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To assess the safety, tolerability, and pharmacodynamics (PD) of ketohexokinase inhibitor PF-06835919 in participants with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM).This double-blind, placebo-controlled, parallel-group study enrolled adults with NAFLD (≥8% whole liver fat [WLF] using MRI proton density fat fraction [MRI-PDFF]) and T2DM on stable doses of metformin ≥500 mg/day. Participants received once-daily placebo, PF-06835919 150 mg or 300 mg for 16 weeks. Randomization (1:1:1) was via an interactive response technology system. Endpoints included percentage change from baseline (CFB) in WLF using MRI-PDFF (primary endpoint) and CFB in HbA1c (coprimary endpoint) at 16 weeks, PD, safety, and tolerability.Among 164 participants randomized and treated, 145 completed the treatment (placebo n=50; PF-06835919 150 mg n=46; PF-06835919 300 mg n=49). At Week 16, least squares mean (90% confidence interval) percentage CFB in WLF was -5.26 (-12.86, 2.99), -17.05 (-24.01, -9.46), and -19.13% (-25.51, -12.20) in the placebo, PF-06835919 150-, and 300-mg groups, respectively (PF-06835919 300-mg group vs. placebo, P=0.0288). Modest numerical reductions in HbA1c were observed in all groups that did not reach statistical significance. Treatment-emergent adverse event incidence was similar across groups (40.7%, 45.5%, and 32.7% in the placebo, PF-06835919 150-mg, and 300-mg groups, respectively), with no apparent dose-related trend.PF-06835919 administration over 16 weeks was generally safe and well-tolerated and resulted in reductions in WLF in participants with NAFLD and T2DM. This article is protected by copyright. All rights reserved.

This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), which is a novel, oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM).This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice-daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight.In the 37 participants randomized, the most common treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse events were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady state (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo-adjusted difference of up to -67.89 (-88.98, -46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to -40.87 (-53.77, -27.98) mg/dl], glycated haemoglobin [up to -1.41% (-2.01%, -0.82%)] and body weight [up to -1.87 (-3.58, -0.17) kg].In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady state and robustly reduced glycaemic parameters and body weight after 8 weeks of dosing, with a safety profile consistent with the mechanism of action.

Agonism of the glucagon-like peptide-1 receptor (GLP-1R) results in glycemic lowering and body weight loss and is a therapeutic strategy to treat type 2 diabetes (T2D) and obesity. We developed danuglipron (PF-06882961), an oral small-molecule GLP-1R agonist and found it had comparable efficacy to injectable peptidic GLP-1R agonists in a humanized mouse model. We then completed a placebo-controlled, randomized, double-blind, multiple ascending-dose phase 1 study ( NCT03538743 ), in which we enrolled 98 patients with T2D on background metformin and randomized them to receive multiple ascending doses of danuglipron or placebo for 28 d, across eight cohorts. The primary outcomes were assessment of adverse events (AEs), safety laboratory tests, vital signs and 12-lead electrocardiograms. Most AEs were mild, with nausea, dyspepsia and vomiting most commonly reported. There were no clinically meaningful AEs in laboratory values across groups. Heart rate generally increased with danuglipron treatment at day 28, but no heart-rate AEs were reported. Systolic blood pressure was slightly decreased and changes in diastolic blood pressure were similar with danuglipron treatment at day 28, compared with placebo. There were no clinically meaningful electrocardiogram findings. In this study in T2D, danuglipron was generally well tolerated, with a safety profile consistent with the mechanism of action of GLP-1R agonism. Results from a phase 1 study testing a new oral GLP-1 receptor agonist, danuglipron, in patients with type 2 diabetes demonstrate acceptable safety, tolerability and pharmacokinetic profiles of the drug, with exploratory analyses suggesting potential beneficial effects on glycemic control.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

