Comparison of repaglinide and metformin versus metformin alone for type 2 diabetes: a meta-analysis of randomized controlled trials

DIAB-6091; No. of Pages 6

Brief Report

Comparison of repaglinide and metforminversus metformin alone for type 2 diabetes:a meta-analysis of randomized controlled trials

Jinjin Yin a,b,1, Houliang Deng a,b,1, Shumin Qin c, Waijiao Tang b, Lu Zeng b,Benjie Zhou b,*aDepartment of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150,

PR ChinabDepartment of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR Chinac Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai

200032, PR China

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e x x x ( 2 0 1 4 ) x x x . e 1 – x x x . e 6

a r t i c l e i n f o

Article history:

Received 4 December 2013

Received in revised form

2 June 2014

Accepted 15 June 2014

Available online xxx

Keywords:

Repaglinide

Metformin

Combination therapy

Type 2 diabetes mellitus

Meta-analysis

a b s t r a c t

We conducted a meta-analysis to compare the efficacy and safety of repaglinide plus

metformin with metformin alone on type 2 diabetes. Twenty-two studies were included

in this meta-analysis. Results showed combination therapy was safe and could gain better

outcomes in glycemic control. Well-designed studies are required to confirm this conclu-

sion.

# 2014 Elsevier Ireland Ltd. All rights reserved.

Contents available at ScienceDirect

Diabetes Researchand Clinical Practice

journal homepage: www.elsevier.com/locate/diabres

1. Introduction

Metforminisa worldwideacceptedbiguanide antidiabeticagent,

which is now recommended as the first agent for blood glucose

lowering in T2DM patients [1], however, metformin monother-

apy is capable of maintaining a target glycemic control only for a

* Corresponding author at: Department of Pharmacy, Zhujiang HospitTel.: +86 02061634549; fax: +86 02084300639.

E-mail addresses: [email protected], [email protected] (B1 These authors contributed equally to this work.

Please cite this article in press as: Yin J, et al. Comparison of repaglinideanalysis of randomized controlled trials. Diabetes Res Clin Pract (2014), h

http://dx.doi.org/10.1016/j.diabres.2014.06.0090168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.

short term [2]. For this reason, most T2DM patients, after a few

years from diagnosis, require combination therapy in order to

reach therapeutic goals. Repaglinid has also been widely used in

the treatment of T2DM. Recently, several randomized clinical

trials (RCTs) have compared the effects of repaglinide and

metformin versus metformin on the glycemic control and lipid

profiles, andhave foundthat formerachieved significantlybetter

al, Southern Medical University, Guangzhou 510282, PR China.

. Zhou).

and metformin versus metformin alone for type 2 diabetes: a meta-ttp://dx.doi.org/10.1016/j.diabres.2014.06.009

http://dx.doi.org/10.1016/j.diabres.2014.06.009

mailto:[email protected]

mailto:[email protected]


http://www.sciencedirect.com/science/journal/01688227

www.elsevier.com/locate/diabres


Fig. 1 – Flow diagram of included studies.

Table 1 – Characteristics of included studies.

Author (year) N (R + M/M) Agea

(R + M/M)Sex

(male/female)

Treatment Trailduration

Jadedscore

R + M M (mg/day) Additionalmedication

R (mg/day)

M (mg/day)

Ma 2003 [3] 81 (29/27/25) 53.17 (8.11)/

52.53 (7.24)

26/26 1.5–3 750–1500 750–1500 NO 12 weeks 3

Liu 2005 [4] 40 (20/20) NR NR 1.5–3 1500 1500 NO 8 weeks 1

Chen 2006 [5] 52 (27/25) 53.17 (8.11)/

52.53 (7.24)

26/26 1.5–3 750–1500 750–1500 NO 12 weeks 2

Chen 2007 [6] 78 (40/38) 35–73 46/32 1.5–3 500 500 NO 8 weeks 1

Davies 2007 [7] 51 (26/29) 56.1 (10.8)/

57.9 (10.5)

24/30 1.5–4 Maximum

dose

tolerated

Maximum

dose

tolerated

NPH insulin 4 months 3

Civera 200 8 [8] 24 (12/12) 60.3 (7.7)/

61.6 (9.2)

13/11 6 1700 1700 NPH insulin 6 months 2

Lin 2008 [9] 36 (18/18) 62.8 (8. 7) 20/16 1.5 750 1500 NO 12 weeks 1

Zhang 2008 [10] 80 (28/26/26) 30–65 NR 1–2 750–1000 750–1000 NO 12 weeks 1

Xu 2009 [11] 120 (68/52) 41–72 58/62 NR NO 12 weeks 1

Chen 2010 [12] 62 (32/30) 47.5 (13.9)/

47.1 (11.9)

