Also in this issue
Letter From the Editors
What's New? GLP-1 drug updates, recent research summaries, and a major industry event
Underwriting Updates GUM's new resource hub
Case ReView Underwriting a challenging mammogram case
Longer Life Foundation
RGA's Global Medical Newsletter
Updated Guidelines for Pediatric Obesity by Kim-Anh Vu Bisphenol A (BPA): What are we really eating? by Hilary Henly The Longevity Challenge: Aging societies and the need to adapt with David Sinclair
Featured Articles
Dr. Adela Osman
Vice President Head of Global Medical
adela.osman@rgare.com
Dr. Daniel D. Zimmerman, DBIM
Senior Vice President Chief Science Advisor
dzimmerman@rgare.com
We hope the new all-digital format and dynamic elements introduced this year have improved your ReFlections experience and delivered a broader array of valuable insights. Our feature articles this month tackle a range of important issues. Dr. Kim-Anh Vu reviews guidelines for the evaluation and treatment of pediatric obesity and the implications for insurers; Hilary Henly explores the link between exposure to Bisphenol A (BPA) from plastic products and a variety of serious health conditions; and ReFlections co-editor Dan Zimmerman sits down with David Sinclair, CEO of the International Longevity Centre UK, to discuss the many societal challenges presented by aging populations. Additional articles provide valuable insights for today’s insurance professionals: Dr. Sheetal Salgaonkar’s Case ReView walks readers through underwriting a challenging mammogram case. The What’s New section offers perspectives on GLP-1 receptor agonists from Dr. Steve Woh, as well as summaries of recent studies on dementia prevention and care, tirzepatide for the treatment of sleep apnea and obesity, and cancer rates among US adults born between 1920 and 1990. This issue’s Underwriting Update highlights RGA’s latest Global Underwriting Manual Resource Hub, which features updated guidelines for asthma and Hodgkin lymphoma along with related informational materials and tools. As always, we invite you to provide feedback to help us continue to improve ReFlections. Please use the star ratings to evaluate articles and submit additional comments to indicate topics you would like to see in future issues. We look forward to continuing to serve our readers with the latest and most helpful information on clinical and insurance medicine topics. Thank you, Dan and Adela
Welcome to the October 2024 edition of ReFlections!
ReFlections
From the editors
In this issue
Updated guidelines for pediatric obesity
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Watch the welcome to ReFlections video
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Underwriting Update GUM's new resource hub
Expert Q&A Aging societies and the need to adapt
Bisphenol A (BPA): What are we really eating?
Features
Pediatric Overweight and Obesity: Updated guidelines look beyond BMI for a more comprehensive approach
The prevalence of pediatric overweight and obesity has surged over recent decades and poses a critical public health challenge worldwide. The World Health Organization (WHO) recognizes this surge as a global epidemic, and the American Medical Association labels pediatric obesity (and obesity in general) as a chronic disease. In response, the American Academy of Pediatrics (AAP) released its first clinical practice guidelines for the evaluation and treatment of pediatric obesity in January 2023. The guidelines provide an alternate classification for severe obesity, advocate for early intervention and rigorous screening for associated comorbidities, and expand treatment options to include pharmacotherapy and, in severe cases, bariatric surgery. As life insurers navigate the implications of rising childhood obesity rates on mortality and morbidity risks, these guidelines provide a timely framework to facilitate a nuanced understanding of obesity beyond body mass index (BMI) metrics alone. The framework also includes proactive treatment options that may mitigate associated health risks and improve long-term health outcomes, potentially increasing overall insurability.
Abstract
References
Centers for Disease Control and Prevention BMI Calculator for Child and Teen. Available at: https://www.cdc.gov/healthyweight/bmi/calculator.html Updated: September 2023. Accessed: July 2024. World Health Organization. Obesity and Overweight. Available at: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight Accessed: July 2024. Centers for Disease Control and Prevention. Childhood Obesity Facts. Available at: https://www.cdc.gov/obesity/php/data-research/childhood-obesity-facts.html#:~:text=The%20prevalence%20of%20obesity%20increased,%25%20among%20adolescents%2012%E2%80%9319 Accessed: July 2024. Fryar CD, Carroll MD, Afful J. Prevalence of overweight, obesity, and severe obesity among children and adolescents aged 2–19 years: United States, 1963–1965 through 2017–2018. NCHS E-Health Stats. 2020. Available at: https://www.cdc.gov/nchs/data/hestat/obesity-child-17-18/obesity-child.htm Accessed July 2024. Lange SJ, Kompaniyets L, Freedman DS, et al. Longitudinal trends in body mass index before and during the COVID-19 pandemic among persons aged 2-19 years—United States, 2018-2020. MMWR Morb Mortal Wkly Rep. 2021; 70(37): 1278-1283. doi:10.15585/mmwr.mm7037a3 Ward ZJ, Long MW, Resch SC, Giles CM, Cradock AL, Gortmaker SL. Simulation of growth trajectories of childhood obesity into adulthood. N Engl J Med. 2017;377(22):2145–2153. Centers for Disease Control and Prevention. About Child & Teen BMI. Available at: https://www.cdc.gov/healthyweight/assessing/bmi/childrens_bmi/about_childrens_bmi.html Accessed July 2024. Centers for Disease Control and Prevention. CDC Extended BMI-for-Age Charts. Available at: https://www.cdc.gov/growthcharts/extended-bmi.htm Accessed July 2024. Hampl SE, Hassink SG, Skinner AC, et al. Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity. Pediatrics. 2023;151(2): e2022060640. Ogden CL, Freedman DS, Hales CM. CDC Extended BMI-for-Age Percentiles Versus Percent of the 95th Percentile. Pediatrics. 2023;152(3):e2023062285. Andes LJ, Cheng YJ, Rolka DB, Gregg EW, Imperatore G. Prevalence of prediabetes among adolescents and young adults in the United States, 2005-2016. JAMA Pediatr. 2020;174(2):e194498. D’Adamo E, Caprio S. Type 2 diabetes in youth: epidemiology and pathophysiology. Diabetes Care. 2011;34(Suppl 2):S161–S165. Twig G, Zucker I, Afek A, Cukierman-Yaffe T, Bendor CD, Derazne E, Lutski M, Shohat T, Mosenzon O,Tzur D, Pinhas-Hamiel O, Tiosano S, Raz I, Gerstein HC, Tirosh A. Adolescent Obesity and Early-Onset Type 2 Diabetes. Diabetes Care 1 July 2020; 43 (7): 1487–1495. https://doi.org/10.2337/dc19-1988 Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58(11):1538–1544. 15. Twig G, Yaniv G, Levine H, Leiba A, Goldberger N, Derazne E, et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. N Engl J Med 2016;374:2430–2440. Sutaria S, Devakumar D, Yasuda SS, Das S, Saxena S. Is obesity associated with depression in children? Systematic review and meta-analysis. Arch Dis Child. 2019;104(1):64–74. Engeland A, Bjorge T, Sogaard A, Tverdal A. Body mass index in adolescence in relation to total mortality: 32-year follow-up of 227,000 Norwegian boys and girls. Am J Epidemiol. 2003;157:517–523. US Preventive Services Task Force. Interventions for High Body Mass Index in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. JAMA. Published online June 18, 2024. doi:10.1001/jama.2024.11146 Olbers T, Beamish AJ, Gronowitz E, et al. Laparoscopic Roux-en-Y gastric bypass in adolescents with severe obesity (AMOS): a prospective, 5-year, Swedish nationwide study. Lancet Diabetes Endocrinol. 2017;5(3):174–183.
About the author
Dr. Kim-Ahn Vu is Vice President and Medical Director for RGA's US Individual Life division, where she provides expert medical guidance in facultative underwriting and case consultations. She is proactive in advancing the medical education for underwriters through industry publications and both internal and external teaching presentations. Dr. Vu also serves on the manual committee at RGA, where she conducts topic reviews and contributes to the development of underwriting guidelines. She provides essential client support and maintains a presence in the industry with active involvement in conferences, seminars, and professional associations. Dr. Vu received her undergraduate training at the University of Cincinnati, where she graduated summa cum laude with dual bachelor of science degrees in chemistry and biology. She subsequently earned her doctor of medicine degree from the Ohio State University College of Medicine and completed her residency training in family practice. She is board certified in family medicine and has over 20 years of comprehensive experience in clinical practice, specializing in pediatric, adult, and geriatric medicine. Prior to joining RGA in 2022, Dr. Vu spent six years in the direct life insurance sector working as associate medical director at Ohio National Financial Services.
