Treatment outcomes and safety of metformin versus insulin in gestational diabetes mellitus: A systematic review and meta-analysis

ABSTRACT

Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse maternal and neonatal outcomes. While insulin remains the traditional treatment, metformin has emerged as a potential alternative due to its ease of use and favorable metabolic effects. This systematic review and meta-analysis aimed to compare the efficacy and safety of metformin versus insulin in the management of GDM. This review was registered with International Prospective Register of Systematic Reviews (PROSPERO) (CRD42025644196) and conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed using PubMed and Google Scholar for studies published between 2020 and 2025. Eligible studies were randomized controlled trials (RCTs) comparing metformin and insulin in pregnant women diagnosed with GDM and reporting relevant maternal or neonatal outcomes. Data screening and extraction were performed using Rayyan software. Statistical analysis was conducted using Stata version 17. Pooled effect sizes were calculated using a random-effects model. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess continuous and dichotomous outcomes, respectively. Heterogeneity was evaluated using the I² statistic and Cochran’s Q test. Publication bias was assessed using funnel plots and Egger’s test. Twenty-two RCTs met the inclusion criteria. Metformin achieved glycemic control comparable to insulin, with a pooled SMD for fasting blood glucose (FBG) of –0.29 (95% CI: –0.55 to –0.03; P = 0.03). No significant difference was observed in glycated hemoglobin (HbA1c) levels (SMD = –0.26; 95% CI: –0.75 to 0.23; P = 0.30). Metformin was associated with significantly less maternal weight gain and a reduced risk of neonatal hypoglycemia (OR = 2.72; 95% CI: 1.02–7.26; P = 0.05). The incidence of pre-eclampsia and hypertensive disorders was similar between groups. Patient satisfaction was consistently higher in the metformin group, with most participants preferring it over insulin. Funnel plots and Egger’s test indicated no significant publication bias. Metformin is a safe and effective alternative to insulin for the management of GDM in most pregnant women, offering comparable glycemic control, reduced maternal weight gain, lower risk of neonatal hypoglycemia, and higher patient acceptability. While some patients may still require insulin supplementation, metformin represents a valuable first-line option, especially in settings where injection therapy is less feasible or poorly tolerated.

Introduction

Gestational diabetes mellitus [GDM] has been described as any degree of glucose intolerance with onset or first recognition during pregnancy for many years.[1] It is a result of a combination of genetic predisposition, epigenetic, and environmental influences.[2] GDM is a complication of pregnancy that affects 12% to 18% of pregnancies.[3] Its diagnosis is mostly dependent on the results of the oral glucose tolerance test.[4] Suboptimal glycemic management can lead to unfavorable outcomes for both the mother and the baby during pregnancy and birth,[3,5] which can lead to maternal complications such as weight gain, pre-eclampsia, and cesarean delivery, and neonatal complications such as macrosomia, shoulder dystocia, and neonatal hypoglycemia.[6] Therefore, glycemic control is the cornerstone of GDM management. The primary approach of treatment is lifestyle intervention, including medical nutrition therapy and exercise.

Introduction of medication is considered when a lifestyle approach does not achieve glycemic control.[7] Once lifestyle modification is no longer adequate in the management of glycemic control, medications such as subcutaneous insulin therapy have been considered the gold standard for the management of GDM.[7,8] However, insulin has disadvantages that can affect patients’ compliance with it, as it includes maternal increased appetite leading to weight gain, risk of hypoglycemia, and multiple daily injections.[9] Detailed guidance for dose changes of insulin is, therefore, crucial to ensure the safe self-administration of insulin.[7] On the other hand, one common alternative to insulin is metformin, as it has an excellent efficacy in terms of weight loss, good tolerance, and a reasonable price. However, metformin has its own disadvantages as well, as it can penetrate the placenta and could affect fetal physiology.[6]

Therefore, we performed this updated meta-analysis as a comparison between metformin and insulin outcomes in the treatment of GDM. The objective of our study is to assess the efficacy and safety of metformin vs insulin in the management of GDM. Addressing this particular issue is important due to the increase in metformin management in the management of GDM worldwide.

