Download A Placebo-Controlled, Randomized Study

A Placebo-Controlled, Randomized Study
of Glimepiride in Patients with Type 2 Diabetes
Mellitus for Whom Diet Therapy
is Unsuccessful
David S. Schade, MD, Lois Jovanovic,MD, and fill Schneider. MD
This multicenter, randomized, placebo-controlled study of
glimepiride, a -new oral sulfonylurea, was conducted in
patients with-type 2 diabete, for whom dietary treatment
was unsuccessful (fasting plasma - glucose [FPG] = 151300 mg/dL) during a 1-week screening period. Patients
were randomized to receive glimepiride (n = 123) or placebo (n = 126) once daily for a 10-week dose-titration
period, then maintained on an individually determined
optimal dose (1-8 mg of glimepiride or placebo) for 12
weeks. Glimepiride lowered FPG by 46 mg/dL, hemoglobin
A1c(HbA1c) by 1.4%, and 2-hour postprandial glucose by 72
mg/dL more than placebo. Glimepiride improved post-
prandial insulin and C-peptide responses without produc
ing clinically meaningful increases in fasting insulin
C-peptide levels. Good glycemic control (HbA1c  7.2% was
achieved by 69% of the patients taking glimepiride versus
32% of those taking placebo. The overall incidence of
adverse events was similar in both groups. No clinical
noteworthy abnormal laboratory values or hypoglycemia
(blood glucose < 60 mg/dL] occurred. Glimepiride is safe
and effective for treatment of patients with type 2 diabetes
for whom diet therapy is unsuccessful.
Journal of Clinical Pharmacology. 1998:38:636-641
©1998 The American College of Clinical Pharmacology.
2 diabetes accounts for more than 80% of
Type
thediabetes in Europe and North America. Al-
completely and rapidly absorbed and metabolized
entirely to two major metabolites, neither of which
exhibits significant biologic activity. Like other sul
fonylureas, glimepiride appears to lower blood glu
cose by stimulating the release of insulin through
inhibition of pancreatic -cell ATP-regulated
K+channels.4-6
The hypoglycemic effects of glimepiride also may
involve extrapancreatic processes.7-8 In ani mal
studies and in clinical trials in patients with type
2 diabetes, glimepiride has been shown to be a potent
blood glucose-lowering agent.9-12 Pharmacokinetic
studies have shown glimepiride to have a terminal
half-life -of- 9 -hours which suitable for once daily
administration (Hoechts Marion Roussel, data on
file). A placebo-controlled clinical trial comparing
once- and twice-daily age regimens of glimepiride
(with total doses of and 16 mg/day) showed that
maximum effectiveness can be obtained with 8-mg,
once-daily dose of glimepiride.11
A-14-week, placebo-controlled trial by Goldberg
et.al.12 showed a dose response for the gylcemic
level of patients with type 2 diabetes given 1, 4,
or 8 mg of glimepiride
once
daily, with
significanty greater reductions from baseline
compared
with
placebo for all doses of
glimepiride. Treatment was proceded by
1
though diet is the cornerstone of therapy for type 2
diabetes, many patients are unable to control diabetes
by diet alone. Sulfonylureas, which stimulate -cell
insulin release, have been used since 1955 to
supplement dietary therapy in patients with type 2
diabetes.2 These agents act directly by means of highaffinity -cell receptors and indirectly by pro-moting
target-cell sensitivity to glucose.3 _
Glimepiride is a new oral sulfonylurea developed
as a result of the search for agents with potential
therapeutic advantages over the second generation
agents. Glimepiride is l-[[p-[2-(3-ethyl-4-methyl2-oxo-3 pyrroline 1 carboxamido) ethyl]-4
sulfonyl]-3(trans-4-methylcyclohexyl urea. The
drug is
From the Department of Internal Medicine/Endocrinology University- of New
Mexico, Albuquerque, New Mexico (Dr. Schade), Sansum Medical Research
Foundation, Santa Barbara, California (Dr Jovanovic), and Hoechst Mario
Roussel, Somerville New Jersey (Dr, Schneder) This study was funded by
a research grant from Hoechst Marion Roussel. Submitted for publication
December 1, 1997, accepted in revised form March 19,l998. Address for
reprints: David S.Schade,MD, university of New Mexico School of Medicine,
Department of Internal Medicine/ Endocrinology, #5ACC, 2211 Lomas
Boulevard NE, Albuquerque, NM 87131.
636 • J Clin Pharmacol 1998;38:636-641
GLIMEPIRIDE IN PATIENTS WITH TYPE-21_DlA-BETES-MELLITUS
a 3-week washout period for patients who had previously received sulfonylurea agents.
