Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: Differences in the efficacy and safety of antidiabetic drugs among different ethnic groups are well documented. Metformin is widely used in the treatment of type 2 diabetes in Western countries, but high doses of metformin have been approved only recently for clinical use in Japan. The aim of the present study was to investigate the effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients. MATERIALS AND METHODS: A total of 71 Japanese patients with type 2 diabetes were prospectively studied for the effects of dosage and dosing frequency on the efficacy and safety of metformin during hospitalization. Dose effects were studied in 27 patients treated with 0, 500, 1,000, 1,500 and 2,250 mg/day of metformin. The effect of dosing frequency was compared in 56 patients with 1,500 mg/day of metformin administered either two or three times per day. RESULTS: Significant dose-dependent improvement in daily profiles of blood glucose was observed with metformin dosages up to 1,500 mg/day, with a trend towards further improvement observed at 2,250 mg/day. The efficacy of 1,500 mg of metformin was comparable when the drug was administered either two or three times per day. The most frequently reported side-effects were gastrointestinal symptoms, which were not affected by the dosage or dosing frequency of metformin. CONCLUSIONS: These results show that the efficacy of high-dose metformin is dose-dependent in Japanese patients. The efficacy and safety of metformin were similar when the drug was administered either two or three times per day.

Common phenotype and different non-HLA genes in Graves' disease and alopecia areata.

Our previous observations clarified that Graves' disease (GD) is the most frequent autoimmune disease in patients with alopecia areata (AA), and 42.7% of patients with AA were positive for thyrotropin receptor antibody (TRAb). A class II HLA haplotype DRB1∗15:01-DQB1∗06:02 was suggested to contribute to autoimmunity against the thyroid gland in AA. To further clarify the genetic factors contributing to organ specificity in autoimmune diseases, we studied the contribution of non-HLA genes to organ specificity in GD and AA. A high frequency of AA (13.4%) was observed in patients with GD, indicating strong phenotypic association between GD and AA. CTLA4 and TSHR were significantly associated with GD (Pc=0.007 and Pc<0.002, respectively), but not with AA, even in TRAb-positive patients. The difference in the association between GD and AA suggests that the CTLA4 and TSHR are not main factors contributing to determining common genetic basis among GD and AA.

Organ specificity in autoimmune diseases: thyroid and islet autoimmunity in alopecia areata.

CONTEXT: Multiple autoimmune diseases, such as autoimmunity against the thyroid gland and pancreatic islets, are often observed in a single patient. Although alopecia areata (AA) is one of the most frequent organ-specific autoimmune diseases, the association of AA with other autoimmune diseases and the genetic basis of the association remain to be analyzed. OBJECTIVE: The aim of this study was to clarify the similarities and differences in HLA and clinical characteristics of thyroid and islet autoimmunity in patients with AA. PARTICIPANTS: A total of 126 patients with AA were newly recruited. Anti-islet and antithyroid autoantibodies were tested, and genotypes of HLA genes were determined. RESULTS: Among the autoimmune diseases associated with AA, autoimmune thyroid disease was most frequent (10.0%), followed by vitiligo (2.7%) and rheumatoid arthritis (0.9%) but not type 1 diabetes (0.0%). The prevalence of thyroid-related autoantibodies in patients with AA was significantly higher than that in controls (TSH receptor antibody [TRAb]: 42.7% vs 1.2%, P = 1.6 × 10(-46); thyroid peroxidase antibody: 29.1% vs 11.6%; P = 1.7 × 10(-6)), whereas the prevalence of islet-related autoantibodies was comparable between patients with AA and control subjects. The frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, was significantly higher in TRAb-positive (12.8%, P = .0028, corrected P value [Pc] = .02) but not TRAb-negative (7.1%, not significant) patients with AA than in control subjects (4.5%). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, was significantly lower in patients with AA (TRAb-positive: 8.5%; TRAb-negative: 11.9%) than in those with type 1 diabetes (29.5%, Pc < .0003 and Pc < .0008, respectively). CONCLUSION: AA was associated with thyroid autoimmunity but not islet autoimmunity, which correlated with class II HLA haplotypes susceptible or resistant to each autoimmune disease.