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Fighting the Hydra: Optimizing treatment for type 2 diabetes

Simon, A.C.R.

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Citation for published version (APA):Simon, A. C. R. (2014). Fighting the Hydra: Optimizing treatment for type 2 diabetes.

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Chapter 2The incidence of mild and severe hypoglycaemia in patients

with type 2 diabetes mellitus treated with sulfonylureas:

a systematic review and meta-analysis

Josefine E Schopman, Airin C R Simon, Sanne J M Hoefnagel,

Joost B L Hoekstra, Rob J P M Scholten, Frits Holleman

Diabetes Metab Res Rev. 2014;30(1):11-22

Simon.indd 19 14-8-2014 13:24:37

Chapter 2

20

Abstract

ObjectivePatients 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.

Materials and methodsWe searched MEDLINE and EMBASE for randomised controlled trials that compared

incretin-based drugs to sulfonylureas or insulin and assessed hypoglycaemia incidence

in the latter therapies. Subgroup and meta-regression analyses were performed to

study possible associations with potential risk factors for hypoglycaemia.

ResultsData 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% 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

less 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 little studies had insulin as comparator, so

these data could not be meta-analysed.

ConclusionsThe 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.

Simon.indd 20 14-8-2014 13:24:37

Hypoglycemia with sulfonylureas

21

2

Introduction

Despite the proclaimed benefits of newer glucose-lowering drugs over conventional

therapy, many guidelines still recommend using less expensive conventional 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 incidence 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 comparator 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 (PRISMA)

was used as a guideline for this study.

In June 2011, we performed an electronic search of MEDLINE and EMBASE to

indentify 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 supplemental file. 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 meetings

of the European Association of the Study of Diabetes and the American Diabetes

Association between 2001 and 2011 were manually screened for additional studies.

Simon.indd 21 14-8-2014 13:24:37

Chapter 2

22

Study SelectionTwo reviewers (JS, AS or SH) independently screened the records. Randomized con-

trolled trials with a duration of at least 12 weeks comparing a glucagon-like peptide-1

agonist or a dipeptidylpeptidase-4 inhibitor with sulfonylureas and a once-daily or a

twice-daily insulin regimen with or without additional metformin therapy in patients

with type 2 diabetes mellitus were included. Agreement on final inclusion was reached

by discussion.

Data ExtractionTwo authors (JS, AS or SH) 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 hypoglycaemiaThe definition of mild hypoglycaemia differed between studies. Therefore, we

grouped 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 evidenceWhile 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

Simon.indd 22 14-8-2014 13:24:37


23

2

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 participants are asked to

report or document the episode of hypoglycaemia directly after the occurrence of

the event. Therefore, two reviewers (JE, AS or SH) independently documented the

characteristics of hypoglycaemia assessment. A study was considered to constitute

a low risk of bias when episodes were documented prospectively. Disagreements

between reviewers was discussed and resolved by consensus.

No quality assessment was performed for the measurement 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 methodsThe 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 events and the 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

program, 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.

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

(heterogeneity) 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

Simon.indd 23 14-8-2014 13:24:37

Chapter 2

24

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

(≤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 selection process. After removal of

duplicates, 2338 potentially relevant records were identified. Of these, we excluded

2300 publications by review of the abstract. After 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 occurrence of hypoglycaemia in type 2 diabetes mellitus patients

treated with sulfonylureas (n=22) [6-27], 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 manuscript of a very recent published study that was the

extended 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.

Simon.indd 24 14-8-2014 13:24:37


25

2

2900 records iden�fied:

*MEDLINE: 675*EMBASE: 2225*MANUAL SEARCH: 0

25 included for data analysis:

*sulfonylurea: 22*insulin glargine: 1*pre-mixed insulin: 2

562 duplicates

2300 excluded by review of abstract

1 excluded by data extrac�on:

*no defini�on of hypoglycaemia

12 excluded by review of full ar�cle:

*reported on same popula�on as another study: 7

*hypoglycaemia not reported: 3*used combina�on insulin and sulfonylurea: 2

2338

38

26

Figure 1 Summary of the study identification and selection process

Simon.indd 25 14-8-2014 13:24:37

Chapter 2

26

Tabl

e 1

The

char

acte

ristic

s of

the

25 in

clud

ed s

tudi

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Stud

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arD

rug

Dos

e (m

g/

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IU/

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Oth

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Mild

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(mm

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Seve

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Pros

-pe

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Dia

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Arec

ha-

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ta e

t al

[6]

2011

glim

e-pi

ride

2.1

metf

orm

in

(≥15

00)

T2D

M, s

tabl

e do

se o

f m

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min

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y), d

iet a

nd e

xerc

ise

for a

t lea

st 1

2 w

eeks

pr

ior t

o th

e sc

reen

ing

visi

t

56.2

6.7

30.2

7.5

(58)

-0.5

(5

.5)

7.0

(53)

++

≤3.9

, ≤2.