This study was undertaken to assess the efficacy
and safety of individually titrated once-daily doses
of glimepiride between 1 and 8 mg that would be
optimal for the treatment of patients with type 2
diabetes-whose plasma glucose concentrations cannot be controlled by diet alone. In contrast to the
Goldberg study, patients eligible for this study had.
not been
treated with an oral antidiabetic drug or
insulin for at least the previous 6 months.
PATIENTS AND METHODS
Study Design
Glimepiride therapy was evaluated in a multicenter (25
s i t e in the United States), randomized, placebocontrolled, parallel-group, double-blind, dose-titra-tion
study that consisted of a 10-week titration phase
followed by a 12-week maintenance period in patients with type 2 diabetes. All participants signed
informed consent forms, which were approved by
the institutional review boards at each study site.
Patients were treated by diet alone during a lweek
screening period. Dietary treatment was
considered to be unsuccessful in those with fasting
plasma glucose (FPG) between 151 and 300 mg/dL on
days -7 and -1; these patients then were ran-domized
to receive either glimepiride or placebo.
Initial once-daily doses of 1 mg of assigned study
drug were adjusted upward based on FPG levels (to
a maximum once-daily dose of 8 mg glimepiride or
matching placebo) at 2-week intervals until an optimal dose was established (FPG between approximately 90 and 150 mg/dL). If clinically indicated,
glimepiride doses could be reduced. Daily titration
doses were 1, 2, 3, 4, 6, or 8 mg of glimepiride or
matching placebo. After a 10-week titration period
during which the optimal dose for each patient was
determined, patients were maintained on that dose for
the remaining12 weeks of the study.
Patients were excluded from the study if any of the
following occurred : symptoms of significant hypoglycemia that could not be controlled by decreasing the
dosage of study medication; hyperglycemia (FPG >300
mg/dL) at the maximum dose on two success-sive
visits within 1 week; any severe or unexpected
adverse reaction; or any condition or illness that
affected study results.
Patient Population
Eligible patients were 30 to 75 years of age with a body
weight between 90% and 150% of ideal as specified by
the Metropolitan Life Insurance tables. In addition,
those eligible either: 1) did not have a
history of previous-treatment with an oral
antidia-hetic agent or with insulin or 2) had been
treated with either agent for 1 year or less-but had
not been treated within the preceding 6 months.
Grounds for exclusion included: diabetes other
than type 2-diabetes or a history of ketoacidosis;
evidence of hepatic or renal disease: a suspected allergy
or hypersensitivity to sulfonylureas;concurrent
therapy with drugs that might potentiate the
hypoglycemic action of sulfonylureas (unless the
patient was stabilized on a dose for 2 months
before randomization): a history of poor
compliance with drug or diet therapy; or use of an
investigational drug within 2 weeks of enrollment
into the prerandom-ization phase of this study. In
addition, nursing or pregnant women and women of
childbearihg poten-tial using a contraceptive other
than an IUD or. cer-vical cap were excluded.
A total of 249 patients were treated. 123 with
glimepiride and 126 with placebo. There were no
statistically significant differences between the
glimepiride and placebo groups in gender, race,
mean age (52 ± 10 versus 54 ± 12 years, respective
ly); mean weight (86.8 ± 16.14 versus 87.3 ± 15.0 kg.
respectively), mean duration of diabetes (3.1 ± 4.5
and 3.1 ± 4.3 years, respectively), or FPG at admis
sion (227 ± 43.3 versus 224 ± 43.8 mg/dL. respec
tively). Of these patients 39 (23 in the glimepiride
and 16 in the placebo group) had been treated pre
viously with hypoglycemic agents.
Variables and Schedule of Observations
Medical history was recorded and physical exami nations,
including
laboratory
tests,
were
performed on day -7 of the prerandomization
period. Physical examination and laboratory tests
were repeated at baseline and after 12 and 22
weeks of treatment. Weight, blood pressure, and
FPG levels, were re-corded on days -7 and -1, at
baseline, and then biweekly through week 22.
Patients brought study medications,
including
empty containers, to each
visit, and tablets were counted to provide compliance estimates.
Two-hour postprandial glucose (PPG), hemoglobin A 1G (HbA 1c ), fasting and 2-hour postprandial
C-peptide and insulin, and a lipid profile were recorded at baseline, after 12 weeks and at endpoint
(22 weeks or last treatment evaluation). An electrocardiogram (ECG) was performed at baseline and after
22 weeks of treatment. HbA1c, C-peptide, and insulin
levels were analyzed at the. Diagnostic DiabetesLaboratory of the University of Missouri. Columbia,
Missouri. Other laboratory analyses (serum chemistry,
hematology, urinalysis) were performed at
SmithKline Beecham Clinical Laboratories, Van
Nuys, California.