Methodology

Literature search

This systematic review was registered in PROSPERO (ID: CRD42025644196) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive electronic search was performed across international databases, including PubMed and Google Scholar. The search strategy utilized a range of keywords such as: “gestational diabetes,” “pregnancy diabetes mellitus,” “GDM,” “Metformin,” “Metformin Hydrochloride,” “oral hypoglycemic agents,” “insulin,” “insulin therapy,” “glycemic control,” “blood glucose,” and “pregnancy outcomes.” A detailed description of the full search strategy is provided in Figure 1.

Figure 1.

PRISMA Flow Diagram for the included studies. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Inclusion and exclusion criteria

Inclusion criteria: Studies were considered eligible for inclusion if they met the following criteria: (1) Conducted on pregnant women diagnosed with GDM. (2) Evaluated treatment with metformin, either as monotherapy or in combination with supplemental insulin, compared to insulin as the primary treatment. (3) Reported at least one of the following maternal or neonatal outcomes: weight gain, cesarean section rate, pre-eclampsia, glycemic control, birth weight, macrosomia, preterm birth, or neonatal hypoglycemia. (4) Employed a randomized controlled trial (RCT) design and were published in peer-reviewed journals. (5) The studies must have been published in English between the years 2020 and 2025. Exclusion criteria: Studies were excluded if they (1) included populations with pre-gestational diabetes. (2) Did not report outcomes pertinent to the management of GDM.

Data extraction, screening, and statistical analysis

Using the defined inclusion and exclusion criteria, the Rayyan software for systematic reviews was used to extract and screen the data. Search results were independently filtered by two reviewers, with a third reviewer resolving any disagreements. Relevant data were then extracted using Rayyan templates and organized into tables. Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) was used to analyze all the included articles after the screening process was complete.

Data analysis

All statistical analyses were conducted using Stata version 17 [StataCorp LLC, College Station, TX, USA]. Descriptive data from the included studies were first extracted and summarized using means, standard deviations (SDs), and proportions, as appropriate. Quantitative synthesis was performed using a random-effects model [DerSimonian and Laird method] to account for between-study variability. Effect sizes were presented as standardized mean differences [SMDs] with 95% confidence intervals [CIs] for continuous outcomes [e.g. fasting blood glucose and HbA1c] and as odds ratios [ORs] with 95% CIs for dichotomous outcomes [e.g. neonatal hypoglycemia]. Heterogeneity across studies was assessed using Cochran’s Q statistic and quantified with the I² index, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. A P value < 0.10 for the Q-test was considered indicative of significant heterogeneity.

For studies reporting glycemic control outcomes, pooled SMDs were calculated for fasting blood glucose [FBG] and glycated hemoglobin (HbA1c) levels. The z-test was used to determine the overall effect size significance. Similarly, for neonatal hypoglycemia, ORs were synthesized under a random-effects restricted maximum likelihood [REML] model. Publication bias was assessed visually using funnel plots for the primary outcomes and statistically using Egger’s regression test and Begg’s rank correlation test, where a P value > 0.05 indicated no significant small-study effect. Sensitivity analyses were further conducted by sequentially excluding each study to evaluate the stability of pooled estimates.

Study designs and settings

Most studies were RCTs, with some adopting open-label or double-blind methodologies. For instance, Fidelma Dunne et al.[10] conducted a phase 3, double-blind, placebo-controlled superiority trial, while Picón-Cesar et al.[11] and Banerjee et al.[12] used open-label comparative designs. Huhtala et al.[13] and Huhtala et al.[14] included long-term follow-up components, providing insights into outcomes beyond pregnancy. The studies were conducted in various regions, including China, Ireland, Finland, India, Iraq, Egypt, Pakistan, Spain, Canada, the United States, and Libya, reflecting a broad international interest in optimizing GDM treatment.

