Three different regimens of a new extended-release version of metformin, including two once-a-day regimens, were as effective as immediate-release metformin in reducing hemoglobin A1c levels in adults with type 2 diabetes, Dr. Sherwyn Schwartz reported.
A double-blind, phase III trial randomized 750 patients to 24 weeks of treatment, and 706 patients with efficacy data were included in an intent-to-treat analysis. Patients on antihyperglycemic agents stopped the medications for 6 weeks before all patients began metformin at 1,000 mg once daily. Treatment was titrated over 2–3 weeks to assigned regimens of immediate-release metformin (Glucophage) at 1,500 mg/day b.i.d., or extended-release metformin (Glumetza) in dosages of once-daily 1,500 mg/day, the same dose but b.i.d., or once-daily 2,000 mg/day.
All groups showed significant reductions in hemoglobin A1c (HbA1c) levels by week 12. Levels continued declining until week 20, and were maintained until the end of the study at week 24, said Dr. Schwartz, an endocrinologist in a group practice in San Antonio, and his associates (Diabetes Care 2006;29:759–64). The study was funded by Depomed Inc., which makes Glumetza.
The reductions in mean HbA1c levels were similar to results from clinical trials of Glucophage and of another extended-release metformin product (Glucophage XR, by Bristol-Myers Squibb). Glumetza is the first extended-release metformin formulation, however, to show equal efficacy in daily or twice-daily dosing, Dr. Schwartz said.
Among secondary end points in the current study, all treatment groups significantly reduced fasting plasma glucose concentrations to a comparable extent. Mean fructosamine levels declined in all groups, with a significantly greater drop in the 2,000-mg group.
In the trial, 529 patients who completed the protocol switched to the once-daily 2,000-mg dose of Glumetza in an open-label extension study. The decreases in HbA1c from the randomized trial were maintained in the 24-week extension study.
Each of the Glumetza regimens in the randomized trial produced greater decreases in HbA1c than did Glucophage in several subgroups: in women, in patients 65 years or older, in non-Caucasians, and in patients with a body mass index (kg/
Other studies have reported that the effects of metformin monotherapy are independent of age, ethnicity, and body weight. “Our results indicate that the 2,000-mg/day dose may be more effective in some patient populations,” Dr. Schwartz said.
There was a trend for triglyceride levels to increase slightly in patients on Glumetza (similar to trends in previous trials of extended-release metformin formulations), an effect not seen with Glucophage. The reason for this and its clinical significance are unclear.
Metformin is known to cause gastrointestinal side effects, including abdominal discomfort, nausea, and diarrhea. The overall incidence of adverse events was similar between groups. Patients in the Glumetza groups were less likely to report nausea during the first week of treatment. There was no increase in adverse events seen in the 2,000-mg/day Glumetza group.
Patients in the twice-daily drug regimen groups took 500 mg in the morning and 1,000 mg in the evening. All study drugs and placebo pills were taken after a meal.
Reasons for those who stopped treatment were similar between groups, except that fewer patients in the Glumetza 2,000-mg group stopped because of lack of efficacy compared with the Glucophage group (2% vs. 8%). Reasons included withdrawal of consent, lack of efficacy, and loss to follow-up.