Pharmacological intervention for diabetes after pregnancy prevention in women with prior gestational diabetes: A scoping review

Journal Pre-proofs 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: DOI: Reference:

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

To appear in:

Diabetes Research and Clinical Practice

Received Date: Accepted Date:

3 December 2019 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: [email protected]

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 costeffective (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 3

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 followup 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, 1820] 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). 5

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 7

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 8

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 10

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 8month 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 glucagonlike 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-

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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.

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double-blind, placebo-controlled study [abstract]. In: American Diabetes Association’s 77th scientific sessions; 2017 Jun 9–13; San Diego, CA. Diabetes 2017;66 (Suppl 1):A391. [43] Goveia P, Cañon-Montañez W, Santos DdP, Lopes GW, Ma RCW, Duncan BB, et al. Lifestyle intervention for the prevention of diabetes in women With previous gestational diabetes mellitus: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2018;9:583. doi: 10.3389/fendo.2018.00583.

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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.

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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.

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21

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Table 1. Characteristics of the five included studies. Metformin First author, year of publication Name of study Study design, time frame Setting

Ratner, 2008

Thiazolidinediones Aroda, 2015

Diabetes DPP Outcomes Prevention Study (DPPOS) Program (DPP) Phase 3 Observational trial, 1996– follow-up, 2001 2002–2008 27 clinical centers, USA

Buchanan, 2002

Xiang, 2006

Troglitazone in the Prevention of Diabetes (TRIPOD) Phase 3 trial, 1995–2000

Pioglitazone in the Prevention of Diabetes (PIPOD) Observational follow-up, N/A

Los Angeles County Women’s and Children’s Hospital, USA

Baseline characteristics of women with prior GDM Age (years) 43.0 (7.6) 34.9 (6.6) vs.¶ 34.3 (6.5) 2 BMI (kg/m ) 34.2 (6.2) 30.5 (5.7) Ethnicity 54% Caucasian 100% Hispanic FPG (mmol/L)

5.9 (0.5)

2-hr PG (mmol/L) HbA1c (%) HbA1c (mmol/mol) Time since GDM pregnancy Intervention, adherence

9.2 (1.0)

Comparator, adherence Primary outcome and assessment Assessment of primary outcome

5.9 (0.5) 41

Hospital or outpatient clinics in Germany

31.0 (4.9) 100% Hispanic

5.5 (0.6) vs.¶ 5.4 (0.5) 8.6 (1.5) vs.¶ 8.5 (1.3) N/A N/A

5.6 (0.5)

27.6 vs.¶ 28.9 100% vs.¶ 94.5% Caucasian 5.2 vs.¶ 5.1

8.4 (1.5)

N/A

5.7 (0.5) 39

5.6 38

N/A

Median of 8.6 months

Within 4 years

Metformin 850 mg bid (n = 111), 68.8%* Placebo (n = 122), 72.9%

Metformin 850 mg bid (n = 97), 77%*

Troglitazone Pioglitazone 45 400 mg daily (n mg daily (n = = 114), 85 (16) 86), N/A % Placebo (n = None 122), 87 (10) % Diabetes, 1997 ADA criteria§

FPG q 6 months, OGTT q 1 year

Phase 2 trial, 2008–2015

35.8 vs.¶ 33.1

N/A

Diabetes, 1997 ADA criteria§

N/A

39 (6.6)

Mean of 12 years

Placebo (n = 100), N/A

DPP-4 inhibitor Hummel, 2018

FPG q 3 months, OGTT q year

FPG, HbA1C q 2 months x 6, then

Vildagliptin 50 mg bid (n = 58), N/A Placebo (n = 55), N/A Diabetes, 2012 ADA criteria† OGTT q 6 months

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Follow-up

Mean of 3 years

Median of 6 years

Effects estimate

50.4% reduction in DAP incidence

40.4% reduction in DAP incidence

Median of 30.9 vs.¶ 28.1 months Adjusted HR 0.44

q 3 months; OGTT q year Median of 35.9 months Average annual DAP incidence rate of 5.2%

Median of 1.92 vs.¶ 2.50 years HR 0.59 (95% CI 0.14–2.47)

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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 author, criteria country Glucagon-like peptide (GLP) 1 receptor agonist ElkindNCT01234649 BMI >25 Metformin + Hirsch, kg/m2, within liraglutide vs. USA 1 year of metformin GDM, IFG and/or IGT Vilsbøll, NCT01795248 BMI 25–45 Liraglutide Denmark kg/m2, within 5 years of GDM Sodium glucose co-transporter (SGLT) 2 inhibitors ElkindNCT02338193 BMI >25 Metformin + Hirsch, kg/m2, within dapagliflozin vs. USA 1 year of dapagliflozin vs. GDM, IFG metformin and/or IGT Kramer, NCT03215069 Within 6–36 Empagliflozin vs. Canada months of placebo GDM

Duration

Primary outcome

Estimated date of completion

84 weeks

IS-SI

June 2019

5 years

Change in glucose tolerance

August 2020

24 weeks

Change in body weight

March 2019

48 weeks

IS-SI

September 2022

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