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Pharmacological Intervention for Diabetes After Pregnancy Prevention in


Women with Prior Gestational Diabetes: A Scoping Review

Jill Pancer, Nancy Wu, Ibtisam Mahmoud, Kaberi Dasgupta

PII: S0168-8227(19)31729-2
DOI: https://doi.org/10.1016/j.diabres.2020.107998
Reference: DIAB 107998

To appear in: Diabetes Research and Clinical Practice

Received Date: 3 December 2019


Accepted Date: 31 December 2019

Please cite this article as: J. Pancer, N. Wu, I. Mahmoud, K. Dasgupta, Pharmacological Intervention for Diabetes
After Pregnancy Prevention in Women with Prior Gestational Diabetes: A Scoping Review, Diabetes Research
and Clinical Practice (2020), doi: https://doi.org/10.1016/j.diabres.2020.107998

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© 2020 Published by Elsevier B.V.


Pharmacological Intervention for Diabetes After Pregnancy Prevention in Women with Prior
Gestational Diabetes: A Scoping Review
Jill Pancer MD1,2, Nancy Wu BSc2, Ibtisam Mahmoud MBSI3, Kaberi Dasgupta MD, MSc1,2

1. Division of Endocrinology and Metabolism, Department of Medicine, McGill University Health


Centre, Montréal, Québec, Canada
2. Centre for Outcomes Research and Evaluation (CORE), Research Institute of the McGill
University Health Centre, Montréal, Québec, Canada; Department of Medicine, McGill University
Health Centre, Montréal, Québec, Canada
3. Medical Library, McGill University Health Centre, Montréal, Québec, Canada

Declarations of interest: None.

Funding statement: This research did not receive any specific grant from any funding
agency in the public, commercial, or not-for-profit sector.

Corresponding author’s contact information:


Kaberi Dasgupta
Centre for Outcomes Research and Evaluation of the RI-MUHC,
5252 boul de Maisonneuve Ouest, Office 3E.09,
Montréal, QC,
Canada H4A 3S5; Email: kaberi.dasgupta@mcgill.ca

Number of words (Abstract): 199


Number of words (Main text, not counting the title page, condensation, acknowledgements,
references, tables, figure legends, and figures): 4638
Tables: 2
Figures: 3

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Abstract:
Women with previous gestational diabetes mellitus (GDM) are at increased risk of developing
diabetes after pregnancy (DAP), especially 5 to 10 years postpartum. Two well-known diabetes
prevention trials demonstrated a significant reduction in DAP incidence using metformin and
troglitazone; however, since their publication, several novel classes of anti-hyperglycemic
agents have emerged. This review aimed to conduct a systematic literature search for new
evidence in support of pharmacotherapy in DAP prevention and to analyze the results based on
special considerations for women of reproductive potential. The only studies whose primary
outcome was DAP incidence were those examining metformin, the thiazolidinediones
troglitazone and pioglitazone, and the dipeptidyl peptidase-4 inhibitor vildagliptin. Metformin
was effective in DAP reduction and was well tolerated, but participants were on average 12
years beyond their GDM pregnancy. Troglitazone was also shown to prevent DAP, but was
withdrawn from the market due to hepatotoxicity. There was no comparator arm in the
pioglitazone study, which limits its interpretability. The vildagliptin study was underpowered.
There are ongoing trials with glucagon-like peptide 1 receptor agonists and sodium-glucose
transporter 2 inhibitors, but none with diabetes incidence as a primary outcome. This review
highlights the limited evidence base for pharmacological prevention of DAP.

Keywords:
gestational diabetes mellitus, diabetes after pregnancy, postpartum diabetes, diabetes
prevention, diabetes and pregnancy

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1. Introduction
Gestational diabetes mellitus (GDM) is a risk factor for the development of diabetes [1-3],
hypertension [3], and cardiovascular disease [3-5] in mothers, in the years following pregnancy
and delivery. Defined as the onset or identification of glucose intolerance during pregnancy (1),
it is common, with an estimated prevalence of 5 to 15% [7]. The greatest risk for the
development of diabetes after pregnancy (DAP) occurs within the first 5 years postpartum, and
plateaus after 10 years [3, 8]. Strategies to prevent or delay the development of DAP are
needed.
There are a number of disease- and intervention-specific criteria that should be satisfied in
order to ensure appropriate selection of targets for prevention strategies. The disease in
question should constitute a significant public health problem, have modifiable risk factors, and
be amenable to treatment. Treatment, in turn, should be widely accepted, have demonstrated
efficacy, exhibit a minimal adverse event profile, target a high-risk population, and be cost-
effective (2). GDM is indeed common with important cardiometabolic complications [1-5] and is
thus a significant public health problem. Modifiable risk factors include excess weight,
suboptimal dietary quality, and low physical activity levels, all of which reduce insulin resistance
and glucose levels, and thus DAP risk [10].
Several large trials have demonstrated that health behaviour change interventions are highly
effective in preventing or delaying diabetes onset in adults with prediabetes [11-14]. One
specifically evaluated a subgroup of women averaging 12 years since a GDM pregnancy; this
subgroup also experienced substantial benefit with an intensive lifestyle intervention that
translated into a 50% reduction in incident diabetes. Metformin therapy translated into a
similar risk reduction (3).
While the potential benefits of health behaviour modifications are substantial, and the focus of
our own work, some women may seek other options, such as prevention through
pharmacological agents. In the present review, we consider the place of pharmacological
agents in DAP prevention, in the context of new diabetes agents. In considering these, we have
imposed some specific considerations: namely, pharmacological interventions must be safe to
use during pregnancy and the lactation period, for both mother and offspring. Safety and
efficacy data should be generated from the results of large, adequately powered randomized
controlled trials with extended follow-up. We conducted a scoping review, identified relevant
studies, and evaluated these with attention to these considerations.

