Comparative efficacy of glimepiride and metformin in monotherapy of type 2 diabetes mellitus: meta-analysis of randomized controlled trials
Diabetology & Metabolic Syndrome
Comparative efficacy of glimepiride and metformin in monotherapy of type 2 diabetes mellitus: meta-analysis of randomized controlled trials
Hongmei Zhu 1
Shuang Zhu 1
Xiuqian Zhang 1
Yang Guo 1
Yunzhen Shi 1
Zhimin Chen 1
Siu-wai Leung 0 1
0 School of Informatics, University of Edinburgh , Edinburgh EH8 9AB , UK
1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macao , China
Background: Metformin treatment has been the most recommended monotherapy of type 2 diabetes mellitus (T2DM) for decades but is challenged by new antidiabetic drugs. This study conducted a meta-analysis of randomized controlled trials (RCT) comparing the efficacy of metformin and glimepiride in monotherapy of T2DM. Methods: A literature search for RCTs on glimepiride and metformin was conducted on the bibliographic databases, including PubMed, Cochrane Library and ScienceDirect, from their inceptions to 25 Mar 2013. All RCTs were selected according to pre-specified eligibility criteria. The quality of articles was assessed with the Cochrane's risk of bias tool. Statistical meta-analysis evaluated the overall effects and biochemical indices of T2DM. Sensitivity and subgroup analyses evaluated the robustness and explained the heterogeneity of the results. Begg and Egger's tests quantified possible publication biases. Results were represented as standard mean difference or odds ratio [95% confidence internals] P value. Results: Fifteen RCTs with 1681 adult T2DM patients were included for meta-analysis. Metformin was not better than glimepiride in overall efficacy in controlling the levels of HbA1c, postprandial blood sugar (PPBS), fasting plasma insulin (FINS), systolic and diastolic blood pressures (SBP and DBP), and high density lipoprotein (HDL). Metformin was only more effective than glimepiride in controlling the levels of total cholesterol (TC, 0.33 [0.03, 0.63], P = 0.03), low-density lipoprotein (LDL, 0.35 [0.16, 0.53], P = 0.0002) and triglycerides (TG, 0.26 [0.05, 0.46], P = 0.01). Odds ratios of adverse events showed that glimepiride was more likely to induce hypoglycemia episodes and metformin was with a higher risk of gastrointestinal upset. Conclusion: Metformin was not significantly better than glimepiride in glycemic control of T2DM, suggesting that glimepiride would be a good choice second to metformin in the monotherapy of T2DM.
Glimepiride; Metformin; Type 2 diabetes mellitus; Meta-analysis
Metformin has been the most recommended
monotherapy of type 2 diabetes mellitus (T2DM) [1,2]. The UK
Prospective Diabetes Study (UKPDS) found metformin
more effective than chlorpropamide, glibenclamide and
insulin . The American Diabetes Association (ADA)
recommended metformin as the first drug of choice for
treating T2DM patients, especially those who are
overweight . The UK National Institute for Health and
Clinical Excellence (NICE) recommended metformin if
the patients are at danger under hypoglycaemia . The
latest recommendations of ADA  and NICE  were
updated with the results of UKPDS [6,7], post-trial
monitoring of UKPDS , and systematic reviews of comparing
metformin with placebo, sulfonylureas and other
antidiabetic drugs [7,9], as well as the randomized controlled
trials (RCTs) comparing metformin monotherapy with
pioglitazone , metformin plus nateglinide , metformin
plus rosiglitazone  and other non-metformin
treatments . A meta-analysis of RCTs on the efficacy of
metformin in treating T2DM  found metformin
lacking clear evidence for efficacy over the
conventional or placebo treatment. A recent literature review
suggested that metformin, albeit old, remained the best
treatment for T2DM  but the review was not a
systematic review or meta-analysis. It did not include
the latest RCTs comparing metformin and glimepiride
in monotherapy of T2DM.
Glimepiride is of the latest generation sulfonylureas
for treating T2DM . It has a lower cardiovascular
risk than conventional sulfonylureas do . Recent
RCTs found it comparable to metformin in treating
T2DM patients [20,21] including those who are not
responding well to non-glimepiride sulfonylureas [22,23].
