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Efficacy of glimepiride/metformin combination versus

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 ARTICLE IN PRESS

Journal of Diabetes and Its Complications xx (2008) xxx – xxx

WWW.JDCJOURNAL.COM

Efficacy of glimepiride/metformin combination versus glibenclamide/

metformin in patients with uncontrolled type 2 diabetes mellitus☆
Manuel González-Ortiz a,b,⁎, Jesús F. Guerrero-Romero c , Rafael Violante-Ortiz d ,
Niels Wacher-Rodarte e , Esperanza Martínez-Abundis a,b , Carlos Aguilar-Salinas f ,
Sergio Islas-Andrade g , Rosario Arechavaleta-Granell h , Jorge González-Canudas i ,
Martha Rodríguez-Morán c , Etelvina Zavala-Suárez e , Maria G. Ramos-Zavala a , Roopa Metha f ,
Cristina Revilla-Monsalve g , Teresita J. Beltrán-Jaramillo h
a
Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty,
West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico
b
Cardiovascular Research Unit, Physiology Department, Health Sciences University Center, University of Guadalajara, Guadalajara, Mexico
c
Biomedical Research Unit, Mexican Institute of Social Security, Durango, Mexico
d
Endocrinology Department, Regional General Hospital, Mexican Institute of Social Security, Tampico, Mexico
e
Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty,
National Medical Center Century XXI, Mexican Institute of Social Security, Mexico, DF
f
Endocrinology and Metabolism Department, National Institute of Medical Sciences and Nutrition, Mexico, DF
g
Medical Research Unit in Metabolic Diseases, National Medical Center Century XXI, Mexican Institute of Social Security, Mexico, DF
h
Endocrinology Department, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center,
Mexican Institute of Social Security, Guadalajara, Mexico
i
Research Head-in-Chief, Laboratorios Silanes, Mexico, DF

Received 22 February 2008; received in revised form 29 July 2008; accepted 13 September 2008

Abstract

Aim: The aim of this study was to compare the efficacy of glimepiride/metformin combination versus glibenclamide/metformin for reaching
glycemic control in patients with uncontrolled type 2 diabetes mellitus. Patients and Methods: A randomized, double-blind, multicenter clinical
trial was performed in 152 uncontrolled type 2 diabetic patients. Serum fasting and postprandial glucose, hemoglobin A1c (A1C), high-density
lipoprotein cholesterol, and triglycerides were measured. After random allocation, all patients received two pills of glimepiride (1 mg)/metformin
(500 mg) or glibenclamide (5 mg)/metformin (500 mg) po once a day. Dosage was increased to a maximum of four pills in order to reach the
glycemic control goals (fasting glucose ≤7.2 mmol/l, postprandial glucose b10.0 mmol/l, A1C b7%, or an A1C ≥1% reduction). Statistical
analyses were carried out using chi-square, ANOVA, or Student's t test. The protocol was approved by an ethics committee and met all requirements
needed to perform research in human subjects; all patients gave written informed consent. Results: Each study group included 76 patients. No
significant differences in basal clinical and laboratory characteristics between groups were found. At the end of the study, A1C concentration was
significantly lower in the glimepiride/metformin group (P=.025). A higher proportion of patients from the glimepiride group (44.6% vs. 26.8%,
Pb.05) reached the goal of A1C b7% at 12 months of treatment. A higher proportion of hypoglycemic events were observed in the glibenclamide
group (28.9% vs. 17.1%, Pb.047). Conclusion: Glimepiride/metformin demonstrated being more efficacious than glibenclamide/metformin at
reaching the glycemic control goals with less hypoglycemic events in patients with uncontrolled type 2 diabetes mellitus.
© 2008 Elsevier Inc. All rights reserved.
Keywords: Glimepiride; Glibenclamide; Metformin; Combinations; Metabolic control; Glycemic control goals

☆
Financial source: Laboratorios Silanes, Mexico.
⁎ Corresponding author. Montes Urales 1409, Col. Independencia, 44340, Guadalajara, Jalisco, México. Tel.: +52 33 38267022; fax: +52 33 36161218.
E-mail address: uiec@prodigy.net.mx (M. González-Ortiz).

