Journal Reading Divisi Endokrin Metabolik

Nama : Dr. Andhika K. Hamdany

Received: 8 June 2018 | Accepted: 25 July 2018

DOI: 10.1002/jcp.27238
Pembimbing : DR.Dr. Fabiola M.S. Adam, SpPD KEMD
Dibacakan Tanggal 16/4/2019
ORIGINAL RESEARCH ARTICLE

The efficacy of metformin compared with insulin in regulating

blood glucose levels during gestational diabetes mellitus:
A randomized clinical trial

Nayereh Ghomian1 | Seyede Houra Mousavi Vahed1 | Samaneh Firouz1 |

Mohammad Ali Yaghoubi2 | Masoud Mohebbi3 | Amirhossein Sahebkar4,5,6

1
Department of Obstetrics and Gynecology,
Faculty of Medicine, Mashhad University of Abstract
Medical Sciences, Mashhad, Iran Background: Insulin has been a conventional medication in the treatment of female
2
Birjand University of Medical Sciences,
patients suffering from gestational diabetes mellitus (GDM). However, the need for a
Birjand, Iran
3
Metabolic Syndrome Research Center, large number of insulin injections in these patients causes them a lot of discomforts.
Mashhad University of Medical Sciences, Recently, an alternative medication, metformin, has received considerable attention
Mashhad, Iran
4
in the treatment of GDM. The aim of this study was to compare the efficacy of
Biotechnology Research Center,
Pharmaceutical Technology Institute, metformin and insulin in regulating blood glucose levels and fetal outcomes in GDM.
Mashhad University of Medical Sciences,
Methods: This randomized clinical trial included 286 pregnant women diagnosed with
Mashhad, Iran
5
Neurogenic Inflammation Research Center,
positive GDM at 24–28 weeks of pregnancy. The subjects were randomly divided into
Mashhad University of Medical Sciences, two groups of 143 patients, with one group receiving insulin and the other undergoing a
Mashhad, Iran
6
treatment plan using metformin. Fasting plasma glucose (FPG), 2‐hr plasma glucose (PG)
School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran and glycated hemoglobin (HbA1c) were recorded twice a month until delivery. Other
variables, including birth delivery method, cause of cesarean section, gestational age at
Correspondence
Masound Mohebbi, Metabolic Syndrome the delivery time, birth trauma, Apgar score, birth weight, admission at neonatal
Research Center, Mashhad University of intensive care unit (NICU), and neonatal hypoglycemia were also registered.
Medical Sciences, Mashhad 9177948564, Iran.
Email: mohebbim@mums.ac.ir Results: Age of mother, body mass index, history of diabetes in the family, previous
history of GDM, parity, FPG, 1‐ and 2‐hr PG after meals, and 75‐g glucose tolerance test
Funding information
Mashhad University of Medical Sciences; before treatment were not statistically different between the two groups. FPG, PG, and
Research Council at the Mashhad University HbA1c did not show significant differences between the two groups after completing the
of Medical Sciences, Mashhad, Iran
course of treatment. There was also no significant difference between two groups
regarding the birth delivery method, the cause of cesarean section, birth trauma, Apgar
score, birth weight, admission at NICU, and neonatal hypoglycemia.
Conclusion: As mean FPG and 2‐hr PG were not significantly different between the
two groups, it seems that metformin can be recommended as an effective substitute
for insulin in the treatment of GDM. However, there are still some undesirable risk
factors with both treatments that may threaten the mother and the newborn.

KEYWORDS
gestational diabetes mellitus, glucose tolerance test, insulin, metformin, pregnancy,
randomized clinical trial