Probably due to the late launch of glimepiride [24,25]
and lack of head-to-head comparative RCTs, early
UKPDS, ADA and NICEs recommendations did not
include the results of RCTs comparing metformin with
205 records from:
Figure 1 Flow of study selection.
27 full-text articles assessed for eligibility
12 full-text articles excluded
Non-Randomized Controlled Trials (n=2)
Not adult patients or unclear age range (n=2)
Results Incomplete (n=4)
Redundant publications (n=1)
Medication failure before test (n=2)
15 studies included in quantitative synthesis (meta-analysis)
Table 1 Characteristics of included studies
Author (year) Country Age*
glimepiride in monotherapy but they did include the
findings that sulfonlyureas had increased risks in
hypoglycemia, weight gain and cardiovascular issues.
Recent cohort studies confirmed the increased
cardiovascular risks of glimepiride  but did no
cardiovascular harm to the patients with diagnosed coronary
artery disease . This study aimed to compare the
efficacy between metformin and glimepiride in
monotherapy of T2DM through a meta-analysis and supply the
evidence that was missing from previous reviews [9,11]
and clinical guidelines [1,2].
Table 2 Results of overall efficacy
Outcome No. of Pooled sample size
Glimepiride Metformin Glimepiride
50 44 1-6 mg/day
1-6 mg/day 250 mg bid-750 mg tid
1-6 mg/day 250-2000 mg tid
1-6 mg/day 250 mg to maximum bid
2-6 mg/day 250-1500 mg bid
4-6 mg/day 1500 mg/day
2-8 mg/day 500-2000 mg/day
500 mg bid
This study included the RCTs comparing glimepiride
with metformin as monotherapy of T2DM. Participants
in the RCTs were adult patients suffering from T2DM.
Outcome measures of the treatment of T2DM included
BMI (body mass index), SBP (systolic blood pressure),
DBP (diastolic blood pressure), FPG (fasting plasma
glucose), HbA1c (glycosylated hemoglobin level), PPBS
(postprandial blood sugar), TC (total cholesterol), HDL
period (weeks) Ref
Table 3 Cochranes risk of bias
Source of bias
Note: L, low risk of bias; U, unclear risk of bias; H, high risk of bias.
(high-density lipoprotein), LDL (low-density lipoprotein),
TG (triglycerides) and FINS (fasting plasma insulin).
This study excluded the RCTs with the participants who
were non-responders to metformin or glimepiride and
received dosages exceeded the upper recommended limit
(metformin: 2550 mg daily; glimepiride: 8 mg daily) .
The RCTs of extremely small sample size (fewer than 10
patients) were also excluded.
Search and selection of studies
Bibliographical databases, including PubMed, Cochrance
Library, Science Direct, China Academic Journals Web
Publishing Database, China Master Theses Full-text
Database and China Doctor Theses Full-text Database
Figure 2 Cochranes risk of bias.
on the China National Knowledge Infrastructure (CNKI),
WanFang Data and Google, were searched from their
inceptions to 25 Mar 2013.
Search strategies were specified in the working
languages of databases, although the terminologies in
searching Chinese and English databases were
equivalent. Basically, the articles with the terms glimepiride
and metformin in titles, abstracts, and keywords were
retriered. Specific search strategies were:
PubMed: Glimepiride and Metformin in Abstract or
Title; Cochrane Llibrary: Glimepiride and Metformin
in Title, Abstract or Keywords; Science Direct:
Glimepiride and Metformin in Abstract, Title, or
Keywords; China Academic Jounrnals Web Publishing
Database, China Doctor Theses Full-text Database and
China Master Theses Full-text Database: Title = Glimepiride
* Metformin or Keyword = Glimepiride * Metformin or
Abstract = Glimepiride * Metformin (in Chinese); Wan
Fang: Title All Glimepiride Metformin or Keywords All
Glimepiride Metformin or Abstract All Glimepiride
Metformin (in Chinese).
Two groups of reviewers (three reviewers in each
group) independently performed the literature search
and selection. The results from one group were
crosschecked by the other group. Disagreements were
resolved by group discussion.