1056-8727/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.jdiacomp.2008.09.002
 ARTICLE IN PRESS
2 M. González-Ortiz et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx
1. Introduction
Insulin resistance occurs early in type 2 diabetes disease
process and may lead to progressive beta cell failure and
overt diabetes (Abdul-Ghani, Tripathy, & DeFronzo, 2006).
Monotherapy can slow down but does not prevent the
progression of the disease. Successful management requires
combination therapy that addresses both insulin resistance
and beta cell dysfunction (Cefalu, Waldman, & Ryder,
2007). Clinical trials support the use of combinations of
antidiabetic agents with complementary mechanisms of
action such as a sulfonylurea/metformin (Dailey, 2003;
Rendell, 2004). Early aggressive treatment could improve
patient outcomes while reducing overall health care costs.
On one hand, glibenclamide/metformin is the oral
antidiabetic combination most used in the clinical practice
today (Dailey, 2003); on the other hand, glimepiride—
considered as a third-generation sulfonylurea agent—has
several beneficial pharmacological effects over glibencla-
mide, a second-generation sulfonylurea. Glimepiride com-
bined with metformin in a single dose presentation has proved
to be effective and safe for type 2 diabetes patients who fail
with monotherapy on oral antidiabetic agents (González-
Ortiz, Martínez-Abundis, & Grupo para el tratamiento de la
diabetes mellitus con combinaciones, 2004).
At present, there is no evidence in medical literature of a
comparison between the abovementioned combinations;
therefore, the aim of this study was to compare the efficacy
of glimepiride/metformin versus glibenclamide/metformin
in reaching glycemic control in patients with uncontrolled
type 2 diabetes mellitus.
2. Patients and methods
A total of 152 patients with type 2 diabetes mellitus (40 to
65 years of age) were included in a randomized, double-
blind, multicenter clinical trial. Patients were overweight or
obese [body mass index (BMI) between 25 and 40 kg/m2]
and had received monotherapy with metformin (2000 mg/
day) and glibenclamide (20 mg/day) or medical nutritional
therapy in accordance with the American Diabetes Associa-
tion recommendations during at least 3 months. Patients
were required to have fasting glucose concentrations of 8.3
to 14.9 mmol/l and hemoglobin A1c (A1C) N7%. Sample
size was calculated with a clinical trial formula (Jeyaseelan
& Rao, 1989) based on a confidence level of 95%, statistical
power of 80%, standard deviation of A1C in uncontrolled
type 2 diabetes patients of 1.30%, and an expected difference
of 0.65% in A1C. Sample size was 63 patients per group, but
it was increased to 76, estimating a 20% loss to follow-up.
Subjects were not included if they presented one of the
following: pregnancy, alcohol or drug abuse, insulin treatment,
allergy to sulfonylureas or biguanides, heart or renal failure
(considered as serum creatinine N133 in males and N124 μmol/
l in females), coronary heart disease, stroke, visceral neuro-
pathy, cancer, systemic lupus, erythematosus lupus, or HIV
infection. The use of drugs that presented pharmacological
interactions with sulfonylureas or metformin was prohibited,
with the exception of aspirin (≤100 mg/day).
The following were considered as exclusion criteria, but
were statistically analyzed: mild or moderate hypoglycemia
(N2 times); severe hypoglycemia (b3.3 mmol/l) with
treatment at minimum doses; hyperglycemia N14.9 mmol/l
with treatment at maximum dose during 3 months; severe
adverse events; lack of compliance to medical treatment
(b80% of prescribed pills were taken); loss of follow-up, N2
consecutive or 3 alternate visits during the study; hospita-
lization; unauthorized medication; or consent withdrawn.
The following clinical measurements were evaluated:
BMI (weight in kilograms divided by height in meters
squared), waist–hip ratio, blood pressure, fasting and
postprandial glucose (glucose level 2 h after eating a
standardized breakfast composed of 72 g of carbohydrates),
A1C, high-density lipoprotein (HDL) cholesterol, and
triglycerides. If a patient met all selection criteria,
randomization was performed to include him or her in
one of the following fixed combinations: two glimepiride
(1 mg)/metformin (500 mg) pills (Glimetal 1/500, Labor-
atorios Silanes, Mexico) or two glibenclamide (5 mg)/
metformin (500 mg) pills (Bi-Euglucon M5, Laboratorios
Roche, Mexico), to be taken with breakfast as pharmaco-
logical intervention. The allocation was done by simple
randomization by an independent center, and the sequence
was concealed until the end of the statistical analyses. The
medical nutritional therapy in accordance with the Amer-
ican Diabetes Association was followed throughout the
study. If the patient presented an A1C N8% at 3, 6, or 9
months, the dose was doubled (two additional pills with
dinner), reaching the maximum dose. In case of obtaining a
fasting glucose b5 mmol/l every month, the dose was
gradually decreased and the patient is closely observed for
hypoglycemia through daily capillary glucose monitoring.
Blind coded prescription containers were identical for both
drugs. An independent researcher counted the pills in order
to evaluate adherence to treatment.
Clinical measurements and fasting glucose levels were
evaluated every month, postprandial glucose and A1C
concentrations were evaluated every 3 months, and HDL
cholesterol and triglyceride concentrations were evaluated
every 6 months.
Adverse events were recorded continuously and classified
as related or not related to the oral antidiabetic fixed
combinations used in each case.
Efficacy criteria included fasting glucose ≤7.2 mmol/l,
postprandial glucose b10.0 mmol/l, A1C b7%, or a
reduction of A1C ≥1%.
Glucose, HDL cholesterol, and triglycerides were measured
using an enzymatic technique (Abbott Laboratories, Abbott
Park, IL, USA) with intra- and interassay coefficients of
variation b3%. A1C concentrations were estimated using a
fluorescent polarization enzymatic method (Abbott Labora-
tories) with intra- and interassay coefficients of variation b5%.
 ARTICLE IN PRESS
M. González-Ortiz et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx 3

