Diabetes Research and Clinical Practice 66S (2004) S129–S132

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Efficacy of glimepiride in type 2 diabetic patients

treated with glibenclamide
Tomoya Hamaguchia,b,*, Takahisa Hirosea, Hideki Asakawaa,
Yoshiharu Itoha, Keiji Kamadoa, Katsuto Tokunagaa,
Koji Tomitaa, Hiroshi Masudaa, Nobuaki Watanabea,
Mitsuyoshi Nambaa,b
a
HOSS Conference Group, Hyogo, Japan
b
Department of Internal Medicine, Division of Diabetes and Metabolism, Hyogo College of Medicine,
1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
Received 4 November 2003; accepted 2 December 2003

Abstract

Multicentric study was conducted to evaluate the efficacy of glimepiride in the oral hypoglycemic agents therapy of type 2
diabetic patients treated with glibenclamide so far, and to claim an adequate use of this new generation sulfonylurea. In 66
diabetic outpatients, glibenclamide was switched to glimepiride. After 6 months’ therapy, a significant reduction in fasting
plasma IRI was observed in relatively hyperinsulinemic patients. In addition, weight reduction was achieved in patients with
insulin resistance during this study. These findings suggest that glimepiride improves insulin resistance in hyperinsulinemic
patients treated with glibenclamide. Also, glimepiride is favored especially for overweight, insulin-resistant patients inade-
quately controlled by glibenclamide.
# 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Third-generation sulfonylurea; Extrapancreatic effects; Insulin resistance; Metabolic syndrome

1. Introduction cle [1] and reducing endogenous glucose production

Glimepiride, a new third-generation sulfonylurea,
is reported to have some extrapancreatic effects,
such as improving peripheral glucose uptake in mus-
* Corresponding author. Tel.: +81 798 45 6592;
fax: +81 798 45 6593.
E-mail address: tomhamag@hyo-med.ac.jp (T. Hamaguchi).
in liver [2]. These effects are supposed to be achieved
by facilitating insulin action by the agent. And,
through these effects, glimepiride is considered to
have therapeutical benefit in the treatment of type 2
diabetic patients compared with other older genera-
tion sulfonylureas (e.g. glibenclamide) [3]. To study
the efficacy of glimepiride in Japanese type 2 diabetic
patients treated with glibenclamide, we investigated