Data extraction and quality assessment
Two reviewers (HZ, XZ) independently extracted data of
study characteristics and outcome measures from the
selected RCTs. The extracted data were cross-checked
before quality assessment according to the Cochranes
Table 4 Sensitivity analysis (sample size 90)
Outcome No. of Pooled
studies sample size
Excluding the studies
with non-responders to
Excluding the studies with
participants who used other
anti-diabetic drugs before RCTs
risks of bias tool . Disagreement was resolved by
discussion between the reviewers (HZ, XZ). A third
reviewer (SZ) was consulted when necessary.
Extracted data were transferred to Review Manager 5.2
 for meta-analysis with random-effects model.
Numeric outcome measures were represented in
standardized mean differences (SMD) or odds ratios (OR) and
their 95% confidence intervals (CI). Study heterogeneity
was evaluated with T2 test and I2 statistics. P values
below 0.05 were considered statistically significant.
Sensitivity and subgroup analysis
Sensitivity analysis of the efficacy was performed on the
sample sizes, on whether the patients received prior
antidiabetic treatments and on the daily dose of metformin.
Subgroup analysis was performed to explain the
heterogeneity in terms of differences in follow-up periods and
characteristics of the participants.
Below 1000 mg only
1000 mg and above 1000 mg
Above 1000 mg only
Note: NA stands for not applicable.
Adverse events analysis
Adverse events analysis was performed on the hypoglycemia,
gastrointestinal upset and overall side effects with their odds
ratios (OR) and 95% CI.
Funnel plots were generated to visualize possible
publication bias. Begg and Eggers tests using the package
metafor  with statistical software R  evaluated
the statistical significance of the publication bias.
Included studies and their characteristics
Figure 1 shows the selection process of the studies. A
total of 1023 records were identified in accordance with
the search strategies from specific bibliographical
databases, i.e. PubMed (n = 208), Cochrance Library (n = 89),
Science Direct (n = 48), Chinese National Knowledge
Infrastructure (n = 267), WangFang (n = 206) and Google
(n = 205). Among the 440 records after removal of
duplicates, 27 records met the eligibility criteria. After
full-text assessment, 12 of 27 studies were excluded for
the reasons stated in Figure 1. As a result, 15 RCTs with
1681 participants were included for meta-analysis. The
characteristics of the included studies are shown in
Table 7 Subgroup analysis of different follow-up periods
Meta-analysis was performed on the outcome measures
FPG, BMI, HbA1c, PPBS, TC, FINS, HDL, LDL, TG,
SBP and DBP. The SMD, 95% CI and P values for
outcomes between metformin and glimepiride are shown in
Table 2. The SMDs between metformin and glimepiride
were only statistically significant on TC (0.33 [0.03,
0.63], P = 0.03), LDL (0.35 [0.16, 0.53], P = 0.00002), and
TG (0.26 [0.05, 0.46], P = 0.01), indicating that efficacy of
metformin was statistically significant over glimepiride
in lipid metabolism indices. The differences in glycemic
control (e.g. HbA1c and PPBS) and cardiovascular
indices (e.g. blood pressure) were not statistically significant.
As shown in Table 2, there were significant
heterogeneities among studies in SBP (I2 = 86%, P < 0.0001), DBP
(I2 = 87%, P < 0.00001), PPBS (I2 = 81%, P < 0.00001), TC
(I2 = 79%, P < 0.0001), HDL (I2 = 86%, P < 0.00001) and
FINS (I2 = 91%, P < 0.00001). The heterogeneities
justified the use of random-effects model in meta-analysis.
Risk of bias across studies
Cochranes risk of bias tool was used to assess the RCT
quality (Table 3 and Figure 2). The attrition bias of all
included studies was low (few missing data). Other key
aspects among studies were mostly unclear in risk of
bias except two studies [20,36].
-0.08 [-0.27, 0.12]
-0.04 [-0.29, 0.20]
-0.15 [-0.38, 0.08]
0.50 [0.27, 0.72]
0.12 [-0.10, 0.35]
0.28 [-0.00, 0.56]
0.21 [-0.01, 0.44]
0.05 [-0.21, 0.32]
-0.63 [-1.46, 0.20]
0.43 [-0.10, 0.96]
0.39 [-0.15, 0.93]
0.03 [-0.17, 0.23]
0.03 [-0.10, 0.17]
-0.02 [-0.23, 0.20]
0.23 [-0.39, 0.86]
0.10 [-0.64, 0.84]
0.48 [0.29, 0.67]
0.31 [-0.11, 0.73]
0.14 [-0.94, 1.21]
Sensitivity analysis checked whether the overall effects
would be different if only the studies with the sample
size N 90 were included. As shown in Table 4,
metformin outperformed glimepiride only on LDL (0.41 [0.21,
0.61], P < 0.0001) in the studies with sample size N 90.
