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M E T A - A N A L Y S I S

The effects of sulfonylureas plus metformin on lipids, blood pressure, and adverse events in type 2 diabetes: a meta-analysis of randomized controlled trials

Fan Zhang • Hao Xiang • Yunzhou Fan • Tsend-ayush Ganchuluun •

Wenhua Kong • Qian Ouyang • Jingwen Sun • Beibei Cao •

Hongbo Jiang • Shaofa Nie

Received: 28 December 2012 / Accepted: 23 April 2013

� Springer Science+Business Media New York 2013

Abstract To compare the effects of sulfonylureas and

metformin versus metformin on lipid profiles, blood pres-

sure, and adverse events. PubMed, EMbase, Chinese Bio-

Medical Literature on disc, China National Knowledge

Infrastructure, VIP database, and Wanfang database were

searched for randomized controlled trials (RCTs), from

inception to August 2012. Key outcomes were low-density

lipoprotein cholesterol (LDL-C), high-density lipoprotein

cholesterol (HDL-C), triglycerides (TG), total cholesterol

(TC), blood pressure (BP), hemoglobin A1c (HbA1c),

fasting insulin, and adverse events. Twenty RCTs were

included in the analysis. Compared to metformin, the

combination therapy of sulfonylureas and metformin

slightly reduced HDL-C [-0.03, 95 % CI (-0.06, -0.01)]

and HbA1c (-0.79, 95 % CI -0.96 to -0.63). However, it

showed little effects on LDL-C, TG, TC, and BP. Glipizide

plus metformin significantly increased fasting insulin [2.33,

95 % CI (1.94, 2.73)]. Hypoglycemia and nervous system

side events were more frequent among patients treated with

sulfonylureas plus metformin than metformin alone

(RR = 6.79, 95 % CI 3.79–12.17; RR = 1.27, 95 % CI

1.03–1.57; respectively), but less in digestive symptoms

(RR = 0.75, 95 % CI 0.67–0.84). Combination therapy

with sulfonylureas and metformin may be more effective

than metformin alone in improving HbA1c and reducing

gastrointestinal reactions. But it had disadvantage of

decreasing HDL-C, increasing the risk of hypoglycemia

and nervous system side events.

Keywords Metformin � Sulfonylureas � Type 2 diabetes � Blood pressure � Cholesterol � Meta-analysis

Introduction

Type 2 diabetes mellitus (T2DM) results from a progres-

sive insulin secretary defect on the background of insulin

resistance, leads to loss of glycemic control and eventual

diabetes complications. According to the International

Diabetes Federation (IDF), there are 366 million diabetic

patients worldwide in 2011, and this number is expected to

increase to 552 million by 2030 [1]. The healthcare cost of

diabetes all over the world has been arising steadily in the

last decade and it is expected to reach 490 billion dollars in

2030 [2].

Metformin, an oral antidiabetic agent, is always rec-

ommended as the first-line drug in patients with T2DM by

international guidelines [3, 4]. Since it has been used in

clinical therapy for many years, there is clear evidence

supporting its effectiveness and safety. However, it is hard

for many patients to achieve the American Diabetes

Association (ADA) treatment goal of hemoglobin A1c

(HbA1c) \7 % by metformin therapy alone. As a result, second oral agents, including sulfonylureas [5–7], meglit-

inides [8–10], a-glycosidase inhibitors [11, 12], and

Fan Zhang and Hao Xiang contributed equally to this study.

F. Zhang � Y. Fan � T. Ganchuluun � W. Kong � Q. Ouyang � J. Sun � B. Cao � H. Jiang � S. Nie (&) Department of Epidemiology and Biostatistics, School of Public

Health, Tongji Medical College, Huazhong University

of Science and Technology, 13 Hangkong Road,

Wuhan 430030, China

e-mail: [email protected]

H. Xiang

School of Public Health, Wuhan University, Wuhan,

Hubei, China

H. Xiang

Wuhan University Global Health Institute, Wuhan, Hubei, China

123

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DOI 10.1007/s12020-013-9970-6

thiazolidinediones [13–15], were recommended to be

combined with metformin. In these combination therapies,

sulfonylureas plus metformin is the most widely prescribed

option for T2DM treatment. Some guidelines advise the

addition of sulfonylureas as a second-line therapy when

metformin fails to control glucose concentrations to target

level [16, 17]. Sulfonylureas can reduce hyperglycemia by

enhancing insulin secretion, while metformin improves

insulin sensitivity, leading to the reduction of hepatic

glucose output [18]. Because of their complementary

mechanism, the combination of sulfonylureas and metfor-

min is rational and effective.

Clinical trials have demonstrated that the combination

therapy leads to a more significant improvement in HbA1c

and fasting plasma glucose (FPG) than monotherapy [19–

22]. However, little attention has been given to the behavior

of lipids and adverse effects when adding sulfonylureas to

metformin in patients with T2DM. Rao et al. [23] suggested

that the combination therapy of metformin and sulfonylureas

was associated with an increased risk of cardiovascular

hospitalization or mortality. Elevated lipid concentrations are

well-known risk factors for cardiovascular disease. A study

conducted by Wulffele et al. [24] demonstrated that met-

formin had no significant effect on blood pressure, but

reduced total cholesterol (TC), triglycerides (TG), and low-

density lipoprotein cholesterol (LDL-C). When in combina-

tion with sulfonylureas, will such effects be strengthened or

weakened? Recent data have raised safety concerns about the

use of metformin plus sulfonylureas in patients with T2DM.

But published studies related to the effects of metformin plus

sulfonylureas on blood pressure (BP) and lipid profiles have

been small and conflicting. It is necessary to explore its

effects on metabolic changes in type 2 diabetic patients.

In the light of the growing number of patients receiving

sulfonylureas and metformin, in order to provide evidence

for clinical treatment of T2DM, we present the quantitative

meta-analysis of randomized controlled trials (RCTs) on

the effects of metformin plus sulfonylureas on lipids pro-

files, blood pressure, glucose control, insulin, and adverse

events.

