Initiating metformin treatment at gestational diabetes diagnosis was associated with improved glycemic control and reduced gestational weight gain found the results of a randomized, placebo-controlled trial.

Overall, the trial's primary outcome, a composite of insulin initiation or a fasting glucose level ≥ 5.1 mmol/L (92 mg/dL) at gestation weeks 32 or 38, did not differ between women with gestational diabetes randomly assigned to either placebo or metformin. However, women taking metformin were significantly less likely to require insulin and had significantly lower fasting blood glucose levels at weeks 32 and 38.

"With a composite outcome it's more difficult to find a positive result…So, although the primary composite outcome was not positive, the components of the primary outcome that are clinically meaningful were positive," lead study author Fidelma Dunne, PhD, professor and endocrine consultant at the University of Galway, Ireland, told Medscape Medical News.

There were no differences in maternal or neonatal morbidities, but there was a nonsignificant increase in small for gestational age (SGA), a finding that has been seen in some but not all previous studies of metformin use in gestational diabetes.

Dunne presented the findings on October 3 at the annual meeting of the European Association for the Study of Diabetes (EASD), which were simultaneously published in the Journal of the American Medical Association.

Current recommendations from the United Kingdom's National Institute for Health and Care Excellence say metformin is a suitable first-line therapy for gestational diabetes. However, both the American Diabetes Association and the Society of Maternal-Fetal Medicine do not, particularly for pregnancies with hypertension or preeclampsia or in those who are at risk for intrauterine growth restriction.

"Gestational diabetes is now reaching epidemic proportions. And of course, the vast majority of these women are in low- and middle-income countries where insulin might not be available, or the storage may not allow it to be used effectively. If you have a medication that in the majority of women is safe and effective it may actually help a lot of women in [those regions]," Dunne said.

Moreover, she noted, "women with gestational diabetes are testing their sugar with finger pricks four to seven times per day and we ask them to take insulin one to four times a day. So if you can relieve any of that pain related to treatment of their condition than that is benefit for the women as well."

Asked to comment, Katrien Benhalima, MD, PhD, of University Hospital Gasthuisberg, KU Leuven, Belgium, told Medscape Medical News, "I think it's an interesting study because they investigated something novel, to initiate immediately metformin or placebo. Normally what we do with gestational diabetes is once we get the diagnosis, we treat them with lifestyle, and if that's insufficient then we start with medical therapy. So this is a novel approach."

She also agreed with Dunne that the lack of significance for the primary outcome "isn't an issue of power but it is a composite outcome. If you look at the individual outcomes, as can be expected, the women taking metformin had less need for insulin treatment."

But, Benhalima said, the study still leaves open the SGA issue. "It wasn't significant, but it's still something we are worried about in the sense that we feel we need more data, especially in the long-term for the offspring health. You really need to follow them for ten years or longer to see an effect."

So for now, Benhalima said that she wouldn't use metformin as a first-line treatment for gestational diabetes. "Normally, if lifestyle isn't enough we will still start insulin. Another issue is why would you offer everybody medical treatment when pregnancy outcomes can be met with lifestyle alone?"

Then again, she added, "of course metformin is easier than an injection. Treatment satisfaction is improved, and the cost is less."

Primary Outcome Didn't Differ, but Study Findings Point Toward Metformin Benefit 

The double-blind, placebo-controlled trial was conducted at two sites in Ireland, with 510 individuals (535 gestational diabetes pregnancies) enrolled between June 2017 and September 2022. In addition to usual care, they were randomly assigned 1:1 to either placebo or metformin (maximum 2500 mg) at the time of gestational diabetes diagnosis and continued until delivery.

• The primary outcome, a composite of insulin initiation or a fasting glucose ≥ 5.1 mmol/L at gestation weeks 32 or 38, did not differ significantly between the two groups, with risk ratio 0.89 (P = 0.13).

• Insulin initiation occurred in 38.4% of the metformin and 51.1% of the placebo groups (relative risk, 0.75, P = .004). The amount of insulin required at the last assessment prior to delivery did not differ between the two groups (P = .17).

• Mean fasting glucose was significantly lower with metformin vs placebo at gestational week 32 (4.9 vs. 5.0 mmol/L; P = .03) and at gestational week 38 (4.5 vs 4.7 mmol/L; P < .001).

• On average, those in the metformin group gained less weight between randomization and delivery (0.8 kg vs 2.0 kg; P = .003).

• Gestational week at delivery didn't differ between the groups, both 39.1 weeks, nor did preterm births prior to 37 weeks' gestation (9.2% metformin vs 6.5% placebo; P = .33) or any other pregnancy-related complications.

• More participants in the metformin group said that they would choose the drug compared with placebo (76.2% vs 67.1%, P = .04).

• Mean birth weight was lower in the metformin group compared with placebo, 3393 g vs 3506 g (P = .005), with fewer weighing > 4000 g (7.6% vs 14.8%; P= .02) or being large for gestational age, ie, above the 90th percentile (6.5% vs 14.9%; P = .003).

• Proportions of offspring that were SGA (less than 10th percentile) were 5.7% in the metformin group vs 2.7% with placebo (P = .13).

• There were no other significant differences in neonatal variables.