Other outcomes such as FPG, BMI, TC and TG did not
show significant difference between glimepiride and
Sensitivity analysis also considered whether prior use
of anti-diabetic drugs would affect the RCT results.
Table 5 shows that only the effect of metformin on BMI
became statistically significant after excluding the studies
with participants who were non-responders to other
sulfonyureas. The significance of the effects of metformin
on TC, LDL, TG and other aspects remained the same,
indicating the overall results on those aspects were
Sensitivity analysis tested whether the efficiency of
metformin would be different if the daily dose of
metformin was less than 1000 mg. Table 6 shows that
metformin outperformed glimepiride only on BMI (0.33 [0.09,
Table 8 Subgroup analysis of different BMI
Meta-analysis of the subgroups with different follow-up
periods (12-24 weeks and 48-60 weeks) showed that
metformin moderated BMI and TC better than
glimepiride in the shorter term while both drugs were equivalent
in performance in all aspects except LDL in the longer
term. As shown in Table 7, metformin performed better
than glimepiride on both BMI (0.47 [0.24, 0.69], P <
0.0001) and TC (0.50 [0.27, 0.72], P < 0.0001) in 12-24
weeks subgroup. In 48-60 weeks subgroup, metformin
performed better only on LDL (0.48 [0.29, 0.67], P < 0.00001).
Meta-analysis of the subgroups with BMI below or
above 27.5 (i.e. the norm in the countries where the
included RCTs were conducted)  was also conducted.
As shown in Table 8, metformin outperformed
glimepiride on control of FPG (0.34 [0.11, 0.57], P = 0.003), TC
(0.33 [0.08, 0.58], P = 0.01) and LDL (0.32 [0.08, 0.56],
P = 0.008) in the higher BMI subgroup (BMI 27.5).
However, in the lower BMI subgroup (BMI < 27.5)
BMI < 27
-0.27 [-0.98, 0.43]
0.20 [-0.21, 0.60]
0.15 [-0.27, 0.57]
-0.05 [-0.24, 0.13]
0.06 [-0.09, 0.20]
-0.38 [-0.91, 0.15]
0.26 [-0.31, 0.84]
0.11 [-0.58, 0.81]
0.30 [-0.09, 0.70]
0.33 [-0.05, 0.71]
-0.17 [-0.63, 0.29]
0.31 [-0.15, 0.78]
0.69 [-0.25, 1.63]
0.63 [-0.36, 1.63]
0.34 [0.11, 0.57]
0.17 [-0.58, 0.93]
0.09 [-0.18, 0.36]
0.33 [0.08, 0.58]
0.03 [-0.18, 0.23]
0.32 [0.08, 0.56]
0.15 [-0.06, 0.36]
0.56 [-0.45, 1.57]
Table 9 Adverse events
All side effects
metformin and glimepiride were not significantly different
in performance as determined by outcome measures.
Eight out of 15 studies reported adverse events. As shown
in Table 9, glimepiride had more hypoglycemia episodes
than metformin did (4.94 [2.03, 11.99], P = 0.0004).
Incidents of gastrointestinal upset, including diarrhea,
epigastric discomfort, stomach pain and abdominal distension,
were reported more frequently in metformin group (0.07
[0.01, 0.37], P = 0.002). Overall, these two drugs had no
significant difference in side effects (0.35 [0.06, 2.01],
P = 0.24) among the included RCTs.
Funnel plots were generated to visualize possible
publication bias. Major outcomes FPG, BMI, HbA1c, PPBS,
TC, FINS, HDL, LDL, TG, SBP and DBP showed
moderate asymmetries across studies in the funnel plots,
indicating there was publication bias. A typical funnel plot is
shown in Figure 3. The statistical significance of the
moderate publication bias in sugar (FPG and PPBS) and lipid
(HDL and TG) indices was confirmed by the Beggs rank
correlation test . Eggers linear regression method 
further confirmed the statistical significance of the
publication bias in FPG towards metformin (Table 10), indicating
that the difference in glycemic control efficacy between
metformin and glimepiride was less than it seemed.