Materials and methods

Study inclusion criteria

(1) Studies included should be RCTs, published in English

or Chinese language; (2) the participants should be patients

with T2DM defined by ADA or WHO criteria and older

than 18 years; (3) trial groups should be given the com-

bination therapy of metformin and sulfonylureas (glim-

epiride, glipizide, glibenclamide, gliclazide, etc.),

compared to metformin alone in control group. (4) At least

one outcome of interest (blood pressure, lipid parameters,

adverse events, HbA1c, and fasting insulin) was reported.

We excluded reviews, comments, duplicate published

articles, and studies without original data.

Search strategy

Two authors screened titles and abstracts independently.

Published articles involved the combination of sulfonylu-

reas and metformin in T2DM treatment. Electronic search

was conducted in PubMed, EMbase, Chinese BioMedical

Literature on disc (CBM), China National Knowledge

Infrastructure (CNKI), VIP database for Chinese technical

periodicals, and Wanfang database, from inception to

August 2012. Various combination of following keywords

were used: ‘‘diabetes mellitus, type 2’’, ‘‘sulfonylurea

compounds’’, ‘‘metformin’’, ‘‘glimepiride’’, ‘‘glipizide’’,

‘‘glibenclamide’’, and ‘‘gliclazide’’. The search was limited

to studies conducted in human subjects.

Quality assessment

The risk of bias was assessed according to the Cochrane

Handbook risk of bias tool. We assessed the following

domains: random sequence generation, allocation con-

cealment, blinding, incomplete outcome data, selective

reporting, and other bias. Each domain was classified as

low, unclear, and high risk of bias. If all these domains

(sequence generation, allocation concealment and blinding)

had a low risk of bias, the trail was specified to have a low

risk of bias.

Data extraction

Information was extracted by two authors independently.

Any disagreement could be solved via discussion, involv-

ing a third person if necessary. A standard form was used to

record the following information: characteristics of the

study (author, country, year of publication, sample size,

and duration of follow-up); characteristics of the partici-

pants (mean age, intervention, baseline of body mass index,

FPG, HbA1c); and outcomes.

Outcome measures

The primary outcomes were blood pressure, lipid param-

eters, and adverse events. Secondary outcomes were

HbA1c and FINS (fasting insulins). Adverse events were

coded into COSTART terms and body systems. Body as a

whole contains asthenia and back pain. Nervous system

side effects were defined as symptoms of dizziness, anxi-

ety, insomnia, and vertigo. Respiratory system side effects

were defined as symptoms of cough, pharyngitis, and

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rhinitis. Skin and appendages side effects were defined as

rash. Urogenital system side effects were defined as

symptoms of urinary tract infection.

Statistical analysis

Continuous data were expressed as weighted mean differ-

ences (WMD) and dichotomous data as relative risk (RR).

Heterogeneity was assessed by Q test and I2 statistic. If

there is no significant heterogeneity (Q [ 0.05), fixed model was performed to calculate WMD and its 95 % CI.

Otherwise, a random effect model was chosen.

Because great heterogeneity among studies was identi-

fied, we explored heterogeneity between comparable trials

with post hoc subgroup analyses. We conducted subgroup

analyses evaluated the intervention effect in studies on sul-

fonylureas types (glimepiride, glipizide, glibenclamide, and

gliclazide), dose regimens (B2.5, 2.5–5, 5–7.5, and

[7.5 mg) and publication language (English, Chinese). The meta-regression model was used for determining whether

differences in the baselines of HbA1c and FINS significantly

affected the results. Egger’s test was used to estimate pub-

lication bias. A P value of 0.05 was used to indicate sta-

tistical significance. All analyses were performed by

STATA version 11.0 (STATA, College Station, TX, USA).

In order to assess the statistic power of our study, we cal-

culated power (1 - b) by PASS 11.0 software.

Results

Search results

From 1,362 publications identified by initial data searches,

558 duplicated publications were removed, 739 studies

which did not fulfill the inclusion criteria were excluded

either. Another 45 studies were excluded because they

were not eligible according to manually review from two

authors. Consequently, 20 articles [5–7, 18–22, 25–36]

were included in the meta-analysis. A flow chart showing

search results is provided in Fig. 1.

Systemic review

Twenty eligible studies included 3,633 participants, of

whom 2,147 were randomized to receive the combination

therapy of sulfonylureas and metformin. Characteristics of

the included studies are given in Table 1. There were 10

trials published in English and 10 trials in Chinese. The

number of participants ranged from 30 in the study by

Zhang [28] to 482 in the study by Garber et al. [35]. Mean

age ranged from 49.8 to 60.7 years old. The follow-up

duration ranged from 4 to 48 weeks. Even though we

conducted comprehensive literature searches, only studies

utilizing these four types of sulfonylureas that fulfilled our

inclusion criteria were identified. We included four inter-

vention groups: glimepiride and metformin [6, 7, 20, 25,

26, 29], glipizide and metformin [19, 21, 22, 28, 30–33],

glibenclamide and metformin [5, 18, 34–36], and gliclazide

and metformin [27].

Bias risk assessment

The bias risk assessments of included trials are shown in

Table 2. Only six trials had low risk of bias for random

sequence generation and allocation concealment. All trials

had low risk of bias regarding blinding. Based on all the

domains assessed, we considered six trials to have a low

risk of bias.

Primary outcomes

Blood pressure

Four RCTs [7, 20, 26, 28] reported the effect of treatment

on systolic blood pressure. Heterogeneity test suggested

fixed model be used (I 2

= 0.0 %, P [ 0.05). According to WMD calculation (Fig. 2a), the combination therapy of

sulfonylureas and metformin did not change SBP signifi-

cantly when compared with metformin alone (95 % CI

-2.58 to 2.59, P [ 0.05). There was no publication bias found for the pooled analysis by Egger’s test (Q = 0.796).