J Cell Physiol. 2018;1–7. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1

2 |
1 | INTRODUCTION
Gestational diabetes mellitus (GDM) is among the most frequent and
most serious complications following pregnancy (American Diabetes
Association, 1). The incidence of gestational diabetes in the United
States is about 7% (about 200,000 in four million births), and in 90%
of these women, glucose intolerance resolves after pregnancy
(Baptiste‐Roberts et al., 3).
Fetal and neonatal complication of GDM including intrauterine
fetal demise, congenital anomaly, fetal macrosomia, birth traumas,
hypoglycemia, hyperbilirubinemia, respiratory distress, cardiomyo-
pathy, hypocalcemia, prematurity, and pulmonary hyaline membrane
disease (Rastogi & Jain, 19). Further complications that may arise
from GDM in later stages of childhood include metabolic syndrome
and metabolic disorders, such as obesity, hypertension, dyslipidemia,
and glucose intolerance (Metzger et al., 15).
Maternal short‐term complications of GDM include increased
chance of cesarean section, hyperglycemia crisis, urinary tract
infections, and preeclampsia. Moreover, long‐term complications
include predisposition to developing type 2 diabetes as well as
cardiovascular disorders such as hyperlipidemia and hypertension
(Ben‐Haroush, Yogev, & Hod, 4).
Pregnancy is invariably accompanied by two inevitable conse-
quences: Increased resistance to insulin and increased secretion of
insulin from the pancreas. During the pregnancy period, insulin levels
rise by 200–250%. As a result, the expecting mothers develop
hypoglycemia. These metabolic changes are inherently natural and
play a major role in providing the embryo or fetus with appropriate
nutrition. Meanwhile, if the amount of insulin secretion fails to satisfy
the increased need during pregnancy, resistance to insulin will occur
as an incidental condition (Thacker & Petkewicz, 26).
It is imperative for all diabetic pregnant women to perform self‐
monitoring of blood glucose (SMBG) on a daily basis. Ideally, fasting
glucose level should be lower than 95 mg/dl, 1‐hr plasma glucose
(PG) level should be lower than 140 mg/dl, and 2‐hr plasma glucose
(PG) level should be lower than 120 mg/dl. Women with GDM have
been recommended to perform SMBG 3–4 times a day (American
Diabetes Association, 1).
Medical nutrition therapy (MNT) is the standard supportive
approach applied to all women suffering from GDM, which can
relieve both pregnancy and neonatal complications (American
Diabetes Association, 1). MNT approach consists of a set of rules
devised to not only provide the required amounts of calorie and
other nutritional needs but also help expecting mothers to hopefully
achieve the optimum level of blood glucose, without gaining or losing
weight excessively.
In addition to this therapeutic approach, pregnant women are
advised to perform mild exercise and stretches for 30 min a day,
unless they have a contraindication for exercise. The American
Diabetes Association (1) recommends 30 min of moderate exercise
three or more times per week (Colberg et al., 5). Patients fail to
respond to diet or exercise, and will consequently require treatment
using drugs, most typically administration of insulin (American
GHOMIAN ET AL.
Diabetes Association, 1). When fasting plasma glucose (FPG) levels
exceed 105 mg/dl on SMBG or 1‐hr PG exceeds 155 mg/dl and 2‐hr
PG exceeds 130 mg/dl, then diet and exercise regimens will not be
sufficient and starting a medication will be necessary (Thacker &
Petkewicz, 26).
Insulin is the only FDA‐approved medication of choice for
treatment of women suffering from GDM who have not responded
effectively to MNT approach (American Diabetes Association, 1;
Sazonova, Esayan, Kolegaeva, & Gardanova, 22). Glyburide, as an
adjuvant, is mainly used in conjunction with MNT and exercise when
more treatment becomes necessary (American Diabetes Association,
1). Metformin is a medication that belongs to a class of drugs called
biguanides. It regulates serum glucose levels by altering hepatic
metabolism, reducing gluconeogenesis, and decreasing peripheral
insulin resistance (American Diabetes Association, 1; Langer, 11).
Compared with insulin, metformin is more convenient to use, that has
earned this medication growing popularity with physicians and
patients. Although abundant research about the efficacy and
harmlessness of this drug has covered pages of many scientific
journals, the findings have not been adequately convincing, and
therefore further research is still being carried out with perseverance
(Thacker & Petkewicz, 26).
As mentioned already, insulin has been the conventional
medication of choice in the treatment of GDM for a long span of
time. Nevertheless, the need for frequent subcutaneous injections
has caused these patients enormous inconvenience. In addition, it is
associated with increased risk of developing hypoglycemia as well as
weight gain in mothers (Simmons, 23). Other drawbacks linked with
the usage of insulin include the requirement for strict instructions for
injection and the high cost of the drug. Metformin, on the other hand,
is an oral medication; it is easier to use and has been comparatively
well received by patients. This medication can cause decreased
hepatic gluconeogenesis, increased insulin sensitivity as well as
peripheral glucose uptake (Saleh, Abdelsalam, Mowafy, & Abd
ElHameid, 21; Simmons, 23).
The amount of postprandial glucose is more significant in terms
of improving maternal and neonatal results than the preprandial
glucose level (de Veciana et al., 7). Although there have been
numerous studies on the use of metformin in the treatment of GDM,
there is still a division of opinion. The aim of this study was to
compare the efficacy of metformin and insulin in regulating the blood
glucose levels of GDM patients and in terms of managing the
corresponding maternal and neonatal complications.
2 | M A T E R I A L S AN D M E T H O D S
This randomized clinical trial included 286 pregnant women with a
gestational age between 24 and 28 weeks. An oral glucose tolerance
test utilizing 75 g of glucose indicated a positive diagnosis of GDM in
all subjects, who had been referred to three academic hospitals
affiliated with Mashhad University of Medical Sciences. The sample
