metformin was the only therapy associated with the reduction of psoriasis risk among other anti-diabetic medications tested (ie, thiazolidinediones, sulfonylureas, biguanides, or acarbose),8 Ghiasi et al reported that pioglitazone vastly enhances the efficacy of phototherapy in psoriasis patients.60 Immunologically, thiazolidinediones act via a different pathway than metformin, and the relationship between peroxisome proliferator-activated receptor agonists (PPARs), fatty-acid induced transcription factors associated with lipid metabolic disorders, and the innate immune system must be better explored.61
Patients who received combination anti-psoriatic drugs with metformin or pioglitazone were reported to have a significant decrease in CD4+ T cells, IL-2, C-reactive protein (CRP), ceruloplasmin, ALT, and AST levels. Interestingly, no significant changes in the fasting blood glucose levels, HbA1c, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides were identified, which raises the question regarding which biological marker has a direct versus peripheral relationship with psoriasis. El-Gharabawy et al’s study of the mechanisms behind immunomodulating agents revealed that treatment groups who received both anti-psoriatic medication and pioglitazone had increased CD8+ levels while no significant changes in CD8+ were seen in patients treated with anti-psoriatic medication alone or with metformin alone, which contradicts the paradigm regarding the major effector role that Th1/CD8+ plays in the development of psoriasis.3 Furthermore, treatment groups receiving either pioglitazone or metformin experienced an overall significant decrease in CD4+, which are involved in the initiation and maintenance of the pathogenic role of psoriasis.62
Metformin for Acanthosis Nigricans
Longer duration of therapy (>6 months), higher metformin dosages (1,700–2,000mg), and lower baseline weight of patients associated with higher efficacy for the treatment of AN. Factors associated with low efficacy of acanthosis nigricans included low dosages of metformin, slow titration of the metformin, and shorter treatment course, suggesting that more aggressive course of metformin therapy is preferred for treating AN. Studies reviewed suggests that the role of metformin in the treatment of AN involves interactions beyond weight and insulin sensitivity. The activation of insulin like growth factors by increased circulating insulin leading to keratinocyte and dermal fibroblast proliferation in overweight individuals represents an oversimplified and incomplete explanation regarding the role of metformin for the treatment of AN.
For example, while both metformin and rosiglitazone demonstrated skin texture improvement, only rosiglitazone led to quantifiable decrease in insulin levels. Additionally, Wasniewska et al.’s treatment of AN in an adolescent with normal weight suggests the role of metformin in non-obesity associated inflammatory reactions. Some studies even suggest that there is no statistically significant difference in the proinflammatory proinflammatory profile (TNF-α, IL-6 and adiponectin) between obese and non-obese patients with metabolic syndrome. Whether proinflammatory reactors (TNF-α, IL-6 and adiponectin) have a role in the pathogenesis of AN raises the further question regarding our understanding how metformin works.
While topical and oral retinoids are generally accepted to positively benefit patients with AN due to their keratolytic effect, Walling et al’s study warrants further exploration of the synergy between isotretinoin and metformin. It should be noted that of the metformin non-responders reported by Verma et al. and Lee et al, one patient was pubertal with hyperinsulinemia and concomitant weight gain while the other had aromatase deficiency.63,64 Aromatase deficiency can result in an inability to reverse insulin resistance and therefore may explain metformin’s lack of efficacy.
Metformin for Acne
Fourteen of seventeen studies reviewed reported that metformin led to clinically significant improvement in PCOS-related acne. Of note, treating non-PCOS related acne with metformin remains controversial. One study involving men with refractory acne after treatment with oral metformin (dose range, 1000 to 2550mg/day) also showed positive results, however, these results may have been confounded by the initiation of low glycemic diets (P<0.05). A low sample size (n=20) and lack of stratification also calls for further follow-up studies.
Compared to OCPs, aggressive metformin treatment regimens (1700–2000mg/day) resulted in greater reduction of acne as well as menstrual irregularity compared to oral contraceptives. This suggests that metformin’s role in disrupting the pathophysiology of acne should be better scrutinized and differentiated between patients with and without PCOS.65,66
Understanding the role of metformin in the treatment of PCOSrelated acne raises the question whether metformin would achieve similar efficacy in non-PCOS patients. Metformin is theorized to decreases the follicular hyper-keratinization of cells overlying hair follicles through decreasing IGF-1 levels associated with insulin resistance, inflammatory markers (IFNg, IL-1, IL-8, and TNFa) associated with obesity and Propionibacterium acnes, and excess testosterone responsible for stimulating sebaceous oil production.27
Metformin for Hirsutism
Of the total of 46 studies investigated metformin’s efficacy for hirsutism treatment in females with PCOS, 31 reported an improvement of hirsutism with metformin treatment, particularly a higher dose (>1500mg/day). Metformin treatment failure in patients with acne and hirsutism was once again noted using shorter treatment durations and insufficient control of the underlying metabolic disease.
