101.9 (22.46) . . 89.5 . 58.8 (52.8) 7.4 (1.20)
n = 57 (9.92)
Mirogabalin 15 mg/day, 59.6 61.4 106.6 (21.70) . . 89.5 . 92.4 (76.8) 7.5 (1.07)
n = 57 (8.70)
Mirogabalin 20 mg/day, 57.1 60.4 103.4 (21.27) . . 96.4 . 63.6 (52.68) 7.4 (1.19)
n = 56 (8.59)
Mirogabalin 30 mg/day, 56.1 59.3 101.5 (20.13) . . 91.2 . 73.2 (63.12) 7.6 (1.21)
n = 57 (8.54)
ADPS: average daily pain score; CrCl: creatinine clearance; DM: diabetes mellitus; DPN: diabetic peripheral neuropathy; HbA1c: hemoglobin A1c
* Data are presented as mean and SD
** Data are presented as median and range or mean and standard deviation
 Table 2: Subgroup analysis for study outcomes.
Mirogabalin Mirogabalin 10 mg/day Mirogabalin 15 mg/day Mirogabalin 20 mg/day Mirogabalin 30 mg/day
dose
Week MD 95% CI p MD 95% CI p MD 95% CI p MD 95% CI p value
value valu value
e
A. Efficacy measures
Change in the average daily pain score versus placebo over time
The 1st week -0.10 [-0.37, 0.49 -0.12 [-0.31, 0.2 -0.17 [-0.33, - 0.04 -0.26 [-0.43, - 0.002
0.18] 0.07] 0.00] 0.09]
The 2nd week -0.32 [-0.62, 0.04 -0.18 [-0.38, 0.07 -0.27 [-0.43, - 0.002 -0.49 [-0.67, - <0.0000
-0.02] 0.01] 0.10] 0.32] 1
The 3rd week -0.31 [-0.63, 0.05 -0.26 [-0.46, - 0.01 -0.30 [-0.47, - 0.0004 -0.69 [-0.87, - <0.0000
-0.00] 0.06] 0.14] 0.51] 1

The 4th week -0.46 [-0.77, 0.004 -0.25 [-0.45, - 0.01 -0.30 [-0.47, - 0.004 -0.64 [-0.81, - <0.0000
-0.14] 0.05] 0.14] 0.46] 1

The 5th week -0.38 [-0.69, 0.02 -0.21 [-0.41, - 0.05 -0.27 [-0.43, - 0.002 -0.53 [-0.70, - <0.0000
-0.06] 0.00] 0.10] 0.35] 1
The 6th week - - - - - - -0.23 [-0.40, - 0.008 -0.53 [-0.71, - <0.0000
0.06] 0.35] 1
The 7th week - - - - - - -0.10 [-0.29, 0.26 -0.52 [-0.71, - <0.0000
0.08] 0.32] 1
Change in the average daily pain score versus pregabalin over time
The 1st week 0.06 [-0.25, 0.7 - - - -0.17 [-0.49, 0.32 -0.03 [-0.35, 0.86
0.38] 0.16] 0.29]
The 2nd week -0.12 [-0.47, 0.48 - - - -0.21 [-0.57, 0.26 -0.19 [-0.55, 0.29
0.22] 0.15] 0.16]
The 3rd week -0.22 [-0.57, 0.21 - - - -0.46 [-0.83, - 0.01 -0.50 [-0.87, - 0.009
0.13] 0.09] 0.13]
The 4th week -0.29 [-0.65, 0.1 - - - -0.54 [-1.12, 0.07 -0.56 [-1.39, 0.19
0.06] 0.04] 0.27]
The 5th week -0.28 [-0.63, 0.13 - - - -0.39 [-0.77, - 0.04 -0.21 [-0.57, 0.27
0.08] 0.01] 0.16]
Percentage of RR 95% CI p RR 95% CI p RR 95% CI p RR 95% CI p value
patients with value valu value
improvement e
Patients with significant reduction in the average daily pain score versus placebo
≥30% 1.24 [0.99, 0.06 1.55 [1.31, 0.00 1.12 [0.95, 0.19 1.25 [1.07, 0.005
1.56] 1.85] 001 1.32] 1.47]
≥50% 1.25 [0.85, 0.26 1.26 [0.95, 0.11 1.32 [1.02, 0.03 1.58 [1.24, 0.0002
1.84] 1.69] 1.71] 2.00]
Patients with significant reduction in the average daily pain score versus pregabalin
≥30% 1.22 [0.95, 0.26 - - - 1.27 [0.99, 0.11 1.27 [0.99, 0.0002
1.57] 1.62] 1.62]

