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Use of metformin earlier in pregnancy predicts supplemental insulin therapy in women with gestational diabetes
diabetes research and clinical practice
1 1 6 ( 2 0 1 6 ) 9 6 –9 9
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journa l home page: www.e lse vier.com/locate/diabres
Use of metformin earlier in pregnancy predicts supplemental insulin therapy in women with gestational diabetes Rachel T. McGrath a,b,c,*, Sarah J. Glastras a,c, Samantha Hocking a,b,d, Gregory R. Fulcher a,b a
Department of Diabetes, Endocrinology & Metabolism, Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia Northern Clinical School, University of Sydney, Sydney, Australia c Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia d Charles Perkins Centre, University of Sydney, Australia b
A R T I C L E I N F O
A B S T R A C T
Article history:
The use of metformin in gestational diabetes is safe and effective, yet some women require
Received 5 April 2016
additional insulin therapy to achieve glycaemic targets. We found a significant association
Received in revised form
between earlier gestational age at initiation of metformin therapy and the necessity for
26 April 2016
supplemental insulin in women treated with metformin during pregnancy. Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Accepted 26 April 2016 Available online 30 April 2016
Keywords: Gestational diabetes Metformin Insulin Glycaemic control Perinatal outcomes
1.
Introduction
The standard treatment for gestational diabetes mellitus (GDM) is lifestyle modification through dietary manipulation and exercise counselling, followed by pharmacologic therapy if target blood glucose levels are not met [1]. Several studies have found that metformin, the first line oral antihyperglycaemic agent for type 2 diabetes (T2D), is equivalent to insulin at achieving satisfactory glycaemic control in GDM and reducing the risk of adverse perinatal outcomes [2,3]. However, in a proportion of women, despite metformin
therapy, supplementary insulin is required to achieve desirable blood glucose levels [4]. The factors that predict the requirement of subsequent insulin therapy are unclear. Thus, the aim of this study was to examine the predictors of supplemental insulin therapy in a cohort of women with GDM treated with metformin for glycaemic control.
2.
Methods
A retrospective, cohort study was carried out by reviewing the medical records of women with GDM who attended Royal
* Corresponding author at: Department of Diabetes, Endocrinology & Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. Tel./fax: +61 (2) 9463 1045. E-mail address: [email protected] (R.T. McGrath). http://dx.doi.org/10.1016/j.diabres.2016.04.051 0168-8227/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
diabetes research and clinical practice
North Shore Hospital, Sydney, between the years of 2012– 2015. The metformin group comprised women with GDM whose blood glucose levels were adequately controlled with metformin alone, whereas the metformin–insulin group included women requiring additional insulin therapy to achieve glycaemic targets. Approval for this study was obtained from the NSLHD Human Research Ethics Committee. The primary outcome was to identify the differences between women with GDM that were managed with metformin alone versus those requiring insulin in addition to metformin. We further assessed perinatal outcomes. Differences between groups were compared using student’s independent t-test or chi-square test and logistic regression was used to determine the association between individual maternal factors and insulin use. Statistical analyses were carried out using GraphPad Prism V6 and IBM SPSS V22. A p value of <0.05 was considered statistically significant.
3.
Results
Between the years of 2012–2015, 98 women were identified as taking metformin during pregnancy. Several women were excluded from the study due to a pre-existing diagnosis of T2D (n = 16), one patient had steroid-induced hyperglycaemia and six women were taking metformin pre-pregnancy for polycystic ovarian syndrome or insulin resistance. There was insufficient data on the treatment of GDM in the records of ten women. In addition, two women received insulin in pregnancy prior to metformin, leaving a total of 63 women fulfilling the criteria for inclusion in the present study. The proportion of women taking metformin that required supplemental insulin therapy was 53.9%, which is similar to that observed by Rowan et al. [4]. Thus, the study population comprised 29 women (46%) in the metformin group and 34 (54%) in the metformin–insulin group. The predominant reason for women requiring additional insulin therapy was elevated fasting blood glucose levels (n = 22; 64.7%; Supplementary Table 1) and there was a trend towards fasting hyperglycaemia being predictive of women that would fail metformin monotherapy (p = 0.097; Table 1).