Sample sizes and population

Sample sizes showed high variances, ranging from small cohorts like Pandey et al.[15] with 44 participants, to large multicenter trials such as Boggess et al.[16] with 794 participants. Most studies had balanced group allocations, typically comparing metformin and insulin directly, while a few included placebo arms or adjunct therapies. Feig et al.[17] and Fidelma Dunne et al.[10] included placebo groups to assess metformin’s additive effects. Several studies stratified participants by dosage or treatment response, such as Al-Hayani et al.,[18] which analyzed metformin subgroups based on daily dosage.

Interventions and glycemic targets

Metformin was administered in varying dosages, often starting at 500 to 850 mg/day and up to 2000–2550 mg/day depending on glycemic control. Insulin regimens included basal-bolus strategies using detemir and aspart, with doses adjusted based on body weight and glucose monitoring. Glycemic targets were generally consistent across studies, aiming for fasting glucose.

Risk of bias and methodological quality

Risk of bias differs across studies. High-quality trials like Boggess et al.[16] and Fidelma Dunne et al.[10] used centralized randomization, double-blinding, and intention-to-treat analyses, with sufficient follow-up, which reached 95%. In contrast, smaller or single-center studies such as Mir et al.[19] and Pandey et al.[15] had a moderate risk due to a lack of blinding, limited outcome reporting, or small sample sizes. Huhtala et al.[13] showed bias due to missing outcome data and changes in diagnostic criteria over time.

Efficacy outcomes

Glycemic control

Across most studies, metformin achieved glycemic control comparable to, or better than, insulin. Ahmed et al.[20] and Al-Hayani et al.[18] reported significantly lower fasting and postprandial glucose levels in women treated with metformin compared to insulin (P < 0.05). Similarly, Huhtala et al.[13] and Huhtala et al.[14] found no significant differences in HbA1c levels between groups, indicating the non-inferiority of metformin. In addition, Pandey et al.,[15] using continuous glucose monitoring metrics such as Time-in-Range (TIR), confirmed metformin’s effectiveness in maintaining optimal glucose levels throughout pregnancy [Table 1].

Table 1.

Glycemic control outcomes

Study	Glycemic Control Measure	Metformin Outcome	Insulin Outcome	Significance
Ahmed et al.[20]	HbA1c	5.13±0.34	5.43±0.37	Metformin superior
Al-Hayani et al.[18]	FBG and PPG	Lower across all doses	Higher than metformin	P<0.05
Huhtala et al.[14]	HbA1c at OGTT and 36 weeks	5.5%	5.5%	No difference
Jahanshahi et al.[22]	HbA1c at 6 weeks postpartum	4.45	4.51	No difference
Pandey et al.[15]	CGM metrics [TIR, GMI]	Non-inferior	Not directly compared	Moderate evidence
Busarira et al.[25]	FBG, RBG, HbA1c	FBG lower [103.6 mg/dL], HbA1c=6%	FBG higher [112.6 mg/dL], HbA1c=6%	FBG significant [P=0.003]

Need for insulin supplementation

Although metformin was effective for most patients, a subset required supplemental insulin to achieve target glucose levels. Picón-Cesar et al.[11] observed that 21.3% of women needed additional insulin, while Fidelma Dunne et al.[10] reported a higher proportion of 38.4%. Similar findings were described by Huhtala et al.[14] and Nuha et al.,[21] who reported supplementation rates between 23% and 30% [Table 2].

Table 2.

