Metabolic Health Risks Research Articles

Association Between Body Mass Index (BMI), Vitamin D, and Testosterone Levels.

Introduction Obesity is measured scientifically by calculating body mass index (BMI). Body mass index in men is linked to various hormonal imbalances. This study aims to observe the relationships between BMI, vitamin D, and testosterone levels in patients attending the outpatient clinic at Hayatabad Medical Complex, Peshawar, Pakistan. Methods This observational cross-sectional study involved 272 patients, presenting to the medical outpatient department from January 1st, 2023, to December 31st, 2023. Body mass index, serum vitamin D, and testosterone levels were measured for each participant. Body mass index was categorized into normal, overweight, and obese. Statistical analysis was calculated, including descriptive statistics, logistic regression, and correlation analysis to evaluate associations between these variables. Results The mean BMI of the participants was 25.82 ± 7.88 kg/m². A significant inverse correlation was observed between BMI and vitamin D levels (r = -0.79, p < 0.001) and between BMI and testosterone levels (r = -0.87, p < 0.001). A positive correlation was found between vitamin D and testosterone levels (r = 0.87, p < 0.001). Logistic regression analysis revealed that higher BMI in the range of overweight or above was associated with a 2.5-fold increase in the likelihood of vitamin D deficiency (odds ratio (OR) = 2.50, 95% CI = 1.8-3.5, p < 0.001) and a 3.1-fold increase in the likelihood of low testosterone levels (OR = 3.10, 95% CI = 2.2-4.3, p < 0.001). Conclusion In this study, higher BMI is significantly associated with lower vitamin D and testosterone levels. These findings suggest that addressing obesity could help mitigate hormonal imbalances, such as vitamin D deficiency and low testosterone, which are linked to metabolic health risks. It can also be hypothesized that obesity can be a risk factor for vitamin D and testosterone deficiency.

Influence of Type 2 Diabetes and Adipose Tissue Dysfunction on Breast Cancer and Potential Benefits from Nutraceuticals Inducible in Microalgae.

Breast cancer (BC) represents the most prevalent cancer in women at any age after puberty. From a pathogenetic prospective, despite a wide array of risk factors being identified thus far, poor metabolic health is emerging as a putative risk factor for BC. In particular, type 2 diabetes mellitus (T2DM) provides a perfect example bridging the gap between poor metabolic health and BC risk. Indeed, T2DM is preceded by a status of hyperinsulinemia and is characterised by hyperglycaemia, with both factors representing potential contributors to BC onset and progression. Additionally, the aberrant secretome of the dysfunctional, hypertrophic adipocytes, typical of obesity, characterised by pro-inflammatory mediators, is a shared pathogenetic factor between T2DM and BC. In this review, we provide an overview on the effects of hyperglycaemia and hyperinsulinemia, hallmarks of type 2 diabetes mellitus, on breast cancer risk, progression, treatment and prognosis. Furthermore, we dissect the role of the adipose-tissue-secreted adipokines as additional players in the pathogenesis of BC. Finally, we focus on microalgae as a novel superfood and a source of nutraceuticals able to mitigate BC risk by improving metabolic health and targeting cellular pathways, which are disrupted in the context of T2DM and obesity.

Maternal diet during pregnancy and adaptive changes in the maternal and fetal pancreas have implications for future metabolic health.

Fetal and neonatal development is a critical period for the establishment of the future metabolic health and disease risk of an individual. Both maternal undernutrition and overnutrition can result in abnormal fetal organ development resulting in inappropriate birth size, child and adult obesity, and increased risk of Type 2 diabetes and cardiovascular diseases. Inappropriate adaptive changes to the maternal pancreas, placental function, and the development of the fetal pancreas in response to nutritional stress during pregnancy are major contributors to a risk trajectory in the offspring. This interconnected maternal-placental-fetal metabolic axis is driven by endocrine signals in response to the availability of nutritional metabolites and can result in cellular stress and premature aging in fetal tissues and the inappropriate expression of key genes involved in metabolic control as a result of long-lasting epigenetic changes. Such changes result is insufficient pancreatic beta-cell mass and function, reduced insulin sensitivity in target tissues such as liver and white adipose and altered development of hypothalamic satiety centres and in basal glucocorticoid levels. Whilst interventions in the obese mother such as dieting and increased exercise, or treatment with insulin or metformin in mothers who develop gestational diabetes, can improve metabolic control and reduce the risk of a large-for-gestational age infant, their effectiveness in changing the adverse metabolic trajectory in the child is as yet unclear.

Sex-Specific Variation in Metabolic Responses to Diet.

Suboptimal nutrition is a leading cause of cardiometabolic disease and mortality. Biological sex is a variable that influences individual responses to dietary components and may modulate the impact of diet on metabolic health and disease risk. This review describes findings of studies reporting how biological sex may associate with or affect metabolic outcomes or disease risk in response to varying dietary macronutrient content, Mediterranean diet, Western diet, and medical very low-calorie diet. Although few dietary interventions have been specifically designed to identify sex-diet interactions, future studies improving understanding how sex influences dietary responses could inform precision nutrition interventions for disease prevention and management.

Associations between urine glyphosate levels and metabolic health risks: insights from a large cross-sectional population-based study

BackgroundThe prevalence of metabolic syndrome (MetS) in American adults increased from 37.6% in the 2011–12 period to 41.8% in 2017–2018. Environmental exposure, particularly to common compounds such as glyphosate, has drawn increasing attention as a potential risk factor.MethodsWe employed three cycles of data (2013–2018) from the National Health and Nutrition Examination Survey (NHANES) in a cross-sectional study to examine potential associations between urine glyphosate measurements and MetS incidence. We first created a MetS score using exploratory factor analysis (EFA) of the International Diabetes Federation (IDF) criteria for MetS, with data drawn from the 2013–2018 NHANES cycles, and validated this score independently on an additional associated metric, the albumin-to-creatinine (ACR) ratio. The score was validated via a machine learning approach in predicting the ACR score via binary classification and then used in multivariable regression to test the association between quartile-categorized glyphosate exposure and the MetS score.ResultsIn adjusted multivariable regressions, regressions between quartile-categorized glyphosate exposure and MetS score showed a significant inverted U-shaped or saturating dose‒response profile, often with the largest effect for exposures in quartile 3. Exploration of potential effect modification by sex, race, and age category revealed significant differences by race and age, with older people (aged > 65 years) and non-Hispanic African American participants showing larger effect sizes for all exposure quartiles.ConclusionsWe found that urinary glyphosate concentration is significantly associated with a statistical score designed to predict MetS status and that dose–response coefficient is nonlinear, with advanced age and non-Hispanic African American, Mexican American and other Hispanic participants exhibiting greater effect sizes.

Off-label use of clomiphene citrate to treat anabolic androgenic steroid induced hypogonadism upon cessation among men (CloTASH) – A pilot study protocol

BackgroundNon-prescribed anabolic androgenic steroid (AAS) use is associated with AAS-induced hypogonadism (ASIH), and metabolic, cardiovascular, and mental health risks. Symptoms of ASIH (fatigue, depression, anxiety, sexual dysfunction) are hard to endure following cessation, but there is no consensus on whether endocrine treatment should be used to treat ASIH. This proof-of-concept study aims to explore safety of off-label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency, and to study changes in health risks after cessation. MethodsIn this open-labeled non-randomized off-label hormone intervention pilot study, we shall include males with AAS dependence intending to cease use. The 16-week intervention included clomiphene citrate, transdermal testosterone gel for the first four weeks and optional human chorionic gonadotropin (hCG) from week 4 if low treatment response. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention, and at 6- and 12 months post cessation. Change in self-reported symptoms of hypogonadism and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without the medical intervention. The study may provide valuable clinical insights and may be used to inform the design of future intervention studies.

The use of portable abdominal bioimpedance analyzer Yscope in the assessment of abdominal obesity.