Four RCTs [7, 20, 26, 28] reported diastolic blood

pressure. Since the heterogeneity was rejected by Q test

(I2 = 0.0 %, P [ 0.05), a fixed-effect model was used. The results (Fig. 2b) showed that the combination therapy had

no significant decrease in DBP (95 % CI -2.48 to 1.05,

Fig. 1 Flow chart of the systematic review and meta-analysis

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Table 1 Characteristics of the included studies

Study Group N Mean age (years)

BMI (kg/m 2 )

baseline

FPG (mmol/L)

baseline

HbA1C (%)

baseline

Interventions Duration

Cheng [25] T 29 51 – 11.0 ± 3.2 – Glimepiride 2–4 mg/day ?

metformin 750–1,500 mg/

day

12 weeks

C 25 52.5 – 9.0 ± 1.5 – Metformin 0.25–0.75 g/day 12 weeks

Ning et al. [26] T 51 52.7 24.1 ± 2.8 8.6 ± 3.6 8.3 ± 2.7 Glimepiride 1–6 mg/day ?

metformin 250–750 mg/

day

1 year

C 50 52.7 25.9 ± 2.2 8.1 ± 2.1 8.3 ± 2.3 Metformin 250–750 mg/day 1 year

Dai [7] T 50 – 24.5 ± 1.5 8.7 ± 2.0 8.7 ± 1.4 Glimepiride 1–6 mg/day ?

metformin 500 mg/day

8 weeks

C 50 – 24.2 ± 1.8 8.8 ± 2.1 8.8 ± 1.2 Metformin 500 mg/day 8 weeks

Nauck et al. [29] T 100 57 31.2 ± 4.6 10.0 ± 2.6 8.4 ± 1.0 Glimepiride 4 mg/day ?

metformin 1,000 mg/day

26 weeks

C 100 56 31.6 ± 4.4 10.0 ± 2.3 8.4 ± 1.1 Metformin 1,000 mg/day 26 weeks

Bermudez-Pirela et al.

[6]

T 21 49.5 – 13.5 ± 0.7 11.5 ± 0.6 Glimepiride 0.5 mg q.d ?

metformin 500 mg t.i.d.

10 weeks

C 29 54 – 10.6 ± 0.4 10.1 ± 0.3 Metformin 500 mg t.i.d. 10 weeks

Charpentier et al. [20] T 147 56.8 29.5 11.0 ± 2.4 6.4 ± 1.1 Glimepiride 1–6 mg/day ?

metformin 850 mg t.i.d

4 weeks

C 75 55.4 29.2 10.5 ± 2.4 6.8 ± 1.2 Metformin 850 mg/day 4 weeks

Su et al. [32] T 21 55.6 25 9.7 ± 2.5 7.6 ± 1.5 Glipizid 2.5 mg t.i.d ?

metformin 250 mg t.i.d

12 weeks

C 22 54.8 25.4 10.2 ± 2.6 8.3 ± 1.7 Metformin 250 mg t.i.d 12 weeks

Li et al. [22] T 100 55.8 25.6 8.7 ± 1.8 6.9 ± 1.2 Glipizid 2.5 mg t.i.d ?

metformin 250 mg t.i.d

12 weeks

C 50 56.2 25 8.7 ± 1.7 7.0 ± 1.2 Metformin 250 mg t.i.d 12 weeks

Zhang [28] T 20 53 26.1 ± 4.5 8.8 ± 1.4 8.0 ± 1.1 Glipizid 2.5 mg t.i.d ?

metformin 250 mg t.i.d

12 weeks

C 10 49.8 25.4 ± 1.7 8.7 ± 1.5 7.6 ± 1.2 Metformin 250 mg t.i.d 12 weeks

Yao et al. [31] T 116 – – 9.0 ± 1.9 7.5 ± 1.8 Glipizid 2.5 mg t.i.d ?

metformin 250 mg t.i.d

12 weeks

C 118 – – 9.1 ± 2.2 7.5 ± 1.7 Metformin 250 mg t.i.d 12 weeks

Yao et al. [21] T 119 57.7 25.7 ± 3.0 8.7 ± 1.7 7.9 ± 1.4 Glipizid 2.5 mg t.i.d ?

metformin 250 mg t.i.d

12 weeks

C 58 56.8 25.4 ± 3.0 8.7 ± 1.7 7.7 ± 1.0 Metformin 250 mg t.i.d 12 weeks

Ji [30] T 113 – – 8.8 ± 1.7 7.3 ± 1.6 Glipizid 2.5 mg t.i.d ?

metformin 250 mg t.i.d

12 weeks

C 115 – – 8.9 ± 1.6 7.0 ± 1.4 Metformin 250 mg t.i.d 12 weeks

Feinglos et al. [19] T 61 57.7 31.7 ± 4.4 8.6 ± 0.2 7.5 ± 0.1 Glipizid 2.5 mg/day ?

metformin 1,000 mg

16 weeks

C 61 58.8 32.1 ± 4.9 8.7 ± 0.2 7.6 ± 0.1 Metformin 1,000 mg 16 weeks

Goldstein et al. [33] T 87 54.6 31.7 ± 4.9 10.8 8.7 ± 1.2 Glipizid 5 mg ?

metformin 500 mg

18 weeks

C 76 56.6 31.6 ± 4.3 10.6 8.6 ± 1.2 Metformin 500 mg 18 weeks

Garber et al. [18] T 171 55.6 31.4 ± 4.6 10.6 ± 3.2 8.8 ± 1.5 Glyburide 1.25 mg ?

metformin 250 mg

16 weeks

C 164 54.7 31.4 ± 4.0 10.5 ± 3.1 8.5 ± 1.4 Metformin 500 mg 16 weeks

Chien et al. [5] T1 21 60 24.2 ± 3.2 13.7 ± 2.1 8.7 ± 1.1 Glyburide 2.5 mg b.i.d ?

metformin 0.5 g b.i.d

16 weeks

T2 21 57 24.2 ± 2.7 13.5 ± 2.8 8.8 ± 1.2 Glyburide 5.0 mg b.i.d ?

metformin 500 mg b.i.d

16 weeks

C 17 59 25.7 ± 3.2 12.6 ± 2.4 8.9 ± 1.1 Metformin 500 mg b.i.d 16 weeks

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Table 2 Risk of bias assessment of the included trials