size was calculated using the formula for “comparison of two ratios
GHOMIAN ET AL.
related to one qualitative attribute between two independent
populations” and considering α error=0.05 and β error=0.2, leading
to an estimation of 143 individuals in each group.
The inclusion criteria were pregnant women aged between 18
and 40 with a gestational age over 24 weeks diagnosed with GDM,
singleton pregnancy, failure to achieve glycemic control with exercise
and diet during 1 week, absence of overt diabetes mellitus, absence
of lactic acidosis risk factor, absence of fetal anomaly, absence of
medical diseases in mothers such as kidney or liver diseases, and
filling the informed consent for participation in the study. The
exclusion criteria were refusal for attendance in follow‐up sessions
for any reason and not responding to 1500 mg of metformin.
After the study project was approved by the Research Deputy of
Mashhad University of Medical Sciences, it obtained the ethics
approval (IR.MUMS.fm.REC.1394.360) and was subsequently regis-
tered in the Iranian Registry of Clinical Trials System
(IRCT2016080229172N1).
Initially, the patients received treatment in the form of diet and
exercise regimens for 1 week. In the next stage, if their FPG and their
2‐hr PG still remained above 95 and 120 mg/dl, respectively, they
were entered into the study to start medical treatment.
All subjects were required to perform SMBG three times a day at
home to measure and record their FPG as well as their 2‐hr PG using
a glucometer (Oncall Plus, Acon, San Diego, CA).
Using a random number table, study participants were allocated
to two groups (each comprising 143 pregnant women). One group
received insulin as medication and the other was given metformin.
The metformin group started the medication with an initial dose
of 500 mg at noon. The suitable dose, however, was prescribed
during follow‐up visits according to the blood glucose levels recorded
by the patients. The maximum dose of metformin administered
during the study period was 1500 mg in three divided dose.
As for the other group, insulin was initially administered at 0.1 IU/kg
via subcutaneous injections. The Levemir (insulin detemir) before night
sleep and insulin aspart before taking meals were prescribed to control
FPG and 2‐hr PG, respectively. The aim of treatment was to reduce FPG
below 95 mg/dl and 2‐hr postprandial blood glucose below 120 mg/dl.
All patients were instructed to attend follow‐up sessions every 2
weeks until delivery for examination and medication adjustment.
They were also advised to make an earlier visit in case of unusually
high levels of plasma glucose.
In every examination session, which was arranged to happen
every 2 weeks (and every week during the latter stages of pregnancy)
until delivery date, the recorded data by the patient including the
mean FPG as well as 2‐hr PG after lunch, and dinner were registered
in the patient’s record file.
During the study period, the treatment monitoring process was
realized via SMBG for both groups. FPG and glycated hemoglobin
(HbA1c) were checked monthly during the pregnancy, and 2 months
after the delivery oral glucose tolerance test (75 g) was performed for
all patients. FPG was measured by the glucose oxidase method using
Pars Azmon kits (Pars Azmon, Tehran, Iran) and HbA1c was analyzed by
the enzymatic colorimetric method using available commercial kits
| 3
(Roche, Hamburg, Germany). Also, the pregnancy outcomes of both
groups were registered, including delivery method, gestational age at
delivery time, neonatal hypoglycemia, birth weight, Apgar score,
neonatal intensive care unit (NICU) admission and birth trauma. The
outcome assessor and data analyst were blinded to treatment groups.
Descriptive (mean, SD and frequency, percentage) and inferential
analyses (Student’s t test and the χ2 test) were performed using SPSS
software (version 16.0; SPSS Inc., Chicago, IL). All tests were two‐
tailed with a significance level of below 0.05.
3 | RESULTS
Thirty subjects from the metformin group were excluded from the
study later on because they did not respond to this medication and
required insulin. However, these patients were replaced with new
subjects, since the exclusive objective of the study was to evaluate
the efficacy of using insulin versus metformin in terms of blood
glucose control as well as management of fetal or neonatal and
maternal complications (Figure 1).
The demographic specifications of the metformin and insulin
groups indicated no statistically significant difference when the
diagnosis of GDM was established (Table 1).
No statistically significant differences were observed between
the two groups (insulin vs. metformin) in relation to FPG level as well
as 2‐hr PG, neither at the onset of treatment nor during the study
period. Also, no statistically significant differences were detected
during the treatment period until delivery between the two groups
concerning HbA1c (FPG or 2‐hr PG; Table 2).
Comparison of evaluative results revealed no statistically
significant difference between the study groups with regard to
neonatal complications including term birth, preterm birth, Apgar
score, birth weight, birth trauma, neonatal hypoglycemia, and
admission at NICU (Table 3).
Eighty‐seven (60.8%) pregnant women in the metformin group
and 78 (54.5%) pregnant women in insulin group experienced vaginal
delivery (X2 = 1.160; p = 0.281). On the other hand, 25 (42.9%) and 24
(38.5%) of the patients from the metformin and insulin groups,
respectively, underwent cesarean section due to delay in dilatation or
arrest of descent. Also, eight (16.1%) of the patients from the
metformin group and nine (12.3%) of the patients from the insulin
group experienced cesarean section as a result of fetal distress. Also,
23 (41.1%) and 32 (49.2%) of patients had the cesarean section due
to other reasons in metformin and insulin group, respectively. The χ2
test revealed that there was no statistically significant difference
between the two groups as a relation between the type of medication
received, and the cause of cesarean section (X2 = 0.887; p = 0.642).
4 | D I S C U SS I O N
GDM is among the common complications of pregnancy, which has
attracted the attention of many researchers (Ben‐Haroush et al., 4).
4 | GHOMIAN ET AL.

