Efficacy and safety of metformin for melasma treatment: a systematic review and meta-analysis

Objective: Metformin has recently been demonstrated to have an anti-melanogenic activity. Nevertheless, clinical evidence of the effectiveness of metformin in melasma is lacking. The objective of this study was to assess the efficacy and safety of metformin in the treatment of melasma. Methods: MEDLINE, Embase, PubMed, Cochrane Library (CENTRAL), Scopus, CINAHL, and grey literature databases were searched to 4 October 2022 and updated on 26 February 2023. Randomized controlled trials (RCTs), quasi-RCTs, observational studies, case series, and case reports investigating the efficacy and safety of metformin for melasma were included. The Melasma Area Severity Index (MASI) scores that changed from baseline were pooled using fixed-effects model and expressed as standardized mean differences (SMDs) and 95% confidence intervals (CIs). Results: Three RCTs including 140 patients with melasma were included. The results demonstrated that after 8 weeks, 15% topical metformin significantly reduced the Melasma Area Severity Index (MASI) score compared to placebo (1 trial; n = 60; MD, −0.56; 95% CI, −1.07 to −0.04; p = 0.034). Furthermore, when compared to triple combination cream (TCC), 30% topical metformin demonstrated similar efficacy in reducing the MASI score after 8 weeks (2 trials; n = 80; MD, 0.19, 95% CI, −0.25 to 0.63; p = 0.390). Patients using 30% topical metformin had fewer adverse events compared to TCC users, although no statistical difference was found. Conclusion: Topical metformin was as effective as triple combination cream (TCC) in decreasing changes in the MASI score in patients with melasma, with minimum adverse events. Further studies with larger sample sizes, longer follow-up times, and well-designed trials are required. Systematic Review Registration: Identifier PROSPERO (CRD42022351966).


Table S1
Systematic Review Search Strategy S2

Table S2
Grey Literature Search S8

Table S5
Summary Results of Risk-of-Bias Assessment S12

Reporting bias assessment
14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).NA Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
 Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.
 Table S4 Study characteristics 17 Cite each included study and present its characteristics. Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study. Table 1, Table S5 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.
Figure 2 Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. 20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect. Table 2, Figure 2 20c Present results of all investigations of possible causes of heterogeneity among study results.NA 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.NA Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.NA Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. Table S6 DISCUSSION Discussion 23a Provide a general interpretation of the results in the context of other evidence. 23b Discuss any limitations of the evidence included in the review. 23c Discuss any limitations of the review processes used. 23d Discuss implications of the results for practice, policy, and future research. Riomet or Fortamet or Glumetza or Obimet or Dianben or Diabex or Diaformin or Diabetosan or Fluamine or Flumamine or Glifage or Gliguanid or Haurymelin or Imidodicarbonimidic diamide or Islotin or LA-6023 or CCRIS 9321 or DMGG or EINECS 211-517-8 or Melbin or Metiguanide or Siofor or UNII-9100L32L2N).tw,kw,rn.

Table S5 Summary
Results of Risk-of-Bias Assessment Bias

Domain: Version 2 of the Cochrane Risk-of-Bias Assessment Tool for Randomized Trials Author, Year Mapar et al (2019) Banavase Channakeshavaiah et al, 2020 AboAlsoud et al, 2022
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.-