8H

TP

Berg

en-

stal

et a

l [2

9]

2009

insu

lin

aspa

rt96

.1m

etfor

min

(≥

1500

)T2

DM

for >

6 m

onth

s,

insu

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aive

, had

re

ceiv

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in (a

t lea

st 1

500

mg/

day)

and

SU

(at l

east

ha

lf th

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axim

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53.4

9.9

33.5

10.3

(8

9)-0

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(9.8

)7.

6 (6

0)+

+<3

.1H

TP

Bunc

k et

al

[28]

2009

insu

lin

glar

gine

34.0

metf

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dose

of

metf

orm

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030

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4 (5

7)-0

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6.8

(51)

+-

<3.3

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ra e

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[7]

2009

glib

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14.6

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dose

55.1

6.8

28.8

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(1.1

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ipiz

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n.s.

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M, r

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mp

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1 (5

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Simon.indd 26 14-8-2014 13:24:37


27

2

Stud

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Dos

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Mild

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(mm

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Ferr

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ni

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l [10

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5m

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(m

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1898

)

T2D

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tabl

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se o

f m

etfor

min

57.5

5.8

31.7

7.3

(56)

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(5

.5)

6.7

(50)

++

<3.1

HTP

Filo

zof e

t al

[11]

2010

glic

lazi

de23

0.0

metf

orm

in

(≥15

00)

T2D

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tabl

e do

se o

f m

etfor

min

(≥15

00 m

g/da

y)

59.7

6.8

30.8

8.5

(69)

-0.9

(9

.8)

n.s.

++

<3.1

HTP

Fole

y et

al

[12]

2009

glic

lazi

de20

9.0

metf

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in

poss

ible

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M, O

HA

naiv

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MI

22 –

45

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2, F

PG <

15

mm

ol/L

54.3

1.9

30.8

8.7

(72)

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(6

.6)

7.7

(61)

n.s.

n.s.

<3.1

HTP

Gal

lwitz

et

al [

30]

2011

insu

lin

aspa

rt28

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etfor

min

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M, m

etfor

min

57.0

5.0

32.9

7.9

(63)

-1.1

(1

2.0)

n.s.

++

≤3.9

, ≤3.

0H

TP

Gal

lwitz

et

al [

13]

2012

glim

e-pi

ride

3.0

maj

ority

m

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min

(1

500)

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M, m

etfor

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with

or

with

out o

ther

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A (n

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oglit

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59.8

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(61)

-0.4

(4

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≤3.0

, ≤3.

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TP

Gar

ber e

t al

[15]

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glim

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quat

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<3.1

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D-

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2 (6

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2010

glip

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rapy

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Simon.indd 27 14-8-2014 13:24:37

Chapter 2

28

Stud

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et a

l [1

8]20

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-cl

amid

e,

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de

or g

lime-

pirid

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n.s.

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for

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(69)

-0.4

(4

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8.1

(65)

n.s.

n.s.

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chi e

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Matt

hew

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22]

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e-pi

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dequ

ate

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rol w

ith m

etfor

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py

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ck e

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2) [2

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(68)

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(1

0.9)

n.s.

++

<3.1

HTP

Simon.indd 28 14-8-2014 13:24:38


29

2

Stud

yYe

arD

rug

Dos

e (m

g/

day

or

IU/

day)

Oth

er O

HA

durin

g tr

ial

(dos

e m

g/da

y)

Elig

ible

pop

ulati

onA

ge

(yea

rs)

Dia

bete

s-du

ratio

n (y

ears

)

BMI

(kg/

m2 )

HbA

1c

bas (

%

(mm

ol/

mol

))

HbA

1c

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ge

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Simon.indd 29 14-8-2014 13:24:38

Chapter 2

30

Tabl

e 2

Hyp

ogly

caem

ia in

cide

nce

in th

e 25

stu

dies

Author

Year

Drug

n

Trial duration (weeks)

Any hypo ≤3.9 mmol/L

Hypo rate ≤3.9 mmol/L









Any severe hypo

Rate severe hypo

Arec

hava

leta

et a

l [6]

2011

Glim

epiri

de51

830

1.