Dunne told Medscape Medical News that her group has recently received funding for long-term follow-up of the SGA offspring. "As other papers have pointed out, if there's any hint of SGA that's really important to follow up. So we're now beginning our longitudinal follow up of the mother and infants to see if the small number that were SGA will in fact turn out to have an increase in body-mass index and weight in their childhood and adolescent years."

JAMA. Published online October 3, 2023. Full text




October 3, 2023

Early Metformin in Gestational DiabetesA Randomized Clinical Trial

Fidelma Dunne, PhD1,2,3Christine Newman, MD1,2,3Alberto Alvarez-Iglesias, PhD2; et alJohn Ferguson, PhD2Andrew Smyth, PhD1,2,3Marie Browne, PhD2Paula O’Shea, PhD1Declan Devane, PhD1,9Paddy Gillespie, PhD7Delia Bogdanet, PhD1,2,4Oratile Kgosidialwa, MD1,5Aoife Egan, PhD1,8Yvonne Finn, MD1,2,3Geraldine Gaffney, MD1,2,3Aftab Khattak, MD2Derek O’Keeffe, PhD1,2,3Aaron Liew, PhD1,6Martin O’Donnell, PhD1,2,3

Key Points


Does early metformin initiation improve glycemic control and reduce insulin use in pregnant individuals with gestational diabetes?


 In this randomized clinical trial, the composite outcome of insulin initiation and a fasting glucose level of 5.1 mmol/L (92 mg/dL) or greater at gestation weeks 32 or 38 was not significantly different between groups. Secondary outcomes of maternal glycaemic control, weight gain, and infant size were lower in the metformin group. There was no difference in maternal or neonatal morbidities.


Early metformin initiation did not reduce the occurrence of the combination of a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38 or insulin initiation. Ongoing review of rates of small for gestational age should continue when using metformin.




Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain.


To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38.

Design, Setting, and Participants  

Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks’ postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria.


Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care.

Main Outcomes And Measures  

The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38.


Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, −6.9% [95% CI, −15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7.

Conclusion and relevance  

Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials.

Trial Registration Identifier: NCT02980276; EudraCT: 2016-001644-19


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From the article


This randomized clinical trial did not confirm statistical superiority of early metformin over placebo for the primary outcome, a composite of insulin initiation or a fasting blood glucose level of 5.1 mmol/L or greater at gestational week 32 or 38 between groups.

This trial was not powered to establish safety of metformin for individual secondary outcome analyses, and therefore, lack of statistical significance should not be interpreted as evidence of safety.

The mixed results of the prespecified secondary outcomes suggest areas of focus for future research, including some of the secondary neonatal outcomes.

The decreased proportion of large for gestational age infants or infants weighing more than 4000 g in participants randomized to early metformin is consistent with previous clinical trials.13,14,16 Minimizing excessive intrauterine growth reduces increased risks of diabetes, obesity, and hypertension in adulthood.7,23,24 

However, there was an increase in the proportion of infants weighing less than 2500 g or small for gestational age (<10th percentile). This is important in view of the effect of metformin on the mammalian target of rapamycin pathway, which regulates placenta amino acid transport and may contribute to a reduction in lean body mass.

In addition, the decrease in crown-heel length in the metformin group (although within the normal range), which remained significant after adjustment for infant sex and maternal height and weight, requires ongoing careful evaluation. Future longitudinal follow-up is required as this observation in crown-heel length may reflect an adverse effect on lean body mass, which may have a potential for long-term adverse consequence in terms of future adiposity.

Follow-up in the medium and long term is essential to document ongoing implications for child weight and size of metformin-exposed offspring as a previous systematic review has identified overweight or obesity in metformin-exposed children.25

In addition, the findings of this study support benefits of metformin on maternal weight gain, which has been reported in previous clinical trials.13,14,16 Lower weight gain in the metformin group is likely to be due to less insulin use and a direct effect of metformin on food intake.

At randomization, half of participants in this trial had a baseline BMI greater than 30, a level at which minimization of excess weight gain is desirable. Prior studies report significant associations of gestational glycemic control and weight gain with future risk of diabetes and cardiovascular disease.5,6,26,27 Medium- and long-term maternal follow-up of this cohort has begun to assess if early use of metformin has long-term maternal cardio-metabolic benefits.

The proportion of participants requiring insulin in the metformin group was lower than observed in metformin-exposed women in the MiG trial (46.3%)14; this likely reflects the ethnic and BMI differences between the trials as MiG enrolled a broader ethnic group with a greater mean BMI than EMERGE.14 In addition, participants randomized in EMERGE had a gestational diabetes diagnosis based on World Health Organization (WHO) 2013 criteria, which are lower than the criteria used in the MiG trial.

Although metformin is considered a suitable first-line therapy by National Institute for Health and Care Excellence guideline recommendations,24 the American Diabetes Association does not consider metformin as first-line therapy, particularly in pregnant individuals with hypertension or preeclampsia or those at risk for intrauterine growth restriction.10

This trial has several strengths as a large double-blind placebo-controlled trial of early metformin in pregnant individuals with gestational diabetes based on WHO 2013 criteria. Participants across all BMI categories were included, and 50% of participants had a BMI of less than 30, a participant category that has not been well-represented in other gestational diabetes clinical trials. Based on this spread of BMI across all categories, the results of this trial may have greater generalizability. Despite the COVID-19 pandemic, there was low attrition and high adherence to treatment allocation, and 526 (98%) pregnancies are available for the primary outcome.


Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials.