Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

One Year's Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial.

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (-28 (-44;-11) vs. 2 (-13;18) dB/m, p < 0.01) and body weight (-4.7 (-6.4;-2.9) vs. -1.4 (-3;0.3) kg, p < 0.01). One-year's liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.

Women with prior gestational diabetes mellitus and prediabetes are characterised by a decreased incretin effect.

AIMS/HYPOTHESIS: We investigated whether a reduced incretin effect, as observed in patients with type 2 diabetes, can be detected in high-risk individuals, such as women with prior gestational diabetes mellitus (pGDM). METHODS: In this cross-sectional study, 102 women without diabetes with pGDM and 15 control participants without pGDM and with normal glucose tolerance (NGT) underwent a 4 h 75 g OGTT and an isoglycaemic i.v. glucose infusion (IIGI). Women with pGDM were classified as having NGT or prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Insulin sensitivity was assessed using the Matsuda index and HOMA2-IR and the incretin effect was calculated from insulin responses during the study (100% × [AUCinsulin,OGTT - AUCinsulin,IIGI]/AUCinsulin,OGTT). RESULTS: Sixty-three of the 102 women with pGDM (62%) had prediabetes (median [interquartile range]: age, 38.3 [6.5] years; BMI, 32.1 [5.8] kg/m2) and 39 women (38%) had NGT (age, 39.5 [5.6] years; BMI, 31.0 [6.7] kg/m2). Control participants (n = 15) were not significantly different from the pGDM group with regards to age (39.2 [7.4] years) and BMI (28.8 [9.2] kg/m2). Compared with women with NGT and control participants, women with prediabetes had lower insulin sensitivity, as measured by the Matsuda index (3.0 [2.4] vs 5.0 [2.6] vs 1.5 [1.8], respectively; p < 0.001). The incretin effect was 55.3% [27.8], 73.8% [19.0] and 76.7% [24.6] in women with prediabetes, women with normal glucose tolerance and control participants, respectively (p < 0.01). CONCLUSION/INTERPRETATION: Prediabetes was highly prevalent in women with pGDM, and alterations in the incretin effect were detected in this group before the development of type 2 diabetes. TRIAL REGISTRATION: clinicaltrialsregister.eu 2012-001371-37-DK.

Nonalcoholic Fatty Liver Disease Is Prevalent in Women With Prior Gestational Diabetes Mellitus and Independently Associated With Insulin Resistance and Waist Circumference.

OBJECTIVE: Type 2 diabetes increases the risk of nonalcoholic fatty liver disease (NAFLD), which is a potentially reversible condition but is also associated with progressive fibrosis and cirrhosis. Women with prior gestational diabetes mellitus (pGDM) have a higher risk for NAFLD. RESEARCH DESIGN AND METHODS: One hundred women without diabetes who had pGDM (median [interquartile range]: age 38.6 [6.4] years; BMI 31.0 [6.2] kg/m2) and 11 healthy control subjects without NAFLD (age 37.9 [7.8] years; BMI 28.1 [0.8] kg/m2) underwent a 75-g oral glucose tolerance test (OGTT), DXA whole-body scan, and ultrasonic evaluation of hepatic steatosis. RESULTS: Twenty-four (24%) women with pGDM had NAFLD on the basis of the ultrasound scan. None had cirrhosis. Women with NAFLD had a higher BMI (P = 0.0002) and waist circumference (P = 0.0003), increased insulin resistance (P = 0.0004), and delayed suppression of glucagon after the OGTT (P < 0.0001), but NAFLD was not associated with the degree of glucose intolerance (P = 0.2196). Visceral fat mass differed among the three groups, with the NAFLD group having the highest amount of fat and the control subjects the lowest (P = 0.0003). By logistic regression analysis, insulin resistance (P = 0.0057) and waist circumference (P = 0.0109) were independently associated with NAFLD. CONCLUSIONS: NAFLD was prevalent in this cohort of relatively young and nonseverely obese women with pGDM who are considered healthy apart from their increased risk for diabetes. Insulin resistance and a larger waist circumference were independently associated with the presence of NAFLD, whereas glucose intolerance was not.

Prevalence of anal incontinence during pregnancy and 1 year after delivery in a cohort of primiparous women and a control group of nulliparous women.

INTRODUCTION: The aim of the study was to examine the prevalence of anal incontinence (AI) during pregnancy and 1 year after delivery in primiparous women and to compare it with the prevalences in nulliparous women. MATERIAL AND METHODS: A validated questionnaire regarding AI was filled in by 1018 primiparous women after delivery and by 1836 nulliparous women (baseline). A similar questionnaire was filled in 1 year later by both groups. RESULTS: At baseline the prevalence of flatus incontinence was significantly higher in the primiparous than the nulliparous women (35 vs. 25%), while incontinence for liquid stools was significantly less frequent (8 vs. 20%). Prevalences of incontinence for solid stools were similar. One year later the prevalence of AI was similar in the two groups (flatus incontinence 24 vs. 25%, incontinence for liquid stools 18 vs. 19% and incontinence for solid stools 4 vs. 3%). AI 1 year after the delivery was not related to the mode of delivery. Women with grade 3 or 4 perineal lesions had a significantly higher prevalence of flatus incontinence 1 year after the delivery compared with women without such lesions (48 vs. 23%, p = 0.00). CONCLUSIONS: This prospective cohort study showed remarkably high prevalences of AI during pregnancy and 1 year after delivery in primiparous women and likewise in nulliparous women at baseline and 1 year later. These results may indicate that factors other than pregnancy and delivery are of importance for AI in young women.

