|Year : 2019 | Volume
| Issue : 4 | Page : 1376-1381
Comparison the efficacy and safety between Insulin and Metformin in gestational diabetes mellitus management
Ahmed N Abdel Hamid1, Alaa M Abd El-Gayed1, Ibarhim A Saif-Elnasr1, Mohamed H Soliman2
1 Obstetrics and Gynecology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
2 Obstetrics and Gynecology Department, Shebin El-Kom Teaching Hospital, Shebin El-Kom, Egypt
|Date of Submission||25-Sep-2018|
|Date of Decision||21-Oct-2018|
|Date of Acceptance||22-Oct-2018|
|Date of Web Publication||31-Dec-2019|
Mohamed H Soliman
Obstetrics and Gynecology Department, Shebin El-Kom Teaching Hospital, Shebin El-Kom 32717
Source of Support: None, Conflict of Interest: None
The objective of this study was to evaluate the efficacy and safety between insulin and metformin in the management of gestational diabetes mellitus (GDM).
GDM is a common complication of pregnancy. Blood glucose control improves perinatal outcomes. Medical nutrition therapy is the milestone management.
Patients and methods
In a prospective randomized comparative study, 240 antenatal women whose pregnancies had been complicated by GDM and did not respond to diet alone were recruited from antenatal clinics at the Obstetrics Department in Menofia University Hospitals and Shebin El-Kom Teaching Hospital from November 2016 to March 2018. They were divided randomly into two groups; 120 patients in each group were subjected to either insulin or metformin medications. Outcomes were comparing the effects of medications on maternal glycemic control, maternal complications and neonatal outcome.
There was no significant difference in controlling high blood sugar in GDM with the use of insulin or metformin. Maternal complications in both groups had no significant difference, and fetal outcomes were as well similar.
Glycemic control in GDM can be achieved by using metformin orally without increasing the risk for maternal complications with a satisfying neonatal outcome.
Keywords: gestational diabetes mellitus, glucose tolerance test, insulin, medical nutrition therapy, metformin
|How to cite this article:|
Abdel Hamid AN, Abd El-Gayed AM, Saif-Elnasr IA, Soliman MH. Comparison the efficacy and safety between Insulin and Metformin in gestational diabetes mellitus management. Menoufia Med J 2019;32:1376-81
|How to cite this URL:|
Abdel Hamid AN, Abd El-Gayed AM, Saif-Elnasr IA, Soliman MH. Comparison the efficacy and safety between Insulin and Metformin in gestational diabetes mellitus management. Menoufia Med J [serial online] 2019 [cited 2020 Jan 19];32:1376-81. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1376/274256
| Introduction|| |
Gestational diabetes mellitus (GDM) is defined as a condition in women who have carbohydrate intolerance, the onset or recognition of which takes place during pregnancy . Depending on the diagnostic criteria used and ethnicities studied, it is estimated that about 1–14% of women suffer from GDM .
Complications of GDM are manifold, as both mother and fetus are affected. The main adverse perinatal outcomes of GDM are macrosomia, large for gestational age (LGA) babies, shoulder dystocia, birth trauma and birth asphyxia. In addition, such infants are prone to disease conditions such as delayed motor development, obesity and diabetes later in life ,. Furthermore, women with a history of macrosomia have an up to five-fold increased risk for the development of premenopausal breast cancer. Similarly, LGA births are also reported to increase the risk of breast cancer .
Adverse outcomes for the mother are a caesarean section, gestational hypertension, pre-eclampsia, labor induction and an increased risk of developing type 2 diabetes ,. Generally, there is agreement that GDM should be treated with medical nutrition therapy, and insulin therapy is to be initiated if desired glycemic targets are not achieved by dietary intervention ,.
The disadvantages of insulin for the mother include the need to give injections, frequent daily testing for monitoring and risks of hypoglycemia, increase in appetite, weight gain and high cost .
Women may be anxious about being on insulin, and treatment compliance is an issue. It would be useful if there were alternative treatment options to insulin, preferably oral agents.
