HAMBURG, Germany — 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 JAMA.
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.”
The trial was funded by the Health Review Board (HRB) of Ireland, coordinated by the HRB-Clinical Research Facility Galway, and sponsored by the University of Galway, Ireland. Metformin and matched placebo were provided by Merck Healthcare KGaA, Darmstadt, Germany (operating as EMD Serono in the US), and blood glucose monitoring strips were provided by Ascensia.
Dunne reported nonfinancial support from Merck and matched placebo and nonfinancial support from Ascensia blood glucose–monitoring equipment during the conduct of the study. Benhalima receives research funds from Flemish Research Fund, study medication from Novo Nordisk, and devices and unrestricted grants from Medtronic and Dexcom.
JAMA. Published online October 3, 2023. Full text
Miriam E. Tucker is a freelance journalist based in the Washington, DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.
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