Danuglipron is an oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist shown to reduce plasma glucose and body weight after 28 days of treatment in adults with type 2 diabetes mellitus (T2DM) . This randomized, double-blind (sponsor-open) , placebo-controlled, Phase 1 study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of danuglipron in Japanese patients with T2DM. A total of 37 patients with T2DM inadequately controlled on diet and exercise alone were randomized to twice-daily (BID) oral doses of placebo or multiple, ascending doses of danuglipron titrated to 40 mg, 80 mg, and 120 mg for 8 weeks. Multiple, oral doses of danuglipron were generally safe in Japanese participants with T2DM and resulted in approximate dose-proportional increases in exposure and significant reductions in fasting plasma glucose (FPG) , 24-hour mean daily glucose (MDG) , glycated hemoglobin (HbA1c) , and body weight (Table) . Most adverse events (AEs) were mild or moderate, with AEs of nausea, vomiting, abdominal discomfort, diarrhea, and headache reported most frequently. There were no deaths and no serious AEs related to dosing of danuglipron. No clinically significant adverse trends in labs, electrocardiogram, or vital sign abnormalities were apparent. Disclosure R.Ono: Employee; Pfizer Japan Inc. K.Furihata: Other Relationship; Eli Lilly and Company, Pfizer Japan Inc. Y.Ichikawa: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Japan Inc. Y.Nakazuru: Employee; Pfizer Japan Inc., Stock/Shareholder; Pfizer Inc. A.Bergman: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. D.N.Gorman: Employee; Pfizer Inc. A.R.Saxena: Employee; Pfizer Inc. Funding Sponsored by Pfizer Inc.

ImportanceCurrently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration.ObjectiveTo investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks.Design, Setting, and ParticipantsA phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions.InterventionsParticipants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily.Main Outcomes and MeasuresChange from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period.ResultsOf 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of −1.16% (90% CI, −1.47% to −0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of −33.24 mg/dL (90% CI, −45.63 to −20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of −2.04 kg (90% CI, −3.01 to −1.07 kg) for the 80-mg twice daily group and −4.17 kg (90% CI, −5.15 to −3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting.Conclusions and RelevanceIn adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action.Trial RegistrationClinicalTrials.gov Identifier: NCT03985293

PF‐05221304 is a liver‐targeted inhibitor of acetyl‐CoA carboxylase, an enzyme that catalyzes the first committed step in de novo lipogenesis (DNL). This first‐in‐human study investigated safety/tolerability and pharmacokinetics of single and multiple ascending oral PF‐05221304 doses, and fructose‐stimulated DNL inhibition with repeated oral doses. Healthy subjects (n = 96) received single (1‐240 mg) or repeated (2‐200 mg daily) doses for 14 days or single 100‐mg doses with and without food. PF‐05221304 was well tolerated at all doses. Repeated PF‐05221304 doses inhibited hepatic DNL in a dose‐dependent manner, with near‐complete inhibition seen at higher doses. With doses yielding ≥90% DNL inhibition, asymptomatic increases in fasting/postprandial serum triglyceride levels (≥40 mg/day) and declines in platelet count (≥60 mg/day) occurred; these were not observed at ≤80% DNL inhibition. Steady‐state pharmacokinetics generally increased dose‐proportionally, with a half‐life of 14‐18 hours and a minimal food effect on plasma exposure. The observed safety and tolerability, pharmacokinetics, and pharmacodynamics support the continued evaluation of PF‐05221304 for the treatment of nonalcoholic steatohepatitis.

Agonism of the glucagon-like peptide-1 receptor (GLP-1R) results in glycemic lowering and body weight loss and is a therapeutic strategy to treat type 2 diabetes (T2D) and obesity. We developed danuglipron (PF-06882961), an oral small-molecule GLP-1R agonist and found it had comparable efficacy to injectable peptidic GLP-1R agonists in a humanized mouse model. We then completed a placebo-controlled, randomized, double-blind, multiple ascending-dose phase 1 study ( NCT03538743 ), in which we enrolled 98 patients with T2D on background metformin and randomized them to receive multiple ascending doses of danuglipron or placebo for 28 d, across eight cohorts. The primary outcomes were assessment of adverse events (AEs), safety laboratory tests, vital signs and 12-lead electrocardiograms. Most AEs were mild, with nausea, dyspepsia and vomiting most commonly reported. There were no clinically meaningful AEs in laboratory values across groups. Heart rate generally increased with danuglipron treatment at day 28, but no heart-rate AEs were reported. Systolic blood pressure was slightly decreased and changes in diastolic blood pressure were similar with danuglipron treatment at day 28, compared with placebo. There were no clinically meaningful electrocardiogram findings. In this study in T2D, danuglipron was generally well tolerated, with a safety profile consistent with the mechanism of action of GLP-1R agonism.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health.One Sentence SummaryPF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.