2. Materials and Methods


The review was prospectively registered in PROSPERO (CRD42019122079).

2.1 Literature search


We searched 5 electronic bibliographic databases (OVID Medline, Embase, The Cochrane
Library, PubMed, and Web of Science) and research in progress using ClinicalTrials.gov from
inception to November 19, 2018. Subject headings and key words included ‘gestational

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diabetes’ and/or ‘diabetes in pregnancy’, ‘type 2 diabetes’ and related terms, and various terms
related to oral medications used for diabetes management with potential for use in DAP
prevention (e.g., ‘hypoglycemic agents’, ‘anti-diabetic’, ‘dietary supplement’, ‘metformin’,
‘thiazolidinediones’, ‘dipeptidyl-peptidase IV inhibitors’, ‘liraglutide’, ‘sodium-glucose
transporter 2’). The search strategy was developed in collaboration with a health sciences
librarian (IM).

2.2 Study selection


Studies retained met the following criteria: (1) women with a history of GDM; (2) diagnosis of
diabetes ruled out prior to initiation of intervention; (3) pharmacological intervention initiated
in the postpartum period; and (4) primary outcome of postpartum diabetes incidence.
Randomized controlled trials, pre-post designs, and prospective cohort studies were included.
Abstracts, case reports, study protocols, commentaries, guidelines, reviews, and meta-analyses
were excluded. However, we performed a manual search for relevant articles in the reference
lists of pertinent guidelines, review articles, and meta-analyses.
Two reviewers (JP and NW) independently screened titles and abstracts using Rayyan, a free
web-based application that allows multiple users to label citations and assign individual reasons
for exclusion in a blinded fashion initially and then combines the results, highlighting
discrepancies in the inclusion/exclusion process [16]. Duplicate publications were removed.
Full-text articles of potentially eligible studies were then reviewed independently (JP and KD).

2.3 Data extraction


A data extraction sheet was developed based on an existing template to capture the following:
(1) country and setting; (2) population; (3) interventions; (4) outcome measures; (4) study
design; and (5) analytic method.
Two review authors (JP and KD) extracted data independently. Discrepancies were identified
and resolved through discussion.

2.4 Quality assessment


Each study was examined in terms of randomization, blinding, and withdrawals and dropouts
(items of the Jadad score [17]) to evaluate quality and risk of bias.
We organized data in terms of: (1) effectiveness of the intervention; (2) tolerability of
treatment, including compliance and adverse event profile; (3) safety of the intervention in
women of reproductive potential; and (4) whether the intervention was applied to the
appropriate target population.

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3. Results

3.1 Search results


In total, 3706 records (Figure 1) were identified. Following duplicate removal, 2811 titles and
abstracts were screened, resulting in the exclusion of 2782 articles. 29 full-text articles were
subsequently reviewed and 24 articles were excluded after full review (8 did not fulfill study
design requirements; 2 did not examine study population of interest; 3 intervention was not
postpartum; 11 incident diabetes was not examined as an outcome), resulting in 5 articles [15,
18-21] included in the final analysis.
Although the search strategy was designed to include intervention studies using dietary
supplements and/or nutriceuticals, no trials considering these interventions and concurrently
satisfying all other inclusion criteria were identified.

3.2 Study characteristics


The 5 studies identified included: 1 phase 3 trial examining metformin (3) with 1 related follow-
up observational study evaluating longer term effects of metformin [18]; 1 phase 3 trial
examining the thiazolidinedione (TZD) troglitazone (2) with a follow-up observational study in
which the TZD pioglitazone was used [20] as troglitazone had been taken off the market for
safety concerns; and 1 phase 2 trial evaluating the dipeptidyl peptidase-4 (DPP-4) inhibitor
vildagliptin that included incident diabetes among the outcomes evaluated [21]. Across the 3
trials, 729 women with a history of GDM participated with 41% randomized to pharmacological
preventive therapy (Table 1). Four of the studies were conducted in the United States [15, 18-
20] and one in Germany [21].