97
1 1 6 ( 2 0 1 6 ) x x x –x x x
For women that required treatment with supplemental insulin, the average time between commencement of metformin and introduction of insulin was 29 ± 22 days. In addition, 35% of women ceased metformin therapy when insulin was initiated, due to a lack of benefit (66%) or gastrointestinal side effects (33%). The total daily dose of insulin was similar for women that ceased or continued metformin (26.5 ± 22.6 vs. 19.7 ± 14.2 units; p = 0.349). There was no significant difference in maternal age, BMI (recorded at the first antenatal visit), history of GDM or family history of diabetes between groups (Table 1). However, with the exclusion of one woman with a BMI > 60 kg/m2 (greater than 4 standard deviations above the mean) in the metformin group, the difference in maternal BMI was highly significant (p = 0.003). Fasting and 2-h plasma glucose at OGTT, gestational age and HbA1c at diagnosis of GDM were similar for women managed with metformin alone or metformin and insulin. Conversely, women requiring additional therapy with insulin started taking metformin earlier in pregnancy (25.3 ± 5.8 vs. 28.9 ± 4.9 weeks; p = 0.009; Table 1). When the data were adjusted for maternal age, BMI, previous GDM, family history of diabetes and gestation at diagnosis of GDM, gestational age at initiation of metformin therapy remained significantly associated with supplemental insulin (p = 0.02). Of note, the gestational age at which insulin was initiated as first-line therapy (in women with GDM matched to the metformin and metformin–insulin groups for age, gestational age at diagnosis of GDM and previous history of GDM) was 28 ± 5.4 weeks, which was similar to when metformin was started in the metformin group and significantly later than metformin commencement in the metformin–insulin group (p = 0.019). This further suggests that women requiring earlier pharmacologic intervention in pregnancy will require escalation of therapy. Birth weight and gestational age at delivery were similar between the metformin and metformin–insulin groups (Table 2). The incidence of large for gestational age neonates was higher in the metformin–insulin group (26.5% vs. 6.9%; p = 0.042), however this effect lost significance when the data were adjusted for maternal BMI. There was no significant difference in other adverse perinatal outcomes between groups.
Table 1 – Characteristics and demographics of women with GDM treated with metformin alone or metformin and supplemental insulin. Blood glucose levels (BGL) were assessed by review of 4-point self-monitoring of blood glucose profiles.
Maternal age (years) History of GDM Family history of DM Early pregnancy BMI (kg/m2) Gestation at diagnosis of GDM (weeks) Gestation at metformin initiation (weeks) Time between metformin and insulin therapy (days) HbA1c at diagnosis of GDM (%) Fasting plasma glucose at OGTT (mmol/L) 2-h plasma glucose at OGTT (mmol/L) Elevated fasting BGL at metformin initiation Elevated post-prandial BGL at metformin initiation Elevated fasting & post-prandial BGL at metformin initiation
Metformin alone (n = 29)
Metformin–insulin (n = 34)
p
32.9 ± 4.6 17.2% (n = 5) 48.3% (n = 14) 25.9 ± 8.3 24 ± 6 28.9 ± 4.9 – 5.0 ± 0.3 4.8 ± 0.6 8.5 ± 1.4 21.4% (n = 7) 13.8% (n = 4) 62.1% (n = 18)
32.8 ± 5.3 11.8% (n = 4) 44.1% (n = 15) 30.0 ± 7.8 23 ± 6 25.3 ± 5.8 29 ± 22 5.2 ± 0.4 4.9 ± 0.6 8.3 ± 1.4 44.1% (n = 15) 11.8% (n = 4) 44.1% (n = 15)
0.976 0.568 0.824 0.061 0.219 0.009 – 0.078 0.492 0.551 0.097 0.810 0.155
98
diabetes research and clinical practice
1 1 6 ( 2 0 1 6 ) x x x –x x x
Table 2 – Perinatal outcomes for women managed with metformin therapy alone or metformin and insulin.
Birth weight (g) Gestational age at delivery (weeks) Large for gestational age Small for gestational age Neonatal hypoglycaemia Respiratory distress Jaundice NICU admission Neonatal death
4.
