Pregnancy Outcomes: Effects of Metformin Study (POEM Study), a long term randomized controlled study in gestational diabetes mellitus

The POEM Study is an original and new RCT, designed to investigate the
(long-term) effects of metformin on top of standard of care (diet + lifestyle +
insulin rescue if needed) in gestational diabetes mellitus (GDM). The following
outcomes in mother and child are studied:
• pregnancy outcomes at delivery, the GDM Outcome Score (GOS), a composite
primary endpoint consisting of eight components: (1) large for gestational age
baby (LGA), (2) premature delivery, (3) admission for neonatal care, (4)
instrumental delivery, (5) birth trauma, (6) neonatal hypoglycaemia, (7)
caesarean delivery, and (8) pregnancy related hypertension;
• metabolic, growth, cognitive and gender outcomes (like the development of
obesity, diabetes, chronic morbidity and other variables) up to 20 years after
delivery.

Background of GDM.
GDM is an expression of insulin resistance during pregnancy with an increasing
prevalence of 5-10% in registered pregnancies (2007-2010). However, the
occurrence of GDM may be underestimated worldwide, since the screening and
detection of GDM is suboptimal. Moreover, the prevalence of GDM is still
increasing as the pregnant population becomes older and more obese. The
presence of diabetes before pregnancy excludes the diagnosis GDM, since, by
definition, GDM is prediabetes being converted into type 2 diabetes (T2D)
during pregnancy.

Effects of GDM on fetal and maternal outcomes.
GDM may occur from week 16 in pregnancy. Though GDM itself does not affect the
organogenesis in the first 12 weeks of pregnancy, GDM harms mother and child
through unfavorable effects on outcomes of pregnancy with increased risks of
macrosomia (birth weight >4,000 grams) and/or large-for-gestational-age infants
(LGA), being related with fetal steatosis, enlarged placenta and
polyhydramnion; preterm births; dystocia of the shoulder during delivery;
instrumental delivery; Caesarean delivery; fetal neonatal hypoglycemia; fetal
prematurity of organs (neonatal jaundice due to prematurity of the liver);
neonatal admission; maternal pre-eclampsia and eclampsia; maternal urinary
tract infections. Moreover, GDM is associated with increased risks of maternal
T2D (50% within 5 years after GDM) and obesity, as well as T2D in the
offspring. In addition, insulin resistance preceding GDM may also unfavorably
affect the earlier course of pregnancy.

Treatment of GDM and need for insulin sensitizing strategies.
Insulin therapy added to a low carbohydrate diet is still the standard of care
for GDM. Insulin therapy, however, increases appetite, weight gain and the risk
of hypoglycaemia. Even if tight insulin therapy is successful, women with GDM
still have an increased incidence of obstetric and neonatal complications as
compared to non-diabetic controls. All these findings lead to the urgency for
better strategies for the treatment of women with GDM. Not only glucotoxicity,
but also (exaggerated growth inducing) mechanisms related to increased insulin
resistance in pregnancy may contribute to unfavorable outcomes of GDM in mother
and child. Therefore, the insulin sensitizing, orally administered biguanide
metformin may have specific benefits in the treatment of GDM - as have been
shown in T2D, the ultimate state of insulin resistance. However, RCT*s with
metformin in GDM and long term follow up are still lacking. Still no scientific
data are available about the long term effects of metformin during GDM, in
mother and child many years after delivery.

Metformin: new perspectives in the treatment of GDM.
Increasing observational studies on metformin in GDM indicate that treatment
with metformin seems at least as safe and effective compared to insulin with
clinically relevant outcomes. These observations support that pregnant women
treated with metformin may gain less weight, may develop less often
pregnancy-induced hypertension, may have fewer preterm births and may have
improved neonatal outcomes compared with those treated with insulin. Very
recently, prevention of maternal weight gain during and after GDM has appeared
to be an important predictor for the conversion of GDM into T2M. Although
these observational studies are promising, the small numbers and the open label
designs limit definite conclusions. RCT*s offering convincing evidence for the
use of metformin in GDM are needed. Therefore, we designed the POEM trial with
an intensive follow-up during pregnancy and a long term extension period of 20
years thereafter to evaluate the durable safety and efficacy of metformin in
GDM for mother and child.

Metformin: safety in GDM.
Although it is known that metformin crosses the placenta, cohort studies and
meta-analysis did not show a drug safety issue about metformin use in patients
with GDM (exposure to metformin during gestational age of 20-40 weeks), and in
patients with polycystic ovary syndrome - being an indication for metformin
treatment to restore fertility - after becoming pregnant (exposure to metformin
during gestational age of 0-40 weeks), if contraindications are excluded. Very
recently, a systematic review and meta-analysis on glibenclamide, metformin and
insulin for the treatment of GDM shows favorable outcomes for metformin
concerning birth weight, risk of macrosomia, risk of neonatal hypoglycaemia and
maternal weight gain. Metformin is generally considered a safe and
non-teratogenic drug. However, most studies were underpowered for the
evaluation of safety. RCTs are needed to provide conclusive safety data of
metformin in GDM. Trials like the POEM trial are required to determine an
evidence based position of metformin in the new guidelines for the treatment of
GDM.