Dr. Kim-Anh Vu, M.D.
Vice President, Medical Director US Individual Life RGA
KimAnh.Vu@rgare.com
If this trend persists, predictive epidemiologic models estimate that more than half (57%) of US children ages 2-19 will be obese by the time they are 35 years of age, in 2050.6
A mother applies for a $350,000 whole life insurance policy for her 16-year-old son. His build (height: 72 in/183 cm; weight: 253 lbs/115 kg; BMI: 34.3) is above the underwriting manual reference range, and the case is referred to the medical director. According to the US Centers for Disease Control and Prevention (CDC) Child and Teen BMI Calculator,1 the young man’s BMI is in the 98th percentile – equivalent to 124% of the 95th percentile. Additional history indicates he has acanthosis nigricans, blood pressure of 139/74, hemoglobin A1c of 5.8, and total cholesterol of 215 mg/dl/5.6 mmol/L – all of which provide additional cause for concern. Unfortunately, such cases have become increasingly common, and it is important for insurance medical directors and underwriters to monitor pediatric overweight and obesity and to understand the risks these conditions present.
Case presentation
Prevalence of childhood and adolescent obesity
The AAP recommends annual obesity screenings for children and adolescents aged 6 years and older. While BMI does not directly measure fat content, it remains a validated proxy measure for diagnosing overweight or obesity. In the US, the CDC has developed BMI-for-age growth curves as a diagnostic tool. While these growth charts encompass ages 2-19, practitioners can consider a transition to adult BMI calculations and categorization for those older than 18 years. For children under age 2, the CDC recommends using the WHO’s weight-for-length, age-, and sex-specific charts to track weight status. Unlike the cut-points used for adult categories, the CDC’s BMI interpretation in the pediatric population is age- and sex-specific and expressed as a percentile. For example, a BMI of 23 is considered obese for a 10-year-old boy but healthy for a 15-year-old boy (Figure 1).7
Use of BMI as a screening and diagnostic tool
Classification and pathology
There are six subtypes of BOT.4 The majority, about 65% to 70%, are classified as serous (meaning it arose from the serous membrane). The less common subtypes are mucinous, endometrioid, clear cell, seromucinous, and borderline Brenner type. Expert opinion is that each subtype has its own distinct biology, pathology, and molecular profile, which means no single unifying concept exists for the range of BOT subtypes. The architecture of serous BOT is characterized by an overgrowth of cells, leading to multiple layers of stratification within the epithelial lining of the papillae and to tufting (i.e., cell detachment).5 Some tumors can exhibit a complex cribriform (also known as micropapillary) pattern. There is generally an absence of destructive stromal invasion. Serous BOT can also exhibit hierarchical branching of successively smaller papillae arising from larger, more centrally located papillae. Elongated micropapillae can arise directly from large central papillae as well. If this appearance is present in less than 10% of the whole tumor, the term “focal borderline change” is used as the descriptor, rather than BOT. If the cribriform or micropapillary architecture represents more than 10% of the tumor or 5 mm of a confluent area, some experts would label the tumor “micropapillary serous carcinoma.” Others prefer the term “serous borderline tumor with cribriform and/or micropapillary architecture,” as there is no destructive stromal invasion. In comparison with conventional serous BOT, micropapillary/cribriform serous BOTs are also more often bilateral, exophytic, at FIGO stage >1, and show invasive peritoneal implants.7 Although BOTs do not show destructive stromal invasion, microinvasion can be seen in 10% to 20% of these tumors. Microinvasion is defined as single cells, cell clusters, or haphazard nests of cells measuring less than 5 mm that invade the stromal core of the papillae or cyst wall. If the invasive component measures more than 5 mm, the tumor should be classified as an invasive cancer. Although BOT has a distinct histological appearance, some of its aspects can challenge the pathologist in making a correct diagnosis.6
The World Health Organization (WHO) reports that pediatric obesity rates have risen dramatically, from 8% in 1990 to 20% in 2022, with an estimated 390 million children and adolescents ages 5-19 years being overweight.2 In the US, the CDC approximates that 14.7 million children are obese.3 The childhood obesity rate in the US increased from 5% in 1963-1965 to 19% in 2017-2018,4 and the rate of BMI increase in children approximately doubled during the COVID-19 pandemic, from 0.052 kg/m2/month before the pandemic to 0.100 kg/m2/month during the pandemic.5 If this trend persists, predictive epidemiologic models estimate that more than half (57%) of US children ages 2-19 will be obese by the time they are 35 years of age, in 2050.6 In January 2023, the AAP published its first edition of evidence-based clinical practice guidelines for the evaluation and treatment of pediatric obesity. It encourages earlier and more aggressive interventions and treatments, including intensive behavior and lifestyle counseling, pharmacotherapy, and bariatric surgery.
Returning to the case study, it is clear that underwriting pediatric obesity involves more than assessing whether the BMI percentile falls within an acceptable reference range. While the applicant is at 124% of the 95th percentile, or close to the 98th percentile, for his age and sex, he also presents with a complex health profile indicative of severe obesity and early metabolic disturbances, including prediabetes, as evidenced by the acanthosis nigricans and hemoglobin A1c, elevated blood pressure, and hypercholesterolemia. All of this information should be taken into account. Aligning underwriting practices with current clinical guidelines enables insurers to better assess the implications of obesity on morbidity and mortality by balancing the considerations of BMI percentile, associated comorbidities, and likely benefits of proactive treatment. Alignment also provides insurers with contemporary information to help support any adverse underwriting actions. The new guidelines provide valuable clinical insights that underscore the potential for medical interventions to help prevent obesity-related conditions and diminish long-term health risks. Intensive interventions, including pharmacotherapy and bariatric surgery, are now viable options for severe cases, although more evidence on long-term outcomes is needed. Depending on the effectiveness of treatment and reduction of associated health risks, children and adolescents whose obesity is successfully managed with aggressive treatment may improve their insurability from an underwriting standpoint.
Conclusion
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Figure 1: The four FIGO stages
Source: Images courtesy Cancer Research UK (CRUK). This file is licensed under the Creative Commons Attribution – Share Alike 4.0 International license
FIGO 1 = confined to ovary
FIGO 2 = spread to pelvis
FIGO 3 = spread to abdomen
FIGO 4 = distant sites + parenchymal disease
Case Study 1: Critical illness claim
Extrapolation of percentiles beyond the 97th percentile may generate unusual or unexpected results. Therefore, the AAP guidelines suggest using the degree to which a particular BMI percentile is above the 95th percentile to indicate different levels of severe obesity (referred to as percentage above the 95th percentile). Overweight is defined as a BMI ≥ 85th percentile, obesity is BMI ≥ 95th percentile, and severe obesity is BMI ≥ 120% of the 95th percentile. Severe obesity is further divided into class 2 obesity, which is ≥ 120% to <140% of the 95th percentile, and class 3 obesity, which is ≥140% of the 95th percentile.9
How does this categorization compare to the 2022 CDC Extended BMI-for-Age Percentile growth curve? Ogden et al. showed that at younger ages, around 2-6 years, 120% of the 95th percentile is higher than both the extended 98th and 99th BMI-for-age percentiles. However, for ages 7 and older, 120% of the 95th percentile approximates to the extended 98th percentile, and the percentage of adolescents ages 12-19 years with BMI ≥ 120% of the 95th percentile is virtually the same as those with ≥ 98th percentile (Figure 3).10
Clinical behavior of BOT