Study Sequence

generation

Allocation

concealment

Blinding Incomplete

outcome data

Selective outcome

reporting

Free from

other bias

Cheng [25] Adequate Adequate Adequate Unclear Unclear Adequate

Ning et al. [26] Unclear Unclear Adequate Unclear Adequate Unclear

Dai [7] Unclear Unclear Adequate Adequate Adequate Unclear

Nauck et al. [29] Adequate Adequate Adequate Adequate Unclear Adequate

Bermudez-Pirela et al. [6] Unclear Unclear Adequate Adequate Unclear Unclear

Charpentier et al. [20] Adequate Adequate Adequate Adequate Adequate Adequate

Su et al. [32] Unclear Unclear Adequate Adequate Adequate Adequate

Li et al. [22] Unclear Adequate Adequate Adequate Adequate Adequate

Zhang [28] Unclear Adequate Adequate Unclear Unclear Unclear

Yao et al. [31] Unclear Adequate Adequate Adequate Unclear Adequate

Yao et al. [21] Unclear Adequate Adequate Adequate Adequate Adequate

Ji [30] Adequate Adequate Adequate Unclear Adequate Adequate

Feinglos et al. [19] Unclear Unclear Adequate Adequate Unclear Unclear

Goldstein et al. [33] Adequate Adequate Adequate Adequate Adequate Adequate

Garber et al. [18] Adequate Adequate Adequate Adequate Unclear Adequate

Chien et al. [5] Unclear Unclear Adequate Adequate Unclear Unclear

Garber et al. [35] Unclear Unclear Adequate Adequate Adequate Adequate

Blonde et al. [34] Unclear Unclear Adequate Adequate Adequate Unclear

Marre et al. [36] Unclear Unclear Adequate Adequate Unclear Adequate

Luo et al. [27] Unclear Unclear Adequate Unclear Unclear Unclear

Table 1 continued

Study Group N Mean age (years)

BMI (kg/m 2 )

baseline

FPG (mmol/L)

baseline

HbA1C (%)

baseline

Interventions Duration

Garber et al. [35] T1 158 56.9 30.1 ± 4.0 9.8 ± 2.5 8.3 ± 1.1 Glyburide 1.25 mg/day ?

metformin 250 mg/day

20 weeks

T2 165 58.1 29.6 ± 4.5 9.7 ± 2.6 8.2 ± 1.1 Glyburide 2.5 mg/day ?

metformin 500 mg/day

20 weeks

C 159 56 30.4 ± 4.3 9.8 ± 2.4 8.3 ± 1.1 Metformin 500 mg/day 20 weeks

Blonde et al. [34] T1 160 55.4 30.7 ± 4.8 11.8 ± 2.8 9.4 ± 1.5 Glyburide 2.5 mg b.i.d ?

metformin 500 mg b.i.d

16 weeks

T2 162 55.6 30.6 ± 4.9 11.6 ± 2.7 9.4 ± 1.2 Glyburide 5 mg b.i.d ?

metformin 500 mg b.i.d

16 weeks

C 153 57.6 30.6 ± 4.4 11.8 ± 2.8 9.5 ± 1.3 Metformin 500 mg b.i.d 16 weeks

Marre et al. [36] T1 101 58 30.1 ± 4.6 10.7 ± 3.0 7.89 ± 1.62 Glyburide 2.5 mg b.i.d ?

metformin 500 mg b.i.d

16 weeks

T2 103 60.7 29.7 ± 4.2 10.6 ± 2.8 7.62 ± 1.61 Glyburide 5 mg b.i.d ?

metformin 500 mg b.i.d

16 weeks

C 104 57.5 29.9 ± 4.7 11.0 ± 3.2 8.09 ± 1.84 Metformin 500 mg b.i.d 16 weeks

Luo et al. [27] T 50 45.1 25.1 ± 1.4 9.4 ± 1.1 8.1 ± 0.6 Gliclazide 30 mg/day ?

metformin 750 mg b.i.d

16 weeks

C 50 43.2 24.7 ± 1.3 9.3 ± 1.0 8.2 ± 0.5 Metformin 750 mg b.i.d 16 weeks

T trial group (sulfonylureas ? metformin), C control group (metformin alone group), BMI body mass index, FPG fasting plasma glucose

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P [ 0.05). No publication bias was found for the pooled analysis by Egger’s test (Q = 0.871).

Lipid parameters

Four RCTs [25, 33, 36] reported LDL-C. Heterogeneity

test suggested fixed model be used (I2 = 0.0 %, P [ 0.05). According to WMD calculation (Fig. 2c), the combination

therapy of sulfonylureas and metformin did not change

LDL-C significantly when compared with metformin

(95 % CI -0.03 to 0.24, P [ 0.05). There was no publi- cation bias found for the pooled analysis by Egger’s test

(Q = 0.534). Five RCTs [20, 25, 31, 33, 36] reported the effect of

treatment on high-density lipoprotein cholesterol (HDL-C).

Heterogeneity test suggested fixed model be used

(I2 = 8.6 %, P [ 0.05). According to WMD calculation (Fig. 2d), the combination therapy reduced HDL-C signifi-

cantly compared with control treatment (-0.03, 95 % CI

-0.06 to -0.01, P \ 0.05). There was no publication bias found for the pooled analysis by Egger’s test (Q = 0.405).

Seven RCTs [7, 20, 25, 31, 33, 36] reported change in

TG. Heterogeneity test suggested fixed model be used

(I2 = 0.0 %, P [ 0.05). According to WMD calculation (Fig. 2e), the combination therapy of sulfonylureas and

metformin did not change TG significantly when compared

with metformin alone (95 % CI -0.21 to -0.03,

P [ 0.05). There was no publication bias found for the pooled analysis by Egger’s test (Q = 0.973).

Six RCTs [20, 25, 31, 33, 36] reported change in TC as

an outcome measure. Since the heterogeneity was rejected

by Q test, a fixed-effect model was used. The results

Fig. 2 The combination of sulfonylureas and metformin versus metformin alone. a Change in systolic blood pressure, b change in diastolic blood pressure, c change in low-density lipoprotein

cholesterol (LDL-C), d change in high-density lipoprotein cholesterol (HDL-C), e change in triglycerides (TG), and f change in total cholesterol (TC)

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(Fig. 2f) showed no significant increase in TC in the groups

given sulfonylurea plus metformin compared with the

metformin alone groups (0.02, 95 % CI -0.08 to 0.13,

P [ 0.05). There was no publication bias found for the pooled analysis by Egger’s test (Q = 0.119).

Hypoglycemia

Seventeen RCTs [5–7, 18–22, 25–33, 35, 36] reported the

number of patients experiencing hypoglycemia (Fig. 3c).

