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ORIGINAL ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 4  |  Page : 394-400  

Impact of treatment with metformin in comparison with insulin in gestational diabetes in libyan population a randomized controlled study


1 Department of Obstetrics and Gynaecology, Faculty of medicine, Benghazi University, Benghazi, Libya
2 Department of Biochemistry, Faculty of medicine, Benghazi University, Benghazi, Libya
3 Department of Genetics, School of Medicine, St. Matthews University, Grand Cayman, Cayman Islands

Date of Submission13-Mar-2021
Date of Acceptance18-May-2021
Date of Web Publication04-Mar-2022

Correspondence Address:
Dr. Jagannadha Rao Peela
Department of Genetics, School of Medicine, School of Medicine, St Matthews University, Leeward 3, Regatta Office Park, KY1-1204, Grand Cayman
Cayman Islands
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpbs.jpbs_168_21

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   Abstract 


Background: The aim of this study was the comparison of the glycemic control and maternal outcomes in women affected with gestational diabetes mellitus (GDM) managed with metformin versus insulin. Materials and Methods: The participants included in this study were 140 women diagnosed with GDM. They were randomized into two groups, women included in the first group were treated with metformin and the women of the second group were managed with insulin. Results: The glycemic control was similar in both the treatment arms and the only noteworthy difference was found in the mean fasting blood glucose, which was significantly higher in the women receiving insulin as compared to the women receiving metformin. There were no substantial differences in the maternal outcome with the use of metformin compared to insulin in women with GDM. Conclusion: The incidence of operative delivery was higher in metformin-treated group, whereas the hospital admission rate was considerably elevated in insulin-treated group.

Keywords: Gestational diabetes mellitus, glycemic control, insulin, metformin


How to cite this article:
Busarira MO, Getlawi OH, Hawda SM, Falgosh SA, Peela JR. Impact of treatment with metformin in comparison with insulin in gestational diabetes in libyan population a randomized controlled study. J Pharm Bioall Sci 2021;13:394-400

How to cite this URL:
Busarira MO, Getlawi OH, Hawda SM, Falgosh SA, Peela JR. Impact of treatment with metformin in comparison with insulin in gestational diabetes in libyan population a randomized controlled study. J Pharm Bioall Sci [serial online] 2021 [cited 2022 Nov 30];13:394-400. Available from: https://www.jpbsonline.org/text.asp?2021/13/4/394/339084




   Introduction Top


Gestational diabetes mellitus (GDM) has a tremendous impact on public health globally, due to the increase in its prevalence in the past few decades owing to an elevated risk of obesity and Type 2 diabetes mellitus.[1],[2] GDM is defined as glucose intolerance in pregnant women without a prior history of hyperglycemia.[3] Several factors such as obesity, polycystic ovary syndrome, higher maternal age, and a family history of Type 2 diabetes mellitus are associated with an increased risk of developing GDM. Although, GDM generally exhibits no symptoms, the incidence of conditions such as depression, preeclampsia, and the rate of operative delivery increases. In women with poor glycemic control, neonates have a higher incidence of hypoglycemia, obesity, jaundice and are also large for gestational age. These babies are also at increased risk of developing Type 2 diabetes mellitus in their later life.[4] Therefore, optimum glycemic control is of paramount importance in the management of GDM to prevent adverse maternal outcomes.[5]

Majority of women diagnosed with GDM are capable of self-regulating their glycemic status by following a healthy diet and regular exercise regimen. In cases of poor glycemic control, insulin is the most recommended treatment for GDM.[6],[7] However, insulin has many disadvantages such as more number of injections and tendency of hypoglycemia resulting in an increase in cost.[8] These disadvantages could have a negative impact on patient compliance. In addition, insulin dosage requires titration based on the individual body mass index (BMI), glycemic control, and lifestyle.[9] In comparison to insulin, oral agents such as metformin and glyburide are advantageous owing to ease of administration and lesser cost, making them better alternatives than insulin with improved compliance,[10] ensuring optimum treatment adherence.[11] Metformin belongs to the class of biguanides which prevent gluconeogenesis in the liver and increase glucose uptake in the peripheral tissues, thereby bringing the blood glucose levels back to normal.[12]

The aim of the present study was the comparison of the glycemic control and maternal outcomes in women affected with GDM managed with metformin versus insulin.