Obesity, especially abdominal obesity, is strongly correlated with metabolic and other health risks. Diagnosis and assessment of obesity is important in clinical and routine preventive practice. From the point of view of risk, it is necessary to distinguish not only the area of fat tissue accumulation, but also its type. The aim of the study was to use a new portable abdominal bioimpedance analyzer, which is intended for the area of abdominal adipose tissue, as part of the evaluation of the body structure of a selected group of volunteers with a focus on the differentiation of subcutaneous and visceral adipose tissue and to assess its usefulness in practice. Body composition was analyzed using a portable abdominal bioimpedance analyzer Yscope (PA-BIA) in combination with a bioimpedance device InBody 970 (high-frequency bioelectrical impedance/HF-BIA). Eighty-three volunteers at the age of 24.92±7.24 years with representation of both sexes participated in the study. Abdominal fat did not differ significantly between the sexes, women reached an average value of 2.01±1.14 kg, men 2.22±1.60 kg (p>0.05). Gender differentiation was manifested in the case of visceral fat (p<0.01) and visceral fat area (p<0.01), the values of which were lower in women than in men. In the case of subcutaneous fat, we found the opposite trend of values in relation to gender, where lower values were achieved by men, but there were no significant differences (p>0.05). Visceral fat was most correlated with abdominal fat (r=0.86) and waist circumference (r=0.85), subcutaneous fat had the strongest positive correlations with abdominal fat (r=0.93) and with body fat mass (r=0.93). PA-BIA in combination with HF-BIA makes it possible to determine the representation of subcutaneous and visceral fat in the abdominal area, which the conventional MFS-BIA method does not allow. When evaluating body composition, significant gender differentiation is confirmed, which is an important factor affecting different health risks related to gender and the representation of different types of fat tissue localized and accumulated in different parts of the body.

Estimated Cardiorespiratory Fitness and Metabolic Risks.

This review focuses on the emerging evidence for the association between non-exercise fitness testing, estimated cardiorespiratory fitness (eCRF), and metabolic risk factors. Given the challenges associated with directly measuring cardiorespiratory fitness (CRF) in large populations, eCRF presents a practical alternative for predicting metabolic health risks. A literature search identified seven relevant cohort studies from 2020 to 2024 that investigated the association of eCRF with hypertension, hyperglycemia, dyslipidemia, and obesity. This review consistently demonstrates an inverse relationship between higher eCRF and a lower incidence of metabolic risks, which is in line with CRF cohort studies. It highlights the importance of low eCRF as a primordial indicator for metabolic risks and underscores the potential for broader application. Future research directions should include exploring eCRF's predictive ability across diverse populations and health outcomes and testing its real-world applicability in healthcare and public health settings.

Aldehyde oxidase mediated enantioselective metabolic health risk of dinotefuran

Aldehyde oxidase mediated enantioselective metabolic health risk of dinotefuran

Sulfonamide-induced DNA hypomethylation disturbed sugar metabolism in rice (Oryza sativa L.)

DNA methylation is well-accepted as a bridge to unravel the complex interplay between genome and environmental exposures, and its alteration regulated the cellular metabolic responses towards pollutants. However, the mechanism underlying site-specific aberrant DNA methylation and metabolic disorders under pollutant stresses remained elusive. Herein, the multilevel omics interferences of sulfonamides (i.e., sulfadiazine and sulfamerazine), a group of antibiotics pervasive in farmland soils, towards rice in 14 days of 1 mg/L hydroponic exposure were systematically evaluated. Metabolome and transcriptome analyses showed that 57.1–71.4 % of mono- and disaccharides were accumulated, and the differentially expressed genes were involved in the promotion of sugar hydrolysis, as well as the detoxification of sulfonamides. Most differentially methylated regions (DMRs) were hypomethylated ones (accounting for 87–95 %), and 92 % of which were located in the CHH context (H = A, C, or T base). KEGG enrichment analysis revealed that CHH-DMRs in the promoter regions were enriched in sugar metabolism. To reveal the significant hypomethylation of CHH, multi-spectroscopic and thermodynamic approaches, combined with molecular simulation were conducted to investigate the molecular interaction between sulfonamides and DNA in different sequence contexts, and the result demonstrated that sulfonamides would insert into the minor grooves of DNA, and exhibited a stronger affinity with the CHH contexts of DNA compared to CG or CHG contexts. Computational modeling of DNA 3D structures further confirmed that the binding led to a pitch increase of 0.1 Å and a 3.8° decrease in the twist angle of DNA in the CHH context. This specific interaction and the downregulation of methyltransferase CMT2 (log2FC = –4.04) inhibited the DNA methylation. These results indicated that DNA methylation-based assessment was useful for metabolic toxicity prediction and health risk assessment.