Metformin alone (n = 29)
Metformin–insulin (n = 34)
p
3152 ± 559 38.4 ± 1.6 6.9% (n = 2) 10.3% (n = 3) 17.2% (n = 5) 3.4% (n = 1) 31% (n = 9) 20.7% (n = 6) 0
3392 ± 538 38.5 ± 0.9 26.5% (n = 9) 0% (n = 0) 20.6% (n = 7) 11.8% (n = 4) 11.8% (n = 4) 14.7% (n = 5) 0
0.099 0.862 0.042 0.054 0.743 0.225 0.057 0.525 –
Discussion
The use of metformin in the treatment of GDM is beneficial, as it is associated with a reduced risk of hypoglycaemia, less maternal weight gain and has a desirable route of administration, in comparison to insulin [4,5]. Several studies have demonstrated that metformin is efficacious in pregnancy; however a proportion of women will not achieve adequate glycaemic control with metformin alone. In the present study, we identify women that started metformin at an earlier gestational age were more likely to require additional therapy with insulin. Earlier pharmacologic intervention in pregnancy may be indicative of greater insulin resistance or b-cell failure and ensuing hyperglycaemia, which worsens over time and cannot be overcome by metformin therapy alone. Alternatively, women presenting with hyperglycaemia earlier in pregnancy may be trialled on metformin prior to insulin as there is more time in which optimal glycaemic control can be achieved. Our results are in keeping with the results of Tertti et al. who found that women that were randomised to metformin earlier in pregnancy required additional therapy with insulin [6]. We did not observe a difference in other maternal characteristics including maternal age, gestational age at diagnosis of GDM, higher fasting plasma glucose and greater HbA1c, which have previously been identified as factors predicting response to metformin in GDM [4,6–9]. Restriction of the analysis to exclude one outlier showed that women with a higher BMI were more likely to need additional therapy with insulin, which is a similar finding to previous studies [4,7]. A limitation of this study is its observational nature and the small sample size; however our study design is similar to others investigating the requirement for additional therapy with in metformin treated GDM [7,8]. Another potential drawback is that the decision to start metformin was based upon physician and patient preference, rather than specific criteria. In addition, data on ethnicity were not available, which may confound the results.
5.
Conclusions
The use of metformin as an anti-hyperglycaemic agent in GDM gives rise to adequate glycaemic control in approximately half of women treated, and supplemental insulin is
needed for women requiring pharmacological intervention earlier in pregnancy.
Conflict of interest None.
Funding None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.diabres. 2016.04.051.
R E F E R E N C E S
[1] Moses RG, Barker M, Winter M, Petocz P, Brand-Miller JC. Can a low-glycemic index diet reduce the need for insulin in gestational diabetes mellitus? A randomized trial. Diabetes Care 2009;32(6):996–1000. [2] Kitwitee P, Limwattananon S, Limwattananon C, Waleekachonlert O, Ratanachotpanich T, Phimphilai M, et al. Metformin for the treatment of gestational diabetes: an updated meta-analysis. Diabetes Res Clin Pract 2015;109 (3):521–32. [3] Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203(5). 457 e1–9. [4] Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, Mi GTI. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358(19):2003–15. [5] Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study. Diabet Med 2009;26(8):798–802. [6] Tertti K, Ekblad U, Koskinen P, Vahlberg T, Ronnemaa T. Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Diabetes Obes Metab 2013;15(3):246–51. [7] Corbould A, Swinton F, Radford A, Campbell J, McBeath S, Dennis A. Fasting blood glucose predicts response to extended-release metformin in gestational diabetes mellitus. Aust N Z J Obstet Gynaecol 2013;53(2):125–9.
diabetes research and clinical practice
[8] Ashoush S, El-Said M, Fathi H, Abdelnaby M. Identification of metformin poor responders, requiring supplemental insulin, during randomization of metformin versus insulin for the control of gestational diabetes mellitus. J Obstet Gynaecol Res 2016.
1 1 6 ( 2 0 1 6 ) x x x –x x x
99
[9] Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RP. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol 2013;209(1). 34 e1–7.