0168-8227/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.diabres.2003.12.012
S130 T. Hamaguchi et al. / Diabetes Research and Clinical Practice 66S (2004) S129–S132
the effect of the agent on some clinical indices
representing insulin sensitivity and secretion in these
patients.
2. Research design and methods
Open, non-comparative study was managed at
seven study centers (HOSS Conference Group) in
Hyogo prefecture, Japan. Subjects with type 2 diabetes
treated on glibenclamide alone were enrolled in the
study after obtaining their written informed consent.
Patients were selected for study by glycated hemoglo-
bin (HbA1c) level in the range between 6.5 and 9.0%
at entry to minimize the effect of amelioration of
glucose toxicity on any improvement in insulin sensi-
tivity or secretion. Patients with severe diabetic
complications such as retinopathy, nephropathy, neu-
ropathy or ischemic cardiovascular disease were
excluded. During 2 to 3 months’ observation, the
patients who showed unstable glycemic control, and
had more than 10% variation from initial HbA1c level
were also excluded from this trial. After the observa-
tion, glibenclamide was switched to glimepiride at a
rate of 80% mg doses. (As an example, 2.5 mg of
glibenclamide was altered to 2 mg of glimepiride.)
During this study, the dose of glimepiride was titrated
at monthly intervals in an attempt to maintain initial
HbA1c level of each patient. After 6 months’ admin-
istration of glimepiride, several clinical indices (fast-
ing plasma glucose [FPG], fasting immuno-reactive
insulin (IRI), body weight, serum total cholesterol
[TC], triglycerides [TG] and high-density lipoprotein
cholesterol [HDLc]) were compared to evaluate the
efficacy of glimepiride with glibenclamide. Insulin
resistance was evaluated by homeostasis model
assessment (HOMA)-R index, and insulin secrition
was estimated by fasting IRI and HOMA-b. All
subjects were encouraged to maintain their usual diet
and physical activities. In addition, all medications
other than glimepiride, known to influence glucose
tolerance were not added nor withdrawn during this
study.
Data are means  S.D. Statistical analysis was
done by using a paired t-test to check the significance
of the change over the therapies. To compare the two
treatment groups, we used analysis of Student’s t-test.
The P value are two-sided; a P value of less than 0.05
was considered to indicate statistical significance.
Statistical analyses were performed using Stat View
software (version 5.01; SAS Institute, Cary, NC).
3. Results
Sixty-six diabetic outpatients, including 42 male
patients and 24 female patients, aged between 37 and
80 (61.7  8.5 years old), completed the study and
were assessable. Their durations of the disease were
12.7  7.7 years (range <1 to 27 years). The dosage of
glibenclamide was 3.0  1.5 mg/day (range 1.25 to
5.0 mg/day) before switching to glimepiride. And the
average dose of glimepiride was 3.2  1.7 mg/day
(range 1 to 6 mg/day) at the end of this study. Their
initial body mass index (BMI) was 23.6  3.1.
Fasting plasma glucose, HbA1c, TC, TG, and HDLc
levels were not altered between glibenclamide versus
glimepiride therapies (8.3  1.7 mmol/l versus 8.3 
2.0 mmol/l; n.s., 7.6  1.0% versus 7.6  0.9%; n.s.,
5.5  0.88 mmol/l versus 5.7  0.79 mmol/l; n.s., 1.6
 0.92 mmol/l versus 1.8  0.99 mmol/l; n.s., and 1.4
 0.39 mmol/l versus 1.5  0.42 mmol/l; n.s., respec-
tively). In overall patients, fasting plasma IRI also
showed no significant change between these medica-
tions (34  15 pmol/l versus 35  20 pmol/l; n.s.).
However, HOMA-R, an index of insulin resistance, in
hyperinsulinemic patients whose fasting insulin level
was above 48 pmol/l, namely above mean + 1 S.D.,
reduced significantly after switching to glimepiride (2.8
 0.3 versus 2.3  0.3; P < 0.05). On the other hand,
HOMA-R in relatively low-insulinemic patients showed
no significant change. Moreover, the responders of
glimepiride (defined by the reduction in HOMA-R
during the study; n = 10) had a significantly higher
HOMA-R (2.8  0.3 versus 1.7  0.1; P < 0.005) and
fasting plasma IRI level (43  3.6 pmol/l versus 33 
3.0 pmol/l; P < 0.005) than the patients of non-respon-
der group (defined by no-reduction in HOMA-R; n = 56)
before switching to glimepiride (Fig. 1a and b). The
responder group also had a significantly higher HOMA-
b, an index of pancreatic b cell function (34  9.2
versus 25  3.8; P < 0.05). HOMA-b showed no
significant change between two medications (Fig. 1c,
data not shown). In the present study, 14 patients showed
weight reduction (group A; body weight reduction
group), and 30 patients kept or gained their body weight