≥50% 1.14 [0.76, 0.52 - - - 1.49 [1.02, 0.04 1.33 [0.90, 0.15
1.72] 2.17] 1.95]
Mirogabalin Mirogabalin 10 mg/day Mirogabalin 15 mg/day Mirogabalin 20 mg/day Mirogabalin 30 mg/day
dose
Adverse MD 95% CI p MD 95% CI p MD 95% CI p MD 95% CI p value
reaction value valu value
e
B. Safety measures
Mirogabalin versus placebo
Headache 1.54 [0.52, 0.44 - - - 2.24 [0.81, 0.12 0.91 [0.24, 0.89
4.60] 6.16] 3.42]
Nasopharyngitis - - - - - - 1.43 [0.93, 0.1 1.26 [0.82, 0.29
2.19] 1.94]
Vomiting 1.34 [0.37, 0.66 - - - 1.15 [0.28, 0.85 0.89 [0.20, 0.88
4.85] 4.78] 4.06]
Dizziness 3.24 [1.23, 0.02 3.11 [1.36, 0.00 3.70 [1.90, 0.0001 5.63 [2.99, <0.0000
8.59] 7.08] 7 7.20] 10.57] 1
Increased 2.38 [0.30, 0.41 2.56 [0.64, 0.18 5.19 [1.55, 0.008 8.56 [2.67, 0.0003
weight 19.13] 10.23] 17.46] 27.47]
Peripheral 4.90 [1.08, 0.04 4.01 [1.39, 0.01 2.80 [1.01, 0.05 6.51 [2.64, <0.0000
edema 22.27] 11.57] 7.74] 16.05] 1
Somnolence 1.61 [0.59, 0.35 2.44 [1.22, 0.01 3.17 [1.86, <0.000 4.19 [2.51, <0.0000
4.39] 4.85] 5.39] 01 6.99] 1
Mirogabalin versus pregabalin
Dizziness 0.96 [0.45, 0.92 - - - 1.09 [0.52, 0.81 1.91 [1.00, 0.05
2.07] 2.27] 3.67]
Headache 0.83 [0.28, 0.72 - - - 1.22 [0.47, 0.68 0.55 [0.16, 0.32
2.39] 3.18] 1.82]
Increased 0.96 [0.17, 0.96 - - - 2.09 [0.48, 0.32 2.48 [0.59, 0.22
weight 5.43] 9.05] 10.43]
Peripheral 0.75 [0.29, 0.56 - - - 0.55 [0.14, 0.4 1.32 [0.44, 0.62
edema 1.95] 2.23] 4.01]
Somnolence 0.54 [0.25, 0.12 - - - 1.05 [0.56, 0.87 1.55 [0.87, 0.12
1.17] 1.98] 2.75]
Vomiting 0.79 [0.23, 0.7 - - - 0.76 [0.23, 0.66 0.61 [0.16, 0.46
2.68] 2.57] 2.27]

95% CI: 95% confidence interval; MD: mean difference

Table 3. A list of registered but not published clinical trials about mirogabalin in the management of patients with
DPNP.

National clinical Study Study full (official) title Current

trial ID (NCT) phase status
NCT03901352 Phase 3 An Asian, multicenter, randomized, double-blind, placebo- Active, not
controlled, 14-week study of mirogabalin in participants with recruiting
central neuropathic pain followed by a 52-week, open-label
extension
NCT04094662 Phase 3 A phase 3 multicenter, randomized, double-blind, placebo- Recruiting
controlled 14-week study of DS-5565 in Chinese patients with
diabetic peripheral neuropathic pain
NCT02607280 Phase 3 A Japanese, phase 3, open-label, 14-week study of ds-5565 in Completed,
patients with pain associated with diabetic peripheral neuropathy not
with renal impairment or post-herpetic neuralgia with renal published
impairment