Patients who received combination anti-psoriatic drugs with metformin or pioglitazone were reported to have a significant decrease in CD4+ T cells, IL-2, C-reactive protein (CRP), ceruloplasmin, ALT, and AST levels. Interestingly, no significant changes in the fasting blood glucose levels, HbA1c, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides were identified, which raises the question regarding which biological marker has a direct versus peripheral relationship with psoriasis. El-Gharabawy et al’s study of the mechanisms behind immunomodulating agents revealed that treatment groups who received both anti-psoriatic medication and pioglitazone had increased CD8+ levels while no significant changes in CD8+ were seen in patients treated with anti-psoriatic medication alone or with metformin alone, which contradicts the paradigm regarding the major effector role that Th1/CD8+ plays in the development of psoriasis.3 Furthermore, treatment groups receiving either pioglitazone or metformin experienced an overall significant decrease in CD4+, which are involved in the initiation and maintenance of the pathogenic role of psoriasis.62
Metformin for Acanthosis Nigricans
Longer duration of therapy (>6 months), higher metformin dosages (1,700–2,000mg), and lower baseline weight of patients associated with higher efficacy for the treatment of AN. Factors associated with low efficacy of acanthosis nigricans included low dosages of metformin, slow titration of the metformin, and shorter treatment course, suggesting that more aggressive course of metformin therapy is preferred for treating AN. Studies reviewed suggests that the role of metformin in the treatment of AN involves interactions beyond weight and insulin sensitivity. The activation of insulin like growth factors by increased circulating insulin leading to keratinocyte and dermal fibroblast proliferation in overweight individuals represents an oversimplified and incomplete explanation regarding the role of metformin for the treatment of AN.
For example, while both metformin and rosiglitazone demonstrated skin texture improvement, only rosiglitazone led to quantifiable decrease in insulin levels. Additionally, Wasniewska et al.’s treatment of AN in an adolescent with normal weight suggests the role of metformin in non-obesity associated inflammatory reactions. Some studies even suggest that there is no statistically significant difference in the proinflammatory proinflammatory profile (TNF-α, IL-6 and adiponectin) between obese and non-obese patients with metabolic syndrome. Whether proinflammatory reactors (TNF-α, IL-6 and adiponectin) have a role in the pathogenesis of AN raises the further question regarding our understanding how metformin works.
While topical and oral retinoids are generally accepted to positively benefit patients with AN due to their keratolytic effect, Walling et al’s study warrants further exploration of the synergy between isotretinoin and metformin. It should be noted that of the metformin non-responders reported by Verma et al. and Lee et al, one patient was pubertal with hyperinsulinemia and concomitant weight gain while the other had aromatase deficiency.63,64 Aromatase deficiency can result in an inability to reverse insulin resistance and therefore may explain metformin’s lack of efficacy.
Metformin for Acne
Fourteen of seventeen studies reviewed reported that metformin led to clinically significant improvement in PCOS-related acne. Of note, treating non-PCOS related acne with metformin remains controversial. One study involving men with refractory acne after treatment with oral metformin (dose range, 1000 to 2550mg/day) also showed positive results, however, these results may have been confounded by the initiation of low glycemic diets (P<0.05). A low sample size (n=20) and lack of stratification also calls for further follow-up studies.
Compared to OCPs, aggressive metformin treatment regimens (1700–2000mg/day) resulted in greater reduction of acne as well as menstrual irregularity compared to oral contraceptives. This suggests that metformin’s role in disrupting the pathophysiology of acne should be better scrutinized and differentiated between patients with and without PCOS.65,66
Understanding the role of metformin in the treatment of PCOSrelated acne raises the question whether metformin would achieve similar efficacy in non-PCOS patients. Metformin is theorized to decreases the follicular hyper-keratinization of cells overlying hair follicles through decreasing IGF-1 levels associated with insulin resistance, inflammatory markers (IFNg, IL-1, IL-8, and TNFa) associated with obesity and Propionibacterium acnes, and excess testosterone responsible for stimulating sebaceous oil production.27
Metformin for Hirsutism
Of the total of 46 studies investigated metformin’s efficacy for hirsutism treatment in females with PCOS, 31 reported an improvement of hirsutism with metformin treatment, particularly a higher dose (>1500mg/day). Metformin treatment failure in patients with acne and hirsutism was once again noted using shorter treatment durations and insufficient control of the underlying metabolic disease.