Prevalence of obesity and associated health risks in soldiers of the German Armed Forces

BackgroundObesity rates are rising in the armed forces of Western democratic countries, impacting military readiness and health. This highlights the need for preventive health risk assessments and countermeasures.MethodsUsing mandatory health examination data from 2018 to 2022, we analyzed the prevalence of obesity, health risks, and associated specific military risk factors (rank and unit) in 43,214 soldiers of the German Armed Forces. Statistical methods included χ2 contingencies and binary logistic regressions.ResultsThe prevalence of obesity (BMI ≥ 30) was 18.0%. Male soldiers (OR = 3.776) and those with an officer’s rank (OR = 1.244) had an increased chance for obesity. Serving in a combat unit reduced the chance of being obese (OR = .886). Considering BMI and waist circumference, 2.4% of the total sample faced extremely high cardiovascular and metabolic health risks, while 11.0% and 11.6% had very high or high health risks, respectively.ConclusionsOur data underscore the importance of targeting obesity-related health risk factors in soldiers to ensure their well-being and deployment readiness.

Metabolic Health, Overweight or Obesity, and Depressive Symptoms among Older Australian Adults.

The relationship between overweight or obesity and depressive symptoms in individuals with or without cardio-metabolic abnormalities is unclear. In a cross-sectional study we examined the odds of experiencing depressive symptoms in overweight or obese older adults with or without metabolic abnormalities. The participants included 3318 older adults from the Hunter Community Study Cohort with a Body Mass Index (BMI) ≥ 18.5 kgm2, stratified by BMI and metabolic health risk. Obesity was defined as BMI ≥ 30 kgm2 and metabolically healthy as the absence of metabolic risk factors, according to International Diabetic Federation criteria for metabolic syndromes. Moderate to severe depressive symptoms were defined as a Centre for Epidemiological Studies Depression Scale (CES-D) score ≥ 16. Compared to the metabolically healthy normal weight (MHNW) group, the odds of experiencing moderate/severe depressive symptoms were higher in those classified as a metabolically unhealthy normal weight (MUNW) (odds ratio (OR) = 1.25, 95% Confidence Interval (CI): 0.76-2.06) or metabolically unhealthy obesity (MUO) (OR = 1.48, 95% CI: 1.00-2.19), but not in those classified as metabolically unhealthy overweight (MUOW) (OR = 0.96, 95% CI: 0.63-1.45), metabolically healthy overweight (MHOW) (OR = 0.80, 95% CI: 0.51-1.26), and metabolically healthy obesity (MHO) (OR = 1.03, 95% CI: 0.65-1.64). Compared with MHNW males, the odds of moderate/severe depressive symptoms were increased in all other BMI category-metabolic health groups for males and females. Our relatively small sample size and cross-sectional design did not allow us to robustly establish causality. The odds of experiencing moderate/severe depressive symptoms were increased in metabolically unhealthy older adults regardless of normal weight or obesity, with the odds of having moderate/severe depressive symptoms being higher in females than in males.

Metabolic syndrome risk among adolescents in the Deep South and the relationships with behavioral health, food insecurity, and physical activity.