Metformin, an oral biguanide, may be a more logical alternative to insulin for women with GDM who are unable to cope with the increasing insulin resistance of pregnancy. Metformin works primarily by decreasing hepatic glucose output, improving peripheral glucose uptake and decreasing free fatty acid levels, thus reducing insulin resistance without as much risk of resulting hypoglycemia .
| Patients and Methods|| |
This is a prospective randomized comparative study. After obtaining approval from the Hospital Local Medical Ethics Committee, 240 antenatal women whose pregnancies had been complicated by GDM and did not respond to diet modifications or nutritional instructions alone in 2 weeks were recruited from antenatal clinics at the Obstetrics Department in Menofia University Hospitals and Shebin El-Kom Teaching Hospital from November 2016 to March 2018. GDM was diagnosed according to the American Diabetic Association guidelines at 24–28 weeks if blood glucose values were in excess of :
Fasting: more than 92 mg/dl (5.1 mmol/l), 1 h postprandial: more than 180 mg/dl (10.0 mmol/l), 2 h postprandial: more than 153 mg/dl (8.5 mmol/l).
Exclusion criteria were multiple pregnancies, prepregnancy diagnosis of diabetes, contraindications to metformin as renal impairment, fetal anomaly, fetal growth restrictions, gestational hypertension or pre-eclampsia. The research course was completely explained to the participants before receiving their verbal and written informed consent.
All patients were subjected to the following:
- Careful history taking: At the initial visit, a detailed history was obtained including personal history, past history concerning previous history of GDM, family history of diabetes mellitus, any history suggestive of pregestational diabetes such as abortion, repeated unexplained Intra-uterine fetal death (IUFD) or fetal macrosomia and history of hypersensitivity to metformin
- Clinical examination: Careful general clinical examination including body weight, height, blood pressure and lower limb edema was carried out. Maternal BMI was calculated using the earliest available body weight (the weight in kilograms divided by the square of the height in meters)
- Laboratory investigations: Glycosylated hemoglobin (HbA1c), fasting and postprandial blood glucose levels, liver and renal function tests, complete blood picture and urine analysis were carried out
- Fasting and postprandial blood glucose levels: A drop of fresh capillary blood (e.g. from index finger or the thumb) was obtained from each woman and analyzed for fasting and 2 h postprandial blood glucose level every 2 weeks until 28 weeks' gestational age, then every week until delivery using a blood glucose monitor device (Accu-Chek Active, Amazon company)
- HbA1c was assessed every 3 months to determine the efficacy of treatment
- Ultrasonography: It was carried out before starting treatment, especially at 18–20 weeks, to rule out congenital fetal malformations and to confirm gestational age. Then, it was carried out during the follow-up period for assessment of fetal well-being by mindray DP 20 (Mindray Medical India Private Limited, Kshmta Kavra, 16th Floor, Building No. 9B, Gurgaon - Haryana, India)
- Nutritional and life style modification counseling: According to American Diabetic Association recommendations, carbohydrate intake should be ~40% of total calorie intake and should be selected from foods with low glycaemic index values with consuming of 30–32 kcal/kg body weight, especially during the second half of pregnancy with recommendations for exercising three or more times a week for about 30 min.
If glycemic targets were not achieved within 2 weeks, pharmacological therapy began. Patients were divided randomly into two groups by permuted block randomization; each group had 120 pregnant mothers.
- First group: This group received insulin in the form of mixed insulin (Mixtard 30; Novo Nordisk, Baulkham Hills BC NSW 2153, Australia). The starting dose was 0.7 U/kg of actual body weight, given subcutaneously twice daily and increased weekly, as necessary
- Second group: This group received metformin in the form of Cidophage, 850 mg (CID, Omranya-Giza-Egypt) in a dose of 850 mg once daily, which increased by 500 mg weekly up to 2500 mg maximum dose to achieve glycemic control.
Monitoring at home was carried out by estimating blood glucose levels. Fasting and 2-h postprandial blood sugar were measured after the three main meals.
The primary outcome was to achieve glycemic control according to American Diabetic Association  fasting: 95 mg/dl (5.3 mmol/l) and either 1-h postprandial: 140 mg/dl or 2-h postprandial: 120 mg/dl.