3.3 Metformin: The Diabetes Prevention Program (DPP)

3.3.1 The DPP trial design


The DPP, conducted in the United States, randomized overweight adults with impaired glucose
tolerance (IGT) and elevated fasting plasma glucose (FPG) to placebo, intensive health
behaviour change, metformin therapy, or troglitazone therapy (Figure 2). Metformin was
started at a dose of 850 mg once daily and increased to twice daily if tolerated; troglitazone was
given at a fixed dose of 400 mg daily. All DPP participants were provided standard lifestyle
recommendations by a case manager during an annual in-person session and also through
written materials, focusing on the importance of diet, weight loss, exercise, and smoking
cessation. The primary outcome was the development of diabetes; the 1997 American Diabetes
Association (ADA) diagnostic criteria were applied using bi-annual FPG measurements and an
annual 75-g oral glucose tolerance test (OGTT) [22]. Enrolment occurred between 1996 and
1999, and the mean follow-up period was 2.8 years. The blinded treatment phase was
terminated one year early due to achievement of pre-specified efficacy outcomes (3).

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The troglitazone treatment arm was discontinued prematurely in 1998 due to reports of
hepatotoxicity. Data from participants assigned to troglitazone were excluded from analysis in
the DPP [22].

3.3.2 The DPP subgroup analysis of women with and without a history of GDM
A pre-specified analysis of the DPP examined t outcomes in parous women with and without a
history of GDM, although randomization was not stratified by GDM status. Two thirds of
participants enrolled in the DPP were women, approximately 16% of whom had a previous
GDM pregnancy [11]. GDM status was ascertained by self-report. The analysis includedwomen
with at least one live birth, with (n = 350) and without (n = 1416) a history of GDM (3).

3.3.3 Study population


At baseline, women with a self-reported GDM history were on average 43.0 (standard deviation
(SD) 7.6) years of age and obese (body mass index (BMI) 34.2 (SD 6.2) kg/m2). All had
prediabetes. There was a mean 12-year interval from completion of their first GDM pregnancy
to study enrolment (3).
Of note, women with prior GDM were 8.5 years younger (95% confidence interval (CI) 7.41–
9.59; calculated using data provided) than women without GDM; all subsequent analyses in this
cohort of women were adjusted for age at randomization. Some possible explanations for this
age difference provided by the study authors included recruitment strategies used for women
with previous GDM, less screening for GDM during pregnancy in older women, and
development of DAP in older women with a history of GDM prior to the DPP (3).
The DPP used an adaptive randomization strategy stratified by clinical center but not by GDM
status. Although it is possible that a prior diagnosis of GDM was a characteristic used to
minimize imbalances in treatment allocation, it is not clearly specified in the trial protocol [22].

3.3.4 Effectiveness of treatment


Among women with a history of GDM randomized to metformin (n = 111), there were 7.8 cases
of DAP per 100 person-years as compared to 15.2 cases per 100 person-years in those assigned
to placebo (n = 122), representing a 50% risk reduction (3).

3.3.5 Tolerability of treatment


The proportion of women with a history of GDM who were adherent to treatment, defined as
having taken at least 80% of the prescribed dose of study medication, was slightly lower in the
metformin group than in the placebo group (68.8% vs. 72.9%) (3).

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Adverse event rates were not reported separately for the GDM subgroup analysis, but in the
overall DPP population, there was a higher rate of gastrointestinal symptoms in the metformin
than in the placebo arm (77.8 vs. 30.7/100 person-years). Hospitalization and mortality rates
were similar across treatment arms. No deaths were attributable to study medication [11].

3.3.6 Safety of treatment in women of reproductive potential


The DPP itself does not provide us with safety data on the use of metformin in women of
reproductive potential. The DPP excluded women who were pregnant, breastfeeding or within
6 weeks of breastfeeding completion, women planning a pregnancy during the course of the
trial, and women of reproductive potential unwilling to take adequate contraceptive measures
[22].
As per the trial protocol, if a woman randomized to either placebo or metformin were to
become pregnant, study medication would be unblinded and permanently discontinued. If an
enrolled woman became pregnant during the study, study medication would be discontinued
until completion of the pregnancy and breastfeeding [22]. The number of pregnancies that
occurred throughout the course of the DPP trial is not reported.

3.3.7 Beyond the DPP: The Diabetes Prevention Program Outcomes Study (DPPOS)
DPP participants were studied post trial to evaluate longer-term outcomes in the observational
DPPOS. Blinded treatment in the DPP was terminated in July 2001 and participants were invited
to enroll in an extended follow-up study (DPPOS) in September 2002 [23]. The 13-month
interval between the end of the DPP and the start of the DPPOS was termed the bridge (Figure
2).
At commencement of extended follow-up, metformin and placebo were stopped for 1 to 2
weeks and an OGTT completed. Participants on metformin were invited to resume open-label
treatment. All participants were invited to participate in a 16-session lifestyle program similar
to the DPP lifestyle change arm between January and July 2002 [23].
Over the combined 10-year follow-up period of the DPP and DPPOS, women with a history of
GDM randomized to metformin had a 40% reduction in DAP compared to the placebo arm (n =
97 vs. 100; 6.8 vs. 11.4 per 100 person-years) [18].

