15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE
Diabetes Metab Res Rev 2014; 30: 11–22.
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2470

The incidence of mild and severe hypoglycaemia in

patients with type 2 diabetes mellitus treated
with sulfonylureas: a systematic review
and meta-analysis

J. E. Schopman1*
A. C. R. Simon1
S. J. M. Hoefnagel1
J. B. L. Hoekstra1
R. J. P. M. Scholten2
F. Holleman1
1
Department of Internal Medicine,
Academic Medical Center,
Amsterdam, The Netherlands
2 regression analyses were performed to study possible associations with
Clinical Epidemiology,
Biostatistics and Bioinformatics/Dutch
Cochrane Centre,
Academic Medical Center,
Amsterdam, The Netherlands
*Correspondence to: J. E. Schopman,
Department of Internal Medicine,
Academic Medical Center,
Meibergdreef 9, room F4-215, 1105
AZ Amsterdam, The Netherlands.
E-mail: j.e.schopman@amc.uva.nl
Summary
Patients with type 2 diabetes mellitus using sulfonylurea derivatives or insulin
may experience hypoglycaemia. However, recent data regarding the incidence
of hypoglycaemia are scarce. We conducted a systematic review and meta-
analysis to determine the proportion of patients with type 2 diabetes mellitus
that experience hypoglycaemia when treated with sulfonylurea or insulin.
We searched MEDLINE and EMBASE for randomized controlled trials that
compared incretin-based drugs to sulfonylureas or insulin and assessed
hypoglycaemia incidence in the latter therapies. Subgroup and meta-
potential risk factors for hypoglycaemia.
Data of 25 studies were extracted, 22 for sulfonylurea and 3 for insulin.
Hypoglycaemia with glucose ≤3.1 mmol/L or ≤2.8 mmol/L was experienced
by 10.1% [95% confidence interval (CI) 7.3–13.8%] and 5.9% (95% CI
2.5–13.4%) of patients with any sulfonylurea treatment. Severe hypoglycaemia
was experienced by 0.8% (95% CI 0.5–1.3%) of patients. Hypoglycaemia with
glucose ≤3.1 mmol/L and severe hypoglycaemia occurred least frequently with
gliclazide: in 1.4% (95% CI 0.8–2.4%) and 0.1% (95% CI 0–0.7%) of patients,
respectively. None of the risk factors were significant in a stepwise multivariate
meta-regression analysis. Too few studies had insulin as comparator, so these
data could not be meta-analysed.
The majority of patients with type 2 diabetes mellitus on sulfonylurea therapy
in clinical trials remain free of any relevant hypoglycaemia. Gliclazide was
associated with the lowest risk of hypoglycaemia. Because participants in
randomized controlled trials differ from the general population, care should
be taken when translating these data into clinical practice. Copyright © 2013
John Wiley & Sons, Ltd.

Keywords type 2 diabetes mellitus; hypoglycaemia; sulfonylurea; complications

Received: 21 April 2013

Introduction
Revised: 7 September 2013
Accepted: 9 September 2013 Despite the proclaimed benefits of newer glucose-lowering drugs over conven-
tional therapy, many guidelines still recommend using less expensive conventional

Copyright © 2013 John Wiley & Sons, Ltd.


12
therapies such as metformin, sulfonylureas and neutral
protamine Hagedorn (NPH) insulin for the treatment of
type 2 diabetes mellitus [1,2]. Data on the actual inci-
dence of mild and severe hypoglycaemia in patients with
type 2 diabetes mellitus using sulfonylureas or insulin
monotherapy are scarce, but much is made of the risk
for hypoglycaemia with the conventional drugs. As an
old established therapy, few recent studies have focused
on the hypoglycaemia risk with sulfonylureas or basal
insulin per se. However, they are frequently used as compar-
ator in active comparator studies of new glucose-lowering
drugs. Therefore, to estimate the risk of hypoglycaemia,
the comparator groups of randomized controlled trials,
which compare new drugs with sulfonylureas or insulin,
may be a suitable source of information.
The aim of this systematic review and meta-analysis was
to investigate the proportion of patients with type 2 diabetes
mellitus that experience mild or severe hypoglycaemia in
current-day practice when treated with sulfonylureas or a
once-daily or twice-daily insulin regimen with or without
additional metformin therapy.
Materials and methods
The Preferred Reporting Items for Systematic Reviews
and Meta-Analyses was used as a guideline for this study.
In June 2011, we performed an electronic search of
MEDLINE and EMBASE to identify randomized controlled
trials that compared the glucagon-like peptide-1 agonists
or the dipeptidylpeptidase-4 inhibitors with sulfonylureas,
insulin glargine or pre-mixed insulin in patients with type
2 diabetes mellitus. The complete search strategy can be
found in the supporting information. We limited our
search to research performed in humans and reported in
the English language. The reference lists of the included
studies were searched manually for further relevant
studies. The assessment reports of the European Medicines
Agency for liraglutide, exenatide, sitagliptin, vildagliptin
and saxagliptin and the abstract books of the annual meet-
ings of the European Association of the Study of Diabetes
and the American Diabetes Association between 2001 and
2011 were manually screened for additional studies.
Study selection
Two reviewers (J.S., A.S., S.H.) independently screened
the records. Randomized controlled trials with a duration
of at least 12 weeks comparing a glucagon-like peptide-1
agonist or a dipeptidylpeptidase-4 inhibitor with sulfonyl-
ureas and a once-daily or a twice-daily insulin regimen
with or without additional metformin therapy in patients
Copyright © 2013 John Wiley & Sons, Ltd.
15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
J. E. Schopman et al.
with type 2 diabetes mellitus were included. Agreement
on the final inclusion was reached by discussion.
Data extraction
Two authors (J.S. and A.S. or S.H.) independently extracted
the relevant data from the comparator arm of the
included publications: sulfonylurea therapy and once-daily
or twice-daily insulin regimens. The following data were
extracted: first author, year of publication, study design,
trial duration, generic drug name and mean dose,
number of subjects, mild and severe hypoglycaemia
definition, method of hypoglycaemia assessment, number
of patients experiencing mild or severe hypoglycaemia
and total number of mild and severe hypoglycaemic
episodes. Furthermore, we extracted baseline, change and
endpoint HbA1c, body mass index at baseline and the
duration of diabetes.
When studies reported data on hypoglycaemic episodes
but did not clearly describe the definition of mild or severe
hypoglycaemia or the way hypoglycaemic episodes were
assessed, we contacted the corresponding author for
additional information. When different publications reported
on the same dataset, the publication with the longest trial
duration was selected.
Categories of hypoglycaemia
The definition of mild hypoglycaemia differed between
studies. Therefore, we grouped the studies with identical
definitions. These categories were as follows: blood glucose
≤3.9 mmol/L, ≤3.5 mmol/L, ≤3.3 mmol/L, ≤3.1 mmol/L
and ≤2.8 mmol/L. We considered severe hypoglycaemia
as one group, because the majority of studies utilized the
same definition (assistance from a third party is required
to effect treatment).
Quality assessment for individual
studies and overall quality of evidence
While the recall of severe hypoglycaemia in subjects with
type 2 diabetes mellitus is relatively robust over a period
of 1 year [3], reliability of the recall of mild hypoglycaemia
is unknown. In subjects with type 1 diabetes mellitus, the
recall of mild hypoglycaemia is unreliable after an interval
of 1 week [4]. It is therefore important to assess episodes
of mild hypoglycaemia directly after its occurrence. Mild
hypoglycaemic events in clinical trials may be based on
retrospective data if trial participants are asked at a study
visit if they experienced any hypoglycaemic events during
a previous period. Prospective data are retrieved if
Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr

Hypoglycaemia with Sulfonylureas
participants are asked to report or document the episode of
hypoglycaemia directly after the occurrence of the event.
Therefore, two reviewers (J.S., A.S., S.H.) indepen-
dently documented the characteristics of hypoglycaemia
assessment. A study was considered to constitute a low
risk of bias when episodes were documented prospec-
tively. Disagreements between reviewers were discussed
and resolved by consensus.
No quality assessment was performed for the measure-
ment of the incidence of severe hypoglycaemia, because
retrospective measurements of severe hypoglycaemic
events are considered to have a similar reliability as
prospective measurements over a period up to 1 year [3].
Data synthesis and statistical methods
The proportion of subjects with at least one episode of
mild and severe hypoglycaemia and the average number
of hypoglycaemic events (expressed per patient per year)
were extracted or calculated with the total number of
subjects in the intention-to-treat analysis. The proportions
were logit transformed before they were meta-analysed.
When none of the patients in a study experienced
hypoglycaemia, 0.5 was added to the number of
hypoglycaemic and non-hypoglycaemic events so that
the logit transformation resulted in quantities that could
be defined. Meta-analysis was performed by the use of
Review Manager [(RevMan) computer programme,
version 5.0, Copenhagen: The Nordic Cochrane Centre,
The Cochrane Collaboration, 2008]. The logit proportions
were pooled using a random effects model because
heterogeneity between studies was anticipated. The
results were back-transformed to proportions and
presented with their 95% confidence intervals (95% CI).
Heterogeneity was assessed using the I2 statistic and the
Cochran Q. The I2 statistic describes the percentage of the
variability due to differences between studies (heteroge-
neity) where 0% indicates absence of heterogeneity and
100% all variance due to heterogeneity. If Q is significant,
the homogeneity hypothesis is rejected. We stratified
the analyses of hypoglycaemia with blood glucose
≤3.1 mmol/L and severe hypoglycaemia by sulfonylurea
types. These subgroup analyses were defined a priori.
To investigate possible associations between the logit
proportion of subjects with at least one hypoglycaemic event
and baseline HbA1c, analysis of HbA1c change during the
study, age at inclusion, study duration and diabetes duration
meta-regression analysis was performed by the use of Stata
(StataCorp. 2009, Stata Statistical Software: Release 11,
College Station, TX: StataCorp LP) for Windows.
We performed a sensitivity analysis at study level in
order to explore the robustness of the mild hypoglycaemia
data. We repeated the analysis of mild hypoglycaemia
Copyright © 2013 John Wiley & Sons, Ltd.
15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
13
(≤3.1 mmol/L) by restricting the analysis to studies that
were considered to have a low risk of bias (i.e. when
hypoglycaemia episodes were documented prospectively).
The analysis of severe hypoglycaemia was repeated by
restricting the analysis to studies that had defined severe
hypoglycaemia as third party assistance.
Results
Figure 1 summarizes the study identification and selec-
tion process. After removal of duplicates, 2338 potentially
relevant records were identified. Of these, we excluded
2300 publications by review of the abstract. After the
review of 38 full articles, 12 were excluded: 7 because
the publication reported on the same population as
another study that was already included in the selection, 3
because no data on hypoglycaemia were addressed and
2 because patients were on a combination of sulfonylurea
and insulin therapy. One study was excluded during
data extraction as no definition of mild or severe
hypoglycaemia was given, and after contacting the
author, the definition could not be retrieved [5]. Finally,
25 studies could be included in the analysis of the occur-
rence of hypoglycaemia in patients with type 2 diabetes
mellitus treated with sulfonylureas (n = 22) [6–27],
2900 records identified:
*MEDLINE: 675
*EMBASE: 2225
*MANUAL SEARCH: 0
562 duplicates
2338
2300 excluded by review of abstract
38
12 excluded by review of full article:
*reported on same population
as another study: 7
*hypoglycaemia not reported: 3
*used combination insulin and
sulfonylurea: 2
26
1 excluded by data extraction:
*no definition of hypoglycaemia
25 included for data analysis:
*sulfonylurea: 22
*insulin glargine: 1
*pre-mixed insulin: 2
Figure 1. Summary of the study identification and selection
process
Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr

14
insulin glargine (n = 1) [28] and pre-mixed insulin
(n = 2) [29,30]. The corresponding author of one study
[31] answered our data request by sending us a manu-
script of a very recent published study that was the ex-
tended version of the study, and it reported on the same
population [13]. We have chosen to include the extended
version in this meta-analysis.
Table 1 contains the characteristics of the 25 included
studies. The proportion of patients that experienced
hypoglycaemia and the average number of hypoglycaemic
episodes per patient per year are shown in Table 2.
Incidence of mild hypoglycaemia with
sulfonylureas
The analysis of the proportion of patients with a
hypoglycaemic event defined as blood glucose
<3.1 mmol/L contained 5965 patients. Overall pooling
of the data showed that 10.1% had a hypoglycaemic event
(95% CI 7.3–13.8%) with vast heterogeneity between the
studies (I2 = 93%, Figure 2A). the data for sulfonylurea
type showed that a lower proportion of patients taking
gliclazide (n = 1040) experienced hypoglycaemia 1.4%
(95% CI 0.8–2.4%), when compared with those taking
glimepiride (n = 4793) 15.5% (95% CI 12.3–19.2%; test
for subgroup differences: I2 = 98%, p < 0.001, Figure 3).
The analysis of the proportion of patients with at least
one hypoglycaemic event defined by a blood glucose
<2.8 mmol/L contained 822 patients. Pooling of the data
showed that 5.9% had a hypoglycaemic event (95% CI
2.5–13.4%; I2 = 79%, Figure 2B).
The average number of mild hypoglycaemic episodes
per patient per year for various cut-off values is presented
in Table 2.
Incidence of severe hypoglycaemia with
sulfonylureas
The analysis of severe hypoglycaemia contained 6500
patients, and 0.8% experienced hypoglycaemia (95%
CI 0.5–1.3%; I2 = 50%, Figure 2C). One small study solely
included patients with chronic renal insufficiency and
found a relatively high incidence of severe hypoglycaemia
[8]. However, only one episode of severe hypoglycaemia
was observed during the course of this study, and the
pooled estimate of hypoglycaemia remained identical
when this study was left out of the analysis.
A lower proportion of patients experienced severe
hypoglycaemia when taking gliclazide (n = 1040) 0.1%
(95% CI 0–0.7%) than patients taking glipizide
(n = 1014) 2.1% (95% CI 0.9–5.1%; test for subgroup dif-
ferences: I2 = 87%, p < 0.01), and a trend was noted for a
Copyright © 2013 John Wiley & Sons, Ltd.
15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
J. E. Schopman et al.
lower proportion of hypoglycaemia for gliclazide versus
glimepiride therapy (n = 3861) 0.9% (95% CI 0.6–1.3%;
test for subgroup differences: I2 = 74%, p = 0.05,
Figure 3). The proportion of patients with hypoglycaemia
did not differ between gliclazide and glibenclamide use
(n = 488) 0.5% (95% CI 0.1–2.0%; test for subgroup
differences: I2 = 47%, p = 0.17).
The average numbers of episodes of severe
hypoglycaemia per patient per year for various cut-off
values are presented in Table 2.
Incidence of mild and severe
hypoglycaemia with insulin therapy
Too few studies had insulin as comparator, so these could
not be meta-analysed [28–30] (Tables 1 and 2).
Regression analyses
Table 3 presents the odds ratios for each predictor and the
risk for hypoglycaemia. With univariate meta-regression
analysis, no significant associations were found between
the proportion of subjects with at least one mild
hypoglycaemic event (glucose <3.1 mmol/L) and baseline
HbA1c, HbA1c change during the study, age at inclusion,
study duration and diabetes duration. Therefore, multivar-
iate regression analysis was not performed. Two significant
associations with univariate meta-regression analysis were
found for severe hypoglycaemia. HbA1c baseline was in-
versely related with the proportion of patients with severe
hypoglycaemia, an effect corresponding to an odds ratio of
0.33 (95% CI 0.13–0.85, p = 0.03) per 1% HbA1c. Study
duration was associated with an increased proportion of
patients with severe hypoglycaemia, corresponding to an
odds ratio of 1.95 (95% CI 1.12–3.38, p = 0.02) per study
year. All predictors with a p-value <0.25 were entered in
a stepwise multivariate meta-regression analysis, and none
were found significant.
Sensitivity analyses
Details on hypoglycaemia assessment per study are pro-
vided in Table 1. Of the 12 studies [10–12,14,15,19,21–
23,26,27,30] that were selected for the meta-analyses of mild
hypoglycaemia (<3.1 mmol/L), 6 studies [10,11,14,19,23,30]
were assessed having a low risk of bias for the incidence of
hypoglycaemia. One study [15] was considered to have a high
risk of bias, because hypoglycaemia was retrospectively
assessed. The five remaining studies [12,21,22,26,27] had
an uncertain risk of bias. Subgroup analyses showed no signif-
icant difference in the incidence of mild hypoglycaemia
Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr
 Table 1. The characteristics of the 25 included studies

Dose Mild
(mg/ day Other OHA Diabetes HbA1c HbA1c HbA1c hypoglycaemia Severe
or IU/ during trial Eligible Age duration BMI bas [% change [% end [% Hypoglycaemia definition hypoglycaemia
2
Study Year Drug day) (dose mg/day) population (years) (years) (kg/m ) (mmol/mol)] (mmol/mol)] (mmol/mol)] assessment (mmol/L) definition

Prospective Diary

Arechavaleta 2011 Glimepiride 2.1 Metformin T2DM, stable dose 56.2 6.7 30.2 7.5 (58) 0.5 (5.5) 7.0 (53) + + ≤3.9, ≤2.8 HTP
et al. [6] (≥1500) of metformin
(≥1500 mg/day),
diet and exercise
for at least 12 weeks
Hypoglycaemia with Sulfonylureas

Copyright © 2013 John Wiley & Sons, Ltd.