Compared to metformin-controlled groups, the combina-

tion therapy groups were associated with a significant

increase in the proportion of patients with hypoglycemia

(RR = 4.09, 95 % CI 2.13–7.89, P \ 0.05). In subgroup analyses, combination therapy significantly increased

hypoglycemia in glipizide group (RR = 3.36, 95 % CI

1.40–8.08) and in glibenclamide group (RR = 16.05, 95 %

CI 6.22–41.39). The combination therapy significantly

increased hypoglycemia in studies published in English

(RR = 7.48, 95 % CI 2.93–19.07), but not in Chinese

(RR = 1.49, 95 % CI 0.71–3.12) (Fig. 4c). No correlation

was found between dose and the incidence of hypoglyce-

mia. We found no evidence of publication bias (Egger’s

test, Q = 0.051). In the power analysis, we had a power of 1.000 with a sample size of 3,165 (Table 3).

Adverse events

Eleven RCTs [5, 18, 20, 22, 31, 33–35] reported the inci-

dence of nervous system symptoms. Since the heteroge-

neity was rejected by Q test (I2 = 0.0 %, P [ 0.05), a fixed-effect model was used. The results (Table 3) showed

that the combination therapy significantly increased the

incidence of nervous system reactions (RR = 1.27, 95 %

CI 1.03–1.57, P \ 0.05). Eighteen articles [5, 18, 20–22, 25, 27–30, 33–36] studies

reported on digestive system adverse events. Heterogeneity

test suggested fixed model be used (I2 = 35.2 %, P [ 0.05). The analysis of trials where metformin plus sulfonylureas

compared to metformin showed a significant decrease in

digestive system side effects (RR = 0.75, 95 % CI

0.67–0.84, P \ 0.05). Thirteen studies reported diarrhea. The results indicated that a significant decrease in diarrhea

(RR = 0.70, 95 % CI 0.58–0.86, P \ 0.05). Ten studies reported nausea or vomiting. The pooled analysis showed

that a significant decrease was seen in the combination

therapy groups (RR = 0.58, 95 % CI 0.42–0.80, P \ 0.05) (Table 3). We calculated powers for the pooled analysis of

adverse events which are shown in Table 3. More studies

regarding safety of the combination therapy (i.e., musculo-

skeletal system adverse event, dyspepsia) were needed to

increase the power of test.

Fig. 3 The combination of sulfonylureas and metformin versus metformin alone according to sulfonylurea types. a Change in HbA1c, b change in fasting insulin, and c incidence of hypoglycemia

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Secondary outcomes

HbA1c

Fifteen RCTs [5–7, 19–22, 26–28, 30–33] reported a

decrease of HbA1c, while only one [32] study claimed a

reverse result. The result showed that (Fig. 3a) the

combination of sulfonylureas and metformin was associ-

ated with a significant reduction of HbA1c versus metfor-

min alone (-0.79, 95 % CI -0.96 to -0.63, P \ 0.001). Subgroup analyses also showed reductions of HbA1c in

glimepiride group (-0.84, 95 % CI -1.23 to -0.45), as

well as those in glipizide group (-0.66, 95 % CI -0.89 to

-0.42). Moreover, there was a reduction of HbA1c in trials

Fig. 4 The combination of sulfonylureas and metformin versus metformin alone according to publication language. a Change in HbA1c, b change in fasting insulin, and c incidence of hypoglycemia

Table 3 Incidence of adverse events by the body system in the combination therapy of metformin and sulfonylurea

Body system Studies I2 (%) Q Model RR (95 % CI) Power

Body as a whole 6 [5, 20, 30, 34] 0.0 0.554 Fixed-effect 1.05 (0.64, 1.72) 0.550

Nervous system 11 [5, 18, 20–22, 33, 34] 0.0 0.746 Fixed-effect 1.27 (1.03, 1.57)* 0.740

Respiratory system 9 [5, 18, 22, 33–35] 0.0 0.612 Fixed-effect 1.02 (0.86, 1.21) 0.600

Skin and appendages 3 [5, 25] 0.0 0.951 Fixed-effect 4.05 (0.71, 23.16) 0.590

Musculoskeletal system 8 [5, 18, 33–35] 0.0 0.823 Fixed-effect 0.93 (0.75, 1.15) 0.450

Urogenital system 3 [5, 22] 0.0 0.646 Fixed-effect 0.47 (0.11, 2.10) 0.870

Digestive system (total) 18 [5, 18, 20–22, 25, 27–30, 33–36] 35.2 0.070 Fixed-effect 0.75 (0.67, 0.84)* 1.000

Diarrhea 13 [5, 18, 20–22, 29, 30, 33–35] 22.5 0.216 Fixed-effect 0.70 (0.58, 0.86)* 0.959

Nausea/vomiting 10 [5, 18, 25, 30, 33–35] 0.0 0.767 Fixed-effect 0.58 (0.42, 0.80)* 0.887

Abdominal pain 6 [18, 33–35] 0.0 0.824 Fixed-effect 0.82 (0.57, 1.19) 0.630

Dyspepsia 5 [30, 34, 35] 0.0 0.765 Fixed-effect 0.70 (0.42, 1.18) 0.431

Increased appetite 3 [5, 20] 0.0 0.666 Fixed-effect 0.92 (0.34, 2.44) 0.520

Significantly different from metformin monotherapy (*Q \ 0.05)

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published in Chinese (-0.64, 95 % CI -0.82 to -0.45), in

English (-0.98, 95 % CI -1.22 to -0.74) (Fig. 4a). A

meta-regression analysis found that there was no correla-

tion between baseline HbA1c and the reduction of HbA1c.

We found no evidence of publication bias for the analysis

(Egger0s test, Q = 0.618).

Fasting insulin

Ten RCTs [6, 19–22, 26–28, 31, 32] reported the change in

FINS (Fig. 3b). Since I2 showed significant heterogeneity

existed among these studies, a random effect model was

used. Treatment with sulfonylureas and metformin resulted

in no significantly increase in FINS compared with met-

formin (WMD = 1.26 mU/L, 95 % CI -0.78 to 3.30). In

glipizide group, the level of FINS was significantly

increased in the combination therapy (WMD = 2.33 mU/

L, 95 % CI 1.94–2.73). In the subgroup analysis by pub-

lication language, the level of FINS was increased in

studies published in Chinese (1.55 mU/L, 95 % CI

0.13–2.97), not in English (0.40 mU/L, 95 % CI -3.35 to

4.15) (Fig. 4b). There was no correlation found between

baseline FINS and the change in FINS. No publication bias

was found in the analysis (Egger0s test, Q = 0.916).