   Materials and Methods Top


Study design and setting

This study was a randomized, double-blind, parallel-group trial to evaluate the maternal outcome of metformin versus insulin treatment in patients with GDM. The patients enrolled for the study were those registered at a clinic specializing in care for diabetes in pregnancy. The follow-up of the enrolled participants was done at any public or private clinic allocated for patient follow-up and service delivery, free of charge. Contact information of the patient and her husband/birth service plan of the patient (public, private) were collected to ensure follow-up. The desired number of cases was selected over a period of 45 days. The participants were followed up once every 15 days up to the gestational period of 37 weeks and once a week thereafter till delivery. The participants were followed up to 48 h postdelivery. All participants were given a data sheet and history was taken from each participant during the first visit. Clinical examination and diagnostic test results were evaluated to ensure that the participants satisfy the selection criteria. The participants were given a serial number and random allocation of the participants was done to the two treatment arms.

Subjects

The total number of participants in this study was 140, diagnosed with GDM and all of them were followed from 28 weeks to 42 weeks and each participant visited approximately nine times during the study period. All participants were residents of Benghazi, Libya aged between 18 and 44 years with the gestational age of 28–32/40 weeks with single fetus diagnosed with GDM with no commencement of treatment. Most of them had clear obstetric history with a parity of 2–5. None of them had prior insulin-dependent diabetes mellitus (IDDM) or non-IDDM (NIDDM) and also did not have extremes of BMI (<18.5, >29.9). None of the participants were diagnosed with any other medical condition and there were no pregnancy-related complications earlier. Since this study was to evaluate monotherapy, patients requiring more than one anti-diabetic agent were excluded from the study.

Clinical assessment

At every follow-up visit, the following parameters were measured: Blood pressure, blood glucose, evidence of urinary tract infections (UTI), proteinuria, renal function, and any medical treatment for hypoglycemia, etc., At the end of the study, i.e., 48 h postdelivery, blood pressure, blood glucose, glycated haemoglobin (Hb), proteinuria, renal function, postpartum bleeding, visual disturbances, medical complications requiring intensive care were evaluated. Maternal glycemic control was the primary outcome and obstetric complications were the secondary outcomes.

Ethical considerations

The participants were explained about the objectives and impact of the study and all the participants submitted a written informed consent.


   Results Top


Baseline characteristics

One hundred and forty participants were enrolled for this study. The median age was 38 years (quartile interval; 32.5–40.0 years) [Figure 1]. The median BMI was 31.2 kg/m2 (Interquartile interval; 29.6–32.6 kg/m2) [Figure 2]. All the participants were either overweight or obese [Figure 3]. The participants were assigned randomly to either the metformin arm or insulin arm. Only 77 cases continued with their starting regimens (55%); 35 (25%) changed from metformin to insulin and 42 (30%) from insulin to metformin [Table 1] and [Figure 4].
Figure 1: Descriptors of age in gestational diabetes mellitus treatment trial

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Figure 2: Descriptors of body mass index in gestational diabetes mellitus treatment trial

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Figure 3: Distribution of obesity among cases in gestational diabetes mellitus treatment trial

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Table 1: Change in treatment plan in gestational diabetes mellitus treatment

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Figure 4: Change in treatment plan in gestational diabetes mellitus treatment trial

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Indices of glycemic control

The median of mean fasting blood glucose (FBG) readings was 115.8 mg/dl (Interquartile interval; 102.1–128.2). The rate of any high FBG (equal or above 105 mg/dl) was 44.3% (N = 62). The median of mean random blood glucose (RBG) readings was 130.1 mg/dl (Interquartile interval; 118.3–145.8) and only ten cases had RBG in a high range (equal or above to 180 mg/dl; 7.1% of cases) [Figure 5] and [Figure 6].
Figure 5: Descriptors of mean fasting blood glucose in gestational diabetes mellitus treatment trial

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Figure 6: Descriptors of mean random blood glucose in gestational diabetes mellitus treatment trial

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The median glycated Hb (HbA1c%) by the end of pregnancy was only 6.00% with Interquartile interval of 6.00% to 7.00% and only 42.1% (N = 59) of the cases had glycated Hb higher than accepted (more than or equal to 6.5%) [Figure 7] and [Figure 8].
Figure 7: Descriptors of haemoglobin A1c% in gestational diabetes mellitus treatment trial