A combination of physical and psychosocial risk factors put adolescents at risk for poor cardiometabolic health and chronic disease burden, often recognized as metabolic syndrome. The purposes of this study were to (1) identify the prevalence of metabolic syndrome risk among adolescents, utilizing the metabolic syndrome severity index, and (2) determine the relationship between metabolic syndrome risk and behavioral health, food insecurity, and physical inactivity among adolescents. A cross-sectional, descriptive, correlational design was deployed in an inner-city high school in the Deep South. An 8-month recruitment and enrollment period yielded a sample of 55 adolescents. A battery of measures included assessment of demographic data, anthropometric, cardiovascular, and psychosocial data. Utilizing these data elements, a progressive methodological approach was used to identify metabolic severity risk as a continuous variable for use in the adolescent population. All participants identified as African American/Black. Among them, 71% (N = 39) were female and an average age of 16 (SD = 1.3) years old, with 67.3% (N = 37) of the sample at risk for metabolic syndrome. There was not a statistically significant relationship between metabolic syndrome severity score and behavioral health risk, food insecurity, and physical inactivity in this sample. Future use of the continuous metabolic syndrome severity score may guide practice by utilizing longitudinal data to assess the trends of metabolic syndrome severity scores in relation to disease outcomes in adolescents. This may promote the identification of psychosocial and physical interrelationships with metabolic syndrome, thus improving overall health through the development of age-appropriate interventions.

A multicenter prospective randomized controlled trial investigating the effects of combustion-free nicotine alternatives on cardiovascular risk factors and metabolic parameters in individuals with type 2 diabetes who smoke: the DiaSmokeFree study protocol

Stopping smoking is crucial for public health and especially for individuals with diabetes. Combustion-free nicotine alternatives like e-cigarettes and heated tobacco products are increasingly being used as substitutes for conventional cigarettes, contributing to the decline in smoking prevalence. However, there is limited information about the long-term health impact of those products in patients with diabetes. This randomized controlled trial aims to investigate whether switching from conventional cigarettes to combustion-free nicotine alternatives will lead to a measurable improvement in cardiovascular risk factors and metabolic parameters over a period of 2 years in smokers with type 2 diabetes. The multicenter study will be conducted in seven sites across four countries. A total of 576 smokers with type 2 diabetes will be randomly assigned (1:2 ratio) to either standard of care with brief cessation advice (Control Arm) or combustion-free nicotine alternatives use (Intervention Arm). The primary end point is the change in the proportion of patients with metabolic syndrome between baseline and the 2-year follow-up. Additionally, the study will analyze the absolute change in the sum of the individual factors of metabolic syndrome at each study time point. Patient recruitment has started in September 2021 and enrollment is expected to be completed by December 2023. Results will be reported in 2026. This study may provide valuable insights into cardiovascular and metabolic health benefits or risks associated with using combustion-free nicotine alternatives for individuals with type 2 diabetes who are seeking alternatives to tobacco cigarette smoking. The study protocol, informed consent forms, and relevant documents were approved by seven ethical review boards. Study results will be disseminated through articles published in high-quality, peer-reviewed journals and presentations at conferences.

Metabolic phenotyping of BMI to characterize cardiometabolic risk: evidence from large population-based cohorts

Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body mass index (BMI). Conversely, not all obese individuals present with metabolic disorders giving rise to the concept of “metabolically healthy obese”. We use lipidomic-based models for BMI to calculate a metabolic BMI score (mBMI) as a measure of metabolic dysregulation associated with obesity. Using the difference between mBMI and BMI (mBMIΔ), we identify individuals with a similar BMI but differing in their metabolic health and disease risk profiles. Exercise and diet associate with mBMIΔ suggesting the ability to modify mBMI with lifestyle intervention. Our findings show that, the mBMI score captures information on metabolic dysregulation that is independent of the measured BMI and so provides an opportunity to assess metabolic health to identify “at risk” individuals for targeted intervention and monitoring.