637
Table I Fasting Plasma Glucose (FPG), Hemoglobin A1C
(HbA1c) and 2-Hour Postprandial Glucose (PPG) at Baseline
and at Endpoint (Last Treatment) Evaluation in
Patients Receiving Glimepiride or Placebo
Variable
N
Baseline
117
118
212
205
(131-335) 153 (184-360)
(142-353) 192 (90-354)
106
97
9.1
8.9
(6.0-14.3) 6.7 (3.1-11.7)
(5.6-13.3) 7.9 (5.4-12.3)
108
101
291
268
(135-468) 74 (83-395)
(129-475) 237 (90-705)
Values are presented as the median (range)
Statistical Analyses
Between treatment-group comparisons at baseline
(at the beginning of dose titration) were analyzed
using linear models with treatment and investigator
fixedl effects for continuous demographic variables
(age, weight, FPG at admission), and using the Mantel-Haenszel test adjusted for investigator effects for
duration of diabetes and for discrete variables (sex,
race).13
Treatment response was based on change from
baseline, at last treatment evaluation (endpoint).
Baseline data also were analyzed. Because data were not
normally distributed, nonparametric analyses were
performed and medians used as summary statistics for
the primary efficacy variables (FPG, HbAlC, and 2hour PPG). Box plots were used for comparisons
between treatment groups of variability around the
median for FPG and HbA lc. Within each treatment
group ,analyses of changes from baseline to endpoint
were performed using two - tailed Wilcoxon signed
rank tests.14 Between group comparisons for both observed
data and changes from base line were evaluated using
extended Mantel Haenszel tests (two-tailed).15
For the secondary efficacy variables (fasting and 2hour postprandial C-peptide and insulin levels),
changes from baseline were examined to determine
whether clinically meaningful changes had occurred.
The following guidelines for clinically meaningful
changes were used: for C-peptide changes of at least50%, 25%, or 15% for baseline values  l pmol/mL,> l to 2
pmol/mL, or > 2 pmol/mL, respectively; for insulin,
changes of at least 100%, 50%,or 25% for baseline
values of 10 U/mL, > 10 to 20 U/mL, or > 20
U/rnL, respectively. Z-tests were used to compare
proportions of patients.
638 * J Clin-Pharmacol 1998;38:636-641
RESULTS
Endpoint
FPG (mg/dL)
glimepiride
placebo
HbA15 (%)
glimeptride
placebo
2-hour PPG(mg/dL)
glimepiride
placebo
in the glimepiride and plaeebo groups with abnormal
laboratory values.14
The study was completed by 84(67-%) patients taking
placebo and by 104 (85%) patient taking glimepiride.
Hyperglycemia was a more common reason for not
completing the study among patients receiving
placebo than among those receiving glimepiride: 13
patients (10%) in the placebo group had asymptomatic
or symptomatic hyperglycemia compared with two
patients (2%) in the glimepiride group.
There were no dosage data for one patient in each
treatment group. Of the remaining 247 patients, 86
(66%) patients receiving glimepiride and 45 (36%)
receiving placebo were receiving once-daily doses of
glimepiride 1 to 6 mg or matching placebo at end
point. Dose distributions at endpoint were: 14%,
14%, 12%, 14%, 10%, and 36% of patients receiving 1,
2, 3, 4, 6, and 8 mg glimepiride, respectively.
Study drug was received for at least 140 days in 10
(87%) patients in the glimepiride group and 8 (70%)
patients in the placebo group. Compliance was greater
than 80% for all but two patients.
Fasting Plasma Glucose
At baseline, median FPG was similar in the
glimepiride and placebo groups (212 mg/dL and 205
mg/dL, respectively; Table I). At each subsequent
visit, median FPG (Figure 1) was significantly lower
in the glimepiride group than in the placebo group (P
< 0.01). At endpoint, the median FPG was 153 mg/dL
for patients receiving glimepiride and 192 mg/dL for
those receiving placebo (Table I). Overall glimepiride
decreased FPG by 46 mg/dL more than did placebo (P<
0.001; Figure 2).