04

0.20

0.7%

0.02

0

Berg

enst

al e

t al [

29]

2009

Insu

lin a

spar

t 70/

30 B

ID12

424

52%

5.30

6.0%

0.13

0

Bunc

k et

al [

28]

2009

Insu

lin g

larg

ine

3352

24%

0.

0%0.

000

Chac

ra e

t al [

7]20

09G

liben

clam

ide

267

24

1%

0.02

0.0%

0.00

0

Chan

et a

l [8]

2008

Glip

izid

e25

42

4.

0%0.

100

Der

osa

et a

l [9]

2010

Glib

encl

amid

e57

52

5%

0.05

Ferr

anni

ni e

t al [

10]

2009

Glim

epiri

de13

9352

16%

0.40

0.7%

0.00

7

Filo

zof e

t al [

11]

2010

Glic

lazi

de49

452

1%0.

02

0.

0%0.

000

Fole

y et

al [

12]

2009

Glic

lazi

de54

610

4

2%

0.01

0.0%

0.00

0

Gal

lwitz

et a

l [30

]20

11In

sulin

asp

art 7

0/30

BID

173

2621

%

6%

0.0%

0.00

0

Gal

lwitz

et a

l [13

]20

12G

limep

iride

775

114

31%

0.15

13%

0.05

2.0%

0.00

7

Gar

ber e

t al [

15]

2008

Glim

epiri

de14

424

0.7%

0.01

5

0.

7%0.

015

Gar

ber (

LEAD

- 3) e

t al

[14]

2011

Glim

epiri

de24

810

4

26

%1.

75

0.

0%0.

000

Gok

e et

al [

16]

2010

Glip

izid

e43

052

50%

1.15

33%

0.81

9%0.

150.

9%0.

009

Her

man

sen

et a

l [17

]20

07G

limep

iride

106

24

0.

0%0.

000

Kaku

et a

l [18

]20

10

Glim

epiri

de,

glib

encl

amid

e or

gl

icla

zide

8824

0.0%

0.00

0

Kiku

chi e

t al [

19]

2010

Glim

epiri

de10

012

1%0.

04

0.

0%0.

000

Mad

sbad

et a

l [20

]20

04G

limep

iride

2612

15%

0.67

Simon.indd 30 14-8-2014 13:24:38


31

2

Author

Year

Drug

n

Trial duration (weeks)











Any severe hypo

Rate severe hypo

Mar

re e

t al (

LEAD

-1)

[21]

2008

Glim

epiri

de11

426

3%0.

17

0.

0%0.

000

Matt

hew

s et

al [

22]

2010

Glim

epiri

de15

5610

4

18

%0.

27

0.00

5N

auck

(LEA

D-2

) et a

l [2

3]20

09G

limep

iride

242

26

17

%1.

23

0.

0%0.

000

Prat

ley

et a

l [24

]20

09G

liben

clam

ide

9926

8%0.

16

6%

0.12

1.0%

0.02

0

Seck

et a

l [25

]20

10G

lipiz

ide

559

104

0.

47

0.22

0.

053.

0%0.

015

Sein

o et

al [

26]

2010

Glib

encl

amid

e13

224

22%

1.58

0.0%

0.00

0

Yang

et a

l [27

]20

10G

limep

iride

231

16

19

%1.

16

0.

9%0.

030

BID,

twic

e a

day;

hyp

o, h

ypog

lyca

emia

; rat

e, a

vera

ge n

umbe

r of e

piso

des

of h

ypog

lyca

emia

per

pati

ent p

er y

ear.

Simon.indd 31 14-8-2014 13:24:38

Chapter 2

32

Incidence of mild hypoglycaemia with sulfonylureasThe 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). Stratifying 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 sulfonylureasThe 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 insufficiently 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 hypoglycaemia when taking gliclazide

(n=1,040) 0.1% (95% CI 0-0.7%) than patients taking glipizide (n=1014) 2.1% (95% CI

0.9-5.1%; test for subgroup differences: I²=87%, p<0.01), and a trend was noted for a

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.

Figure 2 Meta-analyses of the occurrence of hypoglycaemia (next page)The proportions were pooled using a random effects model. 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 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.

