Metformin Improves Symptoms and Gene Expression in Central Centrifugal Cicatricial Alopecia

Patients with treatment-resistant central centrifugal cicatricial alopecia saw improvement in symptoms and gene expression, suggesting the potential of metformin as a new treatment option. | Image Credit: Prostock-studio - stock.adobe.com

Patients with treatment-refractory central centrifugal cicatricial alopecia displayed symptomatic improvement and dual modulation of gene expression that stimulated hair growth pathways while suppressing fibrosis and inflammation markers, according to a study published in JAMA Dermatology.¹

Cicatricial or scarring alopecia comprise chronic inflammatory hair disorders that result in permanent hair loss from the destruction of hair follicles that are replaced with fibrous scar tissue. This form of hair loss primarily affects Black female individuals, typically during middle age.² Both traction alopecia and central centrifugal cicatricial alopecia are among the most common hair loss disorders presenting in Black women (33% and 15%, respectively).³

Treatment for central centrifugal cicatricial alopecia includes topical glucocorticoids, intralesional triamcinolone injections, and oral tetracycline antibiotics that target the inflammation aspects of the disease.¹ However, these treatments do not address the underlying processes of fibrosis and scarring that ultimately lead to hair loss. Additionally, topical and oral minoxidil agents do not target the core pathogenesis of central centrifugal cicatricial alopecia and offer limited efficacy results.

Metformin, an antidiabetic medication, upregulates adenosine monophosphate kinase (AMPK) and enhances insulin sensitivity. The antifibrotic effects of the medication and blockade of specific pathways have prompted investigators to consider metformin’s potential as a therapeutic candidate for alopecias.

“A preliminary case series demonstrated potential clinical utility of topical metformin for central centrifugal cicatricial alopecia, but the role of systemic oral metformin in cicatricial alopecias remains unexplored,” stated the study authors.

They conducted a retrospective case series of 12 participants, all Black female participants, who were examined at the Johns Hopkins alopecia clinic with biopsy-confirmed central centrifugal cicatricial alopecia that was considered clinically refractory to conventional therapies.

Improvements in scalp pain, scalp resistance, pruritus, and inflammation were identified across 8 patients following metformin treatment. Two patients reported a continued worsening of symptoms after metformin treatment.

There were 6 patients who experienced clinical evidence of scalp hair regrowth following at least 6 months of treatment. However, there was 1 patient who experienced subsequentregression 3 months after metformin discontinuation.

A differential gene expression analysis was conducted to compare pre- and postmetformin samples, accounting for false discovery rates. Of the 16,655 genes analyzed, 34 were significantly upregulated and 8 were significantly downregulated post treatment.

Gene set enrichment analysis identified upregulated pathways associated with keratinocyte differentiation, epidermal development, and hair follicle cycling. Additionally, pathways related to insulin signaling, immune response, and calcium homeostasis were enriched. A significant upregulation of 23 hair keratin–associated proteins was observed.

Conversely, downregulated pathways were linked to extracellular matrix organization, collagen fibril assembly, and collagen metabolism. Prominent downregulated genes included matrix metalloproteinase 7, collagen VI alpha 1, and dermcidin.

The gene set variation analysis computed the posttreatment expression within the previously established pathways. There was a decrease in the mean posttreatment expression of gene sets associated with helper T cell 17 and epithelial mesenchymal transition. Metformin treatment was associated with increased expression of an AMPK signaling gene set and a gene set comprising all keratin-associated proteins.

Study limitations include a small sample size, retrospective design, lack of a placebo control group, and a single-center setting, which may limit the generalizability of the findings. The absence of a validated activity or severity scale for central centrifugal cicatricial alopecia hindered precise assessment of disease progression. Finally, the transcriptomic analysis was restricted by a single posttreatment tissue sample, limiting the ability to compare gene expression changes with nonlesional tissue.

Interestingly, half of the 6 patients with hair regrowth did not use minoxidil during the 6-month metformin treatment period, implying a possible role of metformin in hair regrowth. These results support previous findings showing hair regrowth with topical metformin in central centrifugal cicatricial alopecia.

Metformin's potential to reduce fibrosis and inflammation may explain its therapeutic effects in central centrifugal cicatricial alopecia and other fibrotic hair loss disorders.

“Larger prospective, placebo-controlled randomized clinical trials are needed to rigorously evaluate metformin’s efficacy and optimal dosing for treatment of cicatricial alopecias,” concluded the study authors.

References

1. Bao A, Qadri A, Gadre A, et al. Low-dose metformin and profibrotic signature in central centrifugal cicatricial alopecia. JAMA Dermatol. 2024;160(11):1211-1219. doi:10.1001/jamadermatol.2024.3062

2. Hair loss types: central centrifugal cicatricial alopecia overview. American Academy of Dermatology. March 15, 2022. Accessed November 25, 2024. https://www.aad.org/public/diseases/hair-loss/types/ccca

3. Santoro C. Evaluating hair camouflage as a tool for Black women with alopecia: a critical review. AJMC®. January 18, 2024. Accessed November 25, 2024. https://www.ajmc.com/view/evaluating-hair-camouflage-as-a-tool-for-black-women-with-alopecia-a-critical-review