prior to the
screening visit
Bergenstal 2009 Insulin 96.1 Metformin T2DM for > 6 53.4 9.9 33.5 10.3 (89) 0.9 (9.8) 7.6 (60) + + <3.1 HTP
et al. [29] aspart (≥1500) months, insulin
naive, had received
therapy with
metformin (at least
1500 mg/day) and
SU (at least half the
maximum dose)
Bunck 2009 Insulin 34.0 Metformin T2DM, stable dose 58.3 4.0 30.1 7.4 (57) 0.7 (7.7) 6.8 (51) + <3.3 n.s.
et al. [28] glargine of metformin
Chacra 2009 Glibenclamide 14.6 T2DM, sub maximal 55.1 6.8 28.8 8.4 (68) 0.1 (1.1) 8.5 (69) n.s. n.s. ≤2.8 Medical
et al. [7] SU dose assistance
Chan 2008 Glipizide n.s. T2DM, renal 65.3 13.2 26.9 7.8 (62) 1.0 (10.9) n.s. + + symp HTP
et al. [8] insufficiency
Derosa 2010 Glibenclamide n.s. Metformin T2DM 56.0 n.s. 28.5 8.9 (74) n.s. 7.1 (54) n.s. n.s. <3.3 n.s.
et al. [9] (mean 1500)
Ferrannini 2009 Glimepiride 4.5 Metformin T2DM, stable 57.5 5.8 31.7 7.3 (56) 0.5 (5.5) 6.7 (50) + + <3.1 HTP
et al. [10] (mean 1898) dose of metformin
Filozof 2010 Gliclazide 230.0 Metformin T2DM, stable dose 59.7 6.8 30.8 8.5 (69) 0.9 (9.8) n.s. + + <3.1 HTP
et al. [11] (≥1500) of metformin
(≥1500 mg/day)
Foley 2009 Gliclazide 209.0 Metformin T2DM, OHA naive, 54.3 1.9 30.8 8.7 (72) 0.6 (6.6) 7.7 (61) n.s. n.s. <3.1 HTP
et al. [12] possible BMI 22–45 kg/m 2,
FPG < 15 mmol/l
Gallwitz 2011 Insulin 28.4 Metformin T2DM, metformin 57.0 5.0 32.9 7.9 (63) 1.1 (12.0) n.s. + + ≤3.9, ≤3.0 HTP
et al. [30] aspart
Gallwitz 2012 Glimepiride 3.0 Majority T2DM, metformin 59.8 n.s. 30.3 7.7 (61) 0.4 (4.4) n.s. + + ≤3.0, ≤3.9 HTP
et al. [13] metformin with or without
(1500) other OHA (no
rosiglitazone or
pioglitazone)
Garber 2008 Glimepiride 4.0 T2DM, inadequate 57.9 7.8 31.0 8.5 (69) n.s. n.s. + <3.1 HTP
et al. [15] control by SU
monotherapy
Garber 2011 Glimepiride 8.0 n.s. T2DM 53.4 5.6 33.2 8.2 (66) 0.3 (3.3) 7.5 (58) + + <3.1 HTP
et al.
(LEAD- 3) [14]

DOI: 10.1002/dmrr
15

Diabetes Metab Res Rev 2014; 30: 11–22.

(Continues)

15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 16

Table r2470-tbl-0001.
1. Continued (continued)

Dose Mild
(mg/ day Other OHA Diabetes HbA1c HbA1c HbA1c hypoglycaemia Severe
or IU/ during trial Eligible Age duration BMI bas [% change [% end [% Hypoglycaemia definition hypoglycaemia
2
Study Year Drug day) (dose mg/day) population (years) (years) (kg/m ) (mmol/mol)] (mmol/mol)] (mmol/mol)] assessment (mmol/L) definition

Prospective Diary
Goke 2010 Glipizide 14.7 Metformin T2DM, stable dose 57.6 5.4 31.3 7.7 (61) 0.8 (8.7) 7.5 (58) + + <3.5, ≤2.8 Medical
et al. [16] (≥1000) of metformin assistance

Copyright © 2013 John Wiley & Sons, Ltd.

(≥1500 mg/day),
monotherapy
Hermansen 2007 Glimepiride n.s. Metformin T2DM, insulin naive 55.2 8.0 30.7 8.4 (68) n.s. n.s. n.s. n.s. n.s. Medical
et al. [17] assistance
Kaku 2010 Glibenclamide, n.s. T2DM, Japanese, 58.6 10.1 24.9 8.5 (69) -0.4 (4.4) 8.1 (65) n.s. n.s. n.s. HTP
et al. [18] gliclazide or SU for ≥8 weeks
glimepiride
Kikuchi 2010 Glimepiride 2.5 T2DM, Japanese, 60.3 9.8 24.4 8.2 (64) 0.1 (1.1) n.s. + + <3.1 HTP
et al. [19] inadequate control
with diet, exercise
and glimepiride
monotherapy
Madsbad 2004 Glimepiride 2.7 T2DM, diet or OHA 57.0 3.8 30.2 7.8 (62) n.s. n.s. <2.8 n.s.
et al. [20]
Marre 2008 Glimepiride n.s. T2DM, OHA, 54.7 n.s. 30.3 8.4 (68) 0.2 (2.2) n.s. n.s. n.s. <3.1 HTP
(LEAD-1) et al. insulin naïve
[21]
Matthews 2010 Glimepiride n.s. Metformin T2DM, inadequate 57.5 5.7 31.7 7.3 (56) 0.3 (3.3) n.s. n.s. n.s. <3.1 HTP
et al. [22] control with
metformin monotherapy
Nauck 2009 Glimepiride 4.0 Metformin T2DM, OHA, 57.0 8.0 31.2 8.4 (68) 1.0 (10.9) n.s. + + <3.1 HTP
et al. insulin naive
(LEAD-2) [23]
Pratley 2009 Glibenclamide 11.2 T2DM, inadequate 57.1 7.7 30.0 8.2 (66) 0.0 (0) n.s. + + <3.3 w symp, HTP
et al. [24] control with <2.8 w or w/o
sulfonylurea monotherapy symp
Seck 2010 Glipizide 10.0 T2DM, stable dose 57.0 5.7 31.3 7.3 (56) 0.5 (5.5) 6.8 (51) + + <3.9, <3.3, HTP
et al. [25] of metformin <2.8
Seino 2010 Glibenclamide n.s. T2DM, with and 58.5 8.5 24.4 8.8 (73) 1.2 (13.1) 7.5 (58) n.s. n.s. <3.1 HTP
et al. [26] without OHA
Yang 2010 Glimepiride n.s. Metformin T2DM, at 53.6 7.8 25.3 8.5 (69) 1.4 (15.3) n.s. n.s. n.s. <3.1 w symp HTP
et al. [27] (2000) least 1 OHA

Data are presented as mean, unless otherwise stated.

bas, baseline; BMI, body mass index; end, endpoint; FPG, fasting plasma glucose; HTP, help of a third party; IU, international units; n.s., not specified; OHA, oral hypoglycaemic agent;
symp, symptoms; SU, sulfonylurea derivatives; T2DM, type 2 diabetes mellitus; w, with; w/o, without; +, positive; -, negative.

