Efficacy of metformin vs. doxycycline in treating acne vulgaris: An assessor‐blinded, add‐on, randomized, controlled clinical trial

Insulin‐like growth factor 1 (IGF‐1) plays a role in the pathogenesis of acne vulgaris. Metformin can reduce IGF‐1 levels and insulin resistance, so it may be useful in treating acne.


| INTRODUC TI ON
A common inflammatory condition of the pilosebaceous unit is acne vulgaris. 1Four main factors in its pathogenesis include excess sebum production, hyperkeratinization of the follicular infundibulum, inflammation, and a microorganism called Cutibacterium acnes. 1 Individual, environmental, and genetic factors may also have considerable roles in the onset and progression of this condition. 2The most common sites for acne lesions are the face, chest, and upper back. 2 Acne vulgaris is classified based on the patient's age (including infantile acne, adolescent acne, and adult acne), lesion morphology, and lesion location 3 ; it can also be classified as mild, moderate, or severe.In this regard, mild acne is defined as few-to-several papules and pustules without any nodules, moderate acne is described as several to many papules and pustules, along with a few to several nodules, and severe acne is characterized by many papules and pustules, as well as many nodules. 2,4e choice of acne treatment is based on factors including acne severity, the affected area, the patient's age, and personal preferences.Common treatments for acne vulgaris are topical combinations of antibiotics, retinoids, and comedolytics.Systemic medications such as isotretinoin, antibiotics, and hormone regulators (e.g., oral contraceptives (OCP) and spironolactone) are reserved for patients with severe acne or resistance to topical treatments. 5,6ong the oral antibiotics prescribed for acne vulgaris, tetracyclines such as doxycycline and minocycline are the most common.Doxycycline may be chosen by physicians more readily due to its fewer side effects. 7Nevertheless, it can have gastrointestinal, dermatological (e.g., phototoxic reactions), neurological (e.g., pseudotumor cerebri), cosmetic (e.g., teeth and skin discoloration), or infectious (vaginal and pharyngeal candidiasis) side effects. 8gh insulin levels have been related to increased levels of biological factors such as insulin-like growth factor-1 (IGF-1), insulinlike growth factor-3 (IGF-3), and androgens.These changes can lead to the onset and worsening of acne. 9Metformin is an oral antiglycemic agent for diabetes mellitus, insulin resistance diseases such as hirsutism, hidradenitis suppurativa, and polycystic ovary syndrome (PCOS).Moreover, evidence indicates that metformin can reduce the serum levels of insulin and IGF-1.These effects reduce insulin resistance, which may be helpful in treating acne vulgaris. 10spite the therapeutic effect of antibiotics such as doxycycline and minocycline on acne, these drugs can cause many side effects that can even lead to discontinuation.Therefore, finding alternative treatments with fewer complications can help achieve better control over the disease.Considering the role of IGF-1 in acne and the mechanism of action of metformin, this study investigated the therapeutic effect of metformin on adult patients with acne and compared it against doxycycline.

| Study design and participants
In this assessor-blind, add-on, randomized clinical trial, we enrolled patients aged 15-40 of both sexes with moderate acne.Participants were selected from the patients referred to the Shahid Faghihi Dermatology Clinic affiliated with Shiraz University of Medical Sciences.The inclusion criteria encompassed patients with moderate acne who had not received systemic treatment during the past month or topical treatment in the past 2 weeks.Patients with systemic diseases including diabetes mellitus or kidney/liver dysfunction, pregnant and lactating women, and women with PCOS were excluded from this study.In addition, we excluded patients who were reluctant to continue the study, those who reported a positive history of allergy to the study drugs, those with acne conglobata or acne fulminans, those who used drugs that interact with metformin or doxycycline, and those who used contraceptive medications containing estrogen or progesterone.

