Accepted Manuscript Title: Metformin for the treatment of gestational diabetes: An updated meta-analysis Author: Pimprapa Kitwitee Supon Limwattananon Chulaporn Limwattananon Ornanong Waleekachonlert Tananan Ratanachotpanich Mattabhorn Phimphilai Tuan V. Nguyen Chatlert Pongchaiyakul PII: DOI: Reference:

S0168-8227(15)00247-8 http://dx.doi.org/doi:10.1016/j.diabres.2015.05.017 DIAB 6393

To appear in:

Diabetes Research and Clinical Practice

Received date: Revised date: Accepted date:

21-7-2014 2-3-2015 3-5-2015

Please cite this article as: P. Kitwitee, S. Limwattananon, C. Limwattananon, O. Waleekachonlert, T. Ratanachotpanich, M. Phimphilai, T.V. Nguyen, C. Pongchaiyakul, Metformin for the treatment of gestational diabetes: An updated meta-analysis, Diabetes Research and Clinical Practice (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1. We did an update meta-analysis on 8 RCTs comparing the effects of metformin with insulin in GDM. 2. Treatment with metformin was associated with better clinical outcomes particularly on neonatal hypoglycemia, NICU admission compared with insulin, while glycemic

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control and other outcomes were comparable. 3. Using a Bayesian analysis, the efficacy of metformin was consistently higher than

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insulin with a probability of over 98% on neonatal hypoglycemia and NICU admission.

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Metformin for the treatment of gestational diabetes: An updated meta-analysis

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Pimprapa Kitwitee1, Supon Limwattananon1, Chulaporn Limwattananon1,

Tuan V. Nguyen4, Chatlert Pongchaiyakul5

Social and Administrative Pharmacy Program, Faculty of Pharmaceutical Sciences,

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Ornanong Waleekachonlert2, Tananan Ratanachotpanich2, Mattabhorn Phimphilai3,

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Khon Kaen University, Thailand; 2 Clinical Pharmacy Research Unit, Faculty of Pharmacy, Mahasarakham Univeristy, Thailand; 3 Division of Endocrinology and Metabolism, Department of Medicine, 4

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Faculty of Medicine, Chiang Mai University, Thailand; Bone and Mineral Research Program,

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Garvan Institute of Medical Research, Sydney, Australia; 5 Division of Endocrinology and Metabolism,

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Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand

Correspondence author:

Prof. Chatlert Pongchaiyakul

Division of Endocrinology and Metabolism Department of Medicine, Faculty of Medicine Khon Kaen University, THAILAND 40002 Tel. +66-43-363664

Fax: +66-43-202491

Email: [email protected]

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Abstract Objective: To assess the efficacy of metformin and insulin in the treatment of pregnant women with gestational diabetes mellitus (GDM). Methods: A meta-analysis was conducted by including randomized controlled trials comparing metformin

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and insulin in GDM. An electronic search was conducted to identify relevant studies. Data were synthesized by a random effects meta-analysis model. A Bayesian analysis was also performed to account for

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uncertainties in the treatment efficacy.

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Results: Eight clinical trials involving 1,712 individuals were included in the final analysis. The pooled estimates of metformin-insulin differences were very small and statistically non-significant in fasting plasma

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glucose, postprandial plasma glucose and HbA1c, measured at 36-37 weeks of gestation. Notably, 14-46% of those receiving metformin required additional insulin. Compared with the insulin group, metformin

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treatment was associated with a lower incidence of neonatal hypoglycemia (relative risk, RR 0.74; 95% CI 0.58 to 0.93; P=0.01) and of neonatal intensive care admission (RR 0.76; 95% CI 0.59 to 0.97; P=0.03).

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Bayesian analysis revealed that the efficacy of metformin was consistently higher than insulin with a

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probability of over 98% on these two neonatal complications. Other outcomes were not significantly different between the two treatment groups.

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Conclusion: In women with gestational diabetes, metformin use and insulin therapy have comparable glycemic control profile, but metformin use was associated with lower risk of neonatal hypoglycemia.

Key words: gestational diabetes mellitus, insulin, metformin, oral hypoglycemic agent

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Introduction Gestational diabetes mellitus (GDM) is characterized by glucose intolerance of variable severity with onset of first recognition during pregnancy. GDM can cause significant problems, including maternal and perinatal complications (1). GDM also increases the risk of progression to type 2 diabetes (T2D) and

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metabolic syndrome in the mother as well as increased risk of glucose intolerance, obesity, and possibly

adult cardiovascular disease in the infant (2-4). Although the prevalence of GDM has not been not well

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documented, recent estimate based on birth certificate in the United States suggested that is

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approximately 9% (5) During the past 20 years, the prevalence of GDM has increased between 10 and 100%, depending on ethnicity group (6). In Thailand, data from the National Diabetes Data Group for

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GDM Diagnosis (7,8) suggest that the prevalence of GDM was 5.3 and 4.9% in women with gestation of

Metformin for the treatment of gestational diabetes: An updated meta-analysis.

To assess the efficacy of metformin and insulin in the treatment of pregnant women with gestational diabetes mellitus (GDM)...
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