(P<0.05).26 Interestingly, metformin monotherapy was more efficacious for reducing acne lesion count than combination with calcium and vitamin D.27
Hirsutism
One of the most studied conditions involve women with acne and a history of PCOS or HAIR-AN syndrome, (dose range, 1,000– 2,550mg daily) in 30 RCTs. Yet it is still difficult to conclude given that reported results vary between studies,21,22,28-37 whereas no significant improvements were reported in four RCTs, and five prospective cohort studies in the literature.13,14,19,20,38-42
Combination therapies of metformin with other agents, including spironolactone, ethinyl estradiol-cyproterone acetate (EE-CA), N-acetylcysteine (NAC), myo-inositol, and other diabetic medications generally led to greater decrease in PCOS than monotherapy alone. Metformin along with hormonal therapies including clomiphene citrate (50mg daily for six cycles), flutamide (250mg twice daily) and combination OCPs, drospirenone with ethinyl estradiol (DRP-EE), led to statistically significant reduction in hirsutism scores. Two other RCTs (n=206) demonstrated greater improvement in hirsutism scores for patients treated with combination therapy: spironolactone 50–100mg daily and metformin.43,44 Mixed results were obtained when comparing the clinical efficacy measured by hirsutism reduction when treated with metformin monotherapy (dose range, 500mg two to three times daily) versus EE-CA (2 mg daily) across the duration of t3 months to 1 year.23,24,42,45,46 Of the various combination therapies reported, combination therapy with pioglitazone (7.5mg daily), flutamide (62.5mg daily) and metformin (850mg daily for 6 months) were reported to be the most effective.18,47-49
When comparing the role of metformin in the management of hirsutism to other diabetes medications, metformin was superior to pioglitazone (30mg daily for 6 months), but inferior to rosiglitazone (4mg daily for 24 weeks).50,51 No statistically significant difference in hirsutism reduction was achieved when comparing metformin monotherapy and N-acetyl cysteine (NAC 600mg three times daily for 24 weeks), myo-inositol (4,000mg daily for 6 months), and simvastatin (20mg daily for 3 months).15,25,52
In three different studies, three different combination therapies of metformin with five sessions of intense pulsed light therapy (IPL) for 6 months, simvastatin 20mg daily for 6 months and calcium 1,000 mg daily and Vitamin D 50,000 IU for 4 months supplementations improved hirsutism and qualitative patient satisfaction.26,27,41,53-55
Hirsutism
One of the most studied conditions involve women with acne and a history of PCOS or HAIR-AN syndrome, (dose range, 1,000– 2,550mg daily) in 30 RCTs. Yet it is still difficult to conclude given that reported results vary between studies,21,22,28-37 whereas no significant improvements were reported in four RCTs, and five prospective cohort studies in the literature.13,14,19,20,38-42
Combination therapies of metformin with other agents, including spironolactone, ethinyl estradiol-cyproterone acetate (EE-CA), N-acetylcysteine (NAC), myo-inositol, and other diabetic medications generally led to greater decrease in PCOS than monotherapy alone. Metformin along with hormonal therapies including clomiphene citrate (50mg daily for six cycles), flutamide (250mg twice daily) and combination OCPs, drospirenone with ethinyl estradiol (DRP-EE), led to statistically significant reduction in hirsutism scores. Two other RCTs (n=206) demonstrated greater improvement in hirsutism scores for patients treated with combination therapy: spironolactone 50–100mg daily and metformin.43,44 Mixed results were obtained when comparing the clinical efficacy measured by hirsutism reduction when treated with metformin monotherapy (dose range, 500mg two to three times daily) versus EE-CA (2 mg daily) across the duration of t3 months to 1 year.23,24,42,45,46 Of the various combination therapies reported, combination therapy with pioglitazone (7.5mg daily), flutamide (62.5mg daily) and metformin (850mg daily for 6 months) were reported to be the most effective.18,47-49
When comparing the role of metformin in the management of hirsutism to other diabetes medications, metformin was superior to pioglitazone (30mg daily for 6 months), but inferior to rosiglitazone (4mg daily for 24 weeks).50,51 No statistically significant difference in hirsutism reduction was achieved when comparing metformin monotherapy and N-acetyl cysteine (NAC 600mg three times daily for 24 weeks), myo-inositol (4,000mg daily for 6 months), and simvastatin (20mg daily for 3 months).15,25,52
In three different studies, three different combination therapies of metformin with five sessions of intense pulsed light therapy (IPL) for 6 months, simvastatin 20mg daily for 6 months and calcium 1,000 mg daily and Vitamin D 50,000 IU for 4 months supplementations improved hirsutism and qualitative patient satisfaction.26,27,41,53-55
DISCUSSION
Metformin is a promising therapy for the treatment of cutaneous diseases. This systematic review of 64 studies of its use in cutaneous conditions as both a mono- as well as adjunct therapy suggests that high-dose long-term metformin therapy is beneficial for HS, psoriasis, and acne, while its efficacy for treatment of hirsutism and acanthosis nigricans is less clear. In these studies, oral metformin dosing for treatment of dermatologic diseases was variable, with dosage ranging from 500 to 2,000mg/day over 24 weeks to 3 years. In treatment of diabetes, 500mg represents the suggested starting dose whereas 2,500mg represents the upper limit suggested for patients with severe insulin resistance. As opposed to the studies regarding HS and psoriasis, it should be noted that the studies regarding AN, acne, and hirsutism reviewed primarily involved female patients with PCOS.