33/29 1.5–3 750–1500 750–1500 NO 12 weeks 2

Cha 2011 [13] 60 (20/20/20) 51.78 (5.71)/

51.65 (4.26)

22/18 1.5–3 750–1500 750–1500 NO 8 weeks 1

Jing 2011 [14] 156 (52/52/52) 42.67 (8.52) 71/85 1.5 1500 1500 NO 12 weeks 1

We 2011 [15] 50 (25/25) 40–70 36/14 1.5–3 1500 1500 NO 8 weeks 1

Zhu 2012 [16] 60 (30/30) 40–70 33/27 6 750 750 NO 12 weeks 1

Bai 2012 [17] 90 (30/30/30) 47 48/42 1.5–3 750–1500 750–1500 NO 8 weeks 1

Jin 2012 [18] 65 (32/33) 53.2 38/27 3 1500 1500 NO 12 weeks 3

Zhao [19] 135 (45/45/45) 40.7 (18.3) 74/61 1.5 750 750 NO 12 weeks 2

Dong 2012 [20] 94 (47/47) 49.7 (8.9) 58/36 1.5 1500 1500 NO 8 weeks 1

Lin 2013 [21] 96 (32/32/32) 65.6 (3.2) 56/40 3 750–1500 750–1500 NO 8 weeks 1

Li 2013 [22] 186 (62/62/62) 56.9 102/84 1.5–3 750–1500 750–1500 NO 8 weeks 2

He 2013 [23] 148 (74/74) 47.27 76/72 1.5 750–1500 1500 NO 3 months 1

Xu 2013 [24] 840 (280/280/

280)

38.7 560/280 1.5 1500 1500 NO 3 months 1

Notes: R + M, repaglinide + metformin; M, metformin; NR, not reported.a Presented in range or mean (standard deviation).

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e x x x ( 2 0 1 4 ) x x x . e 1 – x x x . e 6e2


Please cite this article in press as: Yin J, et al. Comparison of repaglinide and metformin versus metformin alone for type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.06.009


Fig. 2 – Mean difference (95% confidence interval) in glycemic control parameters between combination therapy group and

metformin group. (a) HbA1c. (b) FBG. (c) PPG. Notes: R, repaglinide; M, metformin.

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e x x x ( 2 0 1 4 ) x x x . e 1 – x x x . e 6 e3


results [3–5]. Because of the increasing interest in combination

therapy, we conducted a meta-analysis of RCTs which compared

combination therapy and metformin monotherapy.

2. Methods

2.1. Publication search

We searched the electronic database of Pubmed, ScienceDir-

ect, Chinese Bio-Medical Literature on disc, China National

Knowledge Infrastructure, Wangfang database without date


or language restrictions (last search was updated on November,

2013). Various combination of following keywords were used:

‘‘diabetes mellitus, type 2’’, ‘‘repaglinide, NovoNorm’’, ‘‘metfor-

min’’. Studies were included if they met the following criteria:

(1) participants were patients with T2DM, (2) the study design

was a RCT, (3) patients were randomized grouped into repaglinide

plus metformin combination therapy group (with or without

additional medication) and metformin monotherapy group (with

or without the same additional medication), (4) at least one

outcome of interest (HbA1c, FBG, PBG (postprandial blood sugar),

TG (triglycerides), TC (total cholesterol), LDL (low-density

lipoprotein), HDL (high-density lipoprotein)) was reported, (5)



Fig. 3 – Mean difference (95% confidence interval) in lipid parameters between combination therapy group and metformin

group. (a) TG. (b) TC. (c) LDL. (d) HDL. Notes: R, repaglinide; M, metformin.



study duration was at least 8 weeks. We excluded retrospective

studies, observational studies, case series, reviews, comments,

duplicate published articles, and studies without original data.

2.2. Data extraction

Two independent investigators (Yin JJ and Deng HL) reviewed

study titles and abstracts, and studies that satisfied the

inclusion criteria were retrieved for full-text evaluation. Data

extraction was carried out by one researcher and checked by

Please cite this article in press as: Yin J, et al. Comparison of repaglinideanalysis of randomized controlled trials. Diabetes Res Clin Pract (2014),

another. Any disagreements were resolved through discussion.

We extracted following information from the eligible studies:

study design; randomization; blinding; the first author’s name;

publication year; sample size; age, and sex; trial duration;

HbA1c level; FBG; PBG; TG; TC; LDL; HDL; adverse events.