Prolong Sitting: A Metabolic Health Risk among White-collar Workers: A Review Article

Abstract: This article is about the metabolic health risks involved with prolonged sitting also known as sedentary lifestyle. Our bodies are designed to move, and research has shown that sedentary lifestyles increase health risks. In addition to type 2 diabetes, cancers, and cardiovascular diseases, sedentary lifestyles can lead to premature mortality. Often times a sedentary activity such as prolonged sitting is overlooked, when in fact, sitting for long periods of time has a negative effect on health. The goal of this presentation is to research and spread awareness about the health risks involved with prolonged sitting. In order to spread awareness, we have explored most of the common health risk associated with prolong sitting and as well made some crucial recommendations that are needed to elicit the right attitude to prolong sitting among individuals. This topic address sedentary lifestyles as a problem and display what a sedentary lifestyle looks like. It went further to discuss the problem of prolonged sitting and potential solutions. Although there are resources that already exist on the topic of sedentary lifestyles. We have created resources specific to the individuals in order to be more effective in spreading awareness to them. This is a widespread problem with serious consequences, yet simple fixes. This is an attempt to spread awareness to a population that includes individuals at a critical point in life who may not be informed about this issue.

Prospective Association Between Video and Computer Game Use During Adolescence and Incidence of Metabolic Health Risks: Secondary Data Analysis.

Video and computer games are popular activities, with 72% of adolescents aged 13 to 17 years reporting video game use on either a computer, game console, or portable device. Despite high levels of video and computer game use in adolescence, relatively little scientific literature exists examining the association and effects of video and computer games on adolescents. The objective of this study was to examine the prevalence of video and computer game use among US adolescents and rates of positive screens for obesity, diabetes, high blood pressure (BP), and high cholesterol. A secondary data analysis was conducted using the National Longitudinal Study of Adolescent to Adult Health (Add Health) data, including adolescents aged 12 to 19 years between 1994 and 2018. Respondents (n=4190) who played the most video and computer games had a significantly (P=.02) higher BMI and were more likely to self-report having at least one of the evaluated metabolic disorders: obesity (BMI >30 kg/m2), diabetes, high BP (BP >140/90), and high cholesterol (>240). With increased video or computer game use, there was a statistically significant increase in high BP rates in each quartile, with those with more frequent use also having higher rates of high BP. A similar trend was observed for diabetes, though the association did not reach statistical significance. No significant association was observed between video or computer game use and diagnoses of dyslipidemia, eating disorders, or depression. Frequency of video and computer game use is associated with obesity, diabetes, high BP, and high cholesterol in adolescents aged 12 to 19 years. Adolescents who play the most video and computer games have a significantly higher BMI. They are more likely to have at least one of the evaluated metabolic disorders: diabetes, high BP, or high cholesterol. Public health interventions designed to target modifiable disease states through health promotion and self-management may support the health of adolescents aged 12 to 19 years. Video and computer games can integrate health promotion interventions in gameplay. This is an important area for future research as video and computer games are integrated into the lives of adolescents.

1847-PUB: Neutrophil Count Predicts Cardiovascular and Metabolic Health Risk Factors in a Population without Diabetes