| Randomization and blinding
Patients were randomly divided into two groups based on randomization with permutation blocks (block size of 4) using the Random Allocation Software.Dark envelopes were used for allocation concealment.Because the medication forms were different in this study (tablet of metformin vs. capsule of doxycycline), blinding the patients was not applicable.However, the dermatologist who evaluated the patients in each follow-up was blinded to the patient allocation.

| Interventions
One group was treated with 100 mg doxycycline capsules (manufactured by Hakim Pharmaceutical Company) orally once daily; the second group was treated with 500 mg metformin tablets (Rasta Imen Darou Pharmaceutical Company; brand name Apometformin) orally twice daily.Furthermore, the patients in both groups were instructed to apply a fingertip (fourth finger) of 5% benzoyl peroxide gel (Pangel®) topically every night over the lesions, and to wash it off after 30 min.The patients were recommended to use lipid-free sunscreen with a sun protection factor (SPF) above 30 when leaving the house.
Patients were followed up for 2 months and visited monthly.They received the required medication dosage for one month during each visit.During the study, all patients were strongly advised to avoid taking medications that increase or reduce metformin levels, such as captopril, cimetidine, bupropion, or betamethasone; they were also warned to refrain from concurrently using retinoid drugs (e.g., isotretinoin) with doxycycline, which increases intracranial pressure.

| Data collection
Eligible patients were evaluated in terms of demographic characteristics.In addition, we assessed the severity of acne using the Global Acne Grading System (GAGS) score, 11 Investigator Global Assessment for Acne (IGA) score, 12 Cardiff Acne Disability Index (CADI), 13 Total Acne Lesion Count (TLC), 14 as well as the number of inflammatory and noninflammatory lesions.The patients were followed up for 2 months by a dermatologist blinded to the group allocation, and any side effects were recorded.In the case of dissatisfaction, patients could withdraw from the research project at any time.

| Study tools and outcome measurements
In the GAGS grading system, 11 acne lesions are divided into four groups and scored from 0 to 4 based on the type of lesion (no lesion-0; comedones-1; papules-2; pustules-3; and nodules-4).Also, based on the anatomical location of the lesion, a coefficient is assigned (chest and trunk-3; forehead or right/left cheek-2; chin or nose-1).The score of each anatomical region is calculated by multiplying of lesion type score by the location coefficient.Then, the final acne severity score is obtained through the sum of the scores of different regions, considered mild (1-18), moderate (19-30), severe (31-38), or very severe (>39).
The severity of acne was also assessed using the IGA. 12 This scoring system is as follows: 1-clear skin with no lesions; 2-some mild noninflammatory lesions with no more than a few inflammatory lesions but no nodular lesions; 3-moderate up to many noninflammatory lesions and may have some inflammatory lesions but no more than a few nodular lesions; 4-many severe noninflammatory and inflammatory lesions but no more than a few nodular lesions; and 5-many noninflammatory and inflammatory lesions and more than a few nodular lesions.
The TLC was calculated based on the Burke and Cunliffe system. 14During treatment, the reduction in the overall number of lesions determined the response to treatment.In counting the total number of lesions, the number of inflammatory and noninflammatory lesions was determined separately to make it easier to judge the drug's effect on different types of lesions.
Finally, to evaluate the effect of treatment on patients' quality of life, at the beginning of the study and 2 months after treatment, the patients completed a validated Persian version of the CADI questionnaire. 13,15

| RE SULTS
As the CONSORT flowchart shows, 55 patients were examined for eligibility.Among them, 45 were enrolled, but five patients, including three in the metformin group and two in the doxycycline group, were lost to follow-up (Figure 1).Finally, 40 patients, including five men (12.5%) and 35 women (87.5%) with a mean age of 24.82 ± 7.31 (range: 15-38) years, were included in the analysis.There was no significant difference between the two groups regarding their gender and initial, final, and change in IGA, CADI, GAGS, TLC, inflammatory lesion improvement, and noninflammatory lesion improvement scores.Table 1 demonstrates the demographic variables and the acne scores of the patients in our study.
The mean IGA scores in both metformin (p < 0.001) and doxycycline (p < 0.001) groups at the end of the study were significantly lower than at the beginning of the study; however, the mean difference in reduction of IGA score between the two groups was not statistically significant (p = 0.537) (Table 1).
The mean CADI score in both metformin (p < 0.001) and doxycycline (p < 0.001) groups at the end of the study was significantly lower than at the beginning of the study, while the intergroup difference in the mean change over time was not statistically significant (p = 0.659) (Table 1).
In terms of side effects, three patients in the metformin group reported mild-to-moderate gastrointestinal discomfort, especially when they took the drug on an empty stomach.On the contrary, only one patient reported mild photosensitivity in the doxycycline group.None of the patients in either group withdrew from the study because of the mentioned side effects.