FIGURE 1 Flowchart of the participants in the study [Color figure can be viewed at wileyonlinelibrary.com]

Evaluation concerned with the diagnosis of GDM commence during
pregnancy, and in case GDM is established, the mother and her child
should remain under medical monitoring for several years following
delivery due complication such as diabetes as well as other possible
pathologies (American Diabetes Association, 1; Zhu et al., 30). Regulation
of blood glucose during pregnancy is of paramount importance to the
management of GDM and the prevention of its short‐term or long‐term
complications (American Diabetes Association, 1).
Several studies have been done on the treatment modalities and
complications of GDM, especially when it comes to the use of
T A B L E 1 Demographic profile of metformin and insulin groups
Metformin Insulin
group (N = 143) group (N = 143) p Value
metformin versus insulin (Crowther et al., 6; Maymone, Baillargeon,
Menard, & Ardilouze, 13; Niromanesh et al., 17; Tertti, Ekblad,
Vahlberg, & Ronnemaa, 25; Thomaz de Lima et al., 27; Waheed,
Malik, & Mazhar, 28).
A number of studies have compared the effect of metformin
versus insulin on the treatment outcome of GDM patients, including
a study by Saleh et al. (21) involving 75 subjects in two groups; a
study by Waheed et al. (28) with 34 subjects allocated in each of the
two groups; a study by Tertti et al. (25) recruiting two groups with
each comprising 45 patients; and another by Niromanesh et al. (17)
involving a population divided into two groups of 80 subjects. These
studies have indicated the similar effect of metformin and insulin on
reducing FPG. While reporting on the similar effect of the two
medications, some researchers have mentioned the need for
supplementary insulin in a few patients when FPG could not be

Age (years) 28.30 ± 5.25 28.41 ± 6.36 0.87 adequately controlled (Niromanesh et al., 17). In the current study,
the size of the sample population in each group was larger than that
BMI‐mid pregnancy 23.73 ± 1.87 24.0 ± 2.10 0.25
(kg/m2) of the studies above, and no statistically significant difference was
seen between the two groups regarding FPG levels, which is
Parity 2.04 ± 1.60 2.24 ± 1.70 0.25
consistent with the findings of previous studies (Maymone et al.,
Positive family 53 (37) 47 (33) 0.45
history for diabetes 13; Zhu et al., 30).
In the current study, the two groups were homogenous with
Positive history for 34 (24) 29 (20) 0.39
gestational diabetes regard to certain factors, including age of patients, body mass
index, family history of diabetes mellitus, previous history of
Gestational age at 24.80 ± 1.45 25.10 ± 1.05 0.39
diagnosis of GDM, and gestational age at treatment onset, which adds to the
GDM (week) value of the achieved findings regarding indicating the similar
Note. Data represented as mean ± standard deviation or frequency (%) as efficacy of metformin versus insulin in regulation of blood
appropriate. BMI: body mass index; GDM: gestational diabetes mellitus. glucose.
GHOMIAN ET AL. | 5