Need for insulin supplementation

Study	Metformin Group Requiring Insulin	Notes
Picón-Cesar et al.[11]	21.3%	Adjunct insulin due to poor control or intolerance
Fidelma Dunne et al.[10]	38.4%	Higher need for insulin in the metformin group
Huhtala et al.[14]	23 patients	No significant difference in glycemic control
Nuha et al.[21]	30%	Higher BMI and glucose levels linked to insulin need
Al Hayani et al.[18]	4 women on 2000 mg/day	Subgroup analysis

BMI: Body mass index

Safety outcomes

Maternal weight gain

Metformin was consistently associated with less maternal weight gain compared to insulin. Ahmed et al.[20] reported a mean gain of 6.98 ± 0.68 kg in the metformin group versus 9.37 ± 1.60 kg in the insulin group (P < 0.001). Similarly, Picón-Cesar et al.[11] noted lower weight gain (1.35 ± 3.21 kg vs. 3.87 ± 3.50 kg). Studies by Banerjee et al.[12] and Jahanshahi et al.[22] also showed lower postpartum body weight and BMI among women treated with metformin, confirming its favorable metabolic profile [Table 3].

Table 3.

Maternal safety outcomes

Study	Weight Gain [kg]	Pre-eclampsia/Hypertension	Significance
Ahmed et al.[20]	6.98±0.68 [Metformin] vs. 9.37±1.60 [Insulin]	6.9% vs. 5.1%	Weight gain significant
Picón-Cesar et al.[11]	1.35±3.21 vs. 3.87±3.50	17.5% vs. 13.6%	Weight gain significant
Banerjee et al.[12]	6.5 vs. 7.12	14 vs. 29 cases	Hypertension higher in insulin
Jahanshahi et al.[22]	Postpartum weight: 67.14 vs. 70.32	Not reported	Significant difference
Paavilainen et al.[24]	-1.3 kg with metformin	6.5% vs. 8.2%	Weight gain significant

Pre-eclampsia and hypertensive disorders

The overall incidence of pre-eclampsia and hypertensive disorders was similar between the two treatment groups. Dasari et al.[23] and Ahmed et al.[20] reported no statistically significant differences, while Picón-Cesar et al.[11] found slightly higher rates in the metformin group (17.5%) compared with insulin (13.6%), though without statistical significance. Paavilainen et al.[24] also observed some differences (6.5% vs. 8.2%, P = 0.76). These results indicate that metformin and insulin have comparable maternal safety issues concerning hypertensive complications.

Neonatal outcomes

Neonatal outcomes were widely comparable between groups. Most studies reported similar or slightly lower mean birth weights in infants born to metformin-treated mothers. Ahmed et al.[20] found a statistically significant difference (3410 g vs. 3649 g, P < 0.001), while Picón-Cesar et al.[11] and Huhtala et al.[14] found no significant difference. Significantly, neonatal hypoglycemia was reported less frequently among infants exposed to metformin. Jahanshahi et al.[22] reported rates of 6.7% with metformin versus 26.7% with insulin (P = 0.038), and Mir et al.[19] found a similar pattern (0.8% vs. 23.3%, P < 0.05). Boggess et al.[16] concluded comparable Neonatal Intensive Care Unit (NICU) admissions for hypoglycemia (3.3% vs. 3.8%), supporting metformin’s safety in neonatal outcomes [Table 4].

Table 4.

Neonatal safety outcomes

Study	Birth Weight [g]	Hypoglycemia Incidence	Significance
Ahmed et al.[20]	3410 vs. 3649	12.8% vs. 24.0%	Both significant
Picón-Cesar et al.[11]	3171 vs. 3233	16.3% vs. 22.3%	Hypoglycemia lower in metformin
Jahanshahi et al.[22]	Not reported	6.7% vs. 26.7%	P=0.038
Mir et al.[19]	Not reported	0.8% vs. 23.3%	P<0.05
Boggess et al.[16]	Lower odds of LGA infants	NICU admissions: 3.3% vs. 3.8%	No difference

LGA=Large for gestational age, NICU=Neonatal intensive care unit

Patient satisfaction and preferences

Patient satisfaction was higher with metformin over insulin. The majority of participants expressed higher satisfaction with metformin due to its ease of use, oral administration, and fewer injections. Dasari et al.[23] reported that 80% of women preferred metformin and would choose it again in future pregnancies. Similarly, Picón-Cesar et al.[11] found that 70.3% of metformin users expressed willingness to reuse the drug compared to only 32.2% among insulin users. This reflects metformin’s favorable patient acceptability and its potential to enhance adherence in GDM management.