All subjects signed informed consents in order to Table 2

participate in the study. The protocol was approved by an Proportion reaching glycemic control goals
ethics committee and met all requirements to perform Glibenclamide/ Glimepiride/
investigation on human subjects. Metformin Metformin
6 months 12 months 6 months 12 months
Fasting glucose 45.9 39.4 46.6 46.2
3. Statistical analysis
≤7.2 mmol/l
Postprandial glucose 29.7 18.3 27.4 21.9
Numerical data were reported as mean and standard b10.0 mmol/l
deviation, and nominal data were reported as proportion. The Reduction in 78.4 76.1 75.3 67.7
analysis was performed by intention to treat. A chi-square A1C ≥1%
A1C b7% 35.1 26.8 50.7 44.6 ⁎
test was used in order to compare dichotomous variables.
Student's t test was used to compare intra- and intergroup ⁎ Pb.05 between both groups at 12 months.
differences, and ANOVA test was used to evaluate changes
throughout the study. A model of global multiple logistic
out the study (data not shown). A significant difference in
regression was performed to adjust treatment efficacy (A1C
A1C concentration was observed at the end of the study,
b7 at 12 months) by basal BMI and A1C. P values b.05 were
where A1C concentration was lower in the glimepiride
considered statistically significant.
group (7.6±1.2 vs. 7.2±1.0%, P=.025).
No differences were observed between glibenclamide/
4. Results metformin and glimepiride/metformin groups regarding
changes from baseline to the end of the study in fasting
The glibenclamide/metformin group included 45 women (−4.1±3.7 vs. −4.0±4.1 mmol/l, P=.945) and postprandial
and 31 men, and the glimepiride/metformin group included glucose (−4.3±5.3 vs. −4.2±4.6 mmol/l, P=.291) and A1C
48 women and 28 men (P=.410). There were no significant concentration (−2.0±1.5 vs. −2.1±1.6%, P=.712).
age differences between the glibenclamide and glimepiride Table 2 shows the metabolic control goals in both groups
groups (52.9±7.6 years vs. 52.3±7.6 years, P=.618). at 6 and 12 months; the glimepiride group showed the
BMI changes from the baseline to the end of the study highest proportion of patients who reached the A1C b7%
were not significant between glibenclamide and glimepiride goal at 12 months of treatment.
groups (0.7±1.5 vs. 0.4±1.7 kg/m2, P=.254). The model of global multiple logistic regression to
There was no significant difference between both evaluate the efficacy of the treatment (A1C b7% at 12
groups in the time of evolution of diabetes (4.8±4.8 vs. months), adjusting for basal BMI and A1C, showed that the
4.3±4.7 years, glibenclamide and glimepiride groups, efficacy persisted in the glimepiride group (OR=2.170, 95%
respectively; P=.564). CI=1.034–4.559, P=.041), as well as after adjusting for basal
There were no significant differences in clinical and labo- A1C (OR=0.346, 95% CI=0.163–0.734, P=.006), observing
ratory characteristics between groups at baseline (Table 1). an increased difference between both treatments, as basal A1C
There was no significant difference between the percen- increases (A1C b9%: 46.4 vs. 51.7%; A1C ≥9%: 14.0 vs.
tage of patients who increase the dose of drugs throughout 38.9%, glibenclamide and glimepiride groups, respectively).
the study at any time (for a total of 25% in glibenclamide The lipid profile remained without significant changes in
group and 37% in the glimepiride; P=.451). both groups throughout the study.
There were no significant differences between both Three patients in the glimepiride group were excluded for
groups in fasting and postprandial glucose levels through- the following reasons: car accident, pancreatic cancer, and, in
one case, having moved out of the country. Nevertheless, they
were included in the statistical analysis. The adherence was
Table 1 96% and 99% in the glimepiride and glibenclamide groups,
Baseline characteristics respectively. Adverse events were present in 68.4% of
Glibenclamide/ Glimepiride/ patients in the glibenclamide group and in 69.7% of those
Metformin Metformin P in the glimepiride group (P=.842). The most common
Systolic BP (mmHg) 124±12 124±17 .882 adverse events were upper respiratory infectious disease
Diastolic BP (mmHg) 79±10 76±9 .054 (27.7% in glibenclamide group vs. 28.9% in glimepiride
BMI (kg/m2) 29.6±4.3 29.5±4.1 .910 group, P=.851) and sensorial abnormalities in lower
Waist–hip ratio 0.92±0.06 0.92±0.06 .864 extremities (28.9% in glibenclamide group vs. 35.5% in
Fasting glucose (mmol/l) 11.9±3.1 11.7±4.1 .645
Postprandial glucose (mmol/l) 17.5±4.6 16.8±5.2 .427
glimepiride group, P=.318). A higher number (P=.047) of
A1C (%) 9.6±1.6 9.4±1.8 .473 mild and moderate hypoglycemic events was observed in the