T A B L E 2 Fasting plasma glucose and mean 2‐hr plasma glucose (2‐hr PG) level at onset and throughout treatment until delivery (mg/dl)

Metformin group (N = 143) Insulin group (N = 143) p value

FPG at treatment onset (mg/dl) 91.22 ± 4.37 92.21 ± 4.41 0.57

2‐Hr PG at treatment onset (mg/dl) 152.25 ± 5.11 152.58 ± 4.87 0.69
FPG throughout treatment until delivery (mg/dl) 89.16 ± 3.44 88.03 ± 5.00 0.79
2‐Hr PG throughout treatment until delivery (mg/dl) 119.38 ± 4.03 118.99 ± 6.24 0.33
HbA1c throughout treatment until delivery (%) 5.40 ± 0.54 5.55 ± 0.62 0.79
Note. Data represented as mean ± standard deviation. FPG: fasting plasma glucose; HbA1c: glycated hemoglobin.

As far as glucose monitoring was concerned, the findings under treatment using metformin in comparison with the insulin
pertinent to the clinical control of FPG and 2‐hr PG suggest that group (12.1% vs. 7.6%). In the current study, no statistically
the treatment plan was effective in decreasing the plasma glucose significant difference was observed between the two groups
levels below 95 and 120 mg/dl, respectively. The two groups did not regarding preterm births.
show any statistically significant difference in this respect. As for the rate of cesarean section, the current study compared
As for evaluation performed during pregnancy concerning the corresponding incidence index between the two groups and
glycosylated hemoglobin, the findings indicated equal levels of found no statistically significant differences. Likewise, a randomized
HbA1c in both metformin and insulin groups, with no statistically controlled trial conducted in 2016 revealed no statistically significant
significant difference. Results from the study conducted by differences between the metformin and insulin groups in terms of the
Mesdaghinia et al. (14) displayed lower levels of HbA1c in the number of cesarean section cases (Saleh et al., 21). Also, the study of
metformin group. Lucas, Leveno, Williams, Raskin, and Whalley (12) Moor et al. (16) on 32 patients in the metformin group and 31
investigated the total glycosylated hemoglobin in 105 insulin‐treated subjects in the insulin group reported no statistically significant
woman before 16 weeks gestation. They reported that the mean difference between the two groups in regard incidence of cesarean
glycosylated hemoglobin in women with normal infants was section.
significantly lower than those with malformed infants. In the current In contrast, the study carried out by Goh, Sadler, and Rowan (8),
study, HbA1c levels were within normal range and no particular which comprised three treatment groups: Insulin (399 women);
congenital anomalies were observed among the neonates. metformin (465 women—249 receiving metformin alone and 216
As far as gestational age is concerned, several randomized receiving metformin in combination with insulin); and diet regimen
controlled trials have reported a larger number of preterm births in (371 women), reported a statistically significant higher number of
the group of patients under metformin medication compared with cesarean section in the insulin group compared with the other two
the group receiving insulin (Kitwitee et al., 10; Niromanesh et al., 17; groups. In return, Ijas et al. (9) assigned 50 patients to insulin and 47
Rowan, Hague, Gao, Battin, & Moore, 20). Rowan et al. (20) reported patients to metformin and reported a higher incidence rate of
a higher prevalence of preterm delivery among patients who were cesarean section in the metformin group.
Concerning the incidence rate of birth trauma, the current study
detected no statistically significant difference between the two
T A B L E 3 Comparison of neonatal outcomes between the two groups. Another study, involving 363 patients in the metformin
groups of insulin and metformin
group, did not find any significant difference between the two groups,
Insulin either (Rowan et al., 20).
Metformin group With regard to the Apgar score in the current study, the majority
group (N = 143) (N = 143) p value of the neonates were born with an Apgar score ≥7. Various other