Background and Objective Obesity is a chronic disease associated with many serious comorbidities. Pharmacologic therapies are approved for the treatment of obesity; however, short‐term biomarkers to predict weight loss are not well understood. This study aimed to determine the ability of single‐meal energy intake (EI) to predict weight loss in participants with obesity treated with liraglutide. Methods In this randomized, double‐blind, placebo‐controlled study, participants received subcutaneous liraglutide (titrated to 3.0 mg/day) or placebo once daily, with inpatient assessments at baseline and weeks 3 and 6. The primary endpoint was change from baseline (CFB) in EI during consecutive ad libitum lunch meals at weeks 3 and 6. Secondary endpoints included CFB in 24‐ and 48‐h EI, weight, appetite scores, and gastric emptying measures. Results Sixty‐one participants were randomized (n = 32, liraglutide; n = 29, placebo). The least squares mean (LSM) difference (95% CI; p‐value) in CFB in EI during ad libitum lunch meals between the liraglutide and placebo groups was −236 (−322, −149; p

Background: PF-06882961 is an oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist with efficacy in nonclinical models comparable to injectable peptidic GLP-1R agonists. This randomized, double-blind, placebo-controlled, multiple ascending dose, Phase 1 study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of PF–06882961 administered for 28 days in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 98 patients with T2DM taking metformin were randomized, in 8 cohorts (5 planned, 3 optional), to PF–06882961 (up to 120 mg twice daily [BID]) or placebo in a 3:1 ratio for 28 days, and 92 completed the inpatient study. Fasting plasma glucose (FPG), 24-hour mean daily glucose (MDG) and body weight were assessed at baseline and at Day 28. Results: Multiple, oral doses of PF-06882961 were safe and well tolerated in adult participants with T2DM, and resulted in robust reductions in FPG, MDG and body weight at Day 28. The majority of adverse events (AEs) were mild, with AEs of nausea, dyspepsia, diarrhea, headache, constipation, and vomiting most commonly reported. There were no deaths and no serious AEs related to dosing of PF–06882961. No clinically significant adverse trends in labs, electrocardiogram or vital sign abnormalities were apparent. Disclosure A. Saxena: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. D. Gorman: Employee; Self; Pfizer Inc. K. Chidsey: None. C. Buckeridge: Employee; Self; Pfizer Inc. A.M. Kim: Employee; Self; Pfizer Inc. A. Bergman: Employee; Self; Pfizer Inc.

Author(s): Manosroi, Worapaka; Tan, Jia Wei; Rariy, Chevon M; Sun, Bei; Goodarzi, Mark O; Saxena, Aditi R; Williams, Jonathan S; Pojoga, Luminita H; Lasky-Su, Jessica; Cui, Jinrui; Guo, Xiuqing; Taylor, Kent D; Chen, Yii-Der I; Xiang, Anny H; Hsueh, Willa A; Raffel, Leslie J; Buchanan, Thomas A; Rotter, Jerome I; Williams, Gordon H; Seely, Ellen W | Abstract: ContextHypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER-β, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle.ObjectiveTo determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women.MethodsCandidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (l51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging.ResultsMultivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (β = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1.ConclusionsThe variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.

Age, sex, hypertension and dietary sodium are proposed to affect plasma and urinary catecholamines. Yet no prior study has examined the simultaneous effects of these factors within the same study population. So results may have been confounded by factors not determined. We investigate, for the first time, the impact of simultaneously determined predictors of plasma and urinary catecholamines and the relationship of catecholamines with the diagnosis of hypertension. Hypertensive and normotensive subjects (n=308) were studied off antihypertensives in liberal and low sodium balance. 24 h urinary catecholamines (norepinephrine and epinephrine) were measured. Plasma catecholamines were measured supine after overnight fast. Repeated measures multivariate linear regression models examined the effect of sex, race, age, body mass index (BMI), dietary salt (liberal salt vs low salt), hypertension status and mean arterial pressure (MAP) on plasma and urinary catecholamines. Logistic regression determined the relationship of catecholamines with diagnosis of hypertension. Dietary sodium restriction and increasing age predicted increased plasma and urinary norepinephrine, with sodium restriction having the greatest effect. Female sex predicted lower urinary and plasma epinephrine. Neither plasma nor urinary catecholamines predicted the diagnosis of hypertension. In summary, specific demographic factors variably impact catecholamines and should be considered when assessing catecholamines in research and clinical settings.