Figure 3 Funnel plots of publication biases in FPG.
4.94 [2.03, 11.99]
0.07 [0.01, 0.37]
Metformin remains the most effective monotherapy of
T2DM while its advantages are diminishing among
newer anti-diabetic drugs. Past studies comparing the
efficacy between metformin with sulfonylureas showed
that metformin was significantly better in controlling
HbA1c, FPG, BMI, LDL and TG [35,7]. Glimepiride is
a better sulphonylurea in treating T2DM [1719,47,48].
The present meta-analytic study found that metformin
was not significantly better than glimepiride, particularly
in controlling HbA1c, FPG and BMI.
This meta-analysis supported that both metformin and
glimepiride was effective in treating T2DM for glycemic
control. Metformin performed better than glimepiride in
management of BMI and lipid metabolism indices but
the advantages of metformin were only significant in
short follow-up periods.
These results were deemed robust after evaluation by
sensitivity analysis that excluded small RCTs and the
participants who were non-responders to non-glimepiride
sulfonylureas or who received anti-diabetic treatment.
The differences between metformin and glimepiride
became insignificant in large RCTs. Even for treating the
patients who were not responding to conventional
(non-glimepiride) sulfonylureas, glimepiride and
metformin were equivalent in glycemic control. This
finding could not be achieved by comparing sulfonylureas
(including glimepiride) as a group with metformin.
Table 10 Results of Begg and Egger's tests
Adverse events analysis showed that glimepiride had
more hypoglycemia episodes, in agreement with
previous results that metformin was associated with less
hypoglycemia than sulphonylureas  and that
metformin had a higher risk of gastrointestinal upset .
The weight gain side effects were not significant in the
included RCTs, in consistency with the findings of
previous studies  on the weight gain issue of glimepiride.
The daily dose of metformin affected the efficacy and
side effects of metformin. When the daily dose of
metformin was more than 1000 mg, the probability of
gastrointestinal upset would be increased exponentially .
Sensitivity analysis on the daily doses of metformin
showed that metformin outperformed glimepiride only
on BMI with a low daily dose and on LDL with a
relatively high daily dose, but was not significantly better
than glimepiride on controlling HbA1c, FPG and Fins
in all daily doses.
Most of the included RCTs (13 out of 15 in this
metaanalysis) were conducted in Asia; thus, the Asian norm
of BMI for subgroup analysis was adopted. It seems that
Asian patients were less affected by the weight gain side
effect of glimepiride. Multi-country and multi-ethnic
trials are warranted to test whether glimepiride is more
suitable for Asian patients. Double-blind RCTs with
longer follow-up periods should be conducted to assess
other side effects such as those on cardiovascular
system. It is encouraging that new clinical trials comparing
metformin and glimepiride for monotherapy of T2DM
have been registered . Hence, proper updates on this
meta-analysis will be conducted in forthcoming years.
These results provide direct evidence to support ADAs
and NICEs recommendations to consider glimepiride as
one of the alternatives to metformin. Our meta-analysis
of the RCT results demonstrated that the advantages of
metformin over glimepiride were not always significant
particularly in Asian patients.
Metformin and glimepiride were not significantly
different in glycemic control of T2DM, suggesting that
glimepiride would be a good choice second to metformin in
the monotherapy of T2DM.
BMI: Body mass index; DBP: Diastolic blood pressure; FPG: Fasting plasma
glucose; FINS: Fasting plasma insulin; HbA1c: Glycosylated hemoglobin level;
HDL: High-density lipoprotein; LDL: Low-density lipoprotein;
PPBS: Postprandial blood sugar; RCT: Random control trials; SBP: Systolic
blood pressure; TC: Total cholesterol; TG: Triglycerides; T2DM: Type 2
The authors declare that they have no competing interests.
SL supervised this study. HZ and XZ extracted and analyzed the data from
the selected studies according to the eligibility criteria. SZ repeated data
analysis for cross-checking. Other authors assisted in searching the databases,
assessing and selecting studies. HZ, SZ and SL interpreted the data and
drafted a report on the findings. SL revised the manuscript for submission.
