In the Journals

High-dose metformin safe, effective in Japanese adults with type 2 diabetes

In Japanese adults with poorly controlled type 2 diabetes, high doses of metformin administered twice or three times daily improved fasting plasma glucose and 24-hour glycemic profile in a dose-dependent fashion, according to findings reported in the Journal of Diabetes Investigation.

“While the usual dosage of metformin is over 2,000 mg per day in Europe and the USA, the maximum dose allowed for clinical use in Japan has long been limited to 750 mg per day, which is less than half that of Western countries,” Hiroshi Ikegami, MD, PhD, of the department of endocrinology, metabolism and diabetes at Kindai University in Osaka, Japan, and colleagues wrote. “In addition, the recommended prescription of the maximum dose of metformin in Japan (750 mg per day) has been via 250-mg tablets administered three times per day. ... These differences in dosage and dosing frequency of metformin between Japan and Western countries have made it difficult to translate the results of clinical trials in Western countries to Japanese patients.”

In two prospective studies, Ikegami and colleagues analyzed data from 71 Japanese patients with type 2 diabetes recruited between August 2011 and October 2016 from Kindai University Hospital (39 men; mean age, 61 years; mean BMI, 27 kg/m²; mean diabetes duration, 8.4 years; mean FPG, 7.5 mmol/L). All patients were provided standard meals recommended by the Japan Diabetes Society, and treatment with metformin was not initiated until patient FPG reached 11 mmol/L or less, to minimize the confounding effect of an initial improvement in glycemic control due to hospitalization. In the total cohort, 14 patients were treated with metformin monotherapy, whereas 54 patients were prescribed metformin as an add-on therapy to other antidiabetes medications.

For the first study, researchers assessed the effect of increasing metformin doses on glycemic control in 27 patients, administered twice daily after breakfast and dinner for all doses up to 1,500 mg per day. A subset of these patients who did not reach optimal glycemic control (n = 11) were treated with a maximum dose of 2,250 mg per day.

For the second study, researchers examined the effect of dosing frequency on the efficacy and safety of high-dose metformin in 56 patients treated with 1,500 mg daily. In this group, the patients were treated with 500 mg metformin three times per day and then switched to 750 mg twice daily, or the same protocol in reverse order. In both the first and second studies, daily profiles of 9-point blood glucose were monitored before and 2 hours after meals, at bedtime, midnight and 3 a.m.

Researchers observed decreases in blood glucose with increasing doses of metformin. Area under the curve for the 9-point daily blood glucose profiles also decreased with increasing metformin dose, according to researchers, up to the 1,500 mg per day dosage, but tended to decrease with further increases in metformin to 2,250 mg per day. The dose-dependent improvements were observed in both the metformin monotherapy subgroup and among those using metformin as an add-on therapy with and without insulin.

In assessing dosing frequency, researchers observed a slightly higher blood glucose level before dinner in the twice-daily metformin group vs. the three times daily group (6.9 mmol/L vs. 6.3 mmol/L; P = .02).

The most common adverse events reported were gastrointestinal symptoms observed in 29.6% of patients in study 1 and 30.3% of patients in study 2. No serious adverse events occurred during the studies.

The researchers noted that hospitalization of patients may have influenced initial improvement, and that the sample size for the highest dose of metformin was small, which may account for the lack of difference between the 1,500-mg and 2,250-mg doses.

“Further studies with larger numbers of participants are needed to clarify this point,” the researchers wrote. – by Regina Schaffer

Disclosure: One study author reports he has received clinical research grants from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Johnson & Johnson, Kowa, Kyowa Hakko-Kirin, Novo Nordisk, Ono, Otsuka, Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma, Takeda and Tanabe Mitsubishi; and has received lecture honoraria from Kowa, Novo Nordisk and Sumitomo Dainippon Pharma.

In Japanese adults with poorly controlled type 2 diabetes, high doses of metformin administered twice or three times daily improved fasting plasma glucose and 24-hour glycemic profile in a dose-dependent fashion, according to findings reported in the Journal of Diabetes Investigation.

“While the usual dosage of metformin is over 2,000 mg per day in Europe and the USA, the maximum dose allowed for clinical use in Japan has long been limited to 750 mg per day, which is less than half that of Western countries,” Hiroshi Ikegami, MD, PhD, of the department of endocrinology, metabolism and diabetes at Kindai University in Osaka, Japan, and colleagues wrote. “In addition, the recommended prescription of the maximum dose of metformin in Japan (750 mg per day) has been via 250-mg tablets administered three times per day. ... These differences in dosage and dosing frequency of metformin between Japan and Western countries have made it difficult to translate the results of clinical trials in Western countries to Japanese patients.”

In two prospective studies, Ikegami and colleagues analyzed data from 71 Japanese patients with type 2 diabetes recruited between August 2011 and October 2016 from Kindai University Hospital (39 men; mean age, 61 years; mean BMI, 27 kg/m²; mean diabetes duration, 8.4 years; mean FPG, 7.5 mmol/L). All patients were provided standard meals recommended by the Japan Diabetes Society, and treatment with metformin was not initiated until patient FPG reached 11 mmol/L or less, to minimize the confounding effect of an initial improvement in glycemic control due to hospitalization. In the total cohort, 14 patients were treated with metformin monotherapy, whereas 54 patients were prescribed metformin as an add-on therapy to other antidiabetes medications.

For the first study, researchers assessed the effect of increasing metformin doses on glycemic control in 27 patients, administered twice daily after breakfast and dinner for all doses up to 1,500 mg per day. A subset of these patients who did not reach optimal glycemic control (n = 11) were treated with a maximum dose of 2,250 mg per day.

For the second study, researchers examined the effect of dosing frequency on the efficacy and safety of high-dose metformin in 56 patients treated with 1,500 mg daily. In this group, the patients were treated with 500 mg metformin three times per day and then switched to 750 mg twice daily, or the same protocol in reverse order. In both the first and second studies, daily profiles of 9-point blood glucose were monitored before and 2 hours after meals, at bedtime, midnight and 3 a.m.

Researchers observed decreases in blood glucose with increasing doses of metformin. Area under the curve for the 9-point daily blood glucose profiles also decreased with increasing metformin dose, according to researchers, up to the 1,500 mg per day dosage, but tended to decrease with further increases in metformin to 2,250 mg per day. The dose-dependent improvements were observed in both the metformin monotherapy subgroup and among those using metformin as an add-on therapy with and without insulin.

In assessing dosing frequency, researchers observed a slightly higher blood glucose level before dinner in the twice-daily metformin group vs. the three times daily group (6.9 mmol/L vs. 6.3 mmol/L; P = .02).

The most common adverse events reported were gastrointestinal symptoms observed in 29.6% of patients in study 1 and 30.3% of patients in study 2. No serious adverse events occurred during the studies.

The researchers noted that hospitalization of patients may have influenced initial improvement, and that the sample size for the highest dose of metformin was small, which may account for the lack of difference between the 1,500-mg and 2,250-mg doses.

“Further studies with larger numbers of participants are needed to clarify this point,” the researchers wrote. – by Regina Schaffer

Disclosure: One study author reports he has received clinical research grants from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Johnson & Johnson, Kowa, Kyowa Hakko-Kirin, Novo Nordisk, Ono, Otsuka, Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma, Takeda and Tanabe Mitsubishi; and has received lecture honoraria from Kowa, Novo Nordisk and Sumitomo Dainippon Pharma.