Gestational age <37 20 (13.9) 19 (13.2) 0.86 studies have also indicated no significant differences between the
weeks at birth two treatment groups concerning the Apgar score (Mesdaghinia
Apgar score at 19 (13.2) 16 (11.1) 0.58 et al., 14; Moore et al., 16; Tertti et al., 25).
5 min <7
As far as birth weight is concerned, some studies have pointed out a
Hypoglycemia 12 (8.3) 17 (11.8) 0.32 disproportion between the weights of the newborns and gestational age
Birth weight (g) 3,450 ± 548 3,544 ± 57 0.15 in the insulin group. For example, Mesdaghinia et al. (14) mentioned a
Birth trauma 13 (9.0) 12 (8.3) 0.83 greater number of large for gestational age newborns who belonged to
Intensive care unit 29 (20.2) 27 (18.8) 0.76 the insulin group of the study, when compared with the metformin
admission group, which revealed no statistically significant difference. Similarly,
Note. Data represented as mean ± standard deviation or frequency (%) as some other studies did not present any statistically significant
appropriate. difference (Rowan et al., 20; Tertti et al., 25).
6 |
The findings of the study performed by Goh et al. (8), which
involved 1,269 women, revealed macrosomia in 18.5% of the neonate
belonging to the insulin group. The measurement of birth weight in
both groups of the current study indicated that the mean weight of
the neonates from both groups was normal, and that there was no
statistically significant difference between the two groups in this
respect, which are consistent with the findings of the study
by Mesdaghinia et al. (14).
Concerning the occurrence of neonatal hypoglycemia, the
available literature has reported different results as far as the two
GDM treatment methods were concerned (Kitwitee et al., 10; Rowan
et al., 20; Tertti et al., 25; Zhu et al., 30). Rowan et al. (20) compared
two groups of subjects (insulin vs. metformin) and observed a
decreased incidence rate of severe hypoglycemia in the metformin
group, which represented a statistically significant difference.
Spaulonci, Bernardes, Trindade, Zugaib, and Francisco (24) reflected
the lower incidence rate of hypoglycemia as the desirable efficacy of
metformin in decreasing the blood glucose of the involved mothers.
In the current study, although a lower incidence rate of hypoglycemia
was observed in the metformin group, it did not reach a statistical
significance level.
With regard to admission at NICU, Mesdaghinia et al. (14),
Balani, Hyer, Rodin, and Shehata (2), Kitwitee et al. (10), and Rai,
Meenakshi, and Kamath (18) have all remarked that the use of
metformin can reduce the need for admission at NICU. According
to the findings of the current study, however, even though the
number of cases admitted at NICU from the metformin group was
slightly greater than the number from the insulin group, no
statistically significant difference could be established between
the two groups. Similar to the current study, Rowan et al. (20) did
not detect any significant difference between the two groups,
either. One factor which might explain the conflict in the achieved
findings is the high prevalence of preterm labor among the
patients of the insulin group, which has also been mentioned in
the previous studies (Balani et al., 2; Mesdaghinia et al., 14). On
the other hand, although both groups in the current study showed
fairly similar results in terms of labor onset, and consequently
preterm delivery, they revealed no statistically significant
difference.
In our study, a positive family history of diabetes was seen in
37% and 33% of GDM patients in metformin and insulin groups,
respectively. In previous studies, there was a strong association
between the positive family history of diabetes and the increased
likelihood of occurrence of GDM. In the study of Zaman et al. (29),
143 (55%) of GDM patients had a positive family history of
diabetes.
One of the limitations of this study was the prolonged period of it,
as well as the impossibility of prolonged follow‐up of the infants that
metformin used by their mothers. Because of the physical character-
