Ultra-Processed Foods: Fast Food, Fast Life?
Eyes on the Prize: Spotlight on PCSK-9 Inhibitors
Non-Alzheimer’s Dementias: A Closer Look
Longer Life Foundation
An RGA/Washington University Collaboration
The Longer Life Foundation (LLF), a collaboration between RGA and Washington University School of Medicine in St. Louis, is celebrating its 25th year of enhancing longevity and health through research. Please read on for the Foundation’s latest news, and to learn more about LLF’s activities and events, 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.
It is with great sadness we report the passing of Dr. William A. Peck, retired Dean of Washington University School of Medicine in St. Louis and Vice Chancellor of the University, in February 2023 at the age of 89. Dr. Peck, together with Greig Woodring, retired President and Chief Executive Officer of RGA, cofounded the Longer Life Foundation 25 years ago – an act of vision reflecting his career-long dedication to supporting medical research and mentoring researchers. Dr. Peck, a physicianscientist, had a 14-year tenure as both Dean and Vice Chancellor (1989-2003), during which he successfully strengthened Washington University in St. Louis into a center for research and clinical excellence. After his retirement, he established the Center for Economics and Health Policy within Washington University’s Institute for Public Health, which has grown to become a nationally recognized leader in health policy.
Dr. Peck's full obituary
The fourth video of our investigator series, an interview with current grant recipient Dr. Nathan O. Stitziel, is now available on LLF’s dedicated YouTube channel. Dr. Stitziel, whose research focus is on the role of genetics in cardiovascular disease, discusses his current investigation into the SVEP1 protein and the increasing understanding of its role as a causal element for multiple chronic diseases of aging.
A commemorative 25th anniversary video, highlighting LLF’s past, present, and future, is due for release in the coming months. Watch this space!
Watch the interview
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In memoriam: William A. Peck, MD (1934–2023).
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Dr. Adela Osman
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Senior Vice President Chief Science Advisor
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We are very excited to bring to you our latest issue in a completely redesigned and modernized format. ReFlections now resides on an interactive online platform. If you take a look at the Table of Contents dropdown on the upper right corner of the landing page, you will note familiar sections and some new items as well:
Welcome to the February 2024 issue of ReFlections!
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From the editors
Features in this issue explore PCSK-9 inhibitors and their growing role in cholesterol control, and the latest information about ultra-processed foods and frontotemporal dementia.
ReFlections also, for the first time, offers you the opportunity to give us real-time feedback on our features and let us know what you would like to read about in future issues. Please don’t hesitate to take advantage of this new capability. As we enter this new digital era for ReFlections, we would like to thank you, our readers, for your support of this newsletter and its mission to provide insightful medical insurance thought leadership. We look forward to hearing from you! Thank you, Dan and Adela
Features in this issue
Eyes on the Prize: Spotlight on PCSK-9 Inhibitors Ultra-Processed Foods: Fast Food, Fast Life? Non-Alzheimer’s Dementias: A Closer Look - Part 1
Watch the welcome to ReFlections video
Expert Q&A (new) features interviews with prominent medical and insurance thought leaders discussing topics of importance to our industry. This issue has an interview with renowned epidemiologist Dr. Michael T. Osterholm, Director of the Center for Infectious Disease Research and Policy (CIDRAP).
LLF News shares the latest news and highlights from the Longer Life Foundation.
Underwriting Update (new) provides information about the most recent guideline updates in RGA’s Global Underwriting Manual (GUM).
Case ReView (new) offers a brief video presentation of a timely case, its issues, and its resolution. This issue considers a challenging thyroid cancer claim.
What’s New (new) provides reviews of recent research in Research Review, brief discussions of important current issues affecting the health insurance community in Health View, and links to RGA thought leadership articles and webinars.
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Lowering cholesterol is consistent with better cardiovascular (CV) outcomes, including reductions in myocardial infarctions (MI) and strokes. While treatment with statins is the mainstay of lipid-lowering therapy, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK-9) have emerged as a powerful new targeted tool. These treatments are enabling lower levels of cholesterol to be achieved and might improve CV outcomes further, especially in those at higher risk either because of established atherosclerotic cardiovascular disease (ASCVD) or because optimal levels of cholesterol cannot be achieved on statin therapy alone. This article will address the mechanisms of action, indications, drug development, treatment outcomes, and possible impact of this new class of lipid-lowering agents on insurance.
Abstract
While medical society guidelines for treatment using these inhibitors may differ slightly, most have been broadened to include specific LDL treatment targets.