Hemoglobin A1c
Median HbA1c at baseline was 9.1% for patient
receiving glimepiride and 8.9% for those taking placebo
(Table I). At weeks 12 and 22, median HbA 1c values
in the glimepiride group were >1% lower than those in
the placebo group. At endpoint, the median difference
in HbAlC between the glimepiride and placebo groups was
1.4% (P < 0.001, Figure 2). Tight glycemic control
(HbA1c  7.2%) was achieved by endpoint in 69%
of patients treated with glimepiride and 32% of
patients treated with placebo.
GLIMEPIRIDE IN PATIENTS WITH TYPE 2 DIABETES-MELLITUS
Figure 1 Median fasting plasma glucose (FPG) levels in patients
with noninsulin-dependent diabetes mellitus (NIDDM) during 22
weeks of treatment with glimepiride ( ) or placebo (▲ ). *,
significantly lower FPG with glimepiride than placebo (P = 0.003);
**, significantly lower FPG with glimepiride then placebo (P < 0.001).
2-Hour Postprandial Plasma Glucose
At baseline median values for 2-hour PPG were 291
mg/dL and 268 mg/dL in the glimepiride and
placebo groups, respectively. At endpoint, median 2hour PPG was 174 mg/dL among patients receiving
glimepiride and 237 mg/dL among those receiving
placebo (Table I). Overall, glimepiride decreased me-
Figure 3. Mean changes from baseline to endpoint in fasting and-2hour-postprandial (PP.) C-peptide and insulin levels in patients
treated with glimepiride (filled bars) or placebo (open bars).
dian 2- hour PPG by 72 mg/dL more than did placebo
(P < 0.001: Figure 2).
Fasting and 2-Hour Postprandial C-peptide
and Insulin
Differences in mean values between endpoint and
baseline for fasting and 2-hour postprandial C-peptide
and insulin levels are displayed in Figure 3. The results
demonstrate increased C-peptide and insulin levels
postprandially with glimepiride therapy. In contrast,
no meaningful changes were seen under fasting
conditions.
Adverse Events
Figure 2. Median differences between baseline and endpoint
(last treatment evaluation) in hemoglobin (Hb) A1c, fasting plasma
glucose (FPG),and 2-hour postprandial glucose (PPG) in patients
with noninsulin-dependent diabetes mellitus (NIDDM) treated with
glimepiride (filled bars) or placebo (open bars). Because these data
were not normally distributed, error bars are not included.
Adverse events possibly or probably related to
glimepifide were reported by ll% of the patients
receiving glimepiride and 9% of these receiving placebo.The most common adverse events in the glimepiride
group were dizzines (3 %), asthenia (2%), and headache
(2%). No laboratory documented hypoglycemia (blood
glucose < 60 mg/dL) occurred. Three patients receiving
glimepiride dis-continued study medication because
of adverse events. Two (both-receiving 1 mg of
glimepiride) dropped out during the first 2 weeks of
treatment because of symptomatic hypoglycemia
(symptoms with blood glucose 60 mg/dL). The third
patient dropped out after reporting weakness,
dizziness, and blurred vision (beginning on day 74).
Ten patients treated with placebo discontinued
because of adverse events, six because of symptomatic
hyperglycemia.
CLINICAL TRIALS
639
SCHADE, JOVANOVIC, AND SCHNEIDER
LaboratoryData
There were no significant differences between proportions of patients in the glimepiride and placebo
groups with abnormal values for any laboratory variable.
Further, no clinically noteworthy labaoratory values
occurred in any'patient receiving glimepiride.
One patient treated with placebo who had a history of
allergies had elevated eosinophil levels. There were
no significant differences between patients treated
with glimepiride and placebo in heart rate or blood
pressure either at baseline or endpoint. Patients
receiving glimepiride gained an average of 1.8 kg
during the course of the study, compared with an
average weight loss of approximately 0.7 kg in patients receiving placebo.
DISCUSSION
The results of this multicenter, randomized, placebocontrolled, double-blind study support the efficacy and
safety of daily doses of glimepiride 1 to 8 mg when
compared with placebo in patients whose type 2
diabetes could not be controlled by diet alone.
Improvements in all primary efficacy indicators
were significantly greater among patients treated
with glimepiride than among those treated with placebo.
Glucose control was poor in a large percentage of
patients receiving placebo, resulting in a high dropout rate in this group. Thus, 85% of patients in the
glimepiride group completed treatment compared
with 67% of patients in the placebo group. The large
difference in completion rates suggests that
glimepiride provided therapeutic benefits that encouraged patients to continue the treatment regimen.
Median FPG values decreased by 52 mg/dL among
those taking glimepiride, but by only 9 mg/dL among
those taking placebo.
