A systematic review and meta-analysis to determine the efficacy and safety of Mirogabalin treatment in diabetic peripheral neuropathic pain

Mirogabalin was found to safe and more effective than placebo/ pregabalin in treating patients with diabetic peripheral neuropathic pain (DPNP).

DPNP is the most frequently occurring complication of diabetes mellitus, associated with various morbidities such as sleep disturbances, decreased work productivity, anxiety, stress and depression. These morbidities significantly influence the quality of well-being and cause several economic encumbrances in DPNP patients. The mechanisms behind the etiopathogenesis of DPNP are not fully understood yet. However, voltage-dependent calcium channels (VDCCs) seem to play an integral role in the pathogenesis of DPNP. In recent years, VDCCs has become a potential target for primary pharmacological intervention in the management of DPNP patients. 

Several VDCC ligands have been shown to exert pain-relieving and analgesic effects, which is mediated through reducing the influx of calcium into neurons in the central nervous system (CNS). These VDCC ligands include gabapentin and pregabalin, which are considered and used as the first-line therapies for DPNP globally. However, these drugs add no adequate therapeutic value and also exhibits various adverse events such as dizziness, somnolence, and weight gain, thereby limiting their use in the treatment of DPNP patients. Also, most of DPNP patients treated with these drugs were not satisfied with treatment due to insufficient pain relief, poorly tolerated therapeutics, and low rates of analgesic responses. Hence, the efficacy of treatment decreases with time, thereby increasing the need for dose escalation and additional therapy. These factors and reasons ask for an effective medication which shows superior efficacy with minimal adverse events. 

Mirogabalin is one such novel, oral selective ligand targeting the alpha-2/delta subunit of VDCCs in CNS. It has been recommended for the treatment of DPNP and postherpetic neuralgia. Previous studies have demonstrated the superior analgesic efficacy of mirogabalin over pregabalin due to slower dissociation rate from the alpha-2/delta-1 subunit of VDCCs. 

Rationale behind research:

As evidenced from the previous randomized studies there occurs a need to confirm the efficacy and safety of mirogabalin in DPNP patients, therefore this systematic review and meta-analysis were conducted. 

Objective:

The objective of present systematic review and meta-analysis was to determine the efficacy and safety of mirogabalin in the treatment of DPNP.

Literature search

A systematic literature search was performed from scientific databases such as Cochrane Central, PubMed, Scopus, and Web of Science databases using a set of relevant keywords. The keywords used were “Mirogabalin OR Mirogabalin besylate OR Tarlige” AND “Diabetic Peripheral Neuropathic Pain OR Diabetic Peripheral Neuropathy OR Peripheral Neuropathy OR Neuropathic Pain”.

Inclusion criteria 

Studies including patients with DPNP, mirogabalin treatment (10, 15, 20, and 30 mg/day), a comparator group either placebo or pregabalin, efficacy and safety outcomes were included. 

Exclusion criteria 

Studies were excluded if they exhibit the following criteria: 

• Duplicate citations
• Review articles
• Animal studies
• Studies performed on healthy subjects
• Published protocols without a journal full-text
• Citations with irrelevant conditions (for example, postherpetic neuralgia)

Study selection and Data extraction

Research articles searched from the medical databases were screened by two reviewers in two consecutive steps. The first step included the screening of titles and abstracts whereas the second step scrutinized full-texts against the prespecified inclusion and exclusion criteria. Reference lists of reviews published about the topic were also screened manually. Data were extracted from the eligible studies into a predesigned Excel sheet. The various components of data extraction were the baseline characteristics, the risk of bias domains, and the study outcomes. 

Risk of Bias

The risk of bias domains in included studies was assessed using the Cochrane risk of the bias assessment tool. This tool was able to five types of bias which were: performance bias, selection bias, detection bias, reporting bias, and attrition bias. Every bias domain was judged as high, unclear, or low bias.

Data analysis and Statistical assessment

The dichotomous outcomes were pooled as risk ratios (RRs) with 95% confidence intervals (CIs), under the fixed-effect model. The Mantel Haenszel (M–H) method was used to calculate RRs. The Inverse Variance method was utilized to calculate the MDs whereas the Review Manager (RevMan) software, version 5.3 was used to analyze data.

The heterogeneity among pooled studies and degree of heterogeneity was assessed using the Chi-square and I-square (I2) test respectively. The p-value of the chi-square test less than 0.1 was considered heterogeneous. A sensitivity analysis was performed to resolve the heterogeneity problem among studies. A subgroup analysis was also performed 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. The publication bias of the included studies was not able to assess using Egger’s funnel plots. 

Study outcomes

• The primary outcomes included the evaluation of average daily pain score (ADPS) and the proportion of study participants who achieved ≥30% and ≥50% decrease in the ADPS with the baseline between the treatment (mirogabalin) and control (placebo or pregabalin) groups
• Other study outcomes included evaluation of safety using most frequently reported adverse reactions between the treatment and control groups

Outcomes

Study characteristics: 

• The studies included a total of 1732 patients with DPNP. Among 1732 patients, 1057, 534, and 141 patients were administered with mirogabalin, placebo, and pregabalin, respectively
• Only two studies compared the effectiveness of mirogabalin to pregabalin. The dose of pregabalin was 300 mg/day in both studies

Study quality: 

• The quality of included studies was estimated to be moderate to high

Effect of intervention on the outcome:

• There was a significant reduction found in average daily pain score (ADPS) in patients treated with mirogabalin compared to placebo over seven weeks and pregabalin after three, four, and five weeks
• The proportion of patients with ≥30% and ≥50% reduction in the ADPS was significantly higher in the mirogabalin group compared to the placebo and pregabalin group
• Treatment with mirogabalin was significantly associated with more adverse events as compared to placebo. However, the safety profile was comparable between mirogabalin and pregabalin

The findings of the present study demonstrated the efficacy of mirogabalin over placebo and pregabalin in patients with DPNP patients. A significant reduction was observed in ADPS in patients administered with mirogabalin for a treatment period of seven weeks. However, the safety profile was comparable and non-significant in comparison to control group. 

The optimum dose of mirogabalin would be that dose which causes minimal adverse events while delivering effective therapeutic actions. A meta-regression computation analysis would help predict the particular and effective dose of pregabalin, but in this study, computation analysis was not performed due to the inclusion of a limited number of studies. However, an effective dose of 300 mg/day mirogabalin was found to be associated with maximum therapeutic efficacy and comparable adverse events as compared to lower doses. These findings can be clinically significant to establish a safe and effective treatment for DPNP patients. This treatment can be effectively used in different populations. 

These study findings were consistent with the results of previous studies. Vinik et al. demonstrated a significant reduction in pain in DPNP patients administered with 5-30mg of mirogabalin per day. Baba et al. show a similar reduction in pain with safety and tolerability in DPNP administered with mirogabalin 20-30mg/day. Tetsunaga et al. reported a substitution of pregabalin with mirogabalin in DPNP patients due to higher efficacy and reduced side effect profile. 

This is the first scientific report that compared mirogabalin to placebo or pregabalin using the high-quality meta-analysis approach. However, additional clinical trials with longer follow up periods are required to consolidate the long term safety and efficacy of mirogabalin in treatment of DPNP patients. The trials of mirogabalin need a global extension in various countries including people belonging to different ethnicities.