Obesity puts juveniles at risk for serious adverse health outcomes, including hypertension (HTN), dyslipidemia, insulin resistance, type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease, among others. Insulin resistance varies across weight categories and is highest among children with severe obesity. Based on 2005-2016 NHANES data, prediabetes is observed in one out of five adolescents ages 12-18.11 The transition from prediabetes to T2DM occurs faster in children than in adults, within 21 months in children compared to 5-10 years in adults.12 The projected fractions of adult-onset T2DM due to high adolescent BMI (≥85th percentile) are 56.9% in men and 61.1% in women.13 Furthermore, insulin resistance increases oxidative stress and inflammation, elevating the risk of NAFLD, which is estimated to be as high as 34% in children with obesity.9 According to a 2009 study, children with NAFLD experience higher rates of mortality over a 20-year period compared to the general population of the same age and sex.14 The health risks carry into adulthood through increased cardiovascular mortality. In a study of 2.3 million adolescents, even high-normal range BMI (75th to 84th percentile) produced hazard ratios of 2.2 for coronary heart disease and 1.8 for total cardiovascular causes.15 Higher BMI is also associated with obstructive sleep apnea (OSA), which is found in 45% of children with obesity compared to 9% in children with healthy weight.9 A cross-sectional study of overweight and obese children ages 7-18 showed that a one unit increase in BMI standard deviation score increases the odds of having OSA by a factor of 1.92, independent of age, sex, tonsillar hypertrophy, and asthma.9 Pediatric obesity is thought to be associated with depression, although the relationship is less understood. A 2019 systematic review and meta-analysis reported the odds of developing depression are 1.32 higher in obese children in general and 1.44 higher among obese female children compared to their normal-weight counterparts.16 Other comorbidities associated with pediatric obesity include polycystic ovarian disease, idiopathic intracranial hypertension, and orthopedic disorders due to mechanical stress, such as slipped capital femoral epiphysis and Blount disease. Initial studies assessing mortality related to pediatric obesity are limited due to their size, and because mortality is low during adolescence and early adulthood, more accurate assessment requires long-term follow-up. Nevertheless, some studies indicate a higher mortality risk. A 32-year follow-up study in 2002 involving 227,000 Norwegian adolescents ages 14-19 shows an increased risk of death for both males and females with higher BMI percentiles during adolescence. The relative risk (RR) of death for males is 1.29 for the 85th to 94th percentile and 1.82 for the ≥ 95th percentile. The RR of death for females is 1.31 for the 85th to 94th percentile and 2.03 for the ≥ 95th percentile.17
Impact of Pediatric Obesity
Obesity is a chronic disease that necessitates intensive, long-term treatment strategies that address the multifaceted nature of the disease and associated comorbidities. The AAP recommends referring children and adolescents 6 years or older with overweight or high body mass index percentile (BMI ≥ 95th percentile) to comprehensive, intensive health behavior and lifestyle treatment (IHBLT), consisting of a minimum of 26 hours of face-to-face, family-based, multicomponent treatment over at least 3-12 months, including nutrition, physical activity, and behavior-change support. Studies associate IHBLT with BMI reductions and other weight-related beneficial outcomes after 6-12 months, with no inadvertent additional weight stigma, increase in disordered eating, or decrease in self-esteem. Continuous care is crucial for sustained outcomes, as children tend to regain weight and lose the health benefits of weight loss when treatment is discontinued.18 IHBLT forms the foundation of treatment, but if behavior interventions alone prove insufficient, AAP guidelines suggest pharmacotherapy may be considered in conjunction with IHBLT for children 12 years and older at high risk, including those with more immediate or life-threatening comorbidities, older-age children, and those with severe obesity. Medications listed in the guidelines include metformin, orlistat, GLP-1 receptor agonists (liraglutide, exenatide, dulaglutide, and semaglutide), phentermine, and phentermine/topiramate. Evidence remains limited for long-term effectiveness of pharmacotherapy intervention. Compared to placebo, liraglutide produces a 1.6-point greater reduction in BMI, semaglutide a 6-point greater reduction, orlistat a 0.9-point greater reduction, and phentermine/topiramate a 3.7-point to 5.4-point greater reduction.18 Some studies show an immediate weight increase after discontinuation, implying that long-term use of medications may be needed. Risks include gastrointestinal side effects, such as nausea, vomiting, diarrhea, fecal incontinence, flatus, and gallstones. The AAP guidelines also expand treatment options for those 13 years and older with severe obesity (≥ class 2 obesity) to include referral to a comprehensive pediatric metabolic and bariatric surgery center. A 2017 prospective study on laparoscopic Roux-en-Y gastric bypass in adolescents over a five-year period shows substantial and sustained weight loss and improvement or resolution of comorbid conditions. However, risks include potential need for subsequent related procedures in 13-25% of patients up to five years following bariatric surgery and the need for long-term monitoring to assess micronutrient deficiencies.19 In summary, AAP guidelines provide useful information on treatment options to address the pediatric obesity epidemic. Pharmacotherapy and bariatric surgery present possible options for severe cases, but more evidence on long-term outcomes is needed. Depending on the effectiveness of treatment and reduction of associated weight-related health risks, children and adolescents whose obesity is successfully managed with aggressive treatment may improve their insurability from an underwriting standpoint.
Treatment of pediatric obesity
Figure 1. CDC BMI-for-age percentiles for boys.
Because the 2000 CDC BMI-for-Age Growth Charts are based on data from 1963-1980, when the prevalence of obesity was much lower, they are not recommended for use in children with extremely high BMI values, i.e., above the 97th percentile. In 2022, the CDC released the Extended BMI-for-Age Growth Charts based on additional data from 1999-2016 and updated statistical methods, with BMI percentiles up to the 99.99th percentile (Figure 2).8
Figure 2: 2022 CDC Extended BMI-for-Age Growth Charts for boys (left) and girls (right).
Table 1: Child BMI categories and the corresponding sex- and age-specific BMI percentile ranges.
Figure 3: Select CDC extended BMI-for-age percentiles, 95th percentile and 120% and 140% of the 95th percentile, (A) girls and (B) boys. Note: Percentiles above the 95th percentile are CDC extended BMI-for-age percentiles.
BMI Range BMI Category
< 5th Percentile Underweight
5th Percentile to < 85th Percentile Healthy Weight
≥ 85th Percentile to < 95th Percentile Overweight
≥ 95th Percentile Obesity
≥ 120% of the 95th Percentile (or ≥ BMI 35) Severe Obesity
≥ 120% to < 140% of the 95th percentile or BMI ≥ 35 to < 40 Class 2 Obesity
≥ 140% of the 95th percentile or BMI ≥ 40 Class 3 Obesity
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
60 50 40 30 20 10 0
BMI
A
Age(years)
95th percentile
99.99th percentile
99th percentile
98th percentile
120% of 95th percentile
99.9th percentile
140% of 95th percentile
B
Extrapolation of percentiles beyond the 97th percentile may generate unusual or unexpected results. Therefore, the AAP guidelines suggest using the degree to which a particular BMI percentile is above the 95th percentile to indicate different levels of severe obesity (referred to as percentage above the 95th percentile). Overweight is defined as a BMI ≥ 85th percentile, obesity is BMI ≥ 95th percentile, and severe obesity is BMI ≥ 120% of the 95th percentile. Severe obesity is further divided into class 2 obesity, which is ≥ 120% to <140% of the 95th percentile, and class 3 obesity is ≥140% of the 95th percentile.9
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Consumed by Bisphenol A (BPA): What are we really eating?
Estimates suggest that nearly a quarter of all human diseases and disorders result from environmental factors, which play a role in approximately 80% of deadly diseases such as cancer, heart disease, and diabetes.1 Over the past two decades, global organizations have raised concerns about endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), and their impact on human health. People are exposed to BPA via canned food, cardboard food trays, drink containers, dental products, and infant feeding products, as well as air and water pollution. The US Food and Drug Administration (FDA) maintains that BPA is safe at current levels occurring in food. However, studies strongly suggest a link between human exposure to BPA and reproductive disorders, hormone-sensitive cancers (such as breast, ovarian, and endometrial cancer), metabolic dysfunction, and neurodevelopmental disorders in children. As younger generations experience greater long-term exposure to chemicals like BPA, the insurance industry could see changes to incidence and prevalence rates for associated diseases and disorders.