2.3. Quality assessment

The Jadad scale is a 5-point scale for assessing the quality

of RCTs. We assessed the following three dimensions:

and metformin versus metformin alone for type 2 diabetes: a meta-http://dx.doi.org/10.1016/j.diabres.2014.06.009


Fig. 4 – Forest plots for trial outcomes in hypoglycaemia (a), and Funnel plot for repaglinide plus metformin group vs.

metformin alone group for HbA1c (b). Notes: R, repaglinide; M, metformin.

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e x x x ( 2 0 1 4 ) x x x . e 1 – x x x . e 6 e5


randomization, blinding and reasons for withdrawals and

dropouts. The possible maximum score is 5 points, the

studies with the score of 2 points or less are of low quality,

while those with 3 points or more are of high quality.

2.4. Statistical analysis

All analyses were performed using Review Manager 5.2

(Nordic Cochrane Centre). Continuous outcomes between

groups as weighted mean difference (WMD), both with 95%

confidence intervals (95% CI). Heterogeneity of the included

studies was assessed using the chi-squared test, and hetero-

geneity was presented as significant when I2 is over 50% or

P < 0.1. Publication bias was examined by funnel plots.

Random effect model was used for the meta-analysis if there

was significant heterogeneity, and fixed effect model was used

when the heterogeneity was not significant.

3. Results

The study selection process is shown in Fig. 1. The

characteristics of included studies are summarized in Table

1. Briefly, a total of 22 studies [3–24] were identified met our

inclusion criteria, including 2055 participants with T2DM. The

overall analysis showed that combination therapy induced a

greater reduction of HbA1c (pooled mean difference �1.2%

(�13 mmol/mol); 95% CI �1.5 to 0.83, P < 0.00001; Fig. 2a) than

metformin alone. In both subgroups, the level of HbA1c was

significantly lower in the combination therapy group than in

the metformin monotherapy group (pooled mean difference


�1.1% (�12 mmol/mol); 95% CI �1.50 to 0.78; P < 0.00001,

pooled mean difference �1.4% (�15 mmol/mol); 95% CI �1.91

to 0.86; P < 0.00001, respectively). In addition, the results

showed that combination therapy significantly reduced FBG

(95% CI �1.99 to 0.93, P < 0.00001; Fig. 2b), PBG level (95% CI

�2.38 to �1.42, P < 0.00001; Fig. 2c) and TC (95% CI �0.41 to

�0.04, P = 0.02; Fig. 3b) compared with metformin alone.

However, combination therapy did not change TG (95% CI

�0.85 to 0.01, P = 0.06; Fig. 3a), LDL (95% CI �0.30 to 0.04,

P = 0.13; Fig. 3c) and HDL (95% CI �0.19 to 0.14, P = 0.76; Fig. 3d)

compared with metformin alone. Moreover, we found that

compared with metformin alone, there was no increased

hypoglycaemia episode with the combination therapy

(RR = 1.21, 95% CI 0.72 to 2.04, P = 0.48; Fig. 4a). Only one

serious treatment-related hypoglycemia was reported in

combination therapy group. As for gastrointestinal incidents,

most of studies did not report these events in detail, so we did

not compare the rates of gastrointestinal upset. Funnel plots

indicated there was publication bias, and a typical funnel plot

is shown in Fig. 4b.

4. Discussion

This is the first meta-analysis which compared the efficacy

and safety of repaglinide plus metformin with metformin

alone on type 2 diabetes. We found the combination therapy

resulted in better improvement in glucose control, but not

most of lipid parameters compared with metformin alone.

Moreover, the meta-analysis showed that the combination

therapy caused no increase in the risk of hypoglycemia.





There are several limitations in our meta-analysis. First,

most of the studies included in this review had poor

methodological quality. Second, the results of meta-analysis

can be hampered by so-called publication bias.

In conclusion, our meta-analysis shows that combination

therapy is safe and can gain better outcomes in glycemic

control. However, due to the poor methodological quality of

the studies included in this meta-analysis and the short study

duration, well-designed multicenter RCTs are required to

confirm these findings.

Conflict of interest

The authors declare that they have no conflict of interest.

r e f e r e n c e s

[1] Standards of medical care in diabetes – 2013. Diabetes Care2013;36(Suppl. 1):S11–66.

[2] Turner RC, Cull CA, Frighi V, Holman RR. Glycemic controlwith diet, sulfonylurea, metformin, or insulin in patientswith type 2 diabetes mellitus: progressive requirement formultiple therapies (UKPDS 49). UK Prospective DiabetesStudy (UKPDS) Group. JAMA 1999;281(21):2005–12.

[3] Ma WF. Comparative observations on therapeutic efficacyof glimepiride and repaglinide with metformin intreatment of type 2 diabetes. J Hubei Med Staff Coll2003;16(3):13–5.