DOI: 10.1002/dmrr
J. E. Schopman et al.

Diabetes Metab Res Rev 2014; 30: 11–22.

15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 Table 2. Hypoglycaemia incidence in the 25 studies

Trial Any Hypo Any Hypo Any hypo Hypo Any Hypo Any hypo Hypo Any Rate
duration hypo ≤3.9 rate ≤3.9 hypo ≤3.5 rate ≤3.5 ≤3.3 rate ≤3.3 hypo ≤3.1 rate ≤3.1 ≤2.8 rate ≤2.8 severe severe
Author Year Drug n (weeks) mmol/L (%) mmol/L mmol/L (%) mmol/L mmol/L (%) mmol/L mmol/L(%) mmol/L mmol/L(%) mmol/L hypo(%) hypo

Arechavaleta 2011 Glimepiride 518 30 1.04 0.20 0.7 0.020

et al. [6]
Bergenstal 2009 Insulin aspart 124 24 52 5.30 6.0 0.130
et al. [29] 70/30 BID
Bunck 2009 Insulin 33 52 24 0.0 0.000
et al. [28] glargine
Chacra 2009 Glibenclamide 267 24 1 0.02 0.0 0.000
et al. [7]
Chan 2008 Glipizide 25 42 4.0 0.100
Hypoglycaemia with Sulfonylureas

et al. [8]

Copyright © 2013 John Wiley & Sons, Ltd.

Derosa 2010 Glibenclamide 57 52 5 0.05
et al. [9]
Ferrannini 2009 Glimepiride 1393 52 16 0.40 0.7 0.007
et al. [10]
Filozof 2010 Gliclazide 494 52 1 0.02 0.0 0.000
et al. [11]
Foley 2009 Gliclazide 546 104 2 0.01 0.0 0.000
et al. [12]
Gallwitz 2011 Insulin aspart 173 26 21 6 0.0 0.000
et al. [30] 70/30 BID
Gallwitz 2012 Glimepiride 775 114 31 0.15 13 0.05 2.0 0.007
et al. [13]
Garber 2008 Glimepiride 144 24 0.7 0.015 0.7 0.015
et al. [15]
Garber 2011 Glimepiride 248 104 26 1.75 0.0 0.000
(LEAD- 3)
et al. [14]
Goke 2010 Glipizide 430 52 50 1.15 33 0.81 9 0.15 0.9 0.009
et al. [16]
Hermansen 2007 Glimepiride 106 24 0.0 0.000
et al. [17]
Kaku 2010 Glimepiride, 88 24 0.0 0.000
et al. [18] glibenclamide
or gliclazide
Kikuchi 2010 Glimepiride 100 12 1 0.04 0.0 0.000
et al. [19]
Madsbad 2004 Glimepiride 26 12 15 0.67
et al. [20]
Marre 2008 Glimepiride 114 26 3 0.17 0.0 0.000
et al.
(LEAD-1) [21]
Matthews 2010 Glimepiride 1556 104 18 0.27 0.005
et al. [22]
Nauck 2009 Glimepiride 242 26 17 1.23 0.0 0.000
(LEAD-2)
et al. [23]
Pratley 2009 Glibenclamide 99 26 8 0.16 6 0.12 1.0 0.020
et al. [24]
Seck 2010 Glipizide 559 104 0.47 0.22 0.05 3.0 0.015
et al. [25]
Seino 2010 Glibenclamide 132 24 22 1.58 0.0 0.000
et al. [26]
Yang 2010 Glimepiride 231 16 19 1.16 0.9 0.030
et al. [27]

BID, twice a day; hypo, hypoglycaemia; rate, average number of episodes of hypoglycaemia per patient per year.

DOI: 10.1002/dmrr
Diabetes Metab Res Rev 2014; 30: 11–22.
17

15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
18 J. E. Schopman et al.

Figure 2. Meta-analyses of the occurrence of hypoglycaemia. The proportions were pooled using a random effects model. Heteroge-
2 2
neity was assessed using the I statistic and the Cochran Q. The I statistic describes the percentage of the variability due to differ-
ences between studies where 0% indicates absence of heterogeneity and 100% all variance due to heterogeneity. If Q is significant,
the homogeneity hypothesis is rejected. CI, confidence interval

(<3.1 mmol/L) for the studies with a low risk of bias 11.0%
(95% CI 7.0–16.9%) and for all studies 10.1% (95% CI 7.3–
13.8%; Figure 3).
Three studies had a more stringent definition of severe
hypoglycaemia (i.e. medical assistance) [7,16,17]. The
analysis of severe hypoglycaemia was therefore repeated
without these studies. The incidence of severe hypoglycaemia
with third party assistance was 0.8% (95% CI 0.5–1.4%)
and showed no significant difference when compared with
all studies 0.8% (95% CI 0.5–1.3%).

Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr
 15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Hypoglycaemia with Sulfonylureas 19

Figure 3. Subgroup analyses. Results of meta-analyses within subgroups presenting the summary estimates of the percentage and
95% confidence intervals (CIs) of patients with hypoglycaemia that use sulfonylureas

Table 3. Regression analysis

Mild hypoglycaemia Severe hypoglycaemia

95% CI for odds ratio 95% C. for odds ratio

Predictor Odds ratio Lower Upper p Odds ratio Lower Upper p

Univariate analysis
HbA1c baseline (per 1%) 0.41 0.06 2.67 0.32 0.33 0.13 0.85 0.03
HbA1c change (per 1%) 0.40 0.05 3.39 0.34 0.88 0.20 3.89 0.86
Age (per year) 0.86 0.57 1.29 0.43 1.18 0.95 1.45 0.12
Study duration (per year) 1.47 0.40 5.48 0.53 1.95 1.12 3.38 0.02
Duration of diabetes (per year) 1.04 0.57 1.90 0.88 1.13 0.85 1.51 0.37
Multivariate analysis
HbA1c baseline (per 1%) — — — — 0.44 0.15 1.30 0.13
HbA1c change (per 1%) — — — — — — — —
Age (per year) — — — — 1.11 0.91 1.35 0.29
Study duration (per year) — — — — 1.31 0.63 2.73 0.44
Duration of diabetes (per year) — — — — — — — —

Results of univariate and stepwise multivariate meta-regression analyses of the influence of potential risk factors on the proportion of
patients with mild or severe hypoglycaemia in patients with type 2 diabetes mellitus on sulfonylurea therapy. Predictors with a p-value
<0.25 were entered in a stepwise multivariate meta-regression analysis.
CI, confidence interval.

Discussion Outcome Reduction with Initial Glargine Intervention

This meta-analysis of patients with type 2 diabetes
mellitus shows that out of 100 patients treated with
sulfonylurea therapy, 10 experienced mild hypoglycaemia
with a blood glucose <3.1 mmol/L, 6 experienced mild
hypoglycaemia with a blood glucose <2.8 mmol/L and
only 0.8 experienced severe hypoglycaemia with 12 to
104 weeks of treatment. This means that 90% of
patients do not experience any relevant hypoglycaemia.
A similar observation was recently made in the
(ORIGIN) trial: % of the patients in the standard care
group and 43% in the insulin glargine group did not
have any symptomatic hypoglycaemia over a study period
of 6 years [32].
The patients of the included studies in this meta-
analysis experienced between 0.01 and 1.75 episodes
of hypoglycaemia with a glucose ≤3.1 mmol/L and
between 0 and 0.1 episodes of severe hypoglycaemia per
patient per year. This is less than was reported in a
prospective British study that investigated self-reported

Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr

20
hypoglycaemia in patients with type 2 diabetes
mellitus with good glycaemic control (HbA1c 7.5%)
[33]. In this study, subjects were asked to record epi-
sodes of hypoglycaemia if plasma glucose was
<3.0 mmol/L over an average period of approximately
9 months. Of the 103 sulfonylurea-treated patients,
39% experienced at least one episode of mild
hypoglycaemia, for an average number of 1.92 epi-
sodes of mild hypoglycaemia per patient per year.
Severe hypoglycaemia that required the help of a third
party was estimated at 0.1 episodes per patient per
year and affected 7%. More consistent with our find-
ings are the results of another British study: self-
reported mild hypoglycaemia was reported by 17% of
922 sulfonylurea-treated patients [34]. Severe
hypoglycaemia that required medical assistance affected
0.8% of the trial participants, and the average number
of severe hypoglycaemic episodes per patient per year
was 0.009 [35].
One should remember that changing the glucose cut-
off value that defines hypoglycaemia has a major effect
on the reported frequency of hypoglycaemia [36]. To
enable comparison of hypoglycaemia incidence between
studies, subcategories were created. However, vast
heterogeneity between studies remained.
HbA1c at baseline and study duration were significantly
associated with the proportion of patients with severe
hypoglycaemia in a univariate meta-regression analysis,
but neither was found significant in a multivariate meta-re-
gression analysis. A lower proportion of patients taking
gliclazide experienced a mild hypoglycaemic event (1.4%)
compared with those taking glimepiride (15.5%).
Furthermore, a lower proportion of patients taking
gliclazide (0.1%) experienced severe hypoglycaemia
compared with those taking glipizide (2.1%), and a
similar trend was observed for gliclazide versus glimepiride
(0.9%). Thus, our meta-analysis confirms previous
observations of a lower hypoglycaemia risk with
gliclazide versus glimepiride [37] and glipizide [38].
Similar observations have been found for gliclazide
versus glibenclamide but were not confirmed in this
meta-analysis [38,39].
Our study has some limitations. Selected participants
in randomized controlled trials differ from the general
population with type 2 diabetes mellitus. Often,
subjects are excluded from participation if they are older,
had previous severe hypoglycaemia episodes and have
cognitive or renal impairment or other comorbidities
that may increase the risk of hypoglycaemia. Moreover,
the participants in the randomized controlled trials did
not test their blood glucose at set times, and we cannot
guarantee that patients checked their blood glucose
every time they experienced hypoglycaemia. Thus,
some underestimation of the frequency of non-severe
Copyright © 2013 John Wiley & Sons, Ltd.
15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
J. E. Schopman et al.
hypoglycaemia may have occurred. Although the study
subjects were broadly representative of patients using
sulfonylurea derivatives, there was a great variability
between studies in sulfonylurea agents, diabetes
duration, metabolic control, drug combinations and
pharmacological doses. Therefore, the estimated
incidence of hypoglycaemia in this meta-analysis
cannot be directly extrapolated to the entire type 2
diabetes mellitus population, and caution should be
exercised when applying the data of this study to
individual patients.
In conclusion, approximately 90% of patients with
type 2 diabetes mellitus, in randomized controlled
trials on sulfonylurea therapy in combination with or
without metformin therapy, remain free of relevant
hypoglycaemia during 12 to 114 weeks of treatment.
Gliclazide therapy is accompanied by a lower risk of
hypoglycaemia when compared with glimepiride.
Acknowledgements
We acknowledge the contribution of Mrs Heleen C. Dyserinck,
Clinical Librarian, Academic Medical Centre, Amsterdam, for
her help in performing the search. We further acknowl-
edge Novo Nordisk, Novartis, Bristol-Myers Squibb and
Boehringer-Ingelheim for providing us with the requested
information.
Authors’ contributions
J.S. contributed to literature review, data extraction
and data analysis and wrote the manuscript. A.S. and
S.H. contributed to literature review and data extrac-
tion and critically reviewed the manuscript. R.S. con-
tributed to the data analysis and data interpretation
and critically reviewed the manuscript. J.H. and F.H.
contributed to the conception and design and interpre-
tation of the data and critically reviewed the manu-
script. J.S. and F.H. are the guarantors of this work
and, as such, had full access to all of the data in the
study and take responsibility for the integrity of the
data and the accuracy of the data analysis. All authors
significantly contributed to the work and approved the
manuscript for submission.
Conflict of interest
The authors have no conflicts of interest.
Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr

Hypoglycaemia with Sulfonylureas
References
1. National Institute for Health and Clinical
Excellence. CG87 type 2 diabetes –
newer agents (a partial update of
CG66): short guideline, 2011.
2. International Diabetes Federation. Global
guideline for type 2 diabetes, 2012.
3. Akram K, Pedersen-Bjergaard U, Carstensen
B, Borch-Johnsen K, Thorsteinsson B. Pro-
spective and retrospective recording of se-
vere hypoglycaemia, and assessment of
hypoglycaemia awareness in insulin-
treated type 2 diabetes. Diabet Med 2009;
26(12): 1306–1308.
4. Pramming S, Thorsteinsson B, Bendtson
I, Binder C. Symptomatic hypoglycaemia
in 411 type 1 diabetic patients. Diabet
Med 1991; 8: 217–222.
5. Scott R, Wu M, Sanchez M, Stein P.
Efficacy and tolerability of the dipeptidyl
peptidase-4 inhibitor sitagliptin as
monotherapy over 12 weeks in patients
with type 2 diabetes. Int J Clin Pract
2007; 61(1): 171–180.
6. Arechavaleta R, Seck T, Chen Y, et al.
Efficacy and safety of treatment with
sitagliptin or glimepiride in patients
with type 2 diabetes inadequately
controlled on metformin monotherapy:
a randomized, double-blind, non-
inferiority trial. Diabetes Obes Metab
2011; 13(2): 160–168.
7. Chacra AR, Tan GH, Apanovitch A,
Ravichandran S, List J, Chen R.
Saxagliptin added to a submaximal
dose of sulphonylurea improves
glycaemic control compared with
uptitration of sulphonylurea in patients
with type 2 diabetes: a randomised
controlled trial. Int J Clin Pract 2009;
63(9): 1395–1406.
8. Chan JC, Scott R, Arjona Ferreira JC,
et al. Safety and efficacy of sitagliptin
in patients with type 2 diabetes and
chronic renal insufficiency. Diabetes Obes
Metab 2008; 10(7): 545–555.
9. Derosa G, Maffioli P, Salvadeo SA, et al.
Exenatide versus glibenclamide in pa-
tients with diabetes. Diabetes Technol
Ther 2010; 12(3): 233–240.
10. Ferrannini E, Fonseca V, Zinman B, et al.
Fifty-two-week efficacy and safety of
vildagliptin vs. glimepiride in patients
with type 2 diabetes mellitus inade-
quately controlled on metformin
monotherapy. Diabetes Obes Metab
2009; 11(2): 157–166.
11. Filozof C, Gautier JF. A comparison of
efficacy and safety of vildagliptin and
gliclazide in combination with metfor-
min in patients with type 2 diabetes
inadequately controlled with metformin
alone: a 52-week, randomized study.
Diabet Med 2010; 27(3): 318–326.
12. Foley JE, Sreenan S. Efficacy and
safety comparison between the DPP-4
inhibitor vildagliptin and the sulfonyl-
urea gliclazide after two years of
monotherapy in drug-naive patients
Copyright © 2013 John Wiley & Sons, Ltd.
with type 2 diabetes. Horm Metab Res
2009; 41(12): 905–909.
13. Gallwitz B, Rosenstock J, Rauch T, et al.
2-year efficacy and safety of linagliptin
compared with glimepiride in patients
with type 2 diabetes inadequately con-
trolled on metformin: a randomised,
double-blind, non-inferiority trial. Lancet
2012; 380(9840): 475–483.
14. Garber A, Henry RR, Ratner R, Hale P,
Chang CT, Bode B. Liraglutide: a once-
daily human glucagon-like peptide 1
analogue, provides sustained improve-
ments in glycaemic control and weight
for 2 years as monotherapy compared
with glimepiride in patients with type
2 diabetes. Diabetes Obes Metab 2011;
13(4): 348–356.
15. Garber AJ, Foley JE, Banerji MA, et al.
Effects of vildagliptin on glucose control
in patients with type 2 diabetes
inadequately controlled with a monotherapy. Diabetes Obes Metab
sulphonylurea. Diabetes Obes Metab
2008; 10(11): 1047–1056.
16. Goke B, Gallwitz B, Eriksson J, Hellqvist
A, Gause-Nilsson I. Saxagliptin is non-
inferior to glipizide in patients with type
2 diabetes mellitus inadequately
controlled on metformin alone: a 52-
week randomised controlled trial. Int J
Clin Pract 2010; 64(12): 1619–1631.
17. Hermansen K, Kipnes M, Luo E, Fanurik
D, Khatami H, Stein P. Efficacy and
safety of the dipeptidyl peptidase-4
inhibitor, sitagliptin, in patients with
type 2 diabetes mellitus inadequately
controlled on glimepiride alone or on
glimepiride and metformin. Diabetes
Obes Metab 2007; 9(5): 733–745.
18. Kaku K, Rasmussen MF, Clauson P, Seino
Y. Improved glycaemic control with mini-
mal hypoglycaemia and no weight change
with the once-daily human glucagon-like
peptide-1 analogue liraglutide as add-on
to sulphonylurea in Japanese patients
with type 2 diabetes. Diabetes Obes Metab
2010; 12(4): 341–347.
19. Kikuchi M, Haneda M, Koya D, et al.
Efficacy and tolerability of vildagliptin as
an add-on to glimepiride in Japanese pa-
tients with type 2 diabetes mellitus. Diabe-
tes Res Clin Pract 2010; 89(3): 216–223.
20. Madsbad S, Schmitz O, Ranstam J,
Jakobsen G, Matthews DR. Improved
glycemic control with no weight
increase in patients with type 2 diabetes
after once-daily treatment with the
long-acting glucagon-like peptide 1
analog liraglutide (NN2211): a 12-
week, double-blind, randomized,
controlled trial. Diabetes Care 2004; 27
(6): 1335–1342.
21. Marre M, Shaw J, Brandle M, et al.
Liraglutide: a once-daily human GLP-1 an-
alogue, added to a sulphonylurea over
26 weeks produces greater improvements
in glycaemic and weight control compared
with adding rosiglitazone or placebo in
15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
21
subjects with type 2 diabetes (LEAD-1
SU). Diabet Med 2009; 26(3): 268–278.
22. Matthews DR, Dejager S, Ahren B, et al.
Vildagliptin add-on to metformin
produces similar efficacy and reduced
hypoglycaemic risk compared with
glimepiride, with no weight gain: results
from a 2-year study. Diabetes Obes Metab
2010; 12(9): 780–789.
23. Nauck M, Frid A, Hermansen K, et al.
Efficacy and safety comparison of
liraglutide, glimepiride, and placebo,
all in combination with metformin, in
type 2 diabetes: the LEAD (liraglutide
effect and action in diabetes)-2 study.
Diabetes Care 2009; 32(1): 84–90.
24. Pratley RE, Kipnes MS, Fleck PR, Wilson
C, Mekki Q. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor
alogliptin in patients with type 2 diabe-
tes inadequately controlled by glyburide
2009; 11(2): 167–176.
25. Seck T, Nauck M, Sheng D, et al. Safety
and efficacy of treatment with sitagliptin
or glipizide in patients with type 2
diabetes inadequately controlled on
metformin: a 2-year study. Int J Clin
Pract 2010; 64(5): 562–576.
26. Seino Y, Rasmussen MF, Nishida T, Kaku
K. Efficacy and safety of the once-daily
human GLP-1 analogue, liraglutide, vs
glibenclamide monotherapy in Japanese
patients with type 2 diabetes. Curr Med
Res Opin 2010; 26(5): 1013–1022.
27. Yang W, Chen L, Ji Q, et al. Liraglutide
provides similar glycaemic control as
glimepiride (both in combination with met-
formin) and reduces body weight and sys-
tolic blood pressure in Asian population
with type 2 diabetes from China, South Ko-
rea and India: a 16-week, randomized,
double-blind, active control trial(*). Diabe-
tes Obes Metab 2011; 13(1): 81–88.
28. Bunck MC, Diamant M, Corner A, et al.
One-year treatment with exenatide im-
proves beta-cell function, compared
with insulin glargine, in metformin-
treated type 2 diabetic patients: a
randomized, controlled trial. Diabetes
Care 2009; 32(5): 762–768.
29. Bergenstal R, Lewin A, Bailey T, Chang
D, Gylvin T, Roberts V. Efficacy and
safety of biphasic insulin aspart 70/30 ver-
sus exenatide in subjects with type 2 diabe-
tes failing to achieve glycemic control with
metformin and a sulfonylurea. Curr Med
Res Opin 2009; 25(1): 65–75.
30. Gallwitz B, Bohmer M, Segiet T, et al.
Exenatide twice daily versus premixed
insulin aspart 70/30 in metformin-
treated patients with type 2 diabetes: a
randomized 26-week study on glycemic
control and hypoglycemia. Diabetes Care
2011; 34(3): 604–606.
31. Forst T, Uhlig-Laske B, Ring A, et al.
Linagliptin (BI 1356): a potent and
Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr

22
selective DPP-4 inhibitor, is safe and effi-
cacious in combination with metformin
in patients with inadequately con-
trolled type 2 diabetes. Diabet Med
2010; 27(12): 1409–1419.
32. Gerstein HC, Bosch J, Dagenais GR,
et al. Basal insulin and cardiovascular
and other outcomes in dysglycemia. N
Engl J Med 2012; 367(4): 319–328.
33. U.K. Hypoglycaemia Study Group. Risk
of hypoglycaemia in types 1 and 2
diabetes: effects of treatment modalities
and their duration. Diabetologia 2007;
50(6): 1140–1147.
34. U.K. Prospective Diabetes Study Group.
U.K. prospective diabetes study 16.
Supporting information
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Copyright © 2013 John Wiley & Sons, Ltd.
Overview of 6 years’ therapy of type II
diabetes: a progressive disease. Diabetes
1995; 44(11): 1249–1258.
35. Leese GP, Wang J, Broomhall J, et al. Fre-
quency of severe hypoglycemia requiring
emergency treatment in type 1 and type
2 diabetes: a population-based study of
health service resource use. Diabetes Care
2003; 26(4): 1176–1180.
36. Swinnen SG, Mullins P, Miller M,
Hoekstra JB, Holleman F. Changing the
glucose cut-off values that define
hypoglycaemia has a major effect on
reported frequencies of hypoglycaemia.
Diabetologia 2009; 52(1): 38–41.
15207560, 2014, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dmrr.2470 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
J. E. Schopman et al.
37. Schernthaner G, Grimaldi A, Di MU,
et al. GUIDE study: double-blind com-
parison of once-daily gliclazide MR
and glimepiride in type 2 diabetic
patients. Eur J Clin Invest 2004; 34(8):
535–542.
38. Harrower AD. Comparison of effi-
cacy, secondary failure rate, and
complications of sulfonylureas. J
Diabetes Complications 1994; 8(4):
201–203.
39. Tessier D, Dawson K, Tetrault JP,
Bravo G, Meneilly GS. Glibenclamide
vs gliclazide in type 2 diabetes of
the elderly. Diabet Med 1994; 11:
974–980.
Diabetes Metab Res Rev 2014; 30: 11–22.
DOI: 10.1002/dmrr