Discussion

In the analysis, we included 20 RCTs (3,633 participants)

comparing the effects of sulfonylureas and metformin

versus metformin alone on T2DM patients. Where repor-

ted, HDL-C in the combination therapy groups was

decreased, but none of the other lipid parameters and BP

showed any significant change compared with the con-

trolled groups. The combination of sulfonylureas and

metformin reduced HbA1c by 0.79 %, compared with

metformin monotherapy. However, hypoglycemic events

increased when sulfonylurea was added (RR = 4.09, 95 %

CI 2.13–7.89, P \ 0.05). The studies tended to show a decrease in digestive system side effects in the metformin

plus sulfonylurea groups, but a significant increase in the

incidence of nervous side events.

The findings of our study suggested some implications

for clinical practice. Compared to metformin groups, the

level of HDL-C slightly decreased in metformin plus sul-

fonylurea therapy. The decline in HDL-C results from a

glucose lowering independent mechanism. This reaction

may be clinically pathologic symptom of T2DM, which is

complicated by hyperlipidemia. A recent review showed

that decreases in HDL-C had been identified as a signifi-

cant, independent predictor of cardiovascular risk [37].

Although only a slight change in HDL-C has been found in

the analysis, the potential risk should alert our attention. In

our findings, the combination therapy had no effects on

LDL-C, TG, and TC. In addition, the combination therapy

showed no significant effect on blood pressure. Since

almost all trials used glyceamic control as main outcomes,

information bias may exist in BP measurement. A

0.79 mmHg systolic BP lowering effect was found in trial

groups, but it was not statistically significant. Therefore,

we cannot conclude that the combination therapy has an

effect on blood pressure, or will this change be clinically

significant.

Many international institutions recommend the use of

HbA1c to diagnose diabetes in adult populations. In fact,

blood glucose levels are the result of a complex endocrine

system. The level of HbA1c is associated with other vari-

ables in patients with T2DM [6]. Epidemiologic studies

indicated that the level of HbA1c was associated with

diabetes microvascular and nerve complications including

nephropathy, neuropathy, retinopathy, and atherosclerosis

[3]. The combination of sulfonylureas with metformin

exhibited a significant reduction in HbA1c. This result was

consistent with a review conducted by Mcintosh et al. [17],

who recently conducted a study on the safety of second-

line oral antihyperglycemic therapy. When compared with

each of the four types of sulfonylureas separately, we found

that all types were effective in glucose control. In gliben-

clamide group, the pooled value even exceeded 1.0 %. Our

study suggested that the combination of sulfonylureas and

metformin provided an effective strategy for glucose con-

trol in patients whose blood glucose was uncontrolled by

metformin monotherapy.

Fasting insulin is an important sign of insulin secretion

and storage. A logical treatment of T2DM is based on

insulin secretagogue and insulin sensitizer. It is known that

sulfonylurea can help patients with T2DM stimulate insulin

release from beta cells [33]. In the current meta-analysis,

the pooled estimate showed an increase in FINS in gli-

pizide plus metformin groups. The result is strongly sup-

ported by a study conducted by Charpentier et al. [20],

which indicated that sulfonylureas was effective in

improving insulin secretion to help glycemia control. An

opposite result was seen in glimepiride plus metformin

groups, but the result had no statistical significance. There

was a significant heterogeneity identified in WMD for

fasting insulin among trials using glimepiride, which

reflected variability among studies. This variability might

be attributed to different does of glimepiride, to different

country, to different duration, or to different characteristics

of participants. Although a random effect model was used

to reduce variation, it is not safe to draw conclusions

regarding fasting insulin in glimepiride plus metformin

groups.

As improved glucose control is always associated with

an increased risk of hypoglycemia, patients who accepted

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123

combination therapy experienced more episodes [20]. In

this pooled analysis, hypoglycemia events significantly

increased with the combination of sulfonylureas and met-

formin using a fixed-effect model. It is probable that the

high rate of hypoglycemia is a reflection of the fast decline

of glucose. However, the severe hypoglycemia was seldom

found in all trials. According to subgroup analysis, we

found more hypoglycemia in English group. This result

was consistent with the lower reduction of HbA1c in

Chinese papers. The combination therapy significantly

decreased the level of HbA1c, which might have explained

the tendency of an increased risk of hypoglycemia.

Recently, evidence from large clinical trials suggested that

hypoglycemia may be a risk factor for mortality in patients

with T2DM. Moreover, hypoglycemia is associated with a

poorer quality of life, higher healthcare costs, and less

compliance with medicine. In clinical settings, attention

should be paid to the risk for hypoglycemia when using

hypoglycemic drugs treatment regimen [38]. Apart from

hypoglycemia, we investigated the adverse effects associ-

ated with metformin plus sulfonylureas therapy. In general,

the most common adverse events related to oral hypogly-

cemic drugs occurred in the digestive system. The total

incidence of digestive system side events showed a sig-

nificant decrease in the combination therapy. Nausea,

vomiting, and diarrhea were less frequent in patients who

received metformin plus sulfonylurea. However, a signifi-

cant increase in the risk of nervous system side events (i.e.,

dizziness) was seen in the concomitant therapy. Therefore,

attention should be paid to nervous system symptoms when

adding sulfonylurea into metformin therapy.

This is the first meta-analysis to evaluate the effects of

metformin plus sulfonylurea on metabolic outcomes. A

review conducted by Belsey et al. [39] on the effect of

metformin plus sulfonylurea on glyceamic control included

six trials (two in our analysis) and the remaining four trials

were not metformin-controlled. Moreover, the previous

review focused on improvement in HbA1c and FPG, while

our study aimed at evaluating the metabolic effects

including more clinical variables such as TC, TG, HDL-C,

LDL-C, SBP, DBP, and FINS. The strength of this review

is the strict inclusion criteria. The RCT design can meet the

methodological criteria and minimize the potential bias. In

addition, more studies that met inclusion criteria were

identified in this study. We conducted further and more

comprehensive analysis, such as subgroup analyses, to

have some information on the effects of combination

therapy. However, there are still some limitations inherited

from the published studies. A major limitation is that the

follow-up durations of involved studies were no longer

than a year. So the longer term outcomes, such as clinical

complications or death, were not assessed. Moreover, our

study was confined to English and Chinese language

published studies. Language limitations may introduce

selection bias, which is identified as a threat to the validity

of a meta-analysis.