Subclinical inflammation is implicated in cardio-metabolic conditions such as impaired glucose metabolism, diabetes, and hypertension. Neutrophils are first line of immune defense call and play a role in systemic inflammation. We therefore hypothesized that neutrophil quantity will be positively associated with cardio-metabolic risk factors among individuals without diabetes. Purpose: This study sought to determine the relevance of neutrophil count as a biomarker for cardio-metabolic health. Methods: Forty participants without diabetes (11 males, 29 females; age 28.4±10.7 years; BMI 28.2±6.0 kg/m2, fasting blood glucose 97.28±11.09 mg/dL) participated in the study. Following overnight fasting, participants’ blood pressure and resting heart rate were measured, and venous blood draw was performed. All participants completed a 3-hour oral glucose tolerance test with 75g glucose drink. Hematological and serum chemistry analyses were performed. Body composition was measured by dual X-ray absorptiometry. Homeostatic model assessment for insulin resistance (HOMA-IR) was computed from standard equations. Spearman’s correlation was performed to determine relationship between neutrophil count and markers of cardio-metabolic health. Results: Neutrophil count is positively correlated with resting heart (r=0.5, p=0.004), triglycerides (r=0.5, p=0.002), triglycerides-HDL ratio (r=0.5, p=0.002), VLDL (r=0.5, p=0.001), Globulin (r=0.3, p=0.03), BUN/creatinine ratio (r=0.5, p=0.0004), fasting insulin (r=0.7, p=0.004), fasting blood glucose (r=0.5, p=0.0008), 2-hour OGTT glucose (r=0.5, p=0.003), glucose area under the curve (r=0.5, p=0.0001), percent body fat (r=0.6, p=0.0003), HOMA-IR (r=0.6, p=0.008) and negatively correlated with albumin/globulin ratio (r=-0.4, p=0.01), HDL (r=-0.3, p=0.04). Conclusion: Neutrophil count is a biomarker for cardio-metabolic health risk factors in a population without diabetes. Disclosure J.Labadah: None. J.Apaflo: None. G.Narvaez: None. V.M.Rocha: None. A.Mossayebi: None. S.Bajpeyi: None. Funding The University of Texas at El Paso

Abstract 5259: Bazedoxifene plus conjugated estrogen improves metabolic health and reduces mammary gland epithelial proliferation in an ovary intact rat model of obesity and breast cancer risk

Abstract Background: The majority of women risk eligible for primary breast cancer prevention with tamoxifen or aromatase inhibitors refuse uptake due to concerns about side effects, especially vasomotor symptoms. Tamoxifen may also have detrimental metabolic effects in overweight/obese women. Duavee™, a complex of bazedoxifene (BZA) and conjugated estrogen (CE), is FDA approved for relief of hot-flashes and prevention of osteoporosis. Preclinical studies suggest favorable metabolic effects in ovariectomized animals and potential for breast cancer risk reduction. A single arm clinical trial found reduction in Ki-67 and mammographic density such that BZA+CE is being further evaluated in a Phase IIB trial of peri and early postmenopausal women with vasomotor symptoms who are at high risk for breast cancer. Here, in a companion study, we assessed the effect of BZA+ CE on metabolic health and cancer risk in a rat model of carcinogen induced ER+ tumors and high fat diet induced obesity. Methods: Rats received 50 mg/kg N-methylnitrosourea at 7 weeks to increase mammary tumor risk and were fed a high fat diet (46% kcal fat) to promote obesity. At 16 weeks lean and obese rat were selected based on % body fat and were then randomized to 8 weeks of daily oral vehicle control or 3mg BZA + 0.07mg CE/kg body weight. Systemic metabolic variables were measured at 16 and 24 weeks, and RNA from mammary glands analyzed by gene expression microarray (Affymetrix). Results: BZA+CE resulted in systemic as well as mammary changes indicative of improved metabolic health, including: reduction in total and visceral fat (p&amp;lt;0.01), glucose (p&amp;lt;0.05), cholesterol (p&amp;lt;0.001), and triglycerides(p=0.08), as well as an increase in the adiponectin:leptin ratio (p&amp;lt;0.01). BZA+CE vs control increased the ratio of small (insulin sensitive) to large adipocytes in the mammary gland. Gene set enrichment analysis (GSEA) showed BZA+CE downregulated proliferation-associated pathways which had been upregulated in obese rats, consistent with anti-cancer effects. Obese rats treated with BZA+CE also had upregulation of metabolic pathways, including adipocyte differentiation, fatty acid metabolism, and inflammatory response pathways. Conclusions: Unlike tamoxifen, BZA+CE improved whole body and mammary gland metabolic health, particularly in obese rats. Transcriptional profiling and GSEA demonstrated a blunting of cell cycle and proliferation and enrichment of metabolic and immune-related pathways. Together this supports BZA+CE (Duavee) as an agent to be explored for breast cancer risk reduction in obese individuals. Funding: This work was supported in part by P30 CA168524, R00 CA169430, and R25 CA203650. Citation Format: Ramsey M. Jenschke, Karen A. Corleto, Carol J. Fabian, Stephen D. Hursting, Bruce F. Kimler, Danilo Landrock, Tara N. Mahmood, Katherine L. Cook, Erin D. Giles. Bazedoxifene plus conjugated estrogen improves metabolic health and reduces mammary gland epithelial proliferation in an ovary intact rat model of obesity and breast cancer risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5259.

