Reference: BMJ. 2021 Sep 22;374:n2103
Metformin is sometimes called a “miracle drug” with benefits for multiple conditions that we don’t fully understand. Published preliminary evidence with animal data suggested that it might be useful in the management of preeclampsia in humans. Researchers from South Africa and Australia recently published data from a trial that they report provides “proof of concept that treatment of preterm preeclampsia is possible”.
Before this trial, the researchers conducted a pharmacokinetic open-label study measuring levels of extended release metformin on women with preterm pre-eclampsia. The trial we are considering today looked at 180 pregnancies between 26 and 37 weeks of gestation complicated by pre-eclampsia, defined as hypertension plus >300 mg protein/24-hour period. The study population was considered high risk, with a 53% rate of hypertension in patients for whom this was not the first pregnancy and an approximately 20% risk of HIV-positivity.
Patients with multiple gestations, diabetes, fetal compromise, or contraindications to metformin were excluded. Half the patients were allocated to placebo and the other half to one gram of extended release metformin three times a day until delivery. All received standard betamethasone infusions.
The median gestational age at start of trial in both groups was 29 weeks, and both groups had fairly high rates of drop-outs, side effects and dose reductions. The median duration between diagnosis and delivery was 18 days in the metformin group (interquartile range [IQ] 4-24 days) compared with 10 days in the placebo group (IQ 5-29 days), but there were no significant differences in fetal, neonatal, or maternal composite outcomes. However, using a per-protocol analysis including only patients who tolerated the full dosage, the median duration from diagnosis to delivery was 16 days (IQ 5-29 days) with metformin, compared to 5 days (IQ 3-15 days) with placebo and this was statistically significant. It is noteworthy that 68% of patients in the placebo arm tolerated the full dosage and in the metformin arm only 45% tolerated the full dose.
This trial suggests that metformin may safely prolong pregnancy for patients with preterm preeclampsia. Unfortunately, the large percentages in both groups who could not tolerate the intended dosing may significantly limit clinical utility. Of course, a common challenge in conducting pregnancy trials is sorting out drug-related versus pregnancy-related symptoms. A larger trial might find a benefit with some of the clinical outcomes as a result of the longer gestation, but between the low tolerability of both metformin and placebo, and with benefit only found in the per-protocol analysis, it is premature to assume metformin delivers when it comes to managing pre-eclampsia.
For more information, see the topic Hypertensive Disorders of Pregnancy in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, Deputy Editor at DynaMed; Edited by, Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Nicole Jensen, MD, family physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Writer at DynaMed and Christine Fessenden, Editorial Operations Assistant at DynaMed.