Simon.indd 32 14-8-2014 13:24:38


33

2

A. Mild hypoglycemia: <56 mg/dL (3.1 mmol/L)

thgieWIC %59noitroporPNydutS

Ferrannini (2009) 1383 16,2% [14,4%,18,2%] 28,19%

Filozof (2010) 494 1,0% [0,4%,2,4%] 0,73%

Foley (2009) 546 1,7% [0,9%,3,2%] 1,37%

Gallwitz (2012) 775 13,0% [10,8%,15,6%] 13,16%

Garber (2008) 144 0,7% [0,1%,4,8%] 0,15%

Garber (LEAD- 3) (2011) 248 26,0% [20,9%,31,8%] 7,16%

Kikuchi (2010) 100 1,0% [0,1%,6,8%] 0,15%

Marre (LEAD-1) (2008) 114 2,6% [0,8%,7,8%] 0,43%

Matthews (2010) 1556 18,2% [16,4%,20,2%] 34,78%

Nauck (LEAD-2) (2009) 242 17,0% [12,8%,22,3%] 5,13%

Seino (2010) 132 22,0% [15,7%,29,9%] 3,40%

Yang (2010) 231 19,0% [14,4%,24,6%] 5,34%

Overall 5965 10,1% [7,3%,13,8%]

Heterogeneity: Q=158.7, p<0.001; I2=93%

B. Mild hypoglycemia: <50 mg/dL (2.8 mmol/L)


Chacra (2009) 267 0,7% [0,2%,2,9%] 4,09%

Goke (2010) 430 8,8% [6,5%,11,9%] 75,97%

Madsbad (2004) 26 15,4% [5,9%,34,6%] 7,46%

Pratley (2009) 99 6,1% [2,8%,12,9%] 12,48%

Overall 822 5,9% [2,5%,13,4%]

Heterogeneity: Q=14.4, p<0.01; I2=79%

C. Severe hypoglycemia


Arechavaleta (2011) 518 0,6% [0,2%,1,8%] 5,42%

Chacra (2009) 267 0,2% [0%,2,9%] 0,91%

Chan (2008) 25 4,0% [0,6%,23,5%] 1,74%

Ferrannini (2009) 1383 0,7% [0,4%,1,3%] 18,02%

Filozof (2010) 494 0,1% [0%,1,6%] 0,91%

Foley (2009) 545 0,1% [0%,1,4%] 0,91%

Gallwitz (2012) 775 1,5% [0,9%,2,7%] 21,45%

Garber (2008) 144 0,7% [0,1%,4,8%] 1,80%

Garber (LEAD-3) (2011) 248 0,2% [0%,3,1%] 0,91%

Goke (2010) 430 0,9% [0,3%,2,5%] 7,19%

Hermansen (2007) 106 0,5% [0%,7%] 0,90%

Kaku (2010) 88 0,6% [0%,8,3%] 0,90%

Kikuchi (2010) 100 0,5% [0%,7,4%] 0,90%

Marre (LEAD-1) (2008) 114 0,4% [0%,6,6%] 0,90%

Nauck (LEAD-2) (2009) 242 0,2% [0%,3,2%] 0,91%

Pratley (2009) 99 1,0% [0,1%,6,8%] 1,80%

Seck (2010) 559 3,0% [1,9%,4,8%] 29,93%

Seino (2010) 132 0,4% [0%,5,7%] 0,90%

Yang (2010) 231 0,9% [0,2%,3,4%] 3,60%

Overall 6500 0,8% [0,5%,1,3%]

Heterogeneity: Q=35.67, p=0.008; I2=50% 0% 5% 10% 15% 20% 25% 30% 35%

0% 5% 10% 15% 20% 25% 30% 35%

0% 5% 10% 15% 20% 25% 30% 35%

Simon.indd 33 14-8-2014 13:24:38

Chapter 2

34

Mild hypoglycemia ≤56 mg/dL (3.1 mmol/L)

Proportion 95% CI

All studies (n=12) 10,1% [7,3%,13,8%]

Low risk of bias (n=6) 11,0% [7%,16,9%]

Glimepiride (n=9) 15,5% [12,3%,19,2%]

Gliclazide (n=2) 1,4% [0,8%,2,4%]

Severe hypoglycemia

Proportion 95% CI

All studies (n=19) 0,8% [0,5%,1,3%]

Glimepiride (n=10) 0,9% [0,6%,1,3%]

Glibenclamide (n=3) 0,5% [0,1%,2%]

Glipizide (n=3) 2,1% [0,9%,5,1%]

Gliclazide (n=2) 0,1% [0%,0,7%]

0% 5% 10% 15% 20%

0% 5% 10% 15% 20%

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

Incidence of mild and severe hypoglycaemia with insulin therapyToo few studies had insulin as comparator, so these could not be meta-analysed [28-

30] (Table 1, Table 2).

Regression analysesTable 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, multivariate regression

analysis was not performed. Two significant associations with univariate meta-

regression analysis were found for severe hypoglycaemia. HbA1c baseline was

inversely related with the proportion of patients with severe hypoglycaemia, an effect

corresponding to an odds ratio of 0.33 (CI 95% 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 (CI 95% 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.