 T. Hamaguchi et al. / Diabetes Research and Clinical Practice 66S (2004) S129–S132
Fig. 1. Changes in HOMA-R, fasting IRI and HOMA-b during the trial. (a) HOMA-R, (b) fasting IRI, (c) HOMA-b. Values are mean  S.D.
Closed circle represents the responder group (n = 10), and open circle represents the non-responder group (n = 56). GB: glibenclamide, GM:
glimepiride. *P < 0.05, ***P < 0.005.
(group B; body weight unchanged group). In compar-
ison with the group B, the group A showed a signifi-
cantly higher BMI (24.4  2.5 versus 23.2  2.8; P <
0.05), HOMA-R (2.7  0.4 versus 2.0  0.2; P < 0.01)
and fasting insulin level (41  4.2 pmol/l versus 32 
3.6 pmol/l; P < 0.01) at the beginning of this study. The
group A also showed a significantly lower HDLc level
than the group B (0.3  0.08 mmol/l versus 0.5 
0.08 mmol/l; P < 0.01), though HDLc did not change
before-versus-after glimepiride administration in both
groups (0.3  0.08 mmol/l versus 0.4  0.08 mmol/l in
the group A; n.s., and 0.5  0.08 mmol/l versus
0.08 mmol/l versus 0.5  0.07 mmol/l in the group
B; n.s.).
4. Discussion
Type 2 diabetes mellitus is the very common
metabolic disease, and is characterized by the defects
of insulin secretion and/or sensitivity. It is generally
accepted that sulfonylureas exert the hypoglycemic
effect through their receptors on the pancreatic b cell
to augment insulin secretion. Glibenclamide, so-called
a second-generation sulfonylurea is so potent and
long-acting stimulator of insulin secretion that glib-
enclamide provides a higher success rate for the
treatment of type 2 diabetes. On the other hand,
treatment with glibenclamide promotes hyperinsuli-
nemia, and may be resulted in weight gain or hypo-
glycemia, sequentially. Obesity are known to correlate
with insulin resistance, and to interfere the better
glycemic control. So, weight gain during the therapy
S131
with glibenclamide leads to increase the risk of second
failure of this agent [4]. In the obese patients, treat-
ment should be re-evaluated by the viewpoint of
insulin resistance [5].
A new third-generation sulfonylurea, glimepiride
shows a lesser effect on insulin secretion with a
corresponding hypoglycemic potency than glibencla-
mide [6,7]. Unlike other types of sulfonylureas, gli-
mepiride increases metabolic clearance rates of
glucose in glucose-tolerant insulin-resistant offspring
of patients with type 2 diabetes during physiological
hyperinsulinemia by an euglycemic glucose clamp
technic [8]. In vitro experiment demonstrates that
glimepiride increases the availability of glucose trans-
porters GLUT1 and GLUT4 in the cell membranes. In
contrast to these experimental findings, clinical effi-
cacy of this compound are still controversial [9,10].
In this study, glimepiride was as much potent in
ameliorating glucose and lipid metabolism as glib-
enclamide with an almost equivalent dosage. Also, in
our findings, improvement of insulin resistance by
glimepiride was detected characteristically in the
hyperinsulinemic patients with glibenclamide. These
patients also showed a marked reduction of fasting IRI
level. Improvement of insulin resistance and hyper-
insulinemia may spare the excess insulin secretion to
avoid b cell ‘‘exhaustion’’ phenomena [11].
In a same point of view, reduction of body weight is
effective to improve insulin resistance. The relatively
overweight patients who had some features of insulin
resistance and/or metabolic syndrome (represented by
high HOMA-R, hyperinsulinemia, high BMI and low
HDLc) [12] were also shown to decrease their BMI,
S132 T. Hamaguchi et al. / Diabetes Research and Clinical Practice 66S (2004) S129–S132
HOMA-R and fasting IRI level during the study. Their
mean body mass index was 24.4 and a nearly half of
the subjects in the study were in the criterion of
obesity by Japan Society for the Study of Obesity.
So, the results suggest that glimepiride have a favor-
able effect on body weight in relatively obese and
insulin-resistant diabetic patients treated with gliben-
clamide so far. Therefore, subjects with the feature of
metabolic syndrome may be treated more efficiently
with glimepiride than with glibenclamide.
In conclusions, glimepiride improves insulin resis-
tance in hyperinsulinemic patients treated with glib-
enclamide, and so glimepiride is supposed to be
favored for relatively overweight and insulin-resistant
patients with type 2 diabetes inadequately controlled
with glibenclamide.
Acknowledgments
The support of Aventis Pharma Co. is gratefully
acknowledged. This study was presented as an oral
communication at 12th Japan-Korea Symposium on
Diabetes Mellitus which was held in Nagoya (Pre-
sident N. Hotta) on May 10, 2003.
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