BMI: Body mass index

This meta-analysis figure shows that metformin achieved glycemic control comparable to insulin therapy. For FBG, the pooled SMD [SMD = –0.29; 95% CI: –0.55 to –0.03; P = 0.03] favored metformin, indicating slightly lower FBG levels. Regarding HbA1c, no significant difference was observed between groups [SMD = –0.26; 95% CI: –0.75 to 0.23; P = 0.30], with moderate heterogeneity [I² = 85%]. The overall pooled estimate [SMD = –0.28; 95% CI: –0.56 to 0.00; P = 0.05] suggests that metformin is non-inferior to insulin for glycemic control in GDM [Figure 2].

Figure 2.

Forest Plot for glycemic control among Metformin vs. Insulin therapy for GDM: Standardized mean difference with 95% CI. GDM: Gestational diabetes mellitus; CI: Confidence interval

The funnel plot reveals a generally symmetrical distribution of studies around the pooled effect estimate, showing no significant publication bias in the analysis comparing metformin and insulin for glycemic control in GDM. The even spread of studies within the pseudo 95% confidence limits supports the reliability and robustness of the pooled results [Figure 3].

Figure 3.

Funnel Plot for Publication Bias in Studies Comparing Metformin and Insulin for Glycemic Control in GDM. GDM: Gestational diabetes mellitus

The forest plot illustrates that neonates born to mothers treated with metformin had a lower risk of hypoglycemia compared to those whose mothers received insulin. The pooled OR [OR = 2.72; 95% CI: 1.02–7.26; P = 0.05] favors metformin, with a statistically significant reduction in neonatal hypoglycemia. Despite moderate heterogeneity among studies [I² =80.9%, P = 0.01], the overall trend supports metformin’s safety advantage regarding neonatal glucose stability [Figure 4].

Figure 4.

Forest Plot for Neonatal hypoglycemia among Metformin vs. Insulin therapy for GDM: Odds Ratio [OR] with 95% CI. GDM: Gestational diabetes mellitus; CI: Confidence interval

The funnel plot appears asymmetrical, indicating some significant publication bias among studies assessing neonatal hypoglycemia between metformin and insulin groups. The distribution of studies around the pooled effect estimate with an empty lower base suggests that the observed results are somewhat exposed to publication bias or data insufficiency [Figure 5].

Figure 5.

Funnel Plot for Publication Bias in Studies Comparing Metformin and Insulin for Neonatal Hypoglycemia in GDM. GDM: Gestational diabetes mellitus

Discussion

This systematic review included the results of 22 studies comparing the efficacy and safety of metformin versus insulin in managing GDM. Generally, the review revealed that metformin was a clinically effective and safe alternative to insulin in most pregnant women with GDM, with additional benefits in maternal weight control, neonatal outcomes, and patient satisfaction.

Regarding glycemic control, metformin demonstrated comparable glycemic control to insulin, as indicated by FBG levels, HbA1c values, and TIR data from continuous glucose monitoring. Several included studies, such as those by Ahmed et al.[20] and Huhtala et al.[13] reported similar efficacy in achieving target glucose levels, indicating the non-inferiority of metformin. These results match with previous trials, including the landmark MiG trial, which showed no significant differences in glycemic parameters between metformin and insulin-treated groups.[26] Furthermore, the meta-analysis component of this review confirmed a statistically significant, though modest, reduction in FBG levels in the metformin group. These findings simulate the results of a 2017 Cochrane review, which also concluded that metformin achieved similar glycemic control to insulin without an increased risk of adverse maternal or neonatal outcomes.[27]

Considering insulin supplementation, a considerable proportion of women initiated on metformin required supplemental insulin to maintain adequate glycemic control. The need for insulin supplementation, reported in studies such as those by Fidelma Dunne et al.[10] and Picón-Cesar et al.,[11] varied but remained within expected clinical parameters. These findings reflect that while metformin is effective for many, insulin remains essential for those with more severe dysglycemia or higher insulin resistance, particularly in late gestation or with elevated BMI. Previous reviews have similarly indicated that up to 40% of women started on metformin may require insulin augmentation,[28] underscoring the importance of individualized treatment plans and close glucose monitoring.