Reproductive system disorders BPA is known to have adverse effects on human health, especially the reproductive system. It can cause pathological changes in the placenta and obstetric complications, such as decreased fetal growth, miscarriage, pre-term birth, and pre-eclampsia. Additional adverse effects include endometrial hyperplasia, development of ovarian cysts, and infertility. According to the World Health Organization (WHO), the global lifetime infertility prevalence estimates from 1990-2021 were 17.5%, or approximately one in six people experiencing infertility in their lifetime.13 Many experts have associated this high rate with higher exposure to BPA. Studies indicate a relationship between increased levels of BPA in men and their semen quality/infertility,14 with fetal exposure to BPA known to affect the quality and quantity of sperm.3 In some regions, recorded sperm counts have declined by as much as 50% over the past 50 years.1 Mothers with higher BPA plasma concentrations risk a shorter pregnancy duration or premature rupture of membranes.14 In fact, pre-term birth rates in the US have risen by more than 30% since 1981.1 In 2020, the pre-term birth rate in the US was 10.0%, which was higher than the global average of 9.9%.15 By 2022, the US rate rose to 10.4%, the highest figure in 10 years.16 The risk of mortality and morbidity in pre-term infants increases according to the degree of prematurity. Cancer Research connects BPA to the development of hormonal-related cancers, such as breast, ovarian, and endometrial cancer. BPA binds to estrogen receptors, such as Erα and Erβ, which are expressed in more than 60% of human breast cancers. The abnormal expression of estrogen receptors leads to the development of breast, ovarian, and low-grade endometrial cancer. In addition, studies show that BPA can cause resistance to well-known chemotherapy drugs, including doxorubicin, cisplatin, carboplatin, tamoxifen, bevacizumab, PARP inhibitors, and vinblastine.7 BPA also influences the development of male cancers, such as prostate cancer and testicular germ cell cancer, and has been linked to the development of acute myeloid leukemia, lung cancer, colorectal cancer, hepatic cancer, head and neck cancer, thyroid cancer, and osteosarcoma.3 In 2022, over 1.8 million cases of cancer were diagnosed in the US, which had one of the highest age-standardized incidence rates worldwide at 303.6 cases per 100,000 population.17 According to a 2024 analysis examining differences in cancer rates of US adults born between 1920 and 1990, 17 out of 34 cancer variations experienced increasing incidence in younger birth cohorts. Of these 17 cancers, nine had previously shown declining incidence in older birth cohorts, including estrogen-receptor-positive breast cancer, uterine corpus cancer, colorectal cancer, ovarian cancer, and testicular cancer. This may reflect exposure to carcinogenic factors during early life compared to older generations, as well as an increasing incidence in obesity rates. Indeed, the fastest rise in obesity rates has occurred in those aged 2-19 years. Suspected risk factors for the rise in cancer rates among young lives include unhealthy diet, sedentary lifestyle, and exposure to environmental chemicals in early life.18
BPA and disease development
Gore, A.C. et al. (2024). Endocrine disrupting chemicals: threat to human health. Pesticides, plastics, forever chemicals, and beyond. Endocrine Society & IPEN. Available from: edc-report2024finalcompressed.pdf (endocrine.org) Dumitrascu, M.C. et al. (2020). Carcinogenic effects of bisphenol A in breast and ovarian cancers (Review). Oncology Letters 20: 282, 2020. Available from: Carcinogenic effects of bisphenol A in breast and ovarian cancers - PMC (nih.gov) Khan, N.G. et al. (2021). A comprehensive review on the carcinogenic potential of bisphenol A: clues and evidence. Environmental Science and Pollution Research (2021); 28: 19643-19664. Available from: A comprehensive review on the carcinogenic potential of bisphenol A: clues and evidence - PMC (nih.gov) Costa, H.E. et al. (2024). Effects of bisphenol A on the neurological system: a review update. Archives of Toxicology 2024; 98: 1-73. Available from: Effect of bisphenol A on the neurological system: a review update | Archives of Toxicology (springer.com) Liu, Z.Y. et al. (2023). Does anti-inflammatory diet mitigate the deleterious effect of bisphenol A on mortality in US adults? Results from NHANES 2003–2016. Ecotoxicology and Environmental Safety; 253: 114706. Available from: Does anti-inflammatory diet mitigate the deleterious effect of bisphenol A on mortality in US adults? Results from NHANES 2003–2016 (sciencedirectassets.com) Virginia Department of Health (2023). Bisphenol A. Public Health Toxicology. Available from: Bisphenol A - Environmental Health (virginia.gov) Hafezi, S.A., Abdel-Rahman, W.M. (2019). The endocrine disruptor bisphenol A (BPA) exerts a wide range of effects in carcinogenesis and response to therapy. Current Mol Pharmacol, 2019; 12(3): 230-238. Available from: The Endocrine Disruptor Bisphenol A (BPA) Exerts a Wide Range of Effects in Carcinogenesis and Response to Therapy - PubMed (nih.gov) FDA (2023). Bisphenol A (BPA). Available from: Bisphenol A (BPA) | FDA Government of Canada (2020). Safety of BPA. Available from: Bisphenol A (BPA) - Canada.ca Gov.UK (2024). BPA in plastics. Food Standards Agency. Available from: BPA in plastic | Food Standards Agency Ribeiro, E. et al. (2017). Occupational exposure to bisphenol A (BPA): a reality that still needs to be unveiled. Toxics 2017; 5(22): doi 10.3390. Available from: Occupational Exposure to Bisphenol A (BPA): A Reality That Still Needs to Be Unveiled (semanticscholar.org) Duenas-Moreno, J. et al. (2023). Worldwide risk assessment of phthalates and bisphenol A in humans: the need for updating guidelines. Environment International; 181, Nov 2023: 108294. Available from: Worldwide risk assessment of phthalates and bisphenol A in humans: The need for updating guidelines (sciencedirectassets.com) WHO (2023). Infertility prevalence estimates 1990-2021. Available from: 9789240068315-eng.pdf (who.int) Molina-Lopez, A.M. et al. (2023). An overview of the health effects of bisphenol A from a one health perspective. Animals 2023; 13: 2439. Available from: (An Overview of the Health Effects of Bisphenol A from a One Health Perspective (nih.gov) Ohuma, E. et al. (2023). National, regional and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. The Lancet 2023; 402: 1261-71. Available from: National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis (thelancet.com) March of Dimes (2023). The 2023 March of Dimes report card United States. Available from: MarchofDimesReportCard-UnitedStates.pdf WCRF International (2022). Worldwide cancer data. Available from: Cancer trends - WCRF International Sung, H. et al. (2024). Differences in cancer rates among adults born between 1920 and 1990 in the USA: an analysis of population-based cancer registry data. The Lancet Public Health 2024; 9: e583-93. Available from: Differences in cancer rates among adults born between 1920 and 1990 in the USA: an analysis of population-based cancer registry data (thelancet.com) Attina, T. et al. (2016). Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. The Lancet Diabetes and Endocrinology; 4(12) Available from: (12) (PDF) Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis (researchgate.net) Hubbard, A.K. et al. (2019). Trends in international incidence of pediatric cancers in children under 5 years of age: 1988-2012. JNCI Cancer Spectrum (2019); 3(1): pkz007. Available from: Trends in International Incidence of Pediatric Cancers in Children Under 5 Years of Age: 1988–2012 - PMC (nih.gov) Chen, Y.M. et al. (2023). Mitigating the impact of bisphenol A exposure on mortality: Is diet the key? A cohort study based on NHANES. Ecotoxicology and Environment Safety; 267: 115629. Available from: Mitigating the impact of bisphenol A exposure on mortality: Is diet the key? A cohort study based on NHANES (sciencedirectassets.com) Bao, W. et al. (2020). Association between bisphenol A exposure and risk of all-cause and cause-specific mortality in US adults. Jama Network Open 2020 Aug; 3(8): e2011620. Available from: Association Between Bisphenol A Exposure and Risk of All-Cause and Cause-Specific Mortality in US Adults - PMC (nih.gov) Guo, L. et al. (2024). Association of urinary bisphenol A with hyperlipidemia and all-cause mortality: NHANES 2003-2016. Available from: Association of urinary bisphenol A with hyperlipidemia and all-cause mortality: NHANES 2003–2016 - PMC (nih.gov)
Hilary Henly, FCII, is a Global Medical Researcher with RGA’s Strategic Research team. Based in Ireland, she is a Fellow of the Chartered Insurance Institute (FCII) and has more than 30 years of experience in underwriting, claims, and mortality and morbidity research.
By Hilary Henly
Global Medical Researcher Strategic Research
hhenly@rgare.com
BPA is known to have adverse effects on human health, especially the reproductive system.