1 1 6 ( 2 0 1 6 ) 9 6 –9 9
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journa l home page: www.e lse vier.com/locate/diabres
Use of metformin earlier in pregnancy predicts supplemental insulin therapy in women with gestational diabetes Rachel T. McGrath a,b,c,*, Sarah J. Glastras a,c, Samantha Hocking a,b,d, Gregory R. Fulcher a,b a
Department of Diabetes, Endocrinology & Metabolism, Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia Northern Clinical School, University of Sydney, Sydney, Australia c Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia d Charles Perkins Centre, University of Sydney, Australia b
A R T I C L E I N F O
A B S T R A C T
Article history:
The use of metformin in gestational diabetes is safe and effective, yet some women require
Received 5 April 2016
additional insulin therapy to achieve glycaemic targets. We found a significant association
Received in revised form
between earlier gestational age at initiation of metformin therapy and the necessity for
26 April 2016
supplemental insulin in women treated with metformin during pregnancy. Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Accepted 26 April 2016 Available online 30 April 2016
Keywords: Gestational diabetes Metformin Insulin Glycaemic control Perinatal outcomes
1.
Introduction
The standard treatment for gestational diabetes mellitus (GDM) is lifestyle modification through dietary manipulation and exercise counselling, followed by pharmacologic therapy if target blood glucose levels are not met [1]. Several studies have found that metformin, the first line oral antihyperglycaemic agent for type 2 diabetes (T2D), is equivalent to insulin at achieving satisfactory glycaemic control in GDM and reducing the risk of adverse perinatal outcomes [2,3]. However, in a proportion of women, despite metformin
therapy, supplementary insulin is required to achieve desirable blood glucose levels [4]. The factors that predict the requirement of subsequent insulin therapy are unclear. Thus, the aim of this study was to examine the predictors of supplemental insulin therapy in a cohort of women with GDM treated with metformin for glycaemic control.
2.
Methods
A retrospective, cohort study was carried out by reviewing the medical records of women with GDM who attended Royal
* Corresponding author at: Department of Diabetes, Endocrinology & Metabolism, Level 3, Acute Services Building, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. Tel./fax: +61 (2) 9463 1045. E-mail address: [email protected] (R.T. McGrath). http://dx.doi.org/10.1016/j.diabres.2016.04.051 0168-8227/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
diabetes research and clinical practice
North Shore Hospital, Sydney, between the years of 2012– 2015. The metformin group comprised women with GDM whose blood glucose levels were adequately controlled with metformin alone, whereas the metformin–insulin group included women requiring additional insulin therapy to achieve glycaemic targets. Approval for this study was obtained from the NSLHD Human Research Ethics Committee. The primary outcome was to identify the differences between women with GDM that were managed with metformin alone versus those requiring insulin in addition to metformin. We further assessed perinatal outcomes. Differences between groups were compared using student’s independent t-test or chi-square test and logistic regression was used to determine the association between individual maternal factors and insulin use. Statistical analyses were carried out using GraphPad Prism V6 and IBM SPSS V22. A p value of <0.05 was considered statistically significant.
3.
Results
Between the years of 2012–2015, 98 women were identified as taking metformin during pregnancy. Several women were excluded from the study due to a pre-existing diagnosis of T2D (n = 16), one patient had steroid-induced hyperglycaemia and six women were taking metformin pre-pregnancy for polycystic ovarian syndrome or insulin resistance. There was insufficient data on the treatment of GDM in the records of ten women. In addition, two women received insulin in pregnancy prior to metformin, leaving a total of 63 women fulfilling the criteria for inclusion in the present study. The proportion of women taking metformin that required supplemental insulin therapy was 53.9%, which is similar to that observed by Rowan et al. [4]. Thus, the study population comprised 29 women (46%) in the metformin group and 34 (54%) in the metformin–insulin group. The predominant reason for women requiring additional insulin therapy was elevated fasting blood glucose levels (n = 22; 64.7%; Supplementary Table 1) and there was a trend towards fasting hyperglycaemia being predictive of women that would fail metformin monotherapy (p = 0.097; Table 1).