istics, including the different ways of administration, blindness was
difficult in our study. However, the result assessor and data analyst
were blinded to treatment groups and this is a good point for our
study.
GHOMIAN ET AL.
5 | CO NCL USION
In the current study, data related to fasting glucose levels, HbA1c levels,
and 2‐hr PG did not indicate any statistically significant difference
between the two treatment groups (metformin vs. insulin). Therefore,
due to certain advantages of metformin—being more convenient to use
and requiring no injections—it can be recommended as a favorable
substitute for insulin in the treatment of GDM.
AC KNO WL EDG M EN T
This study was supported by a grant from the Research Council at
the Mashhad University of Medical Sciences, Mashhad, Iran.
CON F LI CTS OF I NTERE ST
The authors declare that there are no conflicts of interest.
ORCI D
Amirhossein Sahebkar http://orcid.org/0000-0002-8656-1444
R E F E R E N CE S
1. American Diabetes Association. Standards of medical care in
diabetes. Diabetes Care 41(Suppl 1):S13‐S27.
2. Balani, J., Hyer, S. L., Rodin, D. A., & Shehata, H. (2009). Pregnancy
outcomes in women with gestational diabetes treated with metfor-
min or insulin: A case‐control study. Diabetic Medicine: A Journal of the
British Diabetic Association, 26(8), 798–802.
3. Baptiste‐Roberts, K., Barone, B. B., Gary, T. L., Golden, S. H., Wilson, L.
M., Bass, E. B., & Nicholson, W. K. (2009). Risk factors for type 2
diabetes among women with gestational diabetes: A systematic
review. The American Journal of Medicine, 122(3), 207–214. 207.e204‐
214.e204
4. Ben‐Haroush, A., Yogev, Y., & Hod, M. (2004). Epidemiology of
gestational diabetes mellitus and its association with type 2 diabetes.
Diabetic Medicine: A Journal of the British Diabetic Association, 21(2),
103–113.
5. Colberg, S. R., Sigal, R. J., Fernhall, B., Regensteiner, J. G., Blissmer, B. J.,
Rubin, R. R., … Braun, B. (2010). Exercise and type 2 diabetes: The
American College of Sports Medicine and the American Diabetes
Association: Joint position statement. Diabetes Care, 33(12),
e147–e167.
6. Crowther, C. A., Hiller, J. E., Moss, J. R., McPhee, A. J., Jeffries, W. S., &
Robinson, J. S. (2005). Effect of treatment of gestational diabetes
mellitus on pregnancy outcomes. The New England Journal of Medicine,
352(24), 2477–2486.
7. de Veciana, M., Major, C. A., Morgan, M. A., Asrat, T., Toohey, J. S.,
Lien, J. M., & Evans, A. T. (1995). Postprandial versus preprandial
blood glucose monitoring in women with gestational diabetes
mellitus requiring insulin therapy. The New England Journal of
Medicine, 333(19), 1237–1241.
8. Goh, J. E., Sadler, L., & Rowan, J. (2011). Metformin for gestational
diabetes in routine clinical practice. Diabetic Medicine: A Journal of the
British Diabetic Association, 28(9), 1082–1087.
9. Ijas, H., Vaarasmaki, M., Morin‐Papunen, L., Keravuo, R., Ebeling, T.,
Saarela, T., & Raudaskoski, T. (2011). Metformin should be considered
in the treatment of gestational diabetes: A prospective randomised
GHOMIAN ET AL.
study. BJOG: An International Journal of Obstetrics and Gynaecology,
118(7), 880–885.
10. Kitwitee, P., Limwattananon, S., Limwattananon, C., Waleekachonlert, O.,
Ratanachotpanich, T., Phimphilai, M., … Pongchaiyakul, C. (2015).
Metformin for the treatment of gestational diabetes: An updated
meta‐analysis. Diabetes Research and Clinical Practice, 109(3), 521–532.
11. Langer, O. (2007). From educated guess to accepted practice: The use
of oral antidiabetic agents in pregnancy. Clinical Obstetrics and
Gynecology, 50(4), 959–971.
12. Lucas, M. J., Leveno, K. J., Williams, M. L., Raskin, P., & Whalley, P. J.
(1989). Early pregnancy glycosylated hemoglobin, severity of
diabetes, and fetal malformations. American Journal of Obstetrics and
Gynecology, 161(2), 426–431.
13. Maymone, A. C., Baillargeon, J. P., Menard, J., & Ardilouze, J. L. (2011).
Oral hypoglycemic agents for gestational diabetes mellitus? Expert
Opinion on Drug Safety, 10(2), 227–238.
14. Mesdaghinia, E., Samimi, M., Homaei, Z., Saberi, F., Moosavi, S. G., &