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Figure 8: Distribution of cases in gestational diabetes mellitus treatment trial according to haemoglobin A1c% status

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The glycemic control was similar in both the treatment arms and the only significant difference was found in the mean FBG, which was considerably higher in the women treated with insulin as compared to the women treated with metformin [Table 2].
Table 2: Analysis of glycemic control estimators in treatment groups in gestational diabetes mellitus treatment trial

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Maternal adverse outcomes

The most prevalent adverse maternal event was the cesarean section. UTI, hospital admissions, and high blood pressure ranked second. The median of Mean systolic blood pressure was 118.3 mmHg (Interquartile interval; 115.0–125.0) and the median of Mean diastolic blood pressure (DBP) was 73.3 mmHg (Interquartile interval; 70.0–76.7). Less than quarter of mothers required admission. All mothers exhibited at least one complication [Figure 9].
Figure 9: Percentages of maternal adverse outcomes in gestational diabetes mellitus treatment trial

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The mean DBP was notably higher in women treated with metformin as compared to the women treated with insulin. Some events such as renal function impairment, hospital admissions, antepartum hemorrhage, medical consultations, and complications of surgery were not observed in the metformin-treated group. The incidence of operative delivery was more in metformin-treated group, whereas the hospital admission rate was significantly higher in insulin-treated group [Table 3]. These findings did not change on matching for obesity status [Figure 10] and [Figure 11].
Table 3: Analysis of maternal outcomes in treatment groups in gestational diabetes mellitus treatment trial

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Figure 10: Maternal admissions according to group in obese mothers in gestational diabetes mellitus treatment trial

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Figure 11: Premature labor according to group in obese mothers in gestational diabetes mellitus treatment trial

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Statistical analysis

Cases with change in treatment (n = 63, 45%) were excluded from the analysis. Only cases which continued the initial treatment of GDM were considered in our analysis. Likelihood ratio Chi-square (2 sided) was used to analyze the significance of association between the dependent variable (treatment option) and the categorical outcomes. Fisher exact (1 sided) was reserved for outcomes with expected values that do not fit the requirement of Chi-square test. t-test and Mann-Whitney U-test were used to test the significance of the association of treatment option with numerical variables. Bivariate analysis exhibited no significant differences in population characteristics between groups [Table 4].
Table 4: Analysis of general characteristics in treatment groups in gestational diabetes mellitus treatment trial

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   Discussion Top


There were no substantial maternal outcome differences found with the administration of metformin compared to that of insulin in women with GDM. Mean FPG and RBG were comparable in the two groups making metformin an attractive option compared to insulin for the management of GDM. Metformin, alone or with supplemental insulin, is effective and safe to treat women with GDM who satisfy the criteria for initiating insulin. The route of administration of metformin is oral making it a preferable option to women with GDM.[13],[14] A study comparing metformin and insulin has reported that there was no significant difference between the two groups concerning the method of delivery, reason for cesarean section, birth trauma, Apgar score, weight of the newborn, admission at neonatal intensive care unit and neonatal hypoglycemia. Metformin can significantly improve the sensitivity of liver and peripheral tissue to insulin directly or indirectly resulting in the reduction of output of liver glucose and thereby level of plasma glucose,[15] and it is not associated with major complications or perinatal death.[16] Although metformin can pass through the placenta, it has not been shown to be related to fetal malformations when used in the 1st 3 months of pregnancy.[17] Due to its advantages in terms of economy and convenience, metformin has been increasingly used for treating women with GDM. To comprehend the safety and efficacy of metformin use for the treatment of GDM, we searched several databases for reports of randomized controlled trials which compared insulin and metformin for the management of GDM, and identified 27 randomized controlled trials, comprising 4568 patients, for inclusion in our meta-analysis. Women with GDM have an increased risk of preeclampsia, which may result in complications such as abruption placenta, intrauterine growth retardation, premature birth, and intrauterine death. Twelve studies (n = 2885 patients) were included to analyze the risk of preeclampsia. Our meta-analysis revealed that the risk of preeclampsia reduces with metformin treatment, which is consistent with the observations of a previous review.[18] However, Bao et al., who evaluated the incidence of preeclampsia using an analysis of nine studies concerning 1813 GDM patients, noted that the risk of preeclampsia does not reduce with metformin treatment.[19] The reason for the disparity in our conclusions may be that we have included more studies in our analysis. We analyzed sixteen studies in the incidence of preterm birth in both groups, and the results suggested that metformin does not result in an increased risk of preterm delivery, which is consistent with the results of a previous publication.[20] However, several previous publications noted that metformin led to premature birth.[21],[22] The difference of the above results may be due to the lack of studies included in the two analyses, Balsells et al. included 9 studies,[21] Gui J included 5 studies.[22] However, these two analyses are older and with the gradual development of research, there is evidence suggesting that metformin does not cause an increase in the risk of preterm delivery. These findings support the notion that metformin perhaps is safer and beneficial in the treatment of GDM; however, data on long-term outcomes are still inadequate. Thus, more long-term follow-up studies need to be undertaken.