Dose modifications of drugs were made at each antenatal visit weekly until delivery. The usual obstetric care was offered at antenatal clinics including ultrasound examination, which was performed at first visit (dating scan), then at 16–19 weeks (anomaly scan) and then monthly after 28 weeks, as fetal well-being scan. HbA1c was performed at the beginning of the study and at around 37 weeks of pregnancy. The mode and time of delivery were decided around 38 weeks of pregnancy.
Maternal outcome in terms of glycemic control, medical complications and mode of delivery were documented. Neonatal outcomes were recorded, and all were statistically analyzed.
The results were collected, tabulated and statistically analyzed by an IBM-compatible personal computer with SPSS, version 20 (SPSS Inc., Chicago, Illinois, USA; IBM SPSS for Windows, version 20.0; IBM Corp., Armonk, New York, USA). Quantitative data were expressed as mean ± SD, whereas qualitative data were expressed as numbers and percentages. The Student t-test was used to test significance of difference for quantitative variables and the χ2 was used to test significance of difference for qualitative variables. A probability value of P less than 0.05 was considered statistically significant. Data were analyzed and appropriately presented in tables.
| Results|| |
This prospective comparative study compared the efficacy and safety between insulin and metformin in the management of GDM. A total of 240 patients with GDM were registered in the study, who met the inclusion criteria and were randomized to be treated with insulin or metformin.
The demographic characteristics of insulin or metformin groups at the time of diagnosis of GDM were similar [Table 1].
|Table 1: Comparison between the studied groups according to sociodemographic characters|
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Fasting and 2-h postprandial blood glucose levels were statistically analogous in two groups. Glycemic targets were achieved and maintained throughout pregnancy with no statistical difference in the studied groups [Table 2].
|Table 2: Comparison between the studied groups according to fasting blood sugar and 2 h postprandial blood sugar|
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As regards maternal outcome, no significant differences were found between the studied groups in terms of medical disorders developed during the antenatal period, such as gestational hypertension, pre-eclampsia, hypoglycemia and preterm labor. Moreover, no significant difference was found between the studied groups according to mode of delivery [Table 3].
As regards the neonatal outcome, no significant differences were found between the studied groups according to neonatal outcome in terms of neonatal hypoglycemia, macrosomia, 5 min apgar score less than 7, respiratory distress syndrome, admission to neonatal intensive unit, or need for phototherapy [Table 4].
| Discussion|| |
The results of our study were similar to the studies conducted by Coetzee and Jackson in 1979 to a large extent. They were the first researchers to study the role of metformin during pregnancy in women with insulin-independent diabetes. Their study also had two groups of patients; one received metformin, whereas the other group received insulin. The maternal and perinatal outcomes were the same for both groups . The studies on this issue have been continuing from those conducted by Coetzee and Jackson until Lim's study in 1997 . Lim was the first one to suggest that GDM can be managed efficiently and securely with oral hypoglycemic drugs, with no distinction in pregnancy outcomes. In 2000, Hellmuth et al.  presented a cohort study of type 2 diabetes mellitus pregnant women on metformin in opposition to glibenclamide versus insulin. Their results suggested apprehensions about the use of metformin, because of the increased rate of pre-eclampsia (32% metformin vs. 7% glibenclamide vs. 10% insulin) and intrauterine fetal death (8 vs. 0 vs. 2.3%, respectively). In contrast, this study had become controversial with reviewers arguing that women in the study were not matched. Those women who received the metformin were morbidly obese and started to use the medication later on in the pregnancy. Consequently, the women essentially faced the threat of poor pregnancy outcomes that were unrelated to metformin .
Rowan et al.  conducted a randomized Australian study on women with gestational diabetes between 20 and 33 weeks of pregnancy who were prescribed either metformin or insulin. There was no difference in efficacy between both groups in controlling glucose levels. Infants of the metformin group had a lower rate of hypoglycemia compared with infants of the insulin group with no more neonatal outcomes differences between each other.
The findings of our study are similar to those of the research by Niromanesh et al.  who conducted a randomized clinical trial on women with GDM who have singleton pregnancy at a gestational age between 20 and 34 weeks and did not achieve glycemic control on diet. Patients were assigned randomly to receive either metformin (n = 80) or insulin (n = 80). They found that the two groups were similar in terms of mean fasting (P = 0.68) and postprandial blood sugar measurements (P = 0.87) throughout the GDM treatment.