97
1 1 6 ( 2 0 1 6 ) x x x –x x x
For women that required treatment with supplemental insulin, the average time between commencement of metformin and introduction of insulin was 29 ± 22 days. In addition, 35% of women ceased metformin therapy when insulin was initiated, due to a lack of benefit (66%) or gastrointestinal side effects (33%). The total daily dose of insulin was similar for women that ceased or continued metformin (26.5 ± 22.6 vs. 19.7 ± 14.2 units; p = 0.349). There was no significant difference in maternal age, BMI (recorded at the first antenatal visit), history of GDM or family history of diabetes between groups (Table 1). However, with the exclusion of one woman with a BMI > 60 kg/m2 (greater than 4 standard deviations above the mean) in the metformin group, the difference in maternal BMI was highly significant (p = 0.003). Fasting and 2-h plasma glucose at OGTT, gestational age and HbA1c at diagnosis of GDM were similar for women managed with metformin alone or metformin and insulin. Conversely, women requiring additional therapy with insulin started taking metformin earlier in pregnancy (25.3 ± 5.8 vs. 28.9 ± 4.9 weeks; p = 0.009; Table 1). When the data were adjusted for maternal age, BMI, previous GDM, family history of diabetes and gestation at diagnosis of GDM, gestational age at initiation of metformin therapy remained significantly associated with supplemental insulin (p = 0.02). Of note, the gestational age at which insulin was initiated as first-line therapy (in women with GDM matched to the metformin and metformin–insulin groups for age, gestational age at diagnosis of GDM and previous history of GDM) was 28 ± 5.4 weeks, which was similar to when metformin was started in the metformin group and significantly later than metformin commencement in the metformin–insulin group (p = 0.019). This further suggests that women requiring earlier pharmacologic intervention in pregnancy will require escalation of therapy. Birth weight and gestational age at delivery were similar between the metformin and metformin–insulin groups (Table 2). The incidence of large for gestational age neonates was higher in the metformin–insulin group (26.5% vs. 6.9%; p = 0.042), however this effect lost significance when the data were adjusted for maternal BMI. There was no significant difference in other adverse perinatal outcomes between groups.
Table 1 – Characteristics and demographics of women with GDM treated with metformin alone or metformin and supplemental insulin. Blood glucose levels (BGL) were assessed by review of 4-point self-monitoring of blood glucose profiles.
Maternal age (years) History of GDM Family history of DM Early pregnancy BMI (kg/m2) Gestation at diagnosis of GDM (weeks) Gestation at metformin initiation (weeks) Time between metformin and insulin therapy (days) HbA1c at diagnosis of GDM (%) Fasting plasma glucose at OGTT (mmol/L) 2-h plasma glucose at OGTT (mmol/L) Elevated fasting BGL at metformin initiation Elevated post-prandial BGL at metformin initiation Elevated fasting & post-prandial BGL at metformin initiation
Metformin alone (n = 29)
Metformin–insulin (n = 34)
p
32.9 ± 4.6 17.2% (n = 5) 48.3% (n = 14) 25.9 ± 8.3 24 ± 6 28.9 ± 4.9 – 5.0 ± 0.3 4.8 ± 0.6 8.5 ± 1.4 21.4% (n = 7) 13.8% (n = 4) 62.1% (n = 18)
32.8 ± 5.3 11.8% (n = 4) 44.1% (n = 15) 30.0 ± 7.8 23 ± 6 25.3 ± 5.8 29 ± 22 5.2 ± 0.4 4.9 ± 0.6 8.3 ± 1.4 44.1% (n = 15) 11.8% (n = 4) 44.1% (n = 15)
0.976 0.568 0.824 0.061 0.219 0.009 – 0.078 0.492 0.551 0.097 0.810 0.155
98
diabetes research and clinical practice
1 1 6 ( 2 0 1 6 ) x x x –x x x
Table 2 – Perinatal outcomes for women managed with metformin therapy alone or metformin and insulin.
Birth weight (g) Gestational age at delivery (weeks) Large for gestational age Small for gestational age Neonatal hypoglycaemia Respiratory distress Jaundice NICU admission Neonatal death
4.