This study has been transitioned to CTIS with ID 2024-519386-21-00 check the CTIS register for the current data.

The central aim of the POEM Study: to investigate whether the early start of
metformin on top of standard care may improve the treatment of GDM for mother
and child. Metformin is used as a tool to reduce insulin resistance, the
underlying cause of GDM. In the POEM Study, the effects of metformin on top of
standard care in GDM are compared during pregnancy until 6 weeks after delivery
(Phase A), from 6 weeks until 1 year after delivery (Phase B) and from 1 until
20 years after delivery (Phase C) with more specified objectives reflected by
well-defined clinically relevant endpoints (Table 1 of protocol).

The main hypothesis of the POEM Study: This is the first RCT to test the
hypothesis that metformin (particularly early given from the start of the
diagnosis GDM) versus controls with insulin rescue in both study arms improves
clinically relevant outcomes in mother and child during pregnancy, at delivery
and over the long term of 20 years after delivery - on top of standard of care.
We hypothesize that metformin given to women with GDM will reduce the GOS, a
continuous variable (range: 0-8) expressing the presence of 0-8 outcomes per
pregnancy: large for gestational age baby (LGA), premature delivery, admission
for neonatal care, instrumental delivery, birth trauma, neonatal hypoglycaemia,
caesarean delivery, and pregnancy related hypertension), as well as the future
life risks of obesity, metabolic syndrome and diabetes in mother and child,
puberty and adolescence included.

The approach to test this hypothesis: The standard of care for the treatment of
GDM can be defined as a triad: intensive counseling for diet and lifestyle +
intensified follow-up + rapid insulin rescue if needed, according to validated
international guidelines (ADA and EASD).
The additional reduction of the (growth promoting) hyperinsulinaemia by
metformin is expected to favor the outcomes of GDM in mother and child,
considering the results of observational studies described above. The design of
this RCT will permit a reliable comparison between the two study arms,
metformin users or controls, to test the main hypothesis of the POEM Study.
The early start of the study medication, the design and the long period of
follow up, together, may strengthen this RCT to detect a realistic effect of
metformin (early targeting the causal insulin resistance of GDM) on clinically
relevant outcomes.

This study is a multicenter randomized controlled trial comparing metformin
versus controls in 500 patients with GDM (n1 = n2 = 250, randomized 1:1) on
top of counseling for diet and lifestyle, the standard of care. In cases of
failure to reach treatment goals, insulin rescue will follow in both arms -
expected to be less needed in the metformin group. All patients will be treated
to target accordingly to the guidelines and GCP (intensive follow-up during
pregnancy), reflected in the study protocol. After delivery, mother and child
are followed for a period of 20 years. Study medication is continued until 1
year after delivery. If during the long-term follow-up another pregnancy
occurs, the original treamtent will be repeated according protocol. These
secondary pregnancies will be evaluated within the POEM Study.

Design with three phases. The POEM Study is divided into three phases:
• Phase A - from inclusion until 6 weeks after delivery; interventional study
with exposure of M vs C in mother and (unborn) child;
• Phase B - from 6 weeks until 1 year after delivery; interventional study with
exposure of M vs C in mother;
• Phase C - from 1 until 20 years after delivery; observational extension
study in mother and child.

Setting of the study. The POEM Study will be performed in the setting of the
multidisciplinary outpatients clinics (Endocrinology, Diabetology, Obstetrics)
in The Netherlands.

This study is an RCT comparing metformin versus controls in 500 patients with
GDM (n1 = n2 = 250) on top of counseling for diet and lifestyle. Metformin
tablets of 850 mg will be titrated within the first three weeks after inclusion
from once up to three times daily, if tolerated. The maximally tolerated dose
will be continued until 1 year after delivery. If the aim of target values of
glycaemic control is not met during GDM, insulin rescue will be started
according to best medical care. If the aim of target values of glycaemic
control is not met during Phase B and/or C, anti-hyperglycemic treatment will
be extended (or started) according actual guidelines for the treatment of type
2 diabetes.
Metformin: safety in GDM. Cohort studies and meta-analysis did not show a drug
safety issue about metformin in patients with GDM (gestational age 20-40
weeks), and in patients with polycystic ovary syndrome (PCOS) after becoming
pregnant (gestational age 0-40 weeks), if contraindications are excluded.
Metformin is generally considered a safe and non-teratogenic drug.

The POEM Study and its intervention (metformin on top of standard care) is
considered rather safe and even potentially beneficial, based on observational
data.

Discomfort as mentioned in Section:
- side effects of Metformine (e.g. gastro-intestinal complaints)
- discomfort by blood drawing
- nausea by OGTT.

The POEM Study has a negligible risk according to the METC risk classification
of the VU Medical Center Amsterdam.
Use of metformin has a risk of lactic acidosis in the presence of
contra-indications, like diarrhea, dehydration and sepsis. Therefore, use of
metformin will be stopped if contra-indicated.