This study aims at identifying associations between therapeutics used during labor and the occurrence of postpartum preeclampsia (PPPE), a poorly understood entity.This is a case-control study of women who received an ICD-9 code for PPPE (cases) during the years 2009-2011, compared to women with a normotensive term pregnancy, delivery and postpartum period until discharge (controls), matched on age (±1year) and delivery date (±3months). Cases were defined as women having a normotensive term pregnancy, delivery and initial postpartum period (48h post-delivery) but developing hypertension between 48h and 6weeks postpartum. Single variable and multiple variable models were used to determine significant risk factors.Forty-three women with PPPE were compared to 86 controls. Use of vasopressors and oxytocin did not differ between cases and controls, but rate of fluids administered during labor (OR=1.68 per 100cc/h; 95% CI: 1.09-2.59, p=0.02) and an elevated pre-pregnancy/first trimester BMI (OR=1.18 per kg/mWe identified two potentially modifiable risk factors for PPPE; further studies are needed to better define the role of these two variables in the development of PPPE.

Background Higher exposure to certain phthalates is associated with a diabetes and insulin resistance, with sex differences seen. Yet, little is known about the association between phthalates and metabolic syndrome (MetS), particularly with consideration for differences by sex and menopausal status. Methods We analyzed data from 2719 participants in the National Health and Nutrition Examination Survey (NHANES) 2001–2010 aged 20–80 years. Five urinary phthalate metabolites (MEP, MnBP, MiBP, MBzP, and MCPP) and DEHP metabolites were analyzed by the Centers for Disease Control and Prevention and were evaluated as population-specific quartiles. MetS was defined by National Cholesterol Education Program’s Adult Treatment Panel III report criteria. Prevalence odds ratios (POR) and 95 % confidence intervals (CI) were calculated using multivariable logistic regression, adjusting for potential confounders and stratifying by sex and menopausal status. Results Participants with MetS (32 % of the study population) had higher concentrations for all urinary phthalate metabolites. After full adjustment, higher DEHP metabolite concentrations were associated with an increased odds of MetS in men, but not women (adj. POR for men Q4 versus Q1: 2.20; 95 % CI: 1.32, 3.68 and adj. POR for women Q4 versus Q1: 1.50; 95 % CI: 0.89, 2.52). When evaluating by menopausal status, pre-menopausal women with higher concentrations of MBzP had close to a 4-fold increased odds of MetS compared to pre-menopausal women with the lowest concentrations of MBzP (adj POR: Q4 versus Q1: 3.88; 95 % CI: 1.59, 9.49). Conclusions Higher concentrations of certain phthalate metabolites were associated with an increased odds of MetS. Higher DEHP metabolite concentrations were associated with an increased odds of MetS for men. In women, the strongest association was between higher concentrations of MBzP and MetS, but only among pre-menopausal women. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0136-x) contains supplementary material, which is available to authorized users.

Objective In postmenopausal women, a relationship between luteinizing hormone (LH) and cortisol levels has been suggested. Furthermore, LH receptors in the adrenal gland have been shown to mediate adrenocorticotropic hormone-independent Cushing syndrome. In contrast, follicle-stimulating hormone (FSH) receptors have not been found in the adrenal gland. Our objective was to explore the relationship of LH with adrenal function in postmenopausal women, as assessed by 24-hour urinary free cortisol (UFC) and aldosterone excretion rate (AER). Methods Participants were studied at a single time point in the fasting state in the Clinical Research Center of Brigham and Women's Hospital. We studied 36 postmenopausal women in sodium balance to control for variation in endogenous levels of plasma renin activity and angiotensin II. Serum cortisol, aldosterone, LH, and FSH levels were measured, as were 24-hour UFC and AER. Correlations were performed by calculation of Pearson's correlation coefficient. Results Serum LH correlated significantly with log-transformed UFC (r = 0.43, P = 0.01) and inversely with log AER (r = -0.50, P = 0.002). We found no correlation of serum LH with serum cortisol or aldosterone, nor did we find correlation of FSH with these parameters. Conclusions In postmenopausal women, serum LH levels correlate significantly with UFC (positively) and AER (negatively). LH stimulation may induce subtle shifts in adrenal function toward cortisol secretion.

Objective. To test utility of cystatin-C as a marker of glomerular filtration rate during pregnancy, we performed serial correlations with inulin clearance during pregnancy and postpartum. Methods. Twelve subjects received inulin infusions and serum cystatin-C at three time points. Pearson's correlation coefficient was calculated. Results. Cystatin-C levels ranged 0.66–1.48 mg/L during pregnancy, and 0.72–1.26 mg/L postpartum. Inulin clearance ranged 130–188 mL/min during pregnancy, and 110–167 mL/min postpartum. Cystatin-C did not correlate with inulin clearance at any time point. Conclusion. Serum cystatin-C did not correlate with inulin clearance during pregnancy or postpartum.

Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high- and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; P P =0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P =0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus −18.9 pg/mL; P =0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women.