Yaribakht, M. (2013). Comparison of newborn outcomes in women
with gestational diabetes mellitus treated with metformin or insulin:
A randomised blinded trial. International Journal of Preventive
Medicine, 4(3), 327–333.
15. Metzger, B. E., Gabbe, S. G., Persson, B., Buchanan, T. A., Catalano, P. A.,
Damm, P., … Schmidt, M. I. (2010). International association of diabetes
and pregnancy study groups recommendations on the diagnosis and
classification of hyperglycemia in pregnancy. Diabetes Care, 33(3),
676–682.
16. Moore, L. E., Briery, C. M., Clokey, D., Martin, R. W., Williford, N. J.,
Bofill, J. A., & Morrison, J. C. (2007). Metformin and insulin in the
management of gestational diabetes mellitus: Preliminary results of a
comparison. The Journal of Reproductive Medicine, 52(11), 1011–1015.
17. Niromanesh, S., Alavi, A., Sharbaf, F. R., Amjadi, N., Moosavi, S., &
Akbari, S. (2012). Metformin compared with insulin in the manage-
ment of gestational diabetes mellitus: A randomized clinical trial.
Diabetes Research and Clinical Practice, 98(3), 422–429.
18. Rai, L., Meenakshi, D., & Kamath, A. (2009). Metformin: A convenient
alternative to insulin for Indian women with diabetes in pregnancy.
Indian Journal of Medical Sciences, 63(11), 491–497.
19. Rastogi, R., & Jain, S. K. (2016). Imaging in diabetes mellitus. . Archives
of Clinical Nephrology I, (2), 028–036.
20. Rowan, J. A., Hague, W. M., Gao, W., Battin, M. R., & Moore, M. P.
(2008). Metformin versus insulin for the treatment of gestational
diabetes. The New England Journal of Medicine, 358(19), 2003–2015.
21. Saleh, H. S., Abdelsalam, W. A., Mowafy, H. E., & Abd ElHameid, A. A.
(2016). Could metformin manage gestational diabetes mellitus instead
of insulin? International Journal of Reproductive Medicine, 2016, 3480629.
| 7
22. Sazonova, A. I., Esayan, R. M., Kolegaeva, O. I., & Gardanova, Z. R.
(2016). Efficacy and safety of metformin for the treatment of
gestational diabetes: A new approach to the problem. Diabetes
Mellitus, 19(2), 164–170.
23. Simmons, D. (2010). Metformin treatment for type 2 diabetes in
pregnancy? Best Practice & Research Clinical Endocrinology & Metabo-
lism, 24(4), 625–634.
24. Spaulonci, C. P., Bernardes, L. S., Trindade, T. C., Zugaib, M., &
Francisco, R. P. (2013). Randomized trial of metformin vs insulin in
the management of gestational diabetes. American Journal of
Obstetrics and Gynecology, 209(1), 34.
25. Tertti, K., Ekblad, U., Vahlberg, T., & Ronnemaa, T. (2008).
Comparison of metformin and insulin in the treatment of gestational
diabetes: A retrospective, case‐control study. The Review of Diabetic
Studies, 5(2), 95–101.
26. Thacker, S., & Petkewicz, K. (2009). Gestational diabetes mellitus. US
Pharmacist, 34(9), 43–48.
27. Thomaz de Lima, H., Lopes Rosado, E., Ribeiro Neves, P. A., Correa
Monteiro Machado, R., Mello de Oliveira, L., & Saunders, C. (2013).
Systematic review: Nutritional therapy in gestational diabetes
mellitus. Nutricion Hospitalaria, 28(6), 1806–1814.
28. Waheed, S., Malik, F. P., & Mazhar, S. B. (2013). Efficacy of
metformin versus insulin in the management of pregnancy with
diabetes. Journal of the College of Physicians and Surgeons Pakistan,
23(12), 866–869.
29. Zaman, F., Nouhjah, S., Shahbazian, H., Shahbazian, N., Latifi, S. M., &
Jahanshahi, A. (2018). Risk factors of gestational diabetes mellitus
using results of a prospective population‐based study in Iranian
pregnant women. Diabetes & Metabolic Syndrome: Clinical Research &
Reviews
30. Zhu, B., Zhang, L., Fan, Y. Y., Wang, L., Li, X. G., Liu, T., … Zhao, Z. G.
(2016). Metformin versus insulin in gestational diabetes mellitus: A
meta‐analysis of randomized clinical trials. Irish Journal of Medical
Science, 185(2), 371–381.
How to cite this article: Ghomian N, Vahed SHM, Firouz S,
Yaghoubi MA, Mohebbi M, Sahebkar A. The efficacy of
metformin compared with insulin in regulating blood glucose
levels during gestational diabetes mellitus: A randomized
clinical trial. J Cell Physiol. 2018;1–7.
https://doi.org/10.1002/jcp.27238