All authors read and approved the final version of the manuscript.
The work of HZ, SZ and SL is part of a research project Open systematic
reviewing of clinical trials (MYRG190-Y3-L3-ICMS-LSW) funded by the
University of Macau.
1. The National Collaborating Centre for Chronic Conditions: Type 2 diabetes: national clinical guideline for management in primary and secondary care (update) . London: Royal College of Physicians ; 2008 .
2. Association American Diabetes : Standards of medical care in diabetes-2013 . Diabetes Care 2013 , 36 : S11 - 66 .
3. UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) . Lancet 1998 , 352 : 854 - 865 .
4. Stratton IM , Adler AI , Neil HAW , Matthews DR , Manley SE , Cull CA , Hadden D , Turner RC , Holman RR , on behalf of the UK Prosepective Diabetes Study Group: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study . BMJ 2000 , 321 : 405 - 412 .
5. Adler AI , Stratton IM , Haw N , Yudkin JS , Matthews DR , Cull CA , Wright AD , Turner RC , Holman RR , UK Prospective Diabetes Study Group: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study . BMJ 2000 , 321 : 412 - 419 .
6. Inzucchi SE , Bergenstal RM , Buse JB , Diamant M , Ferrannini E , Nauck M , Peters AL , Tsapas A , Wender R , Matthews DR : Management of hyperglycemiain type 2 diabetes: a patient-centered approach . Diabetes Care 2012 , 35 : 1364 - 1379 .
7. Saenz A , Fernandez-Esteban I , Mataix A , Ausejo Segura M , Roqu i Figuls M , Mohr D : Metformin monotherapy for type 2 diabetes mellitus . Cochrane DB Syst Rev 2009 , 3 :CD002966. doi: 10.1002/14651858.CD002966.pub3.
8. Holman RR , Paul SK , Bethel MA , Matthews DR , Neil HAW : 10 - year follow-up of intensive glucose control in type 2 diabetes . NEJM 2008 , 359 : 1577 - 1589 .
9. Bennett WL , Maruthur NM , Singh S , Segal JB , Wilson LM , Chatterjee R , Marinopoulos SS , Puhan MA , Ranasinghe P , Block L , Nicholson WK , Hutfless S , Bass EB , Bolen S : Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations . Ann Intern Med 2011 , 154 : 602 - 614 .
10. Schernthaner G , Matthews DR , Charbonnel B , Hanefeld M , Brunetti P , on behalf of the quarter study group: Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a doubleblind, randomized trial . J Clin Endocrinol Metab 2004 , 89 : 6068 - 6076 .
11. Marre M , Gaal LV , Usadel KH , Ball M , Whatmough I , Guitard C : Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients . Diabetes Obes Metab 2002 , 4 : 177 - 186 .
12. Bailey CJ , Bagdonas A , Rubes J , McMorn SO , Donaldson J , Biswas N , Stewart MW : Rosiglitazone/metformin fixed-dose combination compared with uptitrated metformin alone in type 2 diabetes mellitus: a 24-week, multicenter, randomized, double-blind, parallel-group study . Clin Ther 2005 , 27 : 1548 - 1561 .
13. Cryer DR , Nicholas SP , Henry DH , Mills DJ , Stadel BV : Comparative outcomes study of metformin intervention versus conventional approach . Diabetes Care 2005 , 28 : 539 - 543 .
14. Boussageon R , Suupper I , Bejan-Angoulvant T , Kellou N , Cucherat M , Boissel JP , Kassai B , Moreau A , Gueyffier F , Cornu C : Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials . PLOS Med 2012 , 9 : e1001204 .
15. Rojas LBA , Gomes MB : Metformin: an old but still the best treatment for type 2 diabetes . Diabetol Metab Syndr 2013 , 5 : 6 - 20 .
16. Hamaguchi T , Hirose T , Asakawa H , Itoh Y , Kamado K , Tokunaga K , Tomita K , Masuda H , Watanabe N , Namba M : Efficacy of glimepiride in type 2 diabetic patients treated with glibenclamide . Diabetes Res Clin Pract 2004 , 66 : S129 - 132 .
17. Rendell M : The role of sulphonylureas in the management of type 2 diabetes mellitus . Drugs 2004 , 64 : 1339 - 1358 .