Evaluation of: Kwasniewska M, Pikala M, Kaczmarczyk-Chalas K et al. Smoking status, the menopausal transition, and metabolic syndrome in women. Menopause 19, 194–201 (2012). This study was a cross-sectional analysis of 7462 randomly selected Polish women, aged 20–74 years, who had completed the WOBASZ, a Polish National Multicenter Health Survey. Components of metabolic syndrome, including waist circumference, fasting plasma glucose, triglycerides, blood pressure and high-density lipoprotein cholesterol were measured in addition to BMI. The authors assessed the prevalence of metabolic syndrome in pre- and postmenopausal women with respect to smoking status (current smoking, past smoking or never smoked). They determined that the prevalence of metabolic syndrome was 3.3-fold higher in postmenopausal women compared with premenopausal women and that past smoking was associated with higher odds of metabolic syndrome, regardless of menopausal status. Previous studies that have examined the risk of developing metabolic syndrome after smoking cessation did not assess menopausal status in women, and also used reported rather than measured anthropomorphic data. This study provides an additional perspective on the metabolic changes that may occur in women after smoking cessation.

This chapter provides 18 Gynecology Board Review Questions.

Background: Phthalates are ubiquitous endocrine disrupting chemicals associated with diabetes. Although women and minorities are more likely to be exposed to phthalates, no prior studies have examined phthalate exposure and markers of diabetes risk evaluating effect modification by gender and race/ethnicity. Methods: We analyzed CDC data for 8 urinary phthalate metabolites from 3,083 non-diabetic, non-pregnant participants aged 12- < 80 years in the National Health and Nutrition Examination Survey (NHANES) 2001–2008. We used median regression to assess the associations between urinary phthalate metabolites and fasting blood glucose (FBG), fasting insulin and Homeostatic Model Assessment of insulin resistance (HOMA-IR), controlling for urinary creatinine as well as several sociodemographic and behavioral factors. Stratified analyses were conducted to compare the gender- and race/ethnicity-specific patterns for the associations. Results: Urinary levels of several phthalate metabolites, including MBzP, MnBP, MiBP, MCPP and ∑DEHP showed significant positive associations with FBG, fasting insulin and HOMA-IR. No clear difference was noted between men and women. Mexican-Americans and non-Hispanic blacks had stronger dose–response relationships for MnBP, MiBP, MCPP and ∑DEHP compared to non-Hispanic whites. For example, the highest quartile of MiBP relative to its lowest quartile showed a median FBG increase of 5.82 mg/dL (95% CI: 3.77, 7.87) in Mexican-Americans, 3.63 mg/dL (95% CI: 1.23, 6.03) in blacks and 1.79 mg/dL (95% CI: -0.29, 3.87) in whites. Conclusions: The findings suggest that certain populations may be more vulnerable to phthalates with respect to disturbances in glucose homeostasis. Whether endocrine disrupting chemicals contribute to gender and racial/ethnic differences in diabetes risk will be an important area for further study.

Background First trimester Pregnancy Associated Plasma Protein A (PAPP-A) levels, routinely measured for aneuploidy screening, may predict development of preeclampsia. This study tests the hypothesis that first trimester PAPP-A levels correlate with soluble fms-like tyrosine kinase-1 (sFlt-1) levels, an angiogenic marker associated with preeclampsia, throughout pregnancy. Methods sFlt-1 levels were measured longitudinally in 427 women with singleton pregnancies in all three trimesters. First trimester PAPP-A and PAPP-A Multiples of Median (MOM) were measured. Student’s T and Wilcoxon tests compared preeclamptic and normal pregnancies. A linear mixed model assessed the relationship between log PAPP-A and serial log sFlt-1 levels. Results PAPP-A and PAPP-A MOM levels were significantly lower in preeclamptic (n = 19), versus normal pregnancies (p = 0.02). Although mean third trimester sFlt-1 levels were significantly higher in preeclampsia (p = 0.002), first trimester sFlt-1 levels were lower in women who developed preeclampsia, compared with normal pregnancies (p = 0.03). PAPP-A levels correlated significantly with serial sFlt-1 levels. Importantly, low first trimester PAPP-A MOM predicted decreased odds of normal pregnancy (OR 0.2, p = 0.002). Conclusions Low first trimester PAPP-A levels suggests increased future risk of preeclampsia and correlate with serial sFlt-1 levels throughout pregnancy. Furthermore, low first trimester PAPP-A status significantly predicted decreased odds of normal pregnancy.