Metformin for Hidradenitis Suppurativa (HS)
Albeit the limited sample size and positive publication bias, the clinical outcome for the treatment of HS with metformin are promising in all of the studies reviewed. HS is thought to result from follicular occlusion in combination with underlying immune dysregulation and an overactive toll-like receptor (TLR) response to bacterial colonization.56 Patients with HS have been found to have elevated CRP, elevated lymphocyte and neutrophil counts, and upregulated cytokine profiles.57 Interestingly, the acute inflammatory markers TNF-α, IL-1, and IL- 6, along with IL-12/23 and TLR ligands found in HS patients are also common amongst psoriasis patients, as both conditions involve theTNF-α induced NF-κB pathway that leads to metabolic dearrangements.57
HS is a highly morbid and notoriously difficult condition to manage, and limited treatment options exist. Adalimumab, a TNF-α inhibitor and a first-line therapy for psoriasis, is currently the only FDA-indicated biologic agent approved for the treatment of moderate-to-severe HS in ages 12 and beyond. Other TNF-α inhibitors such as infliximab have also demonstrated efficacy in treatment of HS.58,59 However, further studies are necessary to better understand not only the efficacy but also pharmacology underlying combining adjunctive therapies on a drug to drug basis.
Metformin for Psoriasis
Long-term use of metformin appears to be useful in prevention as well as management of psoriasis in patients with underlying metabolic syndrome with insignificant side effect. The effect of metformin in patients with lower BMI is less clear, warranting larger sample sizes and better clarification of other potential confounding factors. In practice, clinicians should be mindful of selecting psoriasis patients with metabolic syndrome for adjunctive treatment with metformin for most optimal results.
Scrutinization of the studies reported raises the question whether metformin is the only efficacious adjunctive anti-diabetic agent available. While the study by Rena et al reported that
Metformin for Hidradenitis Suppurativa (HS)
Albeit the limited sample size and positive publication bias, the clinical outcome for the treatment of HS with metformin are promising in all of the studies reviewed. HS is thought to result from follicular occlusion in combination with underlying immune dysregulation and an overactive toll-like receptor (TLR) response to bacterial colonization.56 Patients with HS have been found to have elevated CRP, elevated lymphocyte and neutrophil counts, and upregulated cytokine profiles.57 Interestingly, the acute inflammatory markers TNF-α, IL-1, and IL- 6, along with IL-12/23 and TLR ligands found in HS patients are also common amongst psoriasis patients, as both conditions involve theTNF-α induced NF-κB pathway that leads to metabolic dearrangements.57
HS is a highly morbid and notoriously difficult condition to manage, and limited treatment options exist. Adalimumab, a TNF-α inhibitor and a first-line therapy for psoriasis, is currently the only FDA-indicated biologic agent approved for the treatment of moderate-to-severe HS in ages 12 and beyond. Other TNF-α inhibitors such as infliximab have also demonstrated efficacy in treatment of HS.58,59 However, further studies are necessary to better understand not only the efficacy but also pharmacology underlying combining adjunctive therapies on a drug to drug basis.
Metformin for Psoriasis
Long-term use of metformin appears to be useful in prevention as well as management of psoriasis in patients with underlying metabolic syndrome with insignificant side effect. The effect of metformin in patients with lower BMI is less clear, warranting larger sample sizes and better clarification of other potential confounding factors. In practice, clinicians should be mindful of selecting psoriasis patients with metabolic syndrome for adjunctive treatment with metformin for most optimal results.
Scrutinization of the studies reported raises the question whether metformin is the only efficacious adjunctive anti-diabetic agent available. While the study by Rena et al reported that