   Conclusion Top


In the present study, management of gestational diabetes mellitus with metformin versus insulin was compared. Glycemic control and maternal outcomes were studied. There was similar glycemic control with metformin and insulin. Also the maternal outcomes were similar with both treatment protocols. Therefore, it can be concluded that metformin can be used an alternative to insulin for glycemic control in patients with GDM.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care 2007;30 Suppl 2:S141-6.  Back to cited text no. 1
    
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Wikipedia Contributors. Gestational Diabetes. Wikipedia, The Free Encyclopedia; August, 2017.  Back to cited text no. 4
    
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Glueck CJ, Goldenberg N, Streicher P, Wang P. The contentious nature of gestational diabetes: Diet, insulin, glyburide and metformin. Expert Opin Pharmacother 2002;3:1557-68.  Back to cited text no. 6
    
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Nicholson W, Baptiste-Roberts K. Oral hypoglycaemic agents during pregnancy: The evidence for effectiveness and safety. Best Pract Res Clin Obstet Gynaecol 2011;25:51-63.  Back to cited text no. 7
    
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Petry CJ. Gestational diabetes: Risk factors and recent advances in its genetics and treatment. Br J Nutr 2010;104:775-87.  Back to cited text no. 9
    
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Maymone AC, Baillargeon JP, Ménard J, Ardilouze JL. Oral hypoglycemic agents for gestational diabetes mellitus? Expert Opin Drug Saf 2011;10:227-38.  Back to cited text no. 10
    
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Conway DL, Gonzales O, Skiver D. Use of glyburide for the treatment of gestational diabetes: The San Antonio experience. J Matern Fetal Neonatal Med 2004;15:51-5.  Back to cited text no. 11
    
12.
Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol Endocrinol Metab 2006;291:E182-9.  Back to cited text no. 12
    
13.
Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: A systematic review. Obstet Gynecol 2009;113:193-205.  Back to cited text no. 13
    
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Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003-15.  Back to cited text no. 14
    
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Ghomian N, Vahed SH, 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 2019;234:4695-701.  Back to cited text no. 15
    
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Cosson E, Carbillon L, Valensi P. High fasting plasma glucose during early pregnancy: A review about early gestational diabetes mellitus. J Diabetes Res 2017;2017:8921712.  Back to cited text no. 16
    
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Priya G, Kalra S. Metformin in the management of diabetes during pregnancy and lactation. Drugs Context 2018;7:212523.  Back to cited text no. 17
    
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Bergman JE, Lutke LR, Gans RO, Addor MC, Barisic I, Cavero-Carbonell C, et al. Beta-Blocker use in pregnancy and risk of specific congenital anomalies: A European case-malformed control study. Drug Saf 2018;41:415-27.  Back to cited text no. 18
    
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Bao LX, Shi WT, Han YX. Metformin versus insulin for gestational diabetes: A systematic review and meta-analysis. J Matern Fetal Neonatal Med 2019;26:1-13. doi: 10.1080/14767058.2019.1670804.  Back to cited text no. 19
    
20.
Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L. Short and long term outcomes of metformin compared with insulin alone in pregnancy: A systematic review and meta-analysis. Diabet Med 2017;34:27-36.  Back to cited text no. 20
    
21.
Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: A systematic review and meta-analysis. BMJ 2015;70:305-7.   Back to cited text no. 21
    
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Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: A meta-analysis. PLoS One 2013;8:e64585.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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