3.4 Troglitazone: Troglitazone in the Prevention of Diabetes (TRIPOD)

3.4.1 The TRIPOD trial design


TRIPOD was a single-center, randomized, placebo-controlled trial designed to examine the
effectiveness of troglitazone for DAP prevention in women with a GDM history (troglitazone
400 mg daily vs. placebo). Women were eligible for inclusion if they were 18 years or older; of
Mexican, Guatemalan, or Salvadoran descent; within 4 years of a GDM pregnancy; and had a

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sum of 5 OGTT plasma glucose values ≥34.7 mmol/L (2) (predicting a 5-year diabetes risk of 70%
as per previous analyses [24] in their patient population). All women received standard lifestyle
recommendations at baseline and annually thereafter. DAP was assessed through 3-monthly
FPG and annual OGTT (2). If a woman developed DAP during the course of the trial, she was
placed on open-label troglitazone (Figure 3).
The TRIPOD trial was scheduled to continue until August 2000, but was terminated 4 months
prematurely after withdrawal of troglitazone from the market due to reports of hepatotoxicity
(2).

3.4.2 Study population


Women enrolled in TRIPOD averaged 34 to 35 years of age (SD 6.5) with a mean BMI of 30.5 (SD
5.7) kg/m2 (2). Approximately two thirds of participants had IGT at baseline [25].

3.4.3 Effectiveness of treatment


Among participants who returned for at least one follow-up visit (n = 114), the average annual
diabetes incidence was 56% lower in the troglitazone vs. placebo arm (5.4% vs. 12.1%; hazard
ratio (HR) 0.45 (95% CI 0.25–0.83) during a median follow-up of 30 months on blinded
treatment. When the 11% of women who were lost to follow-up were assigned the diabetes
rate observed in the placebo group, the HR remained similar (2).
Women who did not develop DAP aby the end of the trial (n = 102) were invited to return after
an 8-month drug washout period for repeat OGTT (Figure 3). Almost 90% of participants
underwent post-trial testing, but given the small absolute numbers of incident diabetes cases (6
in the placebo group and 1 in the troglitazone group), results were inconclusive (2).

3.4.4 Tolerability of treatment


Compliance with study medication, assessed by quarterly pill counts, was comparable in both
groups (approximately 85% of tablets consumed). Annual dropout rates were 13.4% in the
placebo group and 16.3% in the troglitazone group (2).
Throughout the course of the trial, 9 women, of whom 6 were assigned to troglitazone,
developed a greater than 3-fold elevation in serum transaminase levels (5.3% of women
randomized to troglitazone with at least one follow-up visit vs. 2.5% of women in placebo
group). After interruption of the study medication, transaminase concentrations returned to
baseline values (2).

3.4.5 Safety of treatment in women of reproductive potential


The TRIPOD trial excluded women who were pregnant or breastfeeding and those planning a
pregnancy within the anticipated 5-year study period. Furthermore, eligible participants had to
be willing to use effective contraceptive measures [26]. Women who became pregnant during

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the trial had their study medication discontinued until completion of breastfeeding. Diabetes
testing was conducted at least 4 months postpartum and 1 month after completion of
breastfeeding (2).
Overall, 8.2% of women assigned to placebo and 7.1% randomized to troglitazone became
pregnant during the TRIPOD trial (2). No adverse obstetrical and/or neonatal outcomes were
reported in the published manuscript.

3.5 Beyond TRIPOD: Pioglitazone in the Prevention of Diabetes (PIPOD)


Women who completed TRIPOD without developing DAP (n = 95) were invited to participate in
PIPOD, an open-label observational study with assignment to pioglitazone. The time interval
between completion of TRIPOD post-trial testing and enrolment in PIPOD is unclear.
Pioglitazone was prescribed as 30 mg daily and increased to 45 mg daily 2 months later in the
absence of fluid retention. Participants were followed every 2 months during the first year and
every 3 months thereafter, at which points FPG and HbA1c were measured. OGTTs were
performed annually. Participants remained on pioglitazone treatment for 3 years (n = 64),
unless HbA1c value exceeded 7.0% (53 mmol/mol) (n = 1) at an earlier time point (Figure 3). At
the end of the PIPOD study, 65 women completed all visits. The annual average dropout rate
was 9.6% [20].
Diabetes incidence rates were calculated based on data from 86 women, 42 of whom were
randomized to the troglitazone arm in the TRIPOD trial, who had at least one follow-up visit
after enrolment in PIPOD. Overall, 11 women developed DAP during the PIPOD follow-up
period. No new cases of diabetes were reported during the drug washout phase. The average
annual diabetes incidence rate was 5.2% during pioglitazone treatment and 4.6% during the
treatment and post-drug washout period [20].