Risk factors for urinary incontinence 1 year after the first vaginal delivery in a cohort of primiparous Danish women.

INTRODUCTION AND HYPOTHESIS: The objective was to examine the relationship between maternal and perinatal factors and the occurrence of stress (SUI) or mixed (MUI) urinary incontinence (UI) 1 year after the first vaginal delivery in primiparous women. METHODS: Participants in this prospective cohort were recruited consecutively from June 2003 to July 2005 from all eligible women who delivered in the department. A validated questionnaire, the International Consultation of Incontinence Questionnaire Short Form (ICIQ-SF) was completed by all participants 2-3 days after delivery, and a similar second questionnaire was filled out 1 year later. Additional data were obtained from the medical records. The first questionnaire was completed by 1,018 women (63 %) and the second by 859 women (84 %). The study group comprised the 575 women without any UI before the pregnancy and who had a vaginal delivery. The primary analysis comprised 117 women with either SUI or MUI 1 year after the vaginal delivery and 403 women without any UI. RESULTS: In univariate analyses, the following factors were associated with SUI or MUI: prepregnancy body mass index (BMI) ≥ 30 (p < 0.05), UI during the pregnancy (p < 0.05), perineal lesions (p < 0.05), and anal sphincter tears (p = 0.05). Logistic regression analysis showed that SUI or MUI was strongly associated with UI during the pregnancy [adjusted odds ratio (OR) 4.7, 95 % confidence interval (CI) 2.9-7.7) and inversely associated with oxytocin augmentation (adjusted OR 0.5, 95 % CI 0.3-0.9). CONCLUSIONS: SUI or MUI 1 year after the first vaginal delivery was strongly associated with UI during the pregnancy and inversely associated with oxytocin augmentation.

The effect of a glucagon-like peptide-1 receptor agonist on glucose tolerance in women with previous gestational diabetes mellitus: protocol for an investigator-initiated, randomised, placebo-controlled, double-blinded, parallel intervention trial.

INTRODUCTION: Pregnancy is associated with decreased insulin sensitivity, which is usually overcome by a compensatory increase in insulin secretion. Some pregnant women are not able to increase their insulin secretion sufficiently, and consequently develop gestational diabetes mellitus (GDM). The disease normally disappears after delivery. Nevertheless, women with previous GDM have a high risk of developing type 2 diabetes (T2D) later in life. We aim to investigate the early development of T2D in women with previous GDM and to evaluate whether treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, may modify their risk of developing T2D. METHODS AND ANALYSES: 100 women with previous GDM will be randomised to either liraglutide or placebo treatment for 1 year (blinded) with an open-label extension for another 4 years. Additionally, 15 women without previous GDM will constitute a baseline control group. Women will be tested with an oral glucose tolerance test (primary endpoint: area under the curve for plasma glucose) and an isoglycaemic intravenous glucose infusion at baseline, after 1 year and after 5 years. Additional evaluations include a glucagon test, dual-energy X-ray absorptiometry, imaging of the liver (ultrasound elastography and fibroscanning), an ad libitum meal for food intake evaluation and questionnaires related to appetite, quality of life and alcohol consumption habits. ETHICS AND DISSEMINATION: The protocol has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark, and the Danish Data Protection Agency and will be carried out under the surveillance and guidance of the GCP unit at Copenhagen University Hospital Bispebjerg in compliance with the ICH-GCP guidelines and in accordance with the Helsinki Declaration. Positive, negative and inconclusive results will be published at scientific conferences and as one or more scientific manuscripts in peer-reviewed journals. REGISTRATIONS: The trial is registered at https://eudract.ema.europa.eu (2012-001371-37) and http://www.clinicaltrials.gov (NCT01795248).

Decreased fetal movements: background, assessment, and clinical management.

A reduction or cessation of fetal movements (FMs) is frequently reported by pregnant women and causes concern and anxiety. However, the clinical significance of a history of reduced FMs remains unclear, and the assessment and management of these pregnancies is controversial. This article is a review of the literature on decreased FMs found in medline and the cochrane library using the search phrases: decreased FMs, perinatal outcome, FM monitoring, and fetal assessment. Formal counting of FMs by the pregnant woman could possibly identify the fetuses, which are at risk of compromise, thus allowing for appropriate action. However, the benefit of this intervention has not been definitely proven. Cardiotocography, umbilical/uterine artery Doppler velocimetry, and ultrasonography have been used for antepartum fetal assessment in pregnancies with decreased FMs, but the evidence of a clinical benefit is limited. The effects of fetal assessment with vibroacoustic stimulation and biophysical profile are unknown and should be further evaluated. Present recommendations on the management of pregnancies with decreased FMs are based on limited and inconsistent scientific evidence. There is a need for further well-designed studies in order to provide evidence-based guidelines in the future.