| DISCUSS ION
The present study showed that both metformin and doxycycline were effective in treating patients with acne vulgaris, without any significant difference between the groups in most study outcomes.
However, the number of inflammatory lesions in patients receiving doxycycline decreased more than in those receiving metformin.
The reduction in the IGA score in both groups demonstrated that both metformin and doxycycline significantly reduced the severity of acne based on IGA criteria to a similar degree.Studies have shown a considerable decrease in acne severity in patients with PCOS under metformin therapy. 16In a self-controlled clinical trial by Nazari et al., 17 30 female adolescents with PCOS were treated with 500 mg of metformin three times a day for 6 months, leading to a significant clinical improvement in acne severity.Studies have also investigated the effects of metformin in non-PCOS patients.Fabbrocini et al. 18 investigated the effects of a low-sugar diet and metformin on treating men with acne resistant to common treatment, revealing a significant improvement in acne after 6 months.While it seems that F I G U R E 1 CONSORT flowchart of the clinical trial that compares the efficacy of oral metformin with doxycycline in the treatment of acne vulgaris.metformin can reduce the severity of acne, studies should investigate this issue further in different populations.
The GAGS scores in both groups decreased significantly.The average global grade of acne in both groups was initially moderate, changing to mild by the end of the study.Based on GAGS criteria, both groups responded well to treatment, with a more significant improvement in the doxycycline group.Elham et al. 19 compared metformin and isotretinoin in treating women with resistant and late-onset acne, revealing a significant reduction in the GAGS score of both groups, with a significantly greater reduction in patients receiving isotretinoin.On the contrary, metformin was more effective in reducing the GAGS score of individuals with PCOS and hirsutism.
They concluded that metformin is beneficial in treating refractory and late-onset acne and improves the metabolic status of patients without serious side effects.Robinson et al. 20 investigated the effect of adding metformin to oral tetracycline (250 mg) plus benzoyl peroxide 2.5% as an adjunct treatment for moderate-to-severe acne vulgaris in patients with PCOS.Their results showed that the treatment success rate was significantly higher in patients receiving metformin.They concluded that metformin has significant effects in treating acne.
Our study showed that the patients' acne disability score based on CADI criteria significantly decreased in both groups, with no meaningful difference between them.In a study by Huang et al. 21 women with PCOS, it was demonstrated that metformin could improve their health-related quality of life by ameliorating psychological disturbances caused by acne, hair loss, and infertility issues, particularly in overweight and hyperandrogenic patients.Based on our study, metformin effectively enhances the quality of life of patients with acne vulgaris.Metformin is an old well-known hypoglycemic agent.22 In this regard, metformin improves insulin sensitivity by reducing IGF-1 signaling and hepatic glucose output, so glucose usage by muscles and adipose tissue will increase in the human body.23 Moreover, the mTORC1/S6K1 signaling pathway, which is upregulated in acne-prone skin, was suppressed by metformin.24,25 Furthermore, evidence revealed that metformin reduces androgen production in both men and women, so it could be considered as an alternative treatment in androgen-excess conditions.23,26,27 In addition, current evidence demonstrated that some hypoglycemic agents, such as metformin, had potential anti-inflammatory activities.28 All of these pharmacological mechanisms of metformin could be helpful in the management of acne vulgaris.TA B L E 1 Comparison of demographic variables and scores of patients with acne undergoing treatment with metformin or doxycycline.
The total number of lesions in the doxycycline and metformin groups decreased significantly by the end of the study.Although the mean percentage reduction in the number of these lesions was not significantly different between the two groups, the decrease in inflammatory lesions was significantly greater in the doxycycline group.The study by Gabaton et al. 29 showed that the mean reduction in the number of lesions was significantly more in patients receiving metformin rather than placebo as an adjunct to lymecycline and adapalene+benzoyl peroxide gel.Moreover, their study showed that metformin is safe and effective as an adjunct treatment in patients with acne vulgaris.
This study did have some limitations.First, this study was conducted with a small sample size, a short treatment duration, and a short follow-up.Therefore, further studies with a larger sample size are recommended.Moreover, our study was not double-blind, so the participants in both groups might share their information.Double-blind, randomized clinical trials are recommended to control biases.In addition, only one dermatologist assessed the treatment outcomes; future studies should include multiple dermatologists to decrease bias in outcome measurements by estimating inter-rater variability.Next, the evaluation of blood level sugar and insulin resistance, as well as the blood level of IGF-1, was not considered a primary or secondary outcome in this study, so we suggest rectifying this issue in future studies.Furthermore, the chronicity of acne was not considered a confounding factor that could affect the treatment results.Finally, because of the small sample size, this study could not be considered an equivalent clinical trial.Therefore, further studies are recommended in an equivalent clinical trial design.