In conclusion, adding sulfonylureas to patients with

T2DM inadequately controlled with metformin mono-

therapy has no clinically significant effect on BP and

metabolic effects except for HDL-C. The combination

therapy can reduce the incidence of digestive symptoms,

but it is associated with high risk of hypoglycemia and

nervous system adverse events. In the light of these results,

more high quality RCTs with a longer follow-up duration

are needed to explore the best approach for glucose low-

ering in people with T2DM.

Conflict of interest The authors declare that they have no conflict of interest.

References

1. D.R. Whiting, L. Guariguata, C. Weil, J. Shaw, IDF diabetes

atlas: global estimates of the prevalence of diabetes for 2011 and

2030. Diabetes Res. Clin. Pract. 94(3), 311–321 (2011) 2. G. Bruno, A. Landi, Epidemiology and costs of diabetes. Transpl.

Proc. 43(1), 327–329 (2011) 3. American Diabetes Association, Standards of medical care in

diabetes—2012. Diabetes Care 35(1), 11–63 (2012) 4. Chinese diabetes society, Chinese guideline for type 2 diabetes

(2007). Natl. Med. J. China 88(18), 1227–1245 (2008) 5. H.H. Chien, C.T. Chang, N.F. Chu, S.H. Hsieh, Y.Y. Huang, I.T.

Lee, W.J. Lee, Y.J. Tang, W.H. Sheu, Effect of glyburide–met-

formin combination tablet in patients with type 2 diabetes.

J. Chin. Med. Assoc. 70(11), 473–480 (2007) 6. V.J. Bermudez-Pirela, C. Cano, M.T. Medina, A. Souki, M.A.

Lemus, E.M. Leal, H.A. Seyfi, R. Cano, A. Ciscek, F. Bermudez-

Arias, F. Contreras, Z.H. Israili, R. Hernandez–Hernandez, M.

Valasco, Metformin plus low-dose glimepiride significantly

improves Homeostasis Model Assessment for insulin resistance

(HOMA(IR)) and beta-cell function (HOMA(beta-cell)) without

hyperinsulinemia in patients with type 2 diabetes mellitus. Am.

J. Ther. 14(2), 194–202 (2007) 7. H. Dai, The efficacy of glimepiride in combination with met-

formin in type 2 diabetes. Med. Inf. 24(9), 4394 (2011) 8. M.A. Baron, Comparison of repaglinide and nateglinide in

combination with metformin: response to Raskin et al. Diabetes

Care 26(12), 3361–3362, 3362–3363 (2003) 9. R. Moses, R. Slobodniuk, S. Boyages, S. Colagiuri, W. Kidson, J.

Carter, T. Donnelly, P. Moffitt, H. Hopkins, Effect of repaglinide

addition to metformin monotherapy on glycemic control in

patients with type 2 diabetes. Diabetes Care 22(1), 119–124 (1999)

10. P. Raskin, L. Klaff, J. McGill, S.A. South, P. Hollander, N.

Khutoryansky, P.M. Hale, Efficacy and safety of combination

therapy: repaglinide plus metformin versus nateglinide plus

metformin. Diabetes Care 26(7), 2063–2068 (2003) 11. S. Jayaram, R.S. Hariharan, R. Madhavan, I. Periyandavar, S.S.

Samra, A prospective, parallel group, open-labeled, comparative,

multi-centric, active controlled study to evaluate the safety, tol-

erability and benefits of fixed dose combination of acarbose and

metformin versus metformin alone in type 2 diabetes. J. Assoc.

Physicians India 58, 679–682, 687 (2010)

Endocrine

123

12. J.S. Wang, S.D. Lin, W.J. Lee, S.L. Su, I.T. Lee, S.T. Tu, Y.H.

Tseng, S.Y. Lin, W.H. Sheu, Effects of acarbose versus gliben-

clamide on glycemic excursion and oxidative stress in type 2

diabetic patients inadequately controlled by metformin: a

24-week, randomized, open-label, parallel-group comparison.

Clin. Ther. 33(12), 1932–1942 (2011) 13. J.L. Borges, J.P. Bilezikian, A.R. Jones-Leone, A.P. Acusta, P.D.

Ambery, A.J. Nino, M. Grosse, L.A. Fitzpatrick, A.R. Cobitz, A

randomized, parallel group, double-blind, multicentre study

comparing the efficacy and safety of Avandamet (rosiglitazone/

metformin) and metformin on long-term glycaemic control and

bone mineral density after 80 weeks of treatment in drug-naive

type 2 diabetes mellitus patients. Diabetes Obes. Metab. 13(11), 1036–1046 (2011)

14. E. Ceriani, G. Costantino, G. Casazza, G.M. Podda, Rosiglitazone

plus metformin to prevent type 2 diabetes mellitus. Lancet

376(9750), 1387–1388 (2010) 15. D.M. Torres, F.J. Jones, J.C. Shaw, C.D. Williams, J.A. Ward,

S.A. Harrison, Rosiglitazone versus rosiglitazone and metformin

versus rosiglitazone and losartan in the treatment of nonalcoholic

steatohepatitis in humans: a 12-month randomized, prospective,

open- label trial. Hepatology 54(5), 1631–1639 (2011) 16. IDF Clinical Guidelines Task Force, Global guideline for type 2

diabetes: recommendations for standard, comprehensive, and

minimal care. Diabet. Med. 23(6), 579–593 (2006) 17. B. McIntosh, C. Cameron, S.R. Singh, C. Yu, T. Ahuja, N.J.