HDL cholesterol (mmol/l) 1.1±0.2 1.1±0.3 .519 glibenclamide group (28.9%) in comparison to the glimepir-
Triglycerides (mmol/l) 2.8±2.3 2.6±1.7 .648 ide group (17.1%). No severe hypoglycemic events were
BP, blood pressure. present in any group.
 ARTICLE IN PRESS
4 M. González-Ortiz et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx
5. Discussion
It has been clearly demonstrated that when the therapeutic
treatment goals for diabetes are not reached, early progres-
sion to combination therapy can maintain adequate control of
blood glucose in comparison to that achieved with single-
agent therapy (U.K. Prospective Diabetes Study Group,
1998). There are very few head-to-head studies that compare
the effect between different combinations of antidiabetic
agents. In the present study, two fixed metformin combina-
tions were chosen: the first, with glibenclamide, a second-
generation sulfonylurea, and the second, with glimepiride, a
third-generation sulfonylurea that exhibits effects different
from glibenclamide, including several extrapancreatic effects
on muscle and adipose cells, elevating active glucose
transport and increasing insulin secretion (Mûller, Satoh, &
Geisen, 1995). There is no information about the comparison
of the clinical effect of both sulfonylureas at specific doses;
we used two common fixed combinations that could not be
equivalent and which could be a limitation of our study. On
the other hand, this investigation has methodological
strength, obtained through controlling several variables by
means of strict selection criteria, as a result of which both
groups have similar clinical and laboratory basal character-
istics, which did not have significant changes throughout the
study. The medical nutritional therapy was permanently
evaluated and modified in accordance to the individual
characteristics of the patients; however, they did not receive
specific indications to increase their physical activity, and
this is another limitation of the study, independently of the
probability of equilibrium of such characteristic in both
groups due to the randomized design.
The first clinical experience with the glimepiride/metfor-
min combination was published in a study wherein
metformin failed as monotherapy; in the same study, a
diminution of A1C of 0.7% was reached after 4 months of
treatment (Charpentier, Fleury, Kabir, Vaur, & Halimi, 2001).
On the other hand, we previously published the use of
glimepiride/metformin in a single dose during a 3-month
follow-up study, demonstrating its efficacy and safety in
patients with type 2 diabetes with secondary failure to
glibenclamide. In the abovementioned study, reduction of
A1C was of 1.3% and approximately half of the patients
showed an A1C reduction of at least 1%. Nevertheless, only a
small percentage of patients reached the A1C goal of less than
7% (González-Ortiz et al., 2004).
In accordance with the new ADA-EASD guidelines, a
sulfonylurea combined with metformin constitutes an
attractive option in the clinical practice (American Diabetes
Association, 2008). This combination can reduce A1C
concentration up to 2% (Krentz & Bailey, 2005). Our results
showed similar reductions in the fasting and postprandial
glucose levels for both antidiabetic combinations used in the
study, reductions that were evident from the first month of
treatment. However, at the end of the study, A1C levels were
significantly lower in the glimepiride group than in the
View publication stats
glibenclamide group. These findings could be explained by
the higher proportion of patients that reached the A1C goal of
less than 7% in the glimepiride/metformin group. Besides, it
is worth mentioning that A1C is a better parameter to identify
metabolic control, because it evaluates the participation of
both basal and postprandial glucose concentrations and their
variability (Monnier, Colette, Dunseath, & Owens, 2007).
Although we waited for a lower rate of treatment adherence,
this was high in both groups and was probably related to the
close clinical attention provided by the medical staff.
Glibenclamide is well-known to induce a higher
frequency of hypoglycemia than other agents, and our
results were in accordance with this fact (Rendell, 2004).
Other adverse events were considered to be not related to the
combination of antidiabetic agents used, probably due to the
natural evolution of diabetes.
In conclusion, glimepiride/metformin showed a greater
efficacy in reaching the metabolic goal of glycemic
control with less hypoglycemic events in patients with
uncontrolled type 2 diabetes mellitus in comparison with
glibenclamide/metformin.
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