3.6 Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for the prevention of diabetes
after pregnancy

3.6.1 Trial design


This study was performed as a single-center, randomized, placebo-controlled trial in Germany.
Women who were within 9 months of an insulin-treated GDM pregnancy were eligible for
randomization to either vildagliptin 100 mg daily (n = 58) or placebo (n = 55) for a planned
duration of 3 years. All participants received standard dietary and physical activity counselling
in the form of an annual in-person consultation and written information, and were provided
with a pedometer. The primary outcome was development of diabetes, assessed by bi-annual
OGTT. The sample size calculation was based on an expected DAP incidence rate of 61% over 3
years [21].
The study was terminated prematurely in 2015 based on an interim analysis performed after
7.75 years that showed a DAP rate much lower than anticipated, thus rendering the study

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underpowered. At study closing, 54% of participants had received study medication for 2 years
and 38% had completed 3 years of treatment [21].

3.6.2 Study population


The median age of enrolled women was 35.8 years in the vildagliptin group and 33.1 years in
the placebo group. The median time after delivery was 8.6 months. Nearly all women in the
study were Caucasian. The vast majority of participants were overweight (BMI >25 kg/m2),
approximately 60% of whom were obese (BMI >30 kg/m2). Less than 10% had impaired fasting
glucose (IFG) and about 20% had IGT at screening. Close to 75% of study participants had a
family history of diabetes [21].

3.6.3 Effectiveness of treatment


Because the study was underpowered, no conclusive effects of vildagliptin on DAP incidence
could be demonstrated. The cumulative incidence of DAP was 5% in the vildagliptin arm and 3%
in the placebo arm with ADA 1997 criteria but 7% vs. 13% applying 2012 criteria (that included
HbA1c ≥6.5% (48 mmol/mol) criterion) [21].

3.6.4 Tolerability of treatment


Adherence to study medication was not reported, but nearly half of randomized participants (n
= 52) withdrew before completing the treatment phase [21].
The most common reported clinical adverse events were headaches (67% in the vildagliptin
group and 54% in the placebo group), viral upper respiratory tract infections (59% vs. 75%), and
gastroenteritis (22% vs. 31%) [21].
One serious adverse event of increased lipase, which has been previously reported with the use
of DPP-4 inhibitors, occurred in the vildagliptin group and led to treatment discontinuation. The
participant was found to have gallstones on abdominal ultrasonography [21].

3.6.5 Safety of treatment in women of reproductive potential


Women were excluded if they were pregnant or breastfeeding, or planning a pregnancy within
the next 2 years. Six women assigned to vildagliptin and 3 to placebo became pregnant during
the trial, and had their study medication discontinued [21]. Maternal, fetal, and neonatal
outcomes were not reported for these pregnancies.

4. Discussion
Our scoping review demonstrates a limited number of clinical trials testing pharmacological
agents for DAP prevention. Metformin [15, 18], troglitazone (2), pioglitazone [20], and
vildagliptin [21] have been evaluated. Metformin demonstrated benefit in a subgroup analysis

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but the study population consisted of women 12 years on average beyond the GDM pregnancy
(3), so applicability in the earlier years postpartum has not been definitively established.
Troglitazone demonstrated effectiveness in a younger patient population but the medication
has been associated with adverse liver effects and was withdrawn from the market (2).
Pioglitazone was not examined in a randomized controlled trial [20]. The trial evaluating
vildagliptin did not have sufficient power to establish effectiveness [21]. There is thus to date
no strong evidence supporting the effectiveness and safety of any medication for DAP
prevention within 5 years of a GDM pregnancy.
When considering the use of a pharmacologic agent in the context of disease prevention, it
must have proven efficacy with rigorous studies demonstrating its ability to reduce disease
incidence. Since the target demographic is at risk, but has not yet developed the disease in
question, the intervention should have a benign adverse event profile (2). Moreover, when a
drug prevention strategy is being contemplated in women of reproductive potential, there are
additional concerns regarding potential drug exposure during pregnancy and teratogenic
and/or longer-term effects on the exposed offspring.
With the limited evidence available, metformin appears to be the most promising. Metformin
was shown to be protective against DAP development in women with prior GDM, with a 50%
risk reduction over the 3 years of the DPP (3). This effect seemed to persist during the
observational follow-up of the DPPOS with a 40% risk reduction over the cumulative 10-year
period after randomization in the DPP [18]. Adherence to metformin was on the order of 70%
in the GDM subgroup analysis (3). We may be able to reasonably extrapolate the DPP GDM
subgroup analysis findings to women closer in time to a GDM pregnancy in terms of metformin
effectiveness. While there does not seem to be an increased risk of major birth defects or
congenital malformations [27, 28], prospective longitudinal follow-up studies of the offspring
exposed to metformin in utero have demonstrated changes in body fat distribution evident at 2
years of age [29], and maintained at 7 to 9 years [30].
In the PIPOD study, there was no comparator group, although the annual diabetes incidence
rate on pioglitazone treatment was similar to the rate seen in women randomized to
troglitazone in TRIPOD, suggesting a benefit in terms of DAP prevention [20]. However, the
inherent risk of diabetes differed over the course of the studies as PIPOD participants (by
eligibility criteria) had not developed diabetes throughout the TRIPOD trial and after the 8-
month drug washout period. Moreover, the TZDs have fallen out of clinical favour due to
concerns of cardiovascular safety [31], and are unlikely to be further developed as therapeutic
targets for the prevention of DAP.
Vildagliptin was not shown to be effective in reducing the risk of DAP, but the study was
underpowered. Eligible women for the vildagliptin study had to have had insulin-treated GDM
within the past year. The majority had normal glucose tolerance and FPG at study entry, and
were of Caucasian race [21]. This may, in part, explain the relatively low incidence of
postpartum diabetes as compared to the DPP (3) and TRIPOD (2) trials, in which participants
had to have some degree of dysglycemia to be eligible for study inclusion and included women
of high-risk ethnic groups. Furthermore, study enrolment and retention were challenging, with
only 155 women being screened over a 7-year period and almost half of randomized

