Clinical Care/Education/Nutrition ORIGINAL ARTICLE Efficacy, Tolerability, and Safety of a Novel Once-Daily Extended-Release Metformin in Patients With Type 2 Diabetes 1 3 SHERWYN SCHWARTZ, MD MARILOU CRAMER formin during 24 weeks of double-blind 2 3 VIVIAN FONSECA, MD, MRCP YU-KUN CHIANG, PHD treatment. When administered with food, 3 4 BRET BERNER, PHD ANDREW LEWIN, MD the extended-release metformin tablet gradually releases drug over 8 h into the upper gastrointestinal tract (4), where OBJECTIVE — The purpose of this study was to determine the efficacy and safety of a novel metformin is primarily absorbed (5). Pro- extended-release metformin in patients with type 2 diabetes. longed release of metformin from extend- ed-release metformin tablets has been RESEARCH DESIGN AND METHODS — Adults with type 2 diabetes (newly diag- demonstrated in pharmacokinetic studies nosed, treated with diet and exercise only, or previously treated with oral diabetic medications) (6,7). Extended-release metformin were randomly assigned to receive one of three extended-release metformin treatment regimens showed slightly lower maximum concen- (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial. trations, longer times to maximum con- centration (7–8 vs. 4–5 h), and similar Ͻ bioavailability compared with immedi- RESULTS — Significant decreases (P 0.001) in mean HbA1c (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups ate-release products (7). This extended given 1,500 mg extended-release metformin (Ϫ0.73 and Ϫ0.74%) were not significantly differ- release could potentially reduce dosing ent from the change in the immediate-release metformin group (Ϫ0.70%), whereas the frequency to once daily compared with 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (Ϫ1.06%; two or three times daily for immediate- mean difference [2,000 mg extended-release metformin Ϫ immediate-release metformin]: release formulations. Ϫ0.36 [98.4% CI Ϫ0.65 to Ϫ0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer RESEARCH DESIGN AND patients in the extended-release metformin groups discontinued treatment due to nausea during METHODS — A randomized, double- the initial dosing period than in the immediate-release metformin group. blind, active-controlled, fixed-dose, phase III clinical trial was conducted at 85 CONCLUSIONS — Once- or twice-daily extended-release metformin was as safe and effec- centers in the U.S. between August 2001 tive as twice-daily immediate-release metformin and provided continued glycemic control for up and October 2003. The study protocol to 24 weeks of treatment. was approved by institutional review boards, and the study was conducted in Diabetes Care 29:759–764, 2006 accordance with the International Con- ference on Harmonization Guidelines for etformin hydrochloride has been Diabetes Study, intensive glucose control Good Clinical Practice. Each patient pro- widely used as an effective and with metformin appeared to reduce the vided written informed consent before M generally well-tolerated glucose- risk of diabetes-related end points in undergoing any study procedures. lowering agent for Ͼ40 years and is the overweight patients and was associated The trial enrolled male and female most frequently prescribed first-line ther- with less weight gain and fewer hypogly- outpatients, 18–79 years of age, with type apy for patients with type 2 diabetes (1). cemic attacks than insulin (3). 2 diabetes. Patients were either drug naı¨ve Metformin typically reduces basal and The objective of this study was to (with newly diagnosed diabetes or treated postprandial hyperglycemia by ϳ25% in evaluate the efficacy, tolerability, and with diet and exercise only) or had re- Ͼ90% of patients when given alone or safety of a novel extended-release oral for- ceived prior drug therapy (monotherapy with other therapies during a program of mulation of metformin compared with with oral hypoglycemic agents other than managed care (2). In the U.K. Prospective conventional immediate-release met- metformin up to the maximum dose al- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● lowed, metformin monotherapy up to From 1Diabetes and Glandular Disease Research Associates, San Antonio, Texas; the 2Tulane University 2,000 mg/day, or metformin up to 1,500 Health Sciences Center, New Orleans, Louisiana; 3Depomed, Menlo Park, California; and the 4National mg/day with sulfonylurea up to one-half Research Institute, Los Angeles, California. the maximum allowed dose). Patients un- Address correspondence and reprint requests to Bret Berner, PhD, Depomed, 1360 O’Brien Dr., Menlo Park, CA 94025. E-mail: [email protected]. derwent a full physical examination in- Received for publication 13 October 2005 and accepted in revised form 9 January 2006. cluding an electrocardiogram before Abbreviations: FPG, fasting plasma glucose. enrollment. Inclusion criteria (deter- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion mined at the screening visit) included factors for many substances. HbA (A1C) levels 7.0–12.0% (drug- © 2006 by the American Diabetes Association. 1c The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby naı¨ve patients) or 6.5–10.0% (prior drug marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. therapy patients), fasting plasma glucose DIABETES CARE, VOLUME 29, NUMBER 4, APRIL 2006 759 Extended-release metformin for type 2 diabetes (FPG) levels 120–400 mg/dl (drug-naı¨ve efficacy (defined as fasting blood glucose to-treat population, and 529 patients patients) or 120–250 mg/dl (prior drug Ͼ250 mg/dl for 1 week or Ͼ300 mg/dl completed the study per protocol. The therapy patients), C-peptide levels Ͼ1.0 for 3 days) was also determined. Adverse most common reasons for discontinua- ng/ml, BMI 22–50 kg/m2, and a negative events were recorded throughout the tion were withdrawal of consent (63 pa- pregnancy test for female patients. Pa- study by direct questioning and observa- tients), lack of efficacy (40 patients), and tients were excluded from the study if tion of patients and from the results of loss to follow-up (21 patients). Reasons they were receiving insulin, systemic cor- physical examinations and clinical labo- for discontinuation were similar among ticosteroids, nicotinic acid, or isoniazid; ratory tests. treatment groups, except that fewer pa- had a history of background retinopathy, tients discontinued treatment due to lack symptomatic autonomic neuropathy, or Statistical methods of efficacy in the 2,000-mg extended- unstable angina; had chronic gastropare- Efficacy and safety analyses were per- release metformin group (1.8%) than in sis or chronic severe gastrointestinal formed using an intent-to-treat popula- the immediate-release metformin group symptoms, a history of gastric or duode- tion, defined as all randomly assigned (8.0%) (P ϭ 0.007). There were no sig- nal ulcers, abdominal surgery within 1 patients who received a study drug and nificant differences among treatment year, or active gastrointestinal disease had available efficacy data. The primary groups for demographic and baseline within 2 years; had any uncontrolled or efficacy parameter, mean change in A1C characteristics (Table 1). untreated cardiovascular, hepatic, pul- concentration from baseline to end point, monary, renal, or neurological system was analyzed using an ANCOVA parallel Efficacy results conditions; or had serum creatinine Ͼ1.5 model that included treatment, center, Significant (P Ͻ 0.001) reductions in mg/dl (male patients) or Ͼ1.4 mg/dl (fe- and stratification factor as fixed factors mean A1C concentrations were observed male patients) or proteinuria. and baseline A1C as a covariate. The least- by week 12 in all treatment groups. A1C Eligible patients were randomly as- squares estimate of the mean change from levels continued to decline until week 20 signed in a 1:1:1:1 ratio within each of baseline for each treatment and its 95% CI and were maintained for the duration of two stratification levels (metformin be- were calculated. A two-sided 98.4% CI of the study (Fig. 1). The mean changes in fore enrollment: yes or no) to receive the pairwise mean difference between A1C concentrations from baseline to end 1,500 mg extended-release metformin each extended-release metformin treat- point in all extended-release metformin q.d. (Glumetza; Depomed, Menlo Park, ment and immediate-release metformin groups were noninferior to those in the CA), 1,500 mg extended-release met- (extended-release metformin Ϫ immedi- immediate-release metformin group formin twice daily (500 mg in the morn- ate-release metformin) in mean change (mean differences for change from base- ing and 1,000 mg in the evening), 2,000 from baseline to end point for A1C levels line in A1C levels [extended-release met- mg extended-release metformin q.d., or was constructed. The three extended- formin Ϫ immediate-release metformin]: 1,500 mg immediate-release metformin release metformin treatment groups were Ϫ0.03 [98.4% CI Ϫ0.32 to 0.26], Ϫ0.04 twice daily (Glucophage; Bristol-Myers each considered noninferior to immedi- [Ϫ0.33 to 0.25], and Ϫ0.36 [Ϫ0.65 to Squibb, Princeton, NJ) (500 mg in the ate-release metformin treatment if the up- Ϫ0.06] for the 1,500-mg q.d., 1,500-mg morning and 1,000 mg in the evening), per boundary of this 98.4% CI was not morning and evening, and 2,000-mg q.d.