The maternal outcomes were reassuring in the present study, and no significant differences were found between the two studied groups with regard to the development of gestational hypertension (P = 0.95), pre-eclampsia (P = 0.81), maternal hypoglycemia (P = 0.2), preterm delivery (P = 0.29), or mode of delivery either by normal vaginal delivery or cesearean section (P = 0.76). This is consistent with the study conducted by Niromanesh et al. , which found that pregnancy-induced hypertension was considerably less frequent in the metformin group than in the insulin group, even though it did not reach statistical significance (5 vs. 13.8%, respectively, P = 0.058). Moreover, Spaulonci et al.  reported no difference in the cesearean section rate between the metformin and the insulin groups (71.7 vs. 65.2%), which is consistent with our results.
The neonatal outcomes were also reassuring in the present study, and no significant differences were found between the two studied groups with regard to neonatal hypoglycemia (P = 0.11), fetal macrosomia (P = 0.71), 5-min Apgar score less than 7 (P = 0.6), respiratory distress syndrome (P = 1), phototherapy (P = 1), and NICU admission (P = 0.8). Consistent with our results, the primary composite outcome of the metformin in gestational diabetes: The Offspring Follow-Up (MiG TOFU) study (neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-min Apgar score <7, prematurity) did not differ for the two treatment groups (32% in each). Secondary outcomes, such as LGA, cord insulin levels and subcutaneous fat thickness were similar. A secondary outcome, severe neonatal hypoglycemia (any blood glucose <28.8 mg/dl), was more common in the insulin group (8%) than in the metformin group (3%) .
Nowadays, more studies center on investigating the effectiveness and safety of oral antidiabetic drugs when used during pregnancy in managing GDM. Some are observational studies, and others are case–control trials . The randomized controlled trials are present but with only a few samples, which are deficient in the authority to represent a valid conclusion about the use of oral antidiabetic drugs for managing GDM.
| Conclusion|| |
There is now a changing trend in the acceptability of using oral hypoglycemic agents in gestational diabetes. According to the current study, oral antidiabetic drugs such as metformin are safe and useful, especially for those who are mildly to moderately hyperglycemic and cannot tolerate multiple daily insulin injections. Moreover, they offer a simple, inexpensive and convenient alternative to insulin in such individuals.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
The American College of Obstetricians and Gynecologists. Gestational diabetes mellitus: clinical management guidelines for obstetricians–gynecologists. Obstet Gynecol 2013; 122
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013; 36(Suppl 1)
Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al
. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358
Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol 2005; 192
Forman MR, Cantwell MM, Ronckers C, Zhang Y. Through the looking glass at early-life exposures and breast cancer risk. Cancer Invest 2005; 23
National Institute for Health and Clinical Excellence London. Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period. 2008. Available from: http://www.nice.org.uk/CG063
. [Last accessed on 2015 Apr 25].
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetesmellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med 1998; 15
Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformincompared with glyburide in gestational diabetes: a randomized controlled trial. Obstet Gynecol 2010; 115
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2016; 39(Suppl 1)
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2016; 39(Suppl 1)
Coetzee EJ, Jackson W. Metformin in management of pregnant insulin-independent diabetics. Diabetologia 1979; 16
Lim J, Tayob Y, O'Brien P, Shaw R. A comparison between the pregnancy outcome of women with gestation diabetes treated with glibenclamide and those treated with insulin. Medical Journal of Malaysia 1997; 52
Hellmuth E, Damm P, Mølsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med 2000; 17
Norman RJ, Wang JX, Hague W. Should we continue or stop insulin-sensitizing drugs during pregnancy? Curr Opin Obstet Gynecol 2004; 16
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358
Niromanesh S, Alavi A, Sharbaf F, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trials. Diabetes Res Clin Pract 2012; 98
Spaulonci C, Bernardes L, Trindade T, Zugaib M, Francisco R. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol 2013; 209
Homko CJ, Sivan E, Reece AE. Is there a role for oral antihyperglycemics in gestational diabetes and type 2 diabetes during pregnancy? Treat Endocrinol 2004; 3
[Table 1], [Table 2], [Table 3], [Table 4]