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participants withdrawing before study completion [21].
There was one serious drug-related adverse event of gallstone pancreatitis that occurred in the
vildagliptin group [21]. There may be a small increased risk of acute pancreatitis in patients with
diabetes treated with DPP-4 inhibitors [32], although this association is not consistently found
across studies [33]. There does not appear to be an increased risk of bile duct and gallbladder
disease with DPP-4 inhibitor use [34]; however, it is unclear if this risk is modified in people with
predisposing clinical features for gallstone development. The classic risk factors of female sex,
pregnancy, and obesity [35] are common in women with a history of GDM, and should warrant
judicious use of medications that might increase the risk of gallstones.
Drug safety data in pregnancy cannot be derived from any of the included studies [15, 18-21],
as all excluded pregnant women and those planning a pregnancy within the study time frame.
Study medication was discontinued in the event of a pregnancy, and no maternal and/or
neonatal outcomes of pregnancies arising on treatment were reported.
There is one published study (1) and several ongoing trials (Table 2) evaluating the effects of
other incretin analogues [37, 38] and sodium glucose cotransporter (SGLT) 2 inhibitors [39, 40]
used alone or in combination with metformin on various glycemic and metabolic parameters in
women with a history of GDM. All studies have excluded pregnant or breastfeeding women,
those planning a pregnancy, and fertile women not using reliable contraceptive measures; and
none are examining DAP incidence as a primary outcome.
In a small, single-center pilot trial that randomized 36 obese women with IFG and/or IGT who
were within 1 year postpartum of a GDM pregnancy to treatment with sitagliptin, a DPP-4
inhibitor, and metformin (50 mg/1000 mg twice daily), metformin alone (1000 mg twice daily),
or placebo for 16 weeks, a significantly higher proportion of women assigned to combination
therapy (9 of 12, 75%) achieved normal OGTT plasma glucose results as compared to those
assigned to metformin monotherapy (4 of 12, 33%) and placebo (2 of 9, 22%). No participants
progressed to diabetes during the study period. The widespread applicability of this study is
limited by its small sample size, relatively short treatment duration, and use of surrogate
metabolic outcomes (1).
Preliminary results published as conference abstracts of treatment with liraglutide, a glucagon-
like protein-1 (GLP-1) receptor agonist, alone [41] or in combination with metformin [42] for 1
year in overweight women with a history of GDM demonstrated improvements in various
glycemic and metabolic parameters, most notably weight loss. In one of the studies that
included a drug washout period, the observed changes in FPG and glucose tolerance were not
sustained when measured off drug treatment [41]. Diabetes incidence at 1-year was not
reported.
Although the primary objective of our review was to analyze the evidence for use of
pharmacologic agents in DAP prevention, health behaviour modifications remain the backbone
of therapy. Several large cohorts have demonstrated that a combination of diet and exercise
can reduce the progression of prediabetes to diabetes in the general population [11-14]. In the
DPP subgroup analysis of women with a history of GDM, women randomized to the intensive
lifestyle intervention had a 53.4% reduction in diabetes incidence (7.4 cases per 100 person-