18. Nissen SE , Nicholls SJ , Wolski K , Nesto R , Kupfer S , Perez A , Jure H , Larochellire R , Staniloae CS , Mavromatis K , Saw J , Hu B , Lincoff AM , Tuzcu EM , for the PERISCOPE Investigators: Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes . JAMA 2008 , 299 : 1561 - 1573 .
19. Schotborgh CE , Wilde AAM : Sulfonylurea derivatives in cardiovascular research and in cardiovascular patients . Cardiovasc Res 1997 , 34 : 73 - 80 .
20. Yamanouchi T , Sakai T , Igarashi K , Ichiyanagi K , Watanabe H , Kawasaki T : Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes . Diabet Med 2005 , 22 : 980 - 985 .
21. Yoon KH , Shin JA , Kwon HS , Lee SH , Min KW , Ahn YB , Yoo SJ , Ahn KJ , Park SW , Lee KW , Sung YA , Park TS , Kim MS , Kim YK , Nam MS , Kim HS , Park IB , Park JS , Woo JT , Son HY : Comparison of the efficacy of glimepiride, metformin, and rosiglitazone monotherapy in korean drug-naive type 2 diabetic patients: the practical evidence of antidiabetic monotherapy study . Diabetes Metab J 2011 , 35 : 26 - 33 .
22. Rong W , Cai LS : Comparing the efficacy of glimepiride and metformin in patients who are secondary sulfonylurea failure . Chinese J Diabetes 2004 , 12 : 211 - 212 .
23. Wang KL , Lei GD , Tang XX , Huang YH : Comparison of the efficacy of glimepiride and metformin in patients who are secondary sulfonylurea failure . Drug Research 2009 , 18 .
24. UK Prospective Diabetes Study . http://www.dtu.ox.ac.uk/ukpds_trial/index.php.
25. HMR's Amaryl Launched For Diabetes In The USA . http://www. thepharmaletter. com/file/69437/hmrs-amaryl-launched-for-diabetes-in-theusa .html.
26. Schramm TK , Gislason GH , Vaag A , Rasmussen JN , Folke F , Hansen ML , Fosbol EL , Kober L , Norgaard ML , Madsen M , Hansen PR , Torp-Pedersen C : Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study . Eur Heart J 2011 , 32 : 1900 - 1908 .
27. Pantalone KM , Kattan MW , Yu C , Wells BJ , Arrigain S , Jain A , Atreja A , Zimmerman RS : Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis . Diabetes Obes Metabol 2012 , 14 : 803 - 809 .
28. Food and Drug Administration (FDA): Appoved drug products with therapeutic equivalence evaluations 32nd . U.S: Department of Health and Human Services , Food and Drug Administration , Center for Drug Evaluation and Research, Office of Pharmaceutical Science, and Office of Generic Drugs; 2012 .
29. Higgins JPT , Green S (Eds): Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011] . The Cochrane Collaboration; 2011 . Available from www.cochrane-handbook .org.
30. Review Manager (RevMan): [Computer program] . Version 5 .2. Copenhagen : The Nordic Cochrane Centre, The Cochrane Collaboration; 2012 .
31. Viechtbauer W : Conducting meta-analyses in R with the metafor package . J Stat Software 2010 , 36 : 1 - 48 .
32. The R Project for Statistical Computing. [http://www.r-project.org/] Accessed in 2013-06-19.
33. Ling ZM : The clinical observation of glimepiride in treating type 2 diabetes . J Clin Med Pract 2003 , 7 : 574 - 575 .
34. Ramachandran A , Snehalatha C , Salini J , Vijay V : Use of glimepiride and insulin sensitizers in the treatment of type 2 diabetes-a study in indians . J Assoc Physicians India 2004 , 52 : 459 - 463 .
35. Derosa G , Franzetti I , Gadaleta G , Ciccarelli L , Fogari R : Metabolic variations with oral antidiabetic drugs in patients with Type 2 diabetes: Comparison between glimepiride and metformin . Dia Nutr Metab 2004 , 17 : 143 - 150 .
36. Gonzlez-Ortiz M , Martnez-Abundis E , Grupo para el Tratamiento de la Diabetes Mellitus con Combinaciones: Efficacy and safety of glimepiride plus metformin in a single presentation, as combined therapy, in patients with type 2 diabetes mellitus and secondary failure to glibenclamide, as monotherapy . Rev Inest Clin 2004 , 56 : 327 - 333 .