Hb.A1c values were reduced from > 9% to< 7% in the
glimepiride group, resulting in a median of 6.7% study,
patients were grouped by HbA 1c above or below 7.2%,
the HBAlc value achieved by the intensively treated group
ic the DCCT trial.16 Overall, tight glycemic control
(HbA1c 7.2% at endpoint) was achieved in 69S% of
patients
receiving glirnepiride compared with 320/o of
those receiving placebo. Furfher, an additional 15% of the
patients-taking glimepiride bad good control
(HBA1c<8.0% at endpoint). These results suggest patients
with high HbA1c levels e.g., patients with more serious
diabetes could be iexpected to benefit from treatment with
glimepiride.
Results of preclinical animal and in vitro studies
suggest that glimepiride has a number of advantages, such
as low dosage, rapid onset, long duration of
640

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Pharmacol
1998;
38:636-641
action and lower insulin and C-peptide levels,
possibly as a result of less stimulation of insulin
secretion and more pronounced extrapancreatic effects.
Although the clinical implications have not been
resolved at this time, glimepiride has a higher
exchange rate for binding to the -cell sulfonylurea
receptor, and dissociates from it more rapidly in rat -cell
tumors and RINm5f cells than does glyburide.18 In
addition, photoaffinity labeling studies in rat -cell
tumor membranes showed binding of glyburide to a
140 kDa moiety and of glimepiride to a 65 kDa protein;
both proteins may be subunits of common receptor
complex. The physiologic relevance of this
differential binding is not known.19
Clinical studies have also shown differences
between glimepiride and glyburide.17,20 The potency of
glimepiride on a mg-to-mg basis, is approximately
twice that of glyburide. 21 In patients with type 2
diabetes, glimepiride had a more rapid onset of
action and a longer duration of action than did
glyburide.17 In addition, a lesser risk of hypoglycemia
with glimepiride than with glyburide was evidenced by
suppression of exercise-induced insulin secretion with
glimepiride but not with glyburide, 17. and by lower
incidence of hypoglycemia.17, 20
In this clinical trial glimepiride therapy in improve
postprandial insulin and C-peptide responses with out
producing clinically meaningful increases in fasting
insulin and C-peptide levels. This metabolic effect is
desirable if insulin increases atherosclerosis in people
with diabetes.22 Further, these observitions lend
support to extrapancreatie insulin-sensitizing and
insulin-mimetic effects on glucose transport
with
glimepiride treatment. A number of preclinical
studies have provided evidence that extrapancreatic
effects may contribute to the activity of glimepiride and
other sulfonylureas.8,9,23 In insulin resistant rat
adipocytes, for example, glimepiride induces the
translocation of the glucose transporter protein to the
cell surface which may stimulate glucose transport.8 In
these rat adipocyte studies glimepiride was observed to
play a role in phosphosylation/dephosphorylation
regulation, which my control glucose transport.
The results of this study demonstrate that
glimepiride is a safe and effective oral antidiabetic
agent for patients with type-2 diabetes for whom
dietary therapy is unsuccessful. Patients treated with
glimepiride showed significantly reduced levels of FPG,
HbA1c, and 2-hour PPG compared with patients treated
with placebo. In addition, glimepiride showed a
favorable safety profile similar to that patients with type2-diabetes receiving other sulfonylureas.24 Further, the
once-daily administration schedule is advantageous for
increasing compliance in patients with type 2
diabetes.
GLIMEPIRIDE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
The authors thank the Glimepiride Protocol #202
Study Group and J.Ziman,PhD, for_biostatistical
analyses of the the data. Glimepiride Protocol #202
Study Gruop –L, Jovanovic,MD,Santa Barbara, CA;
C._Wysham,MD,St. Paul,MN; R. Kreisberg, MD.D
Ross,MD, Mobile,AL; S.Rosanblatt, MD, lrvine,
CA;D.M. Klachko,MD. Columbia, MO; G. Boden,
Philadelphia, PA; J.Cyrus, MD, Louisyille, KY; T.
M. Flood, MD, Atlanta, GA; AGeorgoulos. MD,
Baltimore, MD; S. Holvey, MD, Los_ Angeles, CA:C,
Kilo, MD, St. Louis, MO; J. Synder, MD, Las Vegas,
G.V. Browning, MD. Florence, SC; P.A. Lodewick,
MD, Louisville, KY; D. Gorson, MD, North Miami
Beach, FL; J.K. Burks, MD, Farmers Branch, FL: J.K.
Burks, MD, Farmers Branch, TX;S. Schwartz, MD, San
Antonio, TX and J.J. Ruegemer, MD, Minneapolis,
MN.
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