12
years) as compared to those randomized to placebo (15.2 cases per 100 person-years). There
was no significant difference in diabetes risk reduction conferred by health behaviour
modifications or metformin treatment in women with prior GDM (3), unlike in the overall DPP
cohort, where lifestyle intervention was approximately twice as effective as metformin [11].
However, women were on average 12 years beyond their first GDM pregnancy (3), which
surpasses the highest risk time period for progression to DAP (i.e. within the first 5–10 years
postpartum) [3, 8]. Interestingly, in a recent meta-analysis that included 8 randomized
controlled trials examining the effects of lifestyle behaviour modifications on diabetes
prevention in postpartum women with a history of GDM, there was a 25% risk reduction in DAP
incidence that did not reach statistical significance (RR 0.75, 95% CI 0.55–1.03); however, when
stratified by time of randomization, interventions initiated within 6 months postpartum showed
a statistically significant reduction in DAP (RR 0.61, 95% CI 0.40–0.94) [43]. Such findings must
be interpreted cautiously as some of these trials reported low participation rates and most did
not objectively measure adherence to the studied lifestyle intervention.
This review highlights the limited evidence base for pharmacological prevention of DAP in
women of reproductive age. The best available evidence supports metformin use, but the study
population did not focus on women within 5–10 years postpartum. Ongoing studies using the
new anti-hyperglycemic agents were designed to assess surrogate outcomes of glycemic
measures. Although they may provide evidence for early metabolic changes and prompt further
research, they should not be used in isolation to guide therapeutic decisions in fertile women
with a history of GDM, especially without adequate safety data in pregnancy and breastfeeding.
Large clinical trials with long follow-up are needed to ascertain suitable agents for DAP
prevention; moreover, it is critical that there not be prior evidence of side effects that could
adversely impact pregnancy outcomes.

6. Acknowledgements
Funding: This research did not receive any specific grant from any funding agency in the public,
commercial, or not-for-profit sector.

13
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Figure Caption:

Figure 1. Flow diagram of selection strategy and article reviews in accordance with the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure 2. Schematic representation of the DPP and DPPOS trial designs. Diabetes incidence
was reported for 3 years from time of randomization in the GDM subgroup analysis of the DPP
and for the cumulative 10-year follow-up period from initial randomization in the DPP in the
DPPOS, as represented by the horizontal lines with open circles. The 13-month time interval
(from August 1, 2001 to August 31, 2002) separating the end of the DPP and the start of the
DPPOS was termed the bridge (represented by hatched rectangle). Given the marked efficacy
of intensive lifestyle intervention on diabetes risk reduction, all DPP participants were offered 16
group-administered lifestyle sessions during the bridge over a 6-month period (represented by
the solid gray line). DPP, Diabetes Prevention Program; DPPOS, Diabetes Prevention Program
Outcomes Study; GDM, gestational diabetes mellitus.

Figure 3. Schematic representation of the TRIPOD and PIPOD trials. If a woman developed
postpartum diabetes during the course of the TRIPOD trial, she was placed on open-label
troglitazone. Blinded study medication or open-label troglitazone was continued until premature
discontinuation of TRIPOD in March 2000. Women who did not develop diabetes during the
study period underwent post-trial testing (drug washout period, represented by gray shading);
those who remained diabetes free were eligible for participation in the PIPOD study. It is unclear
how much time elapsed between completion of the TRIPOD and enrolment in the PIPOD study
(represented by break in time line). Participants in the PIPOD study remained on pioglitazone
for 3 years, unless their HbA1c exceeded 7% during follow-up testing. After an initial 3-month
drug washout period, HbA1c was measured; if found to be greater than 7.0% (53 mmol/mol),
post-trial testing was performed immediately. However, if HbA1c was less than or equal to 7.0%
(53 mmol/mol), then post-trial testing was performed 3 months later, a total of 6 months after
pioglitazone discontinuation. DAP, diabetes after pregnancy; HbA1c, glycated hemoglobin;
PIPOD, Pioglitazone in the Prevention of Diabetes; TRIPOD, Troglitazone in the Prevention of
Diabetes.

Table 1. Characteristics of the five included studies. Baseline characteristics are presented as
mean (standard deviation), except for the vildagliptin study, where results are reported as
median values. *Adherence in the DPP and DPPOS was defined as the proportion of participants
who took at least 80% of the prescribed dose of study medication. ¶Results presented as
intervention group vs. comparator group. §1997 ADA criteria: FPG ≥7.0 mmol/L or 2-hr PG ≥11.1
mmol/L; second confirmatory test required within 6 weeks of initial abnormal test. †2012 ADA
criteria: FPG ≥7.0 mmol/L or 2-hr PG ≥11.1 mmol/L; or HbA1C ≥6.5% (48 mmol/mol); second
confirmatory test required within 6 weeks of initial abnormal test. ADA, American Diabetes
Association; bid, twice daily; BMI, body mass index; CI, confidence interval; DAP, diabetes after
pregnancy; FPG, fasting plasma glucose; GDM, gestational diabetes; HbA1c, glycated
hemoglobin; HR, hazard ratio; mg, milligram; n, number; N/A, not available; OGTT, oral glucose
tolerance test; q, every; USA, United States of America; 2-hr PG, 2-hour plasma glucose value on
oral glucose tolerance testing.