37. Tang JZ , Mao JP , Yang ZF , Zhou ZG , Tang WP , Feng Q : Effects of glimepiride and metformin on free fatty acid in patients with type 2 diabetes mellitus . J Cent South Univ Technol 2004 , 29 : 631 - 634 .
38. Ning J , Tang WL , Zhou ZG , Feng Q , Liu YH , Zhou WD : Effect of glimepiride and metformine on insulin resistance in type 2 diabetics . China J Mod Med 2006 , 16 : 2224 - 2227 .
39. Wu PS : The clinical efficacy of glimepiride on previously untreated type 2 diabetes patients . Appl J Gen Pract 2007 , 5 : 1084 - 1085 .
40. Xu ZQ , Yu JB : Clinical observation of glimepiride and metformin in newly diagnosed type 2 diabetes . Chin J Misdiagn 2007 , 7 : 2454 - 2455 .
41. Li F , Tang GF , Tang TC , Yang YH , Zhang ZM : Glimepiride and metformin in the treatment of metabolism syndrome . J Bengbu Med Coll 2007 , 32 : 445 - 446 .
42. Rahman IU , Malik SA , Bashir M , Khan RU , Idrees M : Monotherapy with metformin or glimepiride and changes in serum sialic acid in type 2 diabetes mellitus . British J Diabetes Vascular Med 2011 , 11 : 137 - 140 .
43. Wang H : Observation of 68 cases of obese type 2 diabetes who are treated with metformin . Med Forum Mag 2011 , 32 : 156 - 157 .
44. WHO expert consultation: Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies . Lancet 2004 , 363 : 157 - 163 .
45. Begg CB , Mazumdar M : Operating characteristics of a rank correlation test for publication bias . Biometrics 1994 , 50 : 1088 - 1101 .
46. Egger M , Smith GD , Schneider M , Minder C : Bias in meta-analysis detected by a simple, graphical test . BMJ 1997 , 315 : 629 - 634 .
47. Holstein A , Plaschke A , Egberts EH : Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide . Diabetes Metab Res Rev 2001 , 17 : 467 - 473 .
48. Sato J , Ohsawa I , Oshida Y , Fukuharu M , Hu XC , Tamagawa T , Sato Y : Comparison of the effects of three sulfonylureas on in vivo insulin action . Arzneimittel-Forsch 2001 , 51 : 459 - 464 .
49. Nathan DM , Buse JB , Davidson MB , Ferrannini E , Holman RR , Sherwin R , Zinmann B : Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes . Diabetes Care 2009 , 32 : 193 - 203 .
50. Okayasu S , Kitaichi K , Hori A , Suwa T , Horikawa Y , Yamamoto M , Takeda J , Itoha Y : The evaluation of risk factors associated with adverse drug reactions by metformin in type 2 diabetes mellitus . Biol Pharm Bull 2012 , 35 : 933 - 937 .
51. Bennett WL , Wilson LM , Bolen S , Maruthur N , Singh S , Chatterjee R , Marinopoulos SS , Puhan MA , Ranasinghe P , Nicholson WK , Block L , Odelola O , Dalal DS , Ogbeche GE , Chandrasekhar A , Hutfless S , Bass EB , Segal JB : Oral diabetes medications for adults with type 2 diabetes: an update . In Comparative Effectiveness Review No 27 ( Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No 290-02-0018) AHRQ Publication No. 11-EHC038-EF. Edited by Rockville MD. Agency for Healthcare Research and Quality; 2011 . Available at: http://www.ncbi.nlm. nih.gov/books/NBK55754/.
52. Bugos C , Austin M , Atherton T , Viereck C : Long-term treatment of type 2 diabetes mellitus with glimepiride is weight neutral: a meta-analysis . Diabetes Res Clin Pract 2000 , 50 : 251 - 254 .
53. Garber AJ , Duncan TG , Goodman AM , Mills DJ , Rohlf JL : Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial . Am J Med 1997 , 102 : 491 - 497 .
54. ClinicalTrials.gov. http://clinicaltrials.gov/ct2/results?term=Diabetes +metformin+Glimepiride.