https://imcjms.com Ibrahim Medical College Journal of Medical Science https://imcjms.com/registration/journal_full_text/91 Mon, 26 Sep 2016 09:36:36 +0000 Abstract Methodology and Results: This prospective, controlled trial was conducted in Dermatology OPD of BIRDEM General Hospital, Dhaka from September 2012 to August 2013. All the participants of the study had clinical presentation of AN on different anatomic locations such as neck, axilla, elbow, knuckle and knee and biochemical evidence of IR. Participants were of either sex with age ranging from 18 to 80 years. Any case who had contraindications to metformin therapy were excluded. Severity of AN was examined and assessed by a quantitative scale for measuring acanthosis nigricans. After detecting IR by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), cases and controls were selected by random sampling method. Randomization was done for metformin in ratio of 2:1. Every third patient was a control. Forty study participants were assigned to receive tablet metformin 500mg thrice daily after meal for three months and twenty control participants were continued on their existing therapy. To maintain a static metabolic status, patients were allowed to remain with their previous diet and lifestyle habit. After 3 months of metformin therapy, improvement was assessed and was compared with control group. Conclusion: Metformin therapy for AN with IR had a significant beneficial effect clinically and was safe and well-tolerated. The effect was more pronounced in neck and axilla.   IMC J Med Sci 2016; 10(1): 18-23. DOI: https://doi.org/10.3329/imcjms.v10i1.31101 Address for Correspondence: Dr. Tahmina Akter, Medical Officer, Department of Dermatology and Venereology, BIRDEM General Hospital, 122 Kazi Nazrul Islam Avenue, Shahbag, Dhaka E-mail: rimjhimborsha@yahoo.com   Introduction Metformin is abundantly used in insulin resistant cases [13,14]. It may have some effects on AN by reducing IR and thus ultimately may reduce clinical manifestations of AN [15-17]. This randomized prospective controlled trial was conducted in the Department of Dermatology of Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Shahbag, Dhaka from September, 2012 to August, 2013. One hundred adult cases with clinical presentation of AN on neck and axilla with or without involvement of knuckles, elbows and knees and with the biochemical evidence of IR were primarily selected. Out of which, sixty patients consented to participate in the study. Patients with AN due to causes other than IR namely impaired renal or liver function and pregnant and nursing mothers were excluded. Interview was conducted at a suitable time and place that was convenient to the responder.   Scoring of AN and determination of IR The approximating equation for IR, in the early model, used a fasting plasma sample and was derived by use of the insulin-glucose product, divided by a constant:  HOMA-IR= Glucose x Insulin x 1/22.5(Glucose in mmol/L)  Our cut-off value of having IR in HOMA-IR was 1.82 [19].  Randomization of cases Data were expressed as mean and standard deviation. Paired Student’s t test was done for analysis of variables and Fisher’s Exact test was used to test for differences in proportions for categorical variables. A p value of <0.05 was considered as significant. The International Business Machines Corporation- Statistical Package for the Social Sciences (IBM-SPSS) version 20.0 software was used to analyze the data. Among the sixty participants, forty were in study group and twenty were in control group. Mean age of male: 19.75±2.36 and female: 26.58± 9.38, M:F= 1:14 (M 6.66%, F 93.33%), Body Mass Index (BMI) of male: 32.15 ± 4.15 and female:33.18 ± 8.05. History of gestational diabetes mellitus: 11.76%, family history of diabetes mellitus and/ or hypertension: 88.33%, hirsuitism: 46.55 % and menstrual irregularity: 46.55%. There was no significant difference between study and control groups in case of age, BMI and HOMA-IR levels. Baseline characteristics of the all participants are shown in Table-1.   Table-1: Baseline characteristics of the participants   Variables Mean score ± SD t-test Sig. Study group Control group Age 26.15±10.10 26.1±7.42 -0.02 0.98 BMI   34.45±8.55 30.43±5.41 -1.91 0.06 HOMA-IR*    9.41±8.63 6.34±2.38 -1.55 0.12 Sex (M/F)           3 / 37 1 / 19       *Cut-off value of having insulin-resistance in HOMA-IR was 1.82 [18].   After 3 months treatment with metformin, significant improvement (P< 0.005) of AN was observed clinically on neck and axilla compared to controls. Improvement rates with metformin in case of neck severity, neck texture and axilla were estimated as 67.5%, 62.2% and 70% consequently. However, regarding AN on knuckles, elbows and knees, the improvement rates with metformin were respectively 25%, 29.16% and 37.5% which were not significant. On the other hand, improvement rates of neck severity, neck texture and axilla among cases of control group was11.11%. Improvement rates in cases of control group of elbow, knee and knuckle were 14.28%, 16.66% and 0% respectively. No side-effect except nausea in four subjects was reported during study period.   Table-2: Improvement rates of AN on different anatomic locations   Severity / Presence of AN   Improved (%) Not Improved (%) P value Neck Severity (n= 60) Control (n=20) 11.11 88.89   Drug  (n=40 ) 67.5 32.5 <0.005 Neck Texture (n=60 ) Control (n=20) 11.11 88.89   Drug (n=40 ) 62.2 37.8 <0.005 Axilla (n=60 ) Control (n=20) 11.11 88.89   Drug (n= 40 ) 70.0 30.0 <0.005 Elbow (n=31 ) Control (n=7) 14.28 85.72   Drug (n=24) 29.16 70.84 >0.05 Knee (n=30 ) Control (n=6) 16.66 83.34   Drug (n=24 ) 37.50 62.50 >0.05 Knuckle (n=27 ) Control (n=7) 00.00 100.00   Drug (n=20 ) 25.00 75.00 >0.05     Table-3: Improvement of AN in different sites following metformin treatment as determined by quantitative scale of measuring AN   This study demonstrates that metformin therapy for AN with IR has a significant beneficial effect and is also safe and well tolerated. Improvement was assessed by reduction of score as measured by the quantitative scaling method scale [18] and vice versa. The study also reveals that metformin has different clinical effects on AN in different anatomic location. It seems that its effect is more pronounced in AN affecting axilla and neck. It could be due to the presence of more insulin-like growth factor 1 receptors in these specific sites. But further specific study is needed to elucidate its mechanism in these sites. Correcting hyperinsulinemia was presumably accomplished by metformin and led to improvement or resolution of AN. Oral metformin hydrochloride is a first choice drug in the treatment of AN associated to obesity and IR [1]. Metformin does not induce hypoglycemia but prevents hyperglycemia. In IR, hyperinsulinemia precedes type 2 diabetes mellitus sometimes by many years. AN develops during this non-diabetic hyperinsulinemic period. Thus, recognition of AN identifies those at increased risk of developing type 2 diabetes mellitus, dyslipidemia and hypertension. Therefore, recognition of AN offers an opportunity for both preventive measures and focused intervention. The present study had some limitations. The sample size was small and the long-term effects of metformin on the outcome of AN could not be assessed. The diagnostic and scoring criteria used in the study was based solely on direct visual examination. No histopathological scoring or grading technique of AN was available. Study was precisely directed to AN associated with biochemical evidence of IR and AN due to other causes was not included. This research was funded by Aristopharma Ltd. We express our acknowledgement to Dr. Shahidul Alam Khan, PhD, Chief Research Officer and Head, Dept. of Endocrinology and Immunology, BIRDEM, for overall guidance and support for performing laboratory works; Dr. Md. 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