As for safety, maternal weight gain and metabolic profile were assessed. A consistent and clinically meaningful finding across the studies was the lower maternal weight gain associated with metformin use. Studies by Ahmed et al.,[20] Banerjee et al.,[12] and Picón-Cesar et al.[11] reported significantly reduced gestational weight gain in the metformin group. This is not surprising given metformin’s known mechanism of action, reducing hepatic gluconeogenesis and improving peripheral insulin sensitivity, which likely reduces anabolic fat deposition seen with exogenous insulin. These findings are also supported by earlier work, including the MiG trial,[26] which documented similar outcomes in terms of maternal weight gain, making metformin mainly appealing for overweight or obese women with GDM.

Considering pre-eclampsia and hypertensive disorders, the studies reviewed reported no significant differences in the incidence of pre-eclampsia or gestational hypertension between the two groups, consistent with the existing literature. Previous studies[29,30] found similar rates of hypertensive complications regardless of treatment modality. Although some studies reported slightly higher or lower percentages, these were not statistically significant, with no added risk or benefit of either treatment in this regard. Similar conclusions were drawn in a large retrospective study by Butalia et al., which found no increased risk of hypertensive complications with metformin compared to insulin.[31]

One of the most compelling findings of this review is the reduced incidence of neonatal hypoglycemia associated with metformin. Multiple studies, including Jahanshahi et al.[22] and Mir et al.,[19] found significantly lower rates of neonatal hypoglycemia in the metformin group. This is reasonable, as insulin crosses the placenta minimally, whereas insulin-induced maternal hyperglycemia can cause fetal hyperinsulinemia, increasing the risk of postnatal hypoglycemia.

The meta-analysis confirmed this trend, showing a statistically significant reduction in neonatal hypoglycemia with metformin. This advantage could translate into lower NICU admission rates, shorter hospital stays, and reduced stress for mothers and neonates. These findings are in line with previous analyses, including a systematic review by Tarry-Adkins et al., which concluded that metformin-treated neonates had fewer metabolic complications.[32]

Finally, the patient-centered outcomes (patient satisfaction) revealed a strong preference for metformin over insulin. Women favored oral metformin due to ease of administration, avoidance of injections, and lower burden of glucose monitoring. Studies such as Dasari et al.[23] and Picón-Cesar et al.[11] consistently reported higher satisfaction scores and future willingness to reuse metformin among participants. Patient preference plays a vital role in GDM management, especially in resource-limited settings where insulin availability, injection compliance, and monitoring infrastructure may be constrained. These results align with findings from previous work,[33] who reported that high acceptability was a key factor in the success of metformin-based regimens.

Limitations of the included studies

While the overall quality of evidence was high, a few studies showed methodological limitations, such as a lack of blinding, small sample sizes, and incomplete follow-up. These factors could introduce performance and detection biases. However, the consistency of findings across different populations and study designs strengthens the overall conclusions of this review.

Conclusions and Recommendations

This systematic review and meta-analysis provide strong evidence supporting the clinical use of metformin as an effective and safe alternative to insulin in the management of GDM. Metformin showed comparable efficacy in reaching glycemic control, as evidenced by FBG and HbA1c levels, while offering additional benefits such as reduced maternal weight gain, a lower incidence of neonatal hypoglycemia, and improved patient satisfaction due to its oral administration and ease of use. Based on the findings of this review, we recommend that metformin be considered a first-line pharmacologic agent in the treatment of GDM for women who are unable or unwilling to initiate insulin therapy, provided there are no contraindications. Clinicians should closely monitor treatment response and be prepared to introduce insulin if metformin monotherapy does not achieve adequate glycemic targets.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.