[4] Liu GH. Follow up of type 2 diabetes 60 case treated withrepaglinide in combination with mefformin. Chin J ClinHealthc 2005;8(6):531–2.

[5] Cheng ZG. Comparative observations on therapeaticefficacy of glimepiride and repaglinide with metformin intreatment of type 2 diabetes. J Zhejiang Univ Trad Chin Med2006;30(5):490–1.

[6] Chen QS, Zhang P, Liang H. Efficacy observation ofrepaglinide and metformin in the treatment of type 2diabetes mellitus. Guangxi Med J 2007;29(8):1174–5.

[7] Davies MJ, Thaware PK, Tringham JR, Howe J, Jarvis J,Johnston V, et al. A randomized controlled trial examiningcombinations of repaglinide, metformin and NPH insulin.Diabet Med 2007;24(7):714–9.

[8] Civera M, Merchante A, Salvador M, Sanz J, Martinez I.Safety and efficacy of repaglinide in combination withmetformin and bedtime NPH insulin as an insulin

Please cite this article in press as: Yin J, et al. Comparison of repaglinideanalysis of randomized controlled trials. Diabetes Res Clin Pract (2014),

treatment regimen in type 2 diabetes. Diabetes Res ClinPract 2008;79(1):42–7.

[9] Lin ML. Efficacy observation of repaglinide and metforminin the treatment of diagnosed type 2 diabetes mellitus. JClin Res 2008;25(1):143–4.

[10] Zhang BT, Yi SN. The influence of repaglinide andmetformin on oxidative stress in the treatment of type 2diabetes mellitus. Chin J Med 2008;43(11):36–8.

[11] Xu WH, Cui G, Ding YH. Clinical observations ontherapeutic efficacy of repaglinide and metformin intreatment of new-diagnosed type 2 diabetes mellitus. JPract Diabetology 2009;5(4):30–1.

[12] Chen YP, He YX. The efficacy of repaglinide in combinationwith mefformin in new-diagnosed type 2 diabetes. NatlMed Front China 2010;5(10):25–6.

[13] Cha BY, Yi YL, Xue CC. Efficacy exploration of repaglinideand metformin in the treatment of type 2 diabetes mellitus.Mod J Integr Tradit Chin West Med 2011;20(35):4498–9.

[14] Jing SL. Efficacy observation of repaglinide and metforminin the treatment of newly diagnosed obese type 2 diabetesmellitus. China Pharm 2011;22(20):1876–7.

[15] We S. The efficacy of repaglinide in combination withmefformin in diagnosed obese type 2 diabetes. ChinForeign Med Res 2011;9(12):24–5.

[16] Zhu AQ. Clinical experience of repaglinide and metforminin the treatment of type 2 diabetes mellitus. Chin CommuDoctors 2012;14(7):63–4.

[17] Bai M. Efficacy analysis of repaglinide and metformin in thetreatment of type 2 diabetes mellitus. Inner Mongol J TraditChin Med 2012;31(22):33–4.

[18] Jin Y, Fan R, Cai JG. Clinical efficacy research of metformincombined with dragon for the treatment of type 2 diabetes.Guide China Med 2012;10(13):185–8.

[19] Zhao HY. The efficacy of different drugs in combinationwith mefformin in treatment of new-diagnosed type 2diabetes mellitus. Modern J Integr Tradit Chin Western Med2012;21(25):2785–7.

[20] Dong HP. The efficacy of repaglinide in combination withmefformin in diagnosed obese type 2 diabetes. Strait PharmJ 2012;24(4):201–2.

[21] Lin XY, Cai SY, Xu WL. Elderly of type 2 diabetes mellitus onmetformin combined repaglinide treatment clinicalobservation. Med Inno China 2013;10(20):111–3.

[22] Li CY. The efficacy of repaglinide and metformin treatment2 type diabetes. Henan Med Res 2013;22(3):398–400.

[23] He M. Clinical observations on therapeutic efficacy ofrepaglinide and metformin in treatment of type 2 diabetes.China Phac Med 2013;8(4):144–5.

[24] Xu SL. The efficacy of repaglinide in combination withmefformin in new-diagnosed type 2 diabetes. China PractMed 2013;8(26):144–6.

and metformin versus metformin alone for type 2 diabetes: a meta-http://dx.doi.org/10.1016/j.diabres.2014.06.009

http://refhub.elsevier.com/S0168-8227(14)00277-0/sbref0005
















































































Documents

Comparison of repaglinide and metformin versus metformin alone for type 2 diabetes: a meta-analysis of randomized controlled trials