Simon.indd 34 14-8-2014 13:24:39


35

2

Table 3 Regression analysis

Predictor Mild hypoglycaemia Severe hypoglycaemia

Odds Ratio 95% C.I. for Odds Ratio

p Odds Ratio

95% C.I. for Odds Ratio

p

Lower Upper Lower UpperUnivariate analysisHbA1c 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 0.86Age (per year) 0.86 0.57 1.29 0.43 1.18 0.95 1.45 0.12Study 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 analysisHbA1c baseline (per 1%)

- - - - 0.44 0.15 1.30 0.13

HbA1c change (per 1%) - - - - - - - -Age (per year) - - - - 1.11 0.91 1.35 0.29Study 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

Sensitivity analysesDetails on hypoglycaemia assessment per study are provided 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 significant difference in the incidence of mild

hypoglycaemia (<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

Simon.indd 35 14-8-2014 13:24:39

Chapter 2

36

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%).

Discussion

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 treatment. This means that 90% of patients do not experience any relevant

hypoglycaemia. A similar observation was recently made in the Outcome Reduction

with Initial Glargine Intervention (ORIGIN) trial: 75% 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 hypoglycaemia

in patients with type 2 diabetes with good glycaemic control (HbA1c 7.5%) [33]. In

this study, subjects were asked to record episodes 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 episodes 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 findings 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

Simon.indd 36 14-8-2014 13:24:39


37

2

analysis, but neither was found significant in a multivariate meta-regression 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 obser-

vations 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 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 type 2 diabetes mellitus patients, in

randomized controlled trials on sulfonylurea therapy in combination with or without

metformin therapy, remain free of relevant hypoglycaemia during 12 to 114 weeks

treatment. Gliclazide therapy is accompanied by a lower risk of hypoglycaemia when

compared with glimepiride.

Simon.indd 37 14-8-2014 13:24:39

Chapter 2

38

Supplemental file

Literature searchThe following text terms and medical subheadings (MeSH) were combined:

“Diabetes Mellitus, Type 2”[Mesh], diabetes mellitus type 2[tiab], diabetes

mellitus with type II[tiab], diabetes type II[tiab], diabetes type 2[tiab],

t2DM[tiab], non insulin dependent diabetes[tiab], NIDDM[tiab], type 2 DM[tiab],

type II DM[tiab], type 2 diabetes[tiab], type II diabetes[tiab] AND “Incretins”[Mesh],

“Incretins”[Pharmacological Action], glucagon like peptide*[tiab], “Glucagon-Like

Peptides”[MeSH], glp*[tiab], incretin*[tiab], exenatide”[Supplementary Concept],

exenatide[tiab], “liraglutide”[Supplementary Concept], liraglutide[tiab], victoza[tiab],

byetta[tiab], “Dipeptidyl-Peptidase IV Inhibitors”[Substance], “Dipeptidyl-Peptidase

IV Inhibitors”[MeSH Terms], “sitagliptin”[Substance], “vildagliptin”[Substance],

“saxagliptin”[Substance], “sitagliptin”[tiab], “vildagliptin”[tiab], “saxagliptin”[tiab],

dpp4*[tiab], dpp 4[tiab], Dipeptidyl-Peptidase IV Inhibitor*[tiab], Dipeptidyl-

Peptidase 4 Inhibitor*[tiab], dppIV*[tiab], dpp IV[tiab] AND randomized controlled

trial[pt], controlled clinical trial[pt], randomized[tiab], placebo[tiab], clinical trials as

topic[mesh:noexp], randomly[tiab] and trial[ti].

Simon.indd 38 14-8-2014 13:24:39


39

2

Reference List1. 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. 2012.3. Akram K, Pedersen-Bjergaard U, Carstensen B, Borch-Johnsen K, Thorsteinsson B.

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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, Sheng D, Gonzalez E, Davies MJ 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.

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11. Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin 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 sulfonylurea gliclazide after two years of monotherapy in drug-naive patients with type 2 diabetes. Horm Metab Res 2009; 41(12):905-909.

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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 improvements 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, Ebeling P, Gudbjornsdottir S, Camisasca RP et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a 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.

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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.

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23. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH 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.

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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.

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30. Gallwitz B, Bohmer M, Segiet T, Molle A, Milek K, Becker B 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.

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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.

37. Schernthaner G, Grimaldi A, Di MU, Drzewoski J, Kempler P, Kvapil M et al. GUIDE study: double-blind comparison 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 efficacy, secondary failure rate, and complications of sulfonylureas. J Diabetes Complications 1994; 8(4):201-203.

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