Comparison of Treatment Persistence with Two Formulations of Metformin
Hankin C1, Berner B
2, Wu J
2, Bronstone A
1, Wang Z
(1) BioMedEcon, LLC, South San Francisco, CA, (2) Depomed, Inc., Menlo Park, CA
Evidence shows that tight glycemic control mitigates the adverse microvascular and
We sought to answer the following questions:
macrovascular effects of diabetes. Metformin, an oral anti-hyperglycemic agent, is commonly
% of Patients Achieving ADA Target A1C (< 7%)
prescribed as first-line treatment for type 2 diabetes. Despite metformin's demonstrated efficacy,
• Are there differences in persistence rates associated with immediate-release metformin
low rates of treatment persistence (the proportion of patients remaining on medication for a period
(MIR) versus a novel extended-release metformin (MER) formulation?
of time) are typical among diabetes patients.1 We examined persistence rates associated with
immediate-release metformin (MIR) versus a novel extended-release metformin (MER)
• If there are differences in persistence, do these differences affect A1C outcomes?
formulation designed to improve tolerability and efficacy.
The study was a phase III, 24-week, randomized, double-blind, active-controlled, fixed-
dose trial comparing MIR 1500 mg/day, b.i.d. (MIR-1500B) versus MER at three doses [1,500
mg/day q.d. (MER-1500Q), 1,500 mg/day b.i.d. (MER-1500B), or 2,000 mg/day q.d. (MER-
This was a multicenter, randomized, double-blind (double-dummy), active-controlled, dose-
2000Q)]. Participants were adults with type 2 diabetes who were medication naïve or received
ranging, non-inferiority, parallel-group clinical study designed to compare the efficacy and safety
prior oral hypoglycemic monotherapy. Titration to study dose was achieved over 3 weeks.
of a novel metformin extended-release (MER) formulation at doses of 1500 once daily
Analyses were conducted using a modified intent-to-treat (ITT) approach, whereby participants
target A1C <
(MER1500Q), 500 mg in the morning and 1000 mg in the evening (MER1500 B), and 2000 once
A1C < 7% *
who completed the study titration phase, received one week of study dose, and had at least one
daily (MER 2000Q), to immediate-release metformin 500 mg in the morning and 1000 mg in the
A1C follow-up from baseline were included. Reasons for study withdrawal (initiated by
investigator or patient) included lack of efficacy, serious or non-serious adverse events, death,
Med cal Ch
cal C aracter
patient desire to withdraw, patient noncompliance with protocol, and lost to follow-up. Patients
The MIR dosage was chosen because it is the most commonly used dosage of metformin and is
who prematurely terminated for any reason were defined as non-persistent; those who were
accepted as being safe and effective with a tolerable side effect profile. The MIR dose regimen
* p = 0.0096
titrated to the full study dose and completed the study through week 24 were considered to be
used was as described in the product insert.
* ITT=Intent to Treat, LOCF = Last observation carried forward
Source: Data on File, Trial 003, Depomed, Inc.
The MER1500Q and MER 1500B dosages were chosen to examine the possible advantages of
The ITT analysis included 647 participants with a mean baseline A1C of 8.3% (SD 1.5).
once-daily vs. twice-daily doses of MER at a comparable dose to that of the control group. The
Treatment groups had similar demographics and disease-related characteristics at baseline.
MER2000Q dose was designed to compare the safety and efficacy of this higher dosage to the
Patients who received MER-2000Q were approximately half as likely to prematurely terminate
Premature Termination by Metformin Treatment Group
from the study as those receiving MIR-1500B (Odds Ratio: 0.52, 95% CI 0.28 to 0.96, p=0.04). Patients receiving MER-2000Q had a lower rate of withdrawal due to lack of efficacy (1.8%)
We report persistency and efficacy results of the highest MER dose (MER 2000Q) versus the MIR
Significantly fewer subjects in the MER
• Superior efficacy, as demonstrated by a significantly greater
compared with those receiving MIR-1500B (9.9%, NS) and MER-1500Q (11.4%, p=0.03). Groups
2000Q group dropped out due to
percentage of patients achieving A1C at the ADA target of < 7%, was
were similar with respect to the number, type, and severity of adverse events.
adverse events or lack of treatment
Participants were adults with type 2 diabetes who were drug naïve or previously treated with anti-
efficacy (5.3% vs 13.8%, p=0.007).
Higher treatment persistence is associated with better glycemic control and lower
Dropouts Due to AEs or Lack of Efficacy
• The higher dose of MER 2000Q appears to have been well tolerated.
healthcare costs.2 Persistence rates were two times higher with extended-release versus
immediate-release metformin, possibly due to enhanced tolerability and/or efficacy associated
• Persistence rates were two times higher with extended-release versus
with the maximum Glumetza 2000 mg QD dose.
Figure 1. Study Design
immediate-release metformin, possibly due to enhanced tolerability and/or efficacy associated with higher dose.
Diabetes mellitus is a metabolic disorder characterized by the presence of chronic hyperglycemia
(high blood glucose) due to defects in insulin secretion, insulin action, or both. Type 2 diabetes,
Cramer JA. A systematic review of adherence with medications for diabetes. Diabetes Care
which accounts for 90-95% of all diabetes cases, occurs in response to impaired insulin secretion,
insulin resistance, or excessive hepatic glucose production. Risk factors include obesity and
Stephens JM, Botteman MF, Hay JW. Economic impact of antidiabetic medications and glycemic control
on managed care organizations: a review of the literature. J Manag Care Pharm 2006;12(2):130-42.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or
and macrovascular complications, including retinopathy, neuropathy,
insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes
nephropathy, and cardiovascular disease, may be mitigated by intensive glycemic control.3-5
(UKPDS 33). Lancet 1998;352(9131):837-53.
Source: Data on File, Trial 003, Depomed, Inc.
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on
the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J
The glycosylated hemoglobin (A1C) laboratory test provides a long-term (3 to 4 month) measure
of average glycemic control and predicts the risk for diabetes-related microvascular and
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1
diabetes. N Engl J Med 2005;353(25):2643-53.
Patients who received MER 2000Q were approximately half as likely to
A consensus algorithm recently set forth by the American Diabetes Association (ADA) and the
Nathan DM, Buse JB, Davidson MB, et al. Management of Hyperglycemia in type 2 diabetes: A
prematurely terminate from the study as those receiving MIR 1500B.
European Association for the Study of Diabetes (EASD) recommends lifestyle changes with
consensus algorithm for the initiation and adjustment of therapy . A consensus statement from the
American Diabetes Association and European Association for the Study of Diabetes. Diabetes Care
metformin medication as the first step to intensive control of type 2 diabetes.6
Odds Ratio=0.522 95% CI = 0.283 to 0.964, p=0.0299
PRESENTED AT THE 28th ANNUAL MEETING OF THE SOCIETY FOR MEDICAL DECISION MAKING, CAMBRIDGE, MA, OCTOBER 14-18, 2006.
Benoit Petit-Demouliere . Franck Chenu . Michel BourinForced swimming test in mice: a review of antidepressant activityReceived: 11 June 2004 / Accepted: 21 September 2004 / Published online: 18 November 2004forced swimming test (FST) remains one of the most usedtools for screening antidepressants. Objective: This paperreviews some of the main aspects of the FST in mice. Mostof the sensitivi
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