Welton, M. Dahl, Second-line therapy in patients with type 2

diabetes inadequately controlled with metformin monotherapy: a

systematic review and mixed-treatment comparison meta-analy-

sis. Open Med. 5(1), e35–e48 (2011) 18. A.J. Garber, D.J. Donovan, P. Dandona, S. Bruce, J.S. Park,

Efficacy of glyburide/metformin tablets compared with initial

monotherapy in type 2 diabetes. J. Clin. Endocrinol. Metab.

88(8), 3598–3604 (2003) 19. M. Feinglos, G. Dailey, W. Cefalu, K. Osei, J. Tayek, W. Ca-

novatchel, R. Chaiken, I. Kourides, Effect on glycemic control of

the addition of 2.5 mg glipizide GITS to metformin in patients

with T2DM. Diabetes Res. Clin. Pract. 68(2), 167–175 (2005) 20. G. Charpentier, F. Fleury, M. Kabir, L. Vaur, S. Halimi,

Improved glycaemic control by addition of glimepiride to met-

formin monotherapy in type 2 diabetic patients. Diabet. Med.

18(10), 828–834 (2001) 21. J. Yao, G. Lu, J. Yang, J. Liu, L. Zhu, X. Lü, M. Yuan, D. Zhang,

L. Ma, J. Zheng, X. Lü, G. Wang, Z. Chen, X. Guo, Y. Gao,

Multi-center, randomized, double-masked, double-mimic active-

controlled clinical trial of glipizide/metformin hydrochloride

tablets for patients with type 2 diabetes. Chin. J. Clin. Pharmacol.

24(5), 387–391 (2008) 22. P. Li, W. Chen, L. Li, C. Liu, Z. Shan, B. Su, H. Ge, Muticenter,

randomized, double-masked clinical trials of metformin/glipizide

for patients with type 2 diabetes. Chin. Pharm. J. 12(17), 87–88 (2011)

23. A.D. Rao, N. Kuhadiya, K. Reynolds, V.A. Fonseca, Is the

combination of sulfonylureas and metformin associated with an

increased risk of cardiovascular disease or all-cause mortality? A

meta-analysis of observational studies. Diabetes Care 31(8), 1672–1678 (2008)

24. M.G. Wulffele, A. Kooy, D. de Zeeuw, C.D. Stehouwer, R.T.

Gansevoort, The effect of metformin on blood pressure, plasma

cholesterol and triglycerides in type 2 diabetes mellitus: a sys-

tematic review. J. Intern. Med. 256(1), 1–14 (2004) 25. Z. Cheng, G1imepiride and repaglinide together with dimeth-

yldiguanide treat diabetes II. J. Zhejiang Univ. Tradit. Chin. Med.

30(5), 490–491 (2006) 26. J. Ning, W. Tang, Z. Zhou, F. Qiong, L. Yu-hua, Z. Wei-dong,

Effect of glimepiride and metformine on insulin resistance in type

2 diabetics. China J. Mod. Med. 16(14), 2224–2225, 2227 (2006) 27. Z. Luo, Y. Wang, S. He, A clinical trial on observing the efficacy

of metformin/gliclazide sustained-release capsule on type 2 dia-

betes. Chin. Med. Sci. 10(1), 65–66 (2012) 28. H. Zhang, A Clinical Trial on Observing the Availability and

Safety of Fixed-Dose Metformin/Glipizide on Type 2 Diabetes (Jilin University, Changchun, 2009)

29. M. Nauck, A. Frid, K. Hermansen, N.S. Shah, T. Tankova, I.H.

Mitha, M. Zdravkovic, M. During, D.R. Matthews, 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

32(1), 84–90 (2009) 30. Z. Ji, The Efficacy and Safety of Clinical Observation of the

Compound of Glipizide and Metformin in the Treatment of the Type 2 Diabetes with a Poorly Controlled Blood Glucose (Chi- nese Medical Sciences University, Chengdu, 2011)

31. L. Yao, X. Lv, X. Ji, J. Zhang, Clinical study on efficacy and

security of fixed-dose glipizide/metformin on type 2 diabetes

mellitus (DM). Chin. J. Clin. Pharmacol. Ther. 15(7), 803–808 (2010)

32. X. Su, J. Ma, R. Sun, L. Guo, L. Fu, J. Wu, Glipizide–metformin

compound improves B cell function in type 2 diabetic patients.

J. Med. Postgrad. 23(11), 1160–1163 (2010) 33. B.J. Goldstein, M. Pans, C.J. Rubin, Multicenter, randomized,

double-masked, parallel-group assessment of simultaneous gli-

pizide/metformin as second-line pharmacologic treatment for

patients with type 2 diabetes mellitus that is inadequately con-

trolled by a sulfonylurea. Clin. Ther. 25(3), 890–903 (2003) 34. L. Blonde, J. Rosenstock, A.D. Mooradian, B.A. Piper, D. Henry,

Glyburide/metformin combination product is safe and efficacious

in patients with type 2 diabetes failing sulphonylurea therapy.

Diabetes Obes. Metab. 4(6), 368–375 (2002) 35. A.J. Garber, J. Larsen, S.H. Schneider, B.A. Piper, D. Henry,

Simultaneous glyburide/metformin therapy is superior to com-

ponent monotherapy as an initial pharmacological treatment for

type 2 diabetes. Diabetes Obes. Metab. 4(3), 201–208 (2002) 36. M. Marre, H. Howlett, P. Lehert, T. Allavoine, Improved gly-

caemic control with metformin-glibenclamide combined tablet

therapy (Glucovance) in type 2 diabetic patients inadequately

controlled on metformin. Diabet. Med. 19(8), 673–680 (2002) 37. M.J. Cziraky, K.E. Watson, R.L. Talbert, Targeting low HDL-

cholesterol to decrease residual cardiovascular risk in the man-

aged care setting. J. Manag. Care Pharm. 14(8 Suppl), S3–S28, S30–S31(2008)

38. E. Moghissi, F. Ismail-Beigi, R.C. Devine, Hypoglycemia: min-

imizing its impact in type 2 diabetes. Endocr. Pract. 5(8), 1–33 (2013)

39. J. Belsey, G. Krishnarajah, Glycaemic control and adverse events

in patients with type 2 diabetes treated with metformin ? sul-

phonylurea: a meta-analysis. Diabetes Obes. Metab. 10(11), 23–25 (2008)

Endocrine

123