Abstract P3-03-22: Overweight and obesity trends over 5 years in early stage and metastatic breast cancer patients

Abstract Background: Obesity is associated with 25-33% of all breast cancer (BC) cases, and BC survivors with obesity have a 35% higher risk of BC-related death and 41% higher risk of all-cause mortality. We hypothesized that the prevalence of overweight (body mass index [BMI] 25-29.9 kg/m2) and obesity (BMI ≥30) after a diagnosis of early stage or metastatic BC increases, and baseline characteristics may increase risk of weight gain. Methods: We conducted a retrospective chart review of 222 patients with Stage 0-IV BC who newly presented to Johns Hopkins from 2015-2018. Patients were part of the BC Program Quality Improvement Project Database, had 1 chest CT scan within 6 months of initial visit, and at least 1 subsequent CT. Data extracted from the medical record included: demographics, menopausal status, diagnosis date, cancer characteristics/treatment, recurrence/vital status, family history of BC, and tobacco/alcohol use. All BMI measured on patients were collected. Baseline BMI was defined as the closest measurement to BC diagnosis between 1 year prior and 1 month after diagnosis. We estimated time to overweight/obesity from diagnosis using the Kaplan Meier method and compared between subgroups with the log rank test. Patients who were overweight/obese at diagnosis were included in the analysis with an event time of zero. Results: Among 222 patients, 110 patients (50%) had newly diagnosed early-stage BC, 98 (44%) had de-novo or recurrent metastatic BC, and 14 (6.3%) had locally recurrent BC. Most patients were women (98%) and non-Hispanic (93%). Patients identified as White (62%), Black (23%), and Asian (8%). Among 34% with alcohol use, 5% reported ≥8 drinks/week. There were current (6%) and former smokers (34%). Family history of BC was present in 10%. Among those with early-stage primary BC, most were postmenopausal (61%) and received chemotherapy (61%). Hormone receptor (HR)-positive, HER2-positive and triple negative subtypes were 70%, 24% and 19%, respectively. For those with metastatic BC, most were postmenopausal (62%). Hormone receptor (HR)-positive, HER2-positive and triple negative subtypes were 71%, 12% and 24%. At diagnosis, 73% of the whole cohort had BMI ≥25 kg/m2, with the whole cohort and subgroups having mean BMI ≥25 kg/m2. The incidence of elevated BMI increased in all groups and overall, over 5 years (Table 1). Weight gain was significantly associated with premenopausal status (p=0.04). Stage at diagnosis, smoking/alcohol use, receipt of chemotherapy/radiation/endocrine therapy, and subtype were not associated with weight gain. Conclusion: Patients with early stage and metastatic BC have elevated BMI at diagnosis, and this risk increases over 5 years, especially for those who are premenopausal. Further investigation of the implications of these changes is needed. Additionally, while BMI is accessible, it may underestimate body fat in older people and others who have lost muscle, does not identify fat distribution (a major factor in metabolic health risk), and may not be equally valid across gender, race and ethnicities and age groups. We will assess body composition by CT scan and report correlations with BMI and cancer-related outcomes. Prevalence of BMI≥25 kg/m2 in patients with breast cancer at diagnosis and by 1-, 2-, and 5-years after Prevalence of BMI≥25 kg/m2 increased over 5 years post-diagnosis. Premenopausal status was more associated with BMI≥25 kg/m2 versus postmenopausal status. Citation Format: Terrence Tsou, Amanda L. Blackford, Vered Stearns, Jennifer Y. Sheng. Overweight and obesity trends over 5 years in early stage and metastatic breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-22.