19
Table 2. Ongoing diabetes prevention trials in women with previous gestational diabetes using
new glucose-lowering pharmacologic agents registered on ClinicalTrials.gov. BMI, body mass
index; GDM, gestational diabetes; IFG, impaired fasting glucose; IGT, impaired glucose
tolerance; IS-SI, insulin secretion-insulin sensitivity index; NCT, National Clinical Trial; USA,
United States of America.

20
21
22
23
Table 1. Characteristics of the five included studies.
Metformin Thiazolidinediones DPP-4
inhibitor
First author, Ratner, Aroda, 2015 Buchanan, Xiang, 2006 Hummel, 2018
year of 2008 2002
publication
Name of Diabetes DPP Outcomes Troglitazone in Pioglitazone in N/A
study Prevention Study (DPPOS) the Prevention the Prevention
Program of Diabetes of Diabetes
(DPP) (TRIPOD) (PIPOD)
Study design, Phase 3 Observational Phase 3 trial, Observational Phase 2 trial,
time frame trial, 1996– follow-up, 1995–2000 follow-up, N/A 2008–2015
2001 2002–2008
Setting 27 clinical centers, USA Los Angeles County Women’s and Hospital or
Children’s Hospital, USA outpatient
clinics in
Germany
Baseline characteristics of women with prior GDM
Age (years) 43.0 (7.6) 34.9 (6.6) vs.¶ 39 (6.6) 35.8 vs.¶ 33.1
34.3 (6.5)
BMI (kg/m )
2 34.2 (6.2) 30.5 (5.7) 31.0 (4.9) 27.6 vs.¶ 28.9
Ethnicity 54% Caucasian 100% Hispanic 100% Hispanic 100% vs.¶
94.5%
Caucasian
FPG (mmol/L) 5.9 (0.5) 5.5 (0.6) vs.¶ 5.6 (0.5) 5.2 vs.¶ 5.1
5.4 (0.5)
2-hr PG 9.2 (1.0) 8.6 (1.5) vs.¶ 8.4 (1.5) N/A
(mmol/L) 8.5 (1.3)
HbA1c (%) 5.9 (0.5) N/A 5.7 (0.5) 5.6
HbA1c 41 N/A 39 38
(mmol/mol)
Time since Mean of 12 N/A Within 4 years N/A Median of 8.6
GDM years months
pregnancy
Intervention, Metformin Metformin 850 Troglitazone Pioglitazone 45 Vildagliptin 50
adherence 850 mg bid mg bid (n = 400 mg daily (n mg daily (n = mg bid (n =
(n = 111), 97), 77%* = 114), 85 (16) 86), N/A 58), N/A
68.8%* %
Comparator, Placebo (n = Placebo (n = Placebo (n = None Placebo (n =
adherence 122), 72.9% 100), N/A 122), 55), N/A
87 (10) %
Primary Diabetes, 1997 ADA criteria§ Diabetes, 1997 ADA criteria§ Diabetes,
outcome and 2012 ADA
assessment criteria†
Assessment FPG q 6 months, OGTT q 1 FPG q 3 FPG, HbA1C q 2 OGTT q 6
of primary year months, OGTT months x 6, then months
outcome q year

24
q 3 months;
OGTT q year
Follow-up Mean of 3 Median of 6 Median of 30.9 Median of 35.9 Median of
years years vs.¶ 28.1 months 1.92 vs.¶ 2.50
months years
Effects 50.4% 40.4% Adjusted HR Average annual HR 0.59 (95%
estimate reduction in reduction in 0.44 DAP incidence CI 0.14–2.47)
DAP DAP incidence rate of 5.2%
incidence

25
Table 2. Ongoing diabetes prevention trials in women with previous gestational diabetes
using new glucose-lowering pharmacologic agents registered on ClinicalTrials.gov.
First NCT number Inclusion Intervention Duration Primary Estimated
author, criteria outcome date of
country completion
Glucagon-like peptide (GLP) 1 receptor agonist
Elkind- NCT01234649 BMI >25 Metformin + 84 IS-SI June 2019
Hirsch, kg/m2, within liraglutide vs. weeks
USA 1 year of metformin
GDM, IFG
and/or IGT
Vilsbøll, NCT01795248 BMI 25–45 Liraglutide 5 years Change in August 2020
Denmark kg/m2, within glucose
5 years of tolerance
GDM
Sodium glucose co-transporter (SGLT) 2 inhibitors
Elkind- NCT02338193 BMI >25 Metformin + 24 Change in March 2019
Hirsch, kg/m2, within dapagliflozin vs. weeks body
USA 1 year of dapagliflozin vs. weight
GDM, IFG metformin
and/or IGT
Kramer, NCT03215069 Within 6–36 Empagliflozin vs. 48 IS-SI September
Canada months of placebo weeks 2022
GDM

26