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Bisphenol A (BPA) is an organic compound used in the making of certain plastics and epoxy resins. It is present in everyday items, such as food and drink containers, paper products, toys, medical and dental products (e.g., dental sealants and fillings), cigarette filters, and building materials. Studies suggest that more than 90% of human exposure to BPA comes from food contamination.2 Although oral exposure to BPA is most common, it also can be inhaled or absorbed through the skin and stored in human fat tissue.3 BPA can induce insulin resistance, adipogenesis, cell dysfunction, inflammation, and oxidative stress. It can cross the blood-brain barrier and placenta, and is found in biological fluids and tissues, including urine, blood, amniotic fluid, placental tissue, brain tissue, umbilical cord blood, breast milk, and human colostrum.4 BPA has been detected in more than 90% of the North American population.5 The current FDA limit is 50 micrograms (µg) per kilogram of body weight per day (µg/kg/day).6 Yet recent studies show that as little as 0.2 ug/kg/day can harm health.7 In 2012, the FDA amended its regulations, banning the use of BPA in infant bottles and sippy cups, and in 2013 prohibited its use in coating materials for infant formula packaging.8 The Canadian government states that BPA does not pose a health risk to people, including infants. However, they also note it is illegal to advertise, import, manufacture, or sell baby bottles that contain BPA, and they have phased out packaging for infant formula containing BPA.9 Similarly, the UK’s Food Standards Agency (FSA) does not consider BPA to be harmful but restricts it from product material intended for use in infant and toddler food packaging. The FSA adopted a tolerable daily intake (TDI) limit of 0.2µg/kg/day, which is considered the daily amount of BPA a person can consume over their lifetime without being harmed.10 Meanwhile, the European Union’s European Food Safety Authority (EFSA) limits have evolved over time. In 2015, the EFSA reduced the TDI of BPA from 0.05 mg/kg to 4µg/kg body weight a day.11 In April 2023, the EFSA further reduced the TDI levels to 0.2 nanograms* (0.0002 µg) per kg of body weight.12 *(1µg = 1000ng)
Introduction
Although studies to date suggest BPA exposure increases the risk of all-cause and cause-specific mortality, this association is difficult to prove and quantify without deliberately exposing humans to these chemicals and examining the results. However, some studies do support this association: A study using NHANES data (2003-2016) showed that the highest tertile of urinary BPA levels, when compared to the lowest group, was linked to a 36% increase in all-cause mortality, a 19% increase in cancer mortality, and a 62% increase in CVD mortality. A low urinary BPA level and high dietary quality had the lowest all-cause and CVD mortality (HR 0.42 and 0.30, respectively).21 In another study using NHANES data (2003-2008), when comparing the highest and lowest urinary BPA levels, all-cause mortality in adults age 20 and older was HR 1.49, while CVD mortality was HR 1.46.22 In a study of nearly 9,000 patients with hyperlipidemia, all-cause mortality was 20% higher among the highest tertile of urinary BPA vs. the lowest group.23
The association of BPA with all-cause and cause-specific mortality risk
Preliminary understanding of LBD genetics
There is to date no disease-modifying treatment for LBD syndromes. The current approach to managing LBD is alleviating its symptoms by targeting the culprit neurotransmission impairments with as little pharmacological burden as possible to avoid drug interactions and possible adverse effects or reactions. Still, owing to the range and complexity of the symptoms, polypharmacy is the norm. Physical therapy, occupational therapy, and/or environmental adaptation may also be employed to reduce motor dysfunction and falls, and to help maintain general function and self-care abilities. From moderate disease stage onward, LBD requires intense supportive care.11 The cholinergic dysfunction in LBD appears to respond well to cholinesterase inhibitor agents. Donepezil and rivastigmine are two that are frequently used for cognitive impairment. Levodopa, which is used to treat PD and general Parkinson’s-related motor dysfunctions, can be helpful but may worsen LBD neuropsychiatric symptoms. Its efficacy in treating the Parkinson’s disease-like motor dysfunctions of LBD has also been shown to lessen over time. RBD sleep disturbances may be reduced by melatonin. Atypical antipsychotics are used cautiously for hallucinations and delusions. Autonomic dysfunctions are treated symptomatically.1 With current treatment and management strategies, the lifespan of an LBD patient after onset of cognitive symptoms may be variable but, on average, is only half as long as that for people with AD (about 3.3 years), according to one study.12
Treatment and prognosis
LBD symptomatology and biomarkers
Neurodevelopmental and childhood disorders Neurobehavioral disorders represent EDC exposure’s largest health impact in the US. Gestational exposure to BPA interferes with pre-natal brain development while increasing the risk of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, poor language development, sleep disorders, and uncontrolled behaviors, including aggression, destruction, and hyperactivity.1 Mothers with high BPA concentrations were 3.7 times more likely to give birth to sons with a low language score. Autistic children have shown heightened oxidative stress due to increased exposure to BPA, while ADHD was found to be more common in formula-fed infants in 2007. Infant exposure to BPA has decreased in recent years with the introduction of regulations banning its use in baby bottles and infant formula packaging.4 The prevalence of developmental disabilities in US children increased from approximately 13% in 1997 to 17% in 2022. Concerns have emerged regarding the increasing prevalence of ADHD, where the percentage of children aged 4-17 years with ADHD rose from 7.8% to 9.5% between 2003 and 2007, a 21.8% increase.19 Pediatric cancers are also a concern. Children under the age of five have experienced increasing incidence of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), ependymal tumors, neuroblastoma, and hepatoblastoma.20 Neonatal or early-life exposure to BPA is a risk factor for developing prostate cancer in later life. Other disorders Research indicates that BPA plays a negative role in thyroid disorders, non-alcoholic steatosis, osteoarthritis, inflammatory bowel conditions, alteration of the gut microbiome, obesity, diabetes, cardiovascular disease (CVD), and neurotoxicity.21 While there are some known lifestyle causes – such as poor diet and lack of physical activity – that contribute to increased diabetes and obesity rates, EDCs are understood to have a significant impact by promoting metabolic dysfunction. Initial studies show that BPA can cause changes in human blood glucose levels and insulin resistance, while increased urinary BPA levels in adolescent children have been positively associated with metabolic syndrome.14 Metabolic-disrupting chemicals have also been linked to the abnormal growth of fat mass, which causes weight gain by altering the endocrine system responsible for metabolism and appetite.1
BPA has emerged as a significant public health concern. Over the past two decades, the incidence of female and male reproductive disorders has risen rapidly, as have the rates of neurobehavioral disorders in children and certain cancers. The consumption of, and exposure to, BPA is purported to have significant consequences for future generations worldwide and contribute substantially to disease and reduced lifespan.
Figure 1: Clinical symptoms associated with LBD syndromes5
The NOVA food classification system, which is commonly used to describe population dietary patterns, defines UPFs as “industrial formulations of ingredients that undergo a series of physical, chemical, and biological processes.” First developed in Brazil in 2009, NOVA organizes foods into one of four groups, based on the level of processing involved.3
Categories of UPFs
Table 1: The NOVA Food Classification System3
Groups
Description
Examples
NOVA 1
NOVA 2
NOVA 3
NOVA 4
unprocessed or minimally processed foods
Unprocessed food items (e.g., seeds, fruits, leaves, stems, roots, eggs, milk, fungi) Food items minimally processed via drying, crushing, grinding, roasting, boiling, pasteurizing, chilling, freezing
Oils, butter, lard, sugar, salt; items derived from NOVA1 foods; and items that combine two such ingredients (e.g., salted butter) Items not intended to be consumed on their own but used to enhance the NOVA1 foods from which they are derived
Canned meat, fish, fruit, beans, vegetables; cured meats; fermented beverages; food items with added ingredients from NOVA1 or NOVA2 (e.g., bread) Items containing two or three ingredients that make modified versions of NOVA1 foods
Sweetened beverages (including soft drinks), sweets, cookies, potato/tortilla chips, re-formed meats (e.g., Spam), and ready-to-eat meals composed of substances derived from foods and additives Items containing additives such as preservatives, antioxidants, stabilizers, dyes, flavors, enhancers, sweeteners, and emulsifiers
processed culinary ingredients
processed foods
UPFs (industrial formulations)
Mandatory clinical symptoms for an LBD diagnosis: Dementia Specific impairments in attention, executive function, and visuospatial perception Recurrent and well-formed visual hallucinations readily described by patients, with details involving known people or strangers, animals, or objects One or more Parkinson’s-like motor dysfunctions, such as bradykinesia or involuntary slowing of movement; resting tremor; or muscle rigidity manifesting as stiffness
Core clinical symptoms specific to an early diagnosis of LBD may include: Significant fluctuations of alertness and attention Memory deficit Manifestation of RBD, which involves much motor action during REM sleep, including aggressive physical attacks o This may occur months or years before cognitive dysfunctions Certain characteristic cognitive abnormalities may be detected in mental state screening tests o The tests might not reveal these dysfunctions in early-stage disease due to cognition fluctuations
Non-core clinical symptoms supporting an LBD diagnosis may include: Excessive reactions to neuroleptics medications, which have been observed in many with LBD Severe autonomic dysfunctions leading to orthostatic blood pressure drop, which may exacerbate risk of syncope (fainting) and falls Constipation, incontinence, excessive daytime sleepiness (hypersomnia), and heightened sense of smell (hyperosmia) Auditory and olfactory hallucinations Anxiety and depression
Figure 2: Indicative and supportive biomarkers for LBD5
Supportive biomarkers: Intact medial temporal lobe structures on CT/MRI brain imaging; this differs from the loss of temporal lobe volume seen in AD Reduced occipital lobe metabolism or blood perfusion on molecular scans Presence of cingulate island sign on a fludeoxyglucose (FDG) PET scan EEG showing slow wave activity in posterior brain lobes with periodic fluctuations
Indicative biomarkers: Reduced dopamine transporter uptake in the basal ganglia, detected in a PET scan (PET is not routinely used in all suspected cases) Myocardial scintigraphy will show the cardiac sympathetic nerve damage caused by LB pathology; however, as this finding can also be a symptom of other autonomic neuropathies, it is not a specific LBD biomarker Polysomnographic finding of atonia loss during REM sleep (an LBD precursor), in conjunction with other clinical findings
This discovery also signals potential overlap of the genetic mechanisms of aSyn-spectrum PD and AD.6 As GBA and SNCA are both involved in aSyn protein synthesis or regulation, they are also associated with PD development. In addition, the presence of other gene mutations such as PARK7 and PARKN has demonstrated a high risk for Parkinson’s disease development, which is a precursor of some PDD cases. No highly penetrant pathogenic mutation has been identified for LBD to date, but family history remains a powerful risk prediction factor. Siblings of DLB patients, for example, have been found to have more than twice the risk of developing DLB.4 A more advanced understanding of the culprit genetic mechanisms and of related downstream molecular pathways may yield more effective treatments, diagnostics, and assessment tools in the future.