Metformin alone (n = 29)
Metformin–insulin (n = 34)
p
3152 ± 559 38.4 ± 1.6 6.9% (n = 2) 10.3% (n = 3) 17.2% (n = 5) 3.4% (n = 1) 31% (n = 9) 20.7% (n = 6) 0
3392 ± 538 38.5 ± 0.9 26.5% (n = 9) 0% (n = 0) 20.6% (n = 7) 11.8% (n = 4) 11.8% (n = 4) 14.7% (n = 5) 0
0.099 0.862 0.042 0.054 0.743 0.225 0.057 0.525 –
Discussion
The use of metformin in the treatment of GDM is beneficial, as it is associated with a reduced risk of hypoglycaemia, less maternal weight gain and has a desirable route of administration, in comparison to insulin [4,5]. Several studies have demonstrated that metformin is efficacious in pregnancy; however a proportion of women will not achieve adequate glycaemic control with metformin alone. In the present study, we identify women that started metformin at an earlier gestational age were more likely to require additional therapy with insulin. Earlier pharmacologic intervention in pregnancy may be indicative of greater insulin resistance or b-cell failure and ensuing hyperglycaemia, which worsens over time and cannot be overcome by metformin therapy alone. Alternatively, women presenting with hyperglycaemia earlier in pregnancy may be trialled on metformin prior to insulin as there is more time in which optimal glycaemic control can be achieved. Our results are in keeping with the results of Tertti et al. who found that women that were randomised to metformin earlier in pregnancy required additional therapy with insulin [6]. We did not observe a difference in other maternal characteristics including maternal age, gestational age at diagnosis of GDM, higher fasting plasma glucose and greater HbA1c, which have previously been identified as factors predicting response to metformin in GDM [4,6–9]. Restriction of the analysis to exclude one outlier showed that women with a higher BMI were more likely to need additional therapy with insulin, which is a similar finding to previous studies [4,7]. A limitation of this study is its observational nature and the small sample size; however our study design is similar to others investigating the requirement for additional therapy with in metformin treated GDM [7,8]. Another potential drawback is that the decision to start metformin was based upon physician and patient preference, rather than specific criteria. In addition, data on ethnicity were not available, which may confound the results.
5.
Conclusions
The use of metformin as an anti-hyperglycaemic agent in GDM gives rise to adequate glycaemic control in approximately half of women treated, and supplemental insulin is
needed for women requiring pharmacological intervention earlier in pregnancy.
Conflict of interest None.
Funding None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.diabres. 2016.04.051.
R E F E R E N C E S
[1] Moses RG, Barker M, Winter M, Petocz P, Brand-Miller JC. Can a low-glycemic index diet reduce the need for insulin in gestational diabetes mellitus? A randomized trial. Diabetes Care 2009;32(6):996–1000. [2] Kitwitee P, Limwattananon S, Limwattananon C, Waleekachonlert O, Ratanachotpanich T, Phimphilai M, et al. Metformin for the treatment of gestational diabetes: an updated meta-analysis. Diabetes Res Clin Pract 2015;109 (3):521–32. [3] Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203(5). 457 e1–9. [4] Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, Mi GTI. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358(19):2003–15. [5] Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study. Diabet Med 2009;26(8):798–802. [6] Tertti K, Ekblad U, Koskinen P, Vahlberg T, Ronnemaa T. Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Diabetes Obes Metab 2013;15(3):246–51. [7] Corbould A, Swinton F, Radford A, Campbell J, McBeath S, Dennis A. Fasting blood glucose predicts response to extended-release metformin in gestational diabetes mellitus. Aust N Z J Obstet Gynaecol 2013;53(2):125–9.
diabetes research and clinical practice
[8] Ashoush S, El-Said M, Fathi H, Abdelnaby M. Identification of metformin poor responders, requiring supplemental insulin, during randomization of metformin versus insulin for the control of gestational diabetes mellitus. J Obstet Gynaecol Res 2016.
1 1 6 ( 2 0 1 6 ) x x x –x x x
99
[9] Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RP. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol 2013;209(1). 34 e1–7.