| CON CLUS IONS
Our study indicates that both doxycycline and metformin are effective in reducing acne severity, increasing patients' satisfaction and quality of life, reducing the overall number of lesions, and reducing noninflammatory lesions in patients with acne vulgaris, and both drugs are well-tolerated, with only mild side effects.However, acne

CO N FLI C T O F I NTER E S T S TATEM ENT
Nothing to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available upon request from the corresponding author.The data are not publicly available due to privacy or ethical restriction.

E TH I C S S TATEM ENT
The protocol of this study was approved by the Ethics Committee SPSS software version 25 was used for the statistical analysis of data.The mean and standard deviation (SD) or median was used to describe quantitative variables.In addition, frequency and percentage were used to describe categorical variables.A chi-squared or Fisher's exact test was utilized to compare qualitative variables, while the independent sample t-test was used to compare quantitative variables.The general linear model and multiple measurement tests were used to compare quantitative variables at specified time intervals.Statistical significance was defined by a p-value of 0.05 or less.

F I G U R E 2
Comparison of the Global Acne Grading System (GAGS) score, Total Lesion Count (TLC) score, and inflammatory and noninflammatory lesion improvement between patients in the two groups based on the general linear model.vulgaris lesions of the inflammatory type appear to improve more with doxycycline than metformin.It is necessary to design further clinical trials with a larger sample and longer follow-up to carefully compare the efficacy of doxycycline and metformin and their probable side effects.AUTH O R CO NTR I B UTI O N S MSS, NY, and MMP designed the study.MSS, NY, RS, and RJ collected the data.MSS, NY, MMP, RS, and RJ drafted the manuscript.MMP, MSS, RS, and NY finalized the manuscript.All authors reviewed the manuscript and approved the final version.They take full responsibility for the content and writing of this article.ACK N OWLED G M ENTSThis article was extracted from the thesis written by Dr. Nazafarin Yazdanpanah as partial fulfillment of the requirements for obtaining their specialist degree in Dermatology from Shiraz University of Medical Sciences.We sincerely thank Shiraz University of Medical Sciences Vice-Chancellery of Research for providing financial support for this study(Grant No. 19958).This manuscript was reviewed in terms of language and grammar by a native English-speaking language editor, Dr. Seyed Ali Hosseini (Native Editor Co., Shiraz, Iran).FU N D I N G I N FO R M ATI O NThis study was financially supported by the Vice of Research of Shiraz University of Medical Sciences for financial support of this study(Grant No. 19958).