APOE codes for Apolipoprotein E glycoprotein, which is involved in cholesterol homeostasis. Gene mutations resulting in different APOE alleles can either promote or protect against AD. APOE allele 4, for instance, increases the risk of both AD and LBD. It is not clear, however, if the AD-protective APOE e2 allele has a similar beneficial effect specifically against DLB. BIN 1 is also associated with APOE4, but a more granular understanding of its potential pathogenic role is still to be established.6 GBA gene variants have been linked to PD risk and are associated with DLB pathogenesis. Mutated variants of this gene result in reduced glucocerebrosidase activity, leading to aSyn accumulation.6, 10 SNCA codes for aSyn and has a regulating effect on its expression. SNCA-AS1 is the mirror-image RNA messenger of the SNCA gene. Many mutations of SNCA have been observed, but pathogenic mutations are rare, with variable penetrance resulting in a wide range of phenotypes across multiple aSyn disorders, including PD, PDD, and DLB. Evidently, mutations located at different SNCA loci may be responsible for PD and DLB.6, 10 TMEM 175 is a potassium channel inside lysosomes that may play a role in balancing cellular pH. Deficiencies leading to altered pH and aSyn accumulation have been observed in neurodegenerative disorders, but a fuller understanding is still lacking.6
DLB typically occurs randomly in populations, but familial cases have been documented. A 2017 genome-wide association study (GWAS) identified five proteins of significant association with implications of their related genes in the disease process: APOE, GBA, SNCA-AS1, BIN1, and TMEM 175.6
Click here to read Part 1: Fontotemporal Dementia
Figure 1: Birth cohort incidence and mortality rate ratio trends from 1920 to 1990 for six cancers with reversing trends in incidence compared with older birth cohorts in the US from 2000 to 201918
What’s New?
The complex case of covering GLP-1 drugs
Dr. Lauren Acton, MBChb, has joined RGA South Africa as Chief Medical Officer. Lauren completed her medical studies and obtained her Bachelor of Medicine, Bachelor of Surgery degree at the University of Pretoria in South Africa in 2006. After her internship and community service in Johannesburg, she pursued a Master’s degree in bioethics at the University of Stellenbosch, also in South Africa. Her experience encompasses both clinical and insurance medicine, having worked in a private practice as well as for a direct insurer and a reinsurer before coming to RGA.
After a quarter-century with RGA South Africa, Dr. Anthony (Tony) Crosley, the branch’s Chief Medical Officer, is retiring. Tony came to the South Africa office soon after its 1999 launch, and has played a major role in the success and market standing of the underwriting and medical teams. A physician and veteran of more than half-century in insurance medicine, Tony is a doyen of the field: his immense medical and insurance knowledge, work ethic, capabilities, and collegiality are well known, and will be missed. We wish him the very best in his life’s next journey.
Industry Event:
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Drug Watch: Additional Copy
Tomasik J, et al. JAMA Psychiatry. 2023 October 25; 81(1):101-6. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2811312
Metabolomic biomarker signatures for bipolar and unipolar depression
Editor's note: These findings are part of a growing body of research showing the benefits of glucagon-like peptide-1 (GLP-1) receptor agonists in a wide range of conditions. The study highlights the potential of this class of drug as a treatment option targeting the underlying etiology of obesity-related OSA.
Tirzepatide for the treatment of obstructive sleep apnea and obesity
Livingston G et al. The Lancet Commissions, Volume 404, ISSUE 10452, P572-628, August 10, 2024
Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission
Publications relevant to insurance medicine appearing recently in research literature.
Research Watch
Health View I
Industry Event
Drug Watch
RGA Thought Leadership
The continued interest and research may also lead to increased approvals for new indications for GLP-1 agonists, expanding the use of these drugs and likely impacting insurance coverage. Policymakers may need to address the high costs of these drugs through measures such as price controls or subsidies to ensure broader access. In short, determining the potential impact of GLP-1 agonists on the health insurance industry is complex, involving a balance among short-term costs and long-term savings, coverage decisions, and broader industry dynamics. As use of these medications continues to evolve and demonstrates their value for managing chronic conditions, insurers will need to adapt their strategies to optimize patient outcomes while managing financial sustainability.
Read more about this topic on RGA’s Knowledge Center
Editor’s note: Extensive efforts are needed to identify underlying risk factors responsible for these trends to inform prevention strategies and assist with actuarial modelling.
Differences in cancer rates among adults born between 1920 and 1990 in the USA: An analysis of population-based cancer registry data
Editor’s note: Knowledge about risk factors and potential prevention, detection, and diagnosis of dementia is expanding and will likely improve outcomes and refine risk stratification in the future.
Malhotra A et al. New England Journal of Medicine, June 21, 2024 https://www.nejm.org/doi/abs/10.1056/NEJMoa2404881
Sung H et al. The Lancet, August 2024 https://doi.org/10.1016/S2468-2667(24)00156-7
As life expectancies increase, so does the number of people worldwide living with dementia. The 2024 report of the Lancet Commission on dementia prevention, intervention, and care shared compelling new evidence that untreated vision loss and high LDL cholesterol are risk factors for dementia. Tackling both of these in conjunction with risk factors previously modelled (i.e., less education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity, diabetes, excessive alcohol consumption, traumatic brain injury, air pollution, and social isolation) reduces the risk of developing dementia. Overall, approximately 45% of dementia cases were deemed to be preventable by addressing these 14 modifiable risk factors at different stages of life, irrespective of APOE genetic status.
Read more
Editor’s note: Metabolomic profiling has the potential to improve the differential diagnosis of mood disorders in clinically relevant scenarios which will impact risk assessment and claims adjudication in the future.
This study investigated the safety and efficacy of tirzepatide, a long-acting, glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist, for the treatment of moderate to severe obstructive sleep apnea (OSA) in obese participants (body mass index ≥30 kg/m2) with an established OSA diagnosis. Participants receiving the treatment experienced notable improvements compared to the placebo group, with a reduction in the apnea-hypopnea index (AHI – the number of apnea and hypopnea occurrences during an hour of sleep), from 51.5 events at baseline to 25.3 events after 52 weeks of treatment vs. a reduction of only 5.3 events per hour in the placebo group. The study also noted reductions in body weight, hypoxic burden, C-reactive protein (CRP) concentration, systolic blood pressure, and improved sleep-related patient-reported outcomes.
This analysis of population-based registry data obtained incidence data for the period of January 1, 2000, to December 31, 2019, from the North American Association of Central Cancer Registries (NAACCR) for the 34 most common cancer types diagnosed at ages 25-84 years old. After controlling for age and period effects on cancer incidence rates, the study found that each successive generation born during the second half of the 20th century has had increased incidences of many common cancer types (of heterogeneous aetiologies) compared with preceding generations in the US. The incidence rate for individuals in the 1990 birth cohort was approximately two to three times higher than the 1955 birth cohort for cancers of the small intestine (IRR 3·56 [95% CI 2·96–4·27]), thyroid (3·29 [2·91–3·73]), kidney and renal pelvis (2·92 [2·50–3·42]), and pancreas (2·61 [2·22–3·07]). This suggests the prevalence of carcinogenic exposures (e.g., unhealthy dietary patterns, sedentary lifestyle, altered sleep patterns, and environmental chemicals) is increasing during early life or young adulthood in this generation, which has yet to be elucidated.
Patients with depressive symptoms with misdiagnosed BD showed a distinct profile of metabolites compared with patients with depressive symptoms with MDD, and this metabolic signature enhanced the predictive value of diagnostic models based on self-reported patient information.
Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) because of overlapping symptoms and the lack of objective diagnostic tools. This diagnostic study, which was approved by the University of Cambridge Human Biology Research Ethics Committee, used samples and data from the Delta study, conducted in the U.K. between April 27, 2018, and February 6, 2020, to identify BD in patients with a recent (within the past five years) diagnosis of MDD and current depressive symptoms. Digital questionnaire data were used along with dry blood samples, which were analyzed for 630 metabolites using a targeted mass spectrometry–based metabolomic platform.
Health View
Research
RGA Research: Analysis of US data provides valuable insights into emerging excess mortality
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Managing Pandemic Risk After COVID-19: Lessons from the past, preparing for the future
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https://doi.org/10.1016/S0140-6736(24)01296-0
Underwriting Update
Reference: https://blog.research.google/2024/01/amie-research-ai-system-for-diagnostic_12.html
Dr. Steve Woh
Medical Director and Health Claims
steve.woh@rgare.com
Dr. Lauren Acton, MBChb
Chief Medical Officer RGA South Africa
Lauren.Acton@rgare.com
Dr. Steve Woh, Medical Director and Health Claims, RGA
Glucagon-like peptide-1 (GLP-1) agonists have garnered significant attention for their efficacy in managing type 2 diabetes and obesity. These medications mimic the action of the GLP-1 hormone, which regulates blood sugar levels and appetite. Recent evidence suggests positive outcomes with weight loss and blood sugar control, garnering much interest from patients and doctors alike. GLP-1 agonists’ impact on the health insurance industry is already both multifaceted and profound. With annual treatment costs estimated at thousands of dollars per patient, coupled with increasing utilization, current premiums may not be sustainable. This could lead to higher premiums, greater out-of-pocket expenses for patients, or both. However, the long-term savings arising from the expected reduction in disease complications, as well as from improved overall health outcomes, could also be significant. Further study and ongoing monitoring are required. Pressure is mounting for insurers to reimburse GLP-1 agonists for more recently approved indications, especially for obesity and overweight with additional risks. To manage costs, insurers may decide to introduce copays for the drugs and/or require prior authorization. These control mechanisms, while helping to ensure that insurance premiums remain sustainable, may negatively affect adherence to the drugs. Following the commercial success of the early manufacturers of GLP-1 agonists, competition is expanding, with new innovative drugs, including biosimilars, expected to enter the market. This could lead to competitive pricing and additional options for patients and insurers.
Health View II
Reference: https://www.cgtlive.com/view/excision-suppress-hiv-viral-replication-ebt-101-crispr-gene-therapy
While the implications of this exciting development are huge for mortality and morbidity improvement in affected patients with latent infections from these hard-to-cure viral diseases, their impact on treatment costs needs to be studied, especially from the perspective of health insurance. As with all gene therapies, hefty price tags, in the millions of dollars, are expected for these treatments, making it essential that they be properly studied, tested, and vetted.
A recent article published in the Journals of the American College of Cardiology (JACC) found that patients treated with semaglutide had lower rates of all-cause mortality compared to those taking a placebo. These patients (n=17604) were 45 years old or older with a BMI of 27 or more. They all had established cardiovascular disease, but not diabetes. The lower mortality rates were driven by a reduction in both cardiovascular and non-cardiovascular deaths. Interestingly, the decrease in non-cardiovascular deaths was predominantly due to significantly fewer cases of infectious disease. During the study period, COVID-19 was the most prevalent of these diseases. Fewer COVID-19-related deaths support the hypothesis that several mechanisms may be allowing drugs like semaglutide to counter or delay processes that lead to death. In that context, an editor of the JACC quipped that it would not surprise him if these drugs slow the aging process. Although no direct evidence currently shows that taking semaglutide or another GLP-1 agonist will decelerate the aging process, the study did find a reduction in all-cause death rates from taking the drugs, at least within a select population. A positive effect from GLP-1 agonists on aging is theoretically possible, but further studies are needed.
Can GLP-1 agonists slow the aging process?
Dr. Anthony Crosley
Dr. Anthony (Tony) Crosley
acrosley@rgare.com
Dr. Lauren Acton
Dr. Heather M. Lund, Regional Chief Medical Officer, RGA Asia
ICLAM 2025 The International Committee for Insurance Medicine (ICLAM) will host the ICLAM 2025 Conference May 11-14, 2025 in Estoril, Portugal. This four-day conference, a leading industry event, will welcome expert speakers from around the world and draw a global audience. Information and registration can be found at www.iclam2025.org.
Kishan Bakrania, Senior Health Data Scientist, Risk and Behavioral Science
Tom Yates, Professor of Physical Activity, Sedentary Behaviour and Health. University of Leicester
Marie-Christine Boucher, Assistant Vice President and Actuary, Capital and Analytics
An Actuary’s Perspective: Unlocking the power of structured underwriting data
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Crossing the Streams: How behavioral science enhances automated underwriting
Beyond the Hype: Focusing on value in digital underwriting optimization
Please click the articles below to see some of RGA's recently published thought leadership on underwriting topics.
RGA’s latest all-digital Global Underwriting Manual Resource Hub* provides underwriting updates for asthma and Hodgkin lymphoma. The hub features comprehensively revised and updated guidelines for these two conditions and related informational materials and tools:
Asthma – updated descriptions, competitive risk tables, and research-based recommendations for accurate risk assessment for both mortality and morbidity benefits Hodgkin lymphoma – expanded rating tables, risk classification guidance based on the Ann Arbor Staging System, and insights on etiology, signs and symptoms, and treatment toxicity Plus – minor updates to underwriting guidelines on: Family history of cancer Anal fistulas Gastrointestinal stromal tumor (GIST) Autism spectrum disorder (ASD)
We invite underwriting, medical, and claims professionals to please click here to access and explore the new hub. And don’t hesitate to send us your questions or comments. We look forward to providing you with news and updates on GUM in future issues of ReFlections. *GUM guidelines in North America can vary from those applied across all other markets. RGA clients in US and Canada, please click here to access your customized GUM resources.
Case ReView
Dr. Sheetal Salgaonkar, MBBS, DBIM
Vice President and Medical Director, RGA India
ssalgaonkar@rgare.com
Underwriting a challenging mammogram case
Case presentation: A 40-year-old female applies for $500,000 of life insurance and $50,000 of critical illness (CI) coverage. Her application reveals a recent health checkup that includes a mammogram report. The mammogram report indicates the following: The breast parenchyma is extremely dense. A few scattered punctate calcification clusters appear in both breasts. Focal increased density is visible in the upper half of the left breast, along with fine calcifications within the area of focal increased density. Nodular density is also visible in the right central breast. Impression: BI-RADS 0
Key underwriting considerations: 1. What are the abnormalities in the mammogram, and what does BI-RADS 0 signify? Chief Medical Officer (CMO) response: This screening mammogram report contains multiple abnormalities. First, the breast parenchyma is extremely dense. Increased breast density can mask cancers in dense tissue on a mammogram, leading to lower accuracy of the results. Increased density is an independent risk factor for breast cancer. Compared with the general population, the relative risk for developing breast cancer is 1.2 for women with heterogeneously dense breasts and 2.1 for women with extremely dense breasts. Second, there are significant breast calcifications: a few scattered punctate clusters in both breasts and fine calcifications in the upper half of the left breast. Last, a nodular density in the right central breast is designated as BI-RADS 0. The Breast Imaging Reporting & Database System (BI-RADS), developed by the American College of Radiology, is a widely accepted system that aims to standardize breast imaging interpretations. BI-RADS 0 signifies an incomplete test and indicates that the mammogram images may have been difficult to read or interpret. Hence, additional imaging evaluation (mammographic views or ultrasound) will be needed, as previous images were not available at the time of interpretation.
2. Are the breast calcifications benign or malignant? CMO response: Breast microcalcifications are quite common abnormalities observed in the adult breast. They are associated with more than 85% of all ductal carcinoma in situ (DCIS) cases and a key feature for identifying DCIS. Currently, 30-50% of non-palpable breast cancers are detected solely by microcalcification identification on a mammogram. These well-defined patterns can help distinguish benign from potentially malignant changes: Benign calcifications are typically larger, coarser, popcorn-like, and round with smooth margins, with a scattered or diffuse distribution. Calcifications suggestive of malignancy are typically grouped or clustered, pleomorphic (varying in size and shape), fine, and characterized by linear branching. Punctate calcifications may be benign but are also commonly found in DCIS. Just under 50% of DCIS calcification clusters contain punctate calcifications, and 15% have predominantly punctate calcifications. Breast ultrasonography often lacks the ability to detect microcalcifications. Suspicious calcifications may require further evaluation through a biopsy.
3.What is the underwriting decision? CMO response: In view of the extremely dense breasts, BI-RADS 0 lesion, and pattern of calcifications, the underwriting decision is to postpone a decision pending further evaluation of the mammographic findings. Key takeaways: Increased breast density can mask cancers on a mammogram and is an independent risk factor for breast cancer. BI-RADS 0 signifies an incomplete test and the need for additional imaging. Breast microcalcifications could be a marker of breast cancer, especially DCIS, and should be underwritten with caution. Suspicious calcifications may require further evaluation with a biopsy. One final note: The results of any medical test, including a mammogram, should be underwritten in the context of the known personal and family history.
BI-RADS® ASSESSMENT CATEGORIES
Category 0: Mammography: Incomplete - Need additional imaging evaluation and/or prior mammograms for comparison Ultrasound and MRI: Incomplete - Need additional imaging evaluation Category 1: Negative Category 2: Benign Category 3: Probably benign Caegory 4: Suspicious Mammography and Ultrasound: Category 4A: Low suspicion for malignancy Category 4B: Moderate suspicion for malignancy Category 4C: High suspicion for malignancy Category 5: Highly suggestive of malignancy Category 6: Known biopsy-proven malignancy
Expert Q&A
Q
David Sinclair
Tell me about the ILCUK. What are the Centre’s mission and goals, and how does your work apply globally?
I see the ILCUK as the leading authority on longevity and its impact on society. The Centre focuses on understanding how individuals, businesses, and governments can adapt to demographic changes. We engage with change-makers and take a very broad, rather than deep, approach to problem solving. About half of our work is now global vs. UK-specific. In fact, most of our partners from various geographies in the International Longevity Centre Global Alliance also work globally. We do a lot of bilateral work with other alliance members and are keen to do more collaborative global projects with our network of diverse experts around the world.
How might other organizations such as RGA’s Longer Life Foundation collaborate with your Centre to promote shared interests and goals?
With organizations like the Longer Life Foundation, we look to collaborate in developing solutions to help society adapt to the challenges of people living longer. We can work with the foundation to get its research learnings to policymakers to help drive change.
Are we entering a “perfect storm” era whereby birth rates in many industrialized countries are falling and life expectancy is increasing? How will these demographic shifts create challenges in the next 20+ years? Are there any positive aspects or opportunities to counter these challenges?
The fundamental challenge that many economies around the world face stems from demographic changes related to the number of people working compared to those not working. In wealthier countries people are working less than ever before. The number of hours per week has fallen, and workers are retiring earlier. People in modern economies are struggling to remain productive for as many years as possible. Even into old age, we all need to have a purpose, and the role of work can fulfill that purpose. With declining birth rates, governments have very little power over how many children are born. If you look at countries such as Japan, Korea, Hungary, and Poland – places where the government has encouraged having more children – people have essentially ignored those directives. Governments can do certain things, such as investing in care and ensuring availability of flexible work hours, but simply telling people what to do has not been successful. The “longevity dividend” may present an opportunity. The key is maintaining good health into old age. Essentially, if we stay healthy, we work more, we volunteer more, we care more, and we spend more. Evidence supports the validity of the longevity dividend in the UK as well as globally. At the heart of the opportunity lies the wealth, knowledge, and expertise that comes with long lives. Again, good health is essential. In addition, governments need to remove barriers to consumption and active participation as people age. Just consider what economists have termed the “retirement consumption puzzle”: While most wealth resides with older people, they spend much less than they have. It is therefore clearly important to keep older people engaged economically.
As populations grow older, we need to turn away from ageism and instead find ways to use the wisdom of our elders to tackle the big challenges, from climate change on down. "
With decades of experience in policy and research on aging and demographic change, David Sinclair serves as CEO of the International Longevity Centre UK (ILCUK). He is a recognized expert in aging-society issues, having presented on longevity and demographic change across the world and published reports on topics ranging from transport and technology to health and consumption. He recently sat down with Dr. Daniel D. Zimmerman, Senior Vice President and Chief Science Advisor at RGA and co-editor of ReFlections, to discuss the challenges presented by aging populations, the importance of promoting healthspan as well as lifespan, and his hopes for future generations.
References: 1. https://www.science.org/doi/10.1126/science.1058040 2. https://pubmed.ncbi.nlm.nih.gov/23168792/ 3. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2020/10/screening-for-fetal-chromosomal-abnormalities 4. https://www.nature.com/articles/s41525-024-00404-0
CEO, International Longevity Centre UK
David Sinclair will be a featured keynote presenter at ICLAM 2025 in Portugal on May 11-14, 2025, the tri-annual conference of the International Committee for Insurance Medicine. Learn more about this premier global event at iclam2025.org.
About David Sinclair
The Longevity Challenge: Aging societies and the need to adapt
You published “One hundred not out: A route map for long lives” in December 2023. In this comprehensive white paper, you address multiple topics, including healthspan and financial security. Could you highlight one or two priority issues and next-step solutions you have proposed?
With notable changes in aging populations and rising healthcare costs, societies need to invest in preventive health. As innovations from the pharmaceutical and biotech industries or other sectors tackle the diseases that become more common with age, I think governments will see the value in investing in these advances. With regard to financial security, we should encourage people to save sufficiently by supporting work-pay savings programs and similar programs for the self-employed. I recommend building in “auto-escalating” structures, which increase savings year over year. Today, just 4% of wealth in the UK is held by people under age 40, and this has decreased over the last several years. New approaches must help address the balance of wealth between young and old. Regarding health, I believe more regulation around tobacco and alcohol would be a prudent step. This all ties into extending the healthspan. Ideally, we want to reduce the difference between life expectancy and healthy life expectancy. Even in countries with high life expectancy, healthy life expectancy is 10 years shorter. In South Korea, for example, which performs very well on our Healthy Ageing and Prevention Index, this 10-year gap remains.
What role can the private sector play, specifically life and health insurers and reinsurers, in helping to create social safety nets to supplement government programs to support aging societies?
I think these companies can play a huge role, and that is why we work with the insurance industry – from promoting financial sustainability to improving population health. The industry can adapt products for the changing demography, which is much more complicated now than in the past. The industry also can incentivize the prevention of ill health, promote long-term savings through product design, and even drive public policy in these areas. Supporting workplace health is key, including in small organizations. We should think in terms of delivering a social good, a purpose and invest in future generations and healthy aging.
Regarding aging, what is your greatest concern and what is your greatest hope for the future?
I think the biggest challenge is the gap between healthy life expectancy and life expectancy, which is driven by significant inequality. If we are to fill that gap, we must find a way of marrying them. Without a clear focus on availability and access, for example, new innovations and pharmaceuticals actually pose a risk of widening that gap. Companies must prioritize population health as well as individual health. As populations grow older, we need to turn away from ageism and instead find ways to use the wisdom of our elders to tackle the big challenges, from climate change on down. I am hopeful that policymakers and industry can solve some of the biggest challenges. For example, before we had the smoking ban in the UK, the political narrative was that this would never happen. People stepped up to the challenge. When I was younger, CFCs and their impact on the ozone layer were a big worry, but governments globally regulated CFC emissions and the problem was sorted out. It is important to find ways to allow our political leaders to make difficult decisions.
What drives your work as the CEO of the ILCUK?
I find the work fascinating, and I get to talk with interesting people from around the world. Societal aging is not about a single issue – it involves economics, philosophy, geography, biology, behavioral science, and diplomacy. This is what makes my work so stimulating, but it also makes it difficult to drive change. But times have changed, and many more people are interested in demographic changes, including powerful entities such as central bankers. There is a growing recognition that global economies are changing, and we must learn how to adapt.
The Longer Life Foundation (LLF) is a collaboration of more than a quarter century between RGA and Washington University School of Medicine in St. Louis. We are pleased to bring you our September 2024 newsletter, which discusses the foundation’s many recent activities. To find out more about LLF and the research it has funded to date, please visit www.longerlife.org or reach out to Dr. Daniel D. Zimmerman at dzimmerman@rgare.com or Dr. Preeti Dalawari at preeti.dalawari@rgare.com.
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