Indications for PCSK-9 inhibitor use
References
https://www.heartviews.org/article.asp?issn=1995-705X;year=2019;volume=20;issue=2;spage=74;epage=75;aulast=Hajar https://www.ecrjournal.com/articles/proprotein-convertase-subtilisinkexin-type-9-inhibition-big-step-forward-lipid-control https://pubmed.ncbi.nlm.nih.gov/28304224/ https://pubmed.ncbi.nlm.nih.gov/30403574/ https://pubmed.ncbi.nlm.nih.gov/36031810/ https://pubmed.ncbi.nlm.nih.gov/34325831/ https://jamanetwork.com/journals/jama/fullarticle/2808864 https://jamanetwork.com/journals/jama/fullarticle/2811935 https://pubmed.ncbi.nlm.nih.gov/33663735/ https://www.nature.com/articles/s41586-021-03534-y https://pubmed.ncbi.nlm.nih.gov/36314243/ https://newsroom.heart.org/news/a-single-infusion-of-a-gene-editing-medicine-may-control-inherited-high-ldl-cholesterol https://pubmed.ncbi.nlm.nih.gov/25915661/
About the author
Heather M. Lund, MBBCh, is Chief Medical Officer – Asia at RGA Reinsurance Company. She provides medical consultation expertise and technical assistance for reinsurance underwriting and claims assessment, supporting actuarial business development, marketing, and pricing teams across the Asia region. A native of South Africa, Heather’s Bachelor of Medicine, Bachelor of Surgery (MBBCh) degree is from the University of the Witwatersrand in Johannesburg. Her background is in family medicine, with a special interest in maternal health. She is a frequent contributor to medical publications and has also served on program committees of the International Committee For Insurance Medicine (ICLAM) and the Academy of Insurance Medicine in Asia (AIMA).
Dr. Heather Lund
Regional Chief Medical Officer RGA Asia
hlund@rgare.com
PCSK-9 inhibition is not usually a first-line cholesterol-lowering therapy
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Hepatocytes (liver cells) have low-density lipoprotein (LDL) receptors on their surfaces. Circulating LDL-cholesterol (LDL-C) binds to these receptors. The receptor-cholesterol complex is then taken into the hepatocyte and degraded, after which the LDL receptor recycles back to the cell surface to bind more circulating LDL-C. This process is rapidly and continuously repeated throughout the cell’s 20-hour lifespan, enabling clearance of approximately 100 to 150 LDL-C particles. PCSK-9 is a protein produced primarily in the liver that regulates the number of LDL receptors. It binds to the LDL receptor part of the receptor-cholesterol complex and prevents LDL receptors from recycling back to the cell surface. This reduces the number of LDL receptors on the hepatocytes and increases serum levels of LDL-C. The more PCSK-9 is produced by the liver, the higher the serum LDL-C level. PCSK-9 inhibitors block the activity of PCSK-9, thereby increasing clearance of LDL-C and lowering cholesterol levels by an average of 50% to 60% in patients on statin therapy.1 The PCSK-9 protein is encoded by the PCSK-9 gene on chromosome 1. Mutations alter the function of the gene. Twenty years ago, two breakthrough discoveries related to the gene occurred: A gain-of-function mutation was found to be the cause of familial hypercholesterolemia (FH), and loss-of-function mutations were found to be associated with very low cholesterol levels and associated reduction in the incidence of cardiovascular disease. These discoveries led to the identification of PCSK-9 as a potential drug target for cholesterol control.
PCSK-9 inhibitors: mechanism of action
While PCSK-9 inhibition is incredibly effective at reducing LDL-C levels, most people will achieve LDL-C goals with statin monotherapy. As such, statins are unlikely to be replaced as first-line therapy in the immediate future, particularly because they are both efficacious and cost effective and have significant cardiovascular outcome trials to support their use. Since their approval in the late 1980s, statins have been and remain the mainstay for effective lowering of cholesterol following the discovery of the relationship between lipids and atherosclerosis in the 1960s. Still, there remains a need for alternative potent lipid-lowering therapies. PCSK-9 inhibition is, therefore, another tool in the cholesterol and cardiovascular outcome-reduction toolkit. Interestingly, circulating levels of PCSK-9 are upregulated in the presence of statins, so inhibiting PCSK-9 seems to complement the LDL-C lowering effect of statins.
Are PCSK-9 inhibitors better than statins?
Potential insurance implications
Despite the significant impact of available lipid-lowering agents on improved cardiovascular outcomes, and while lifestyle modification remains a cornerstone of control, the identification of new pathways and drug targets continues to push the boundaries of what might be possible. PCSK-9 inhibition, through various current and potential modes of delivery, appears to be well tolerated and has become a noteworthy evolution. These treatments are a fascinating tale of medical advances and outcome improvements at their best, with potential sequels to follow. Hopefully a tailwind for mortality improvements and positive medical advances will continue for years to come.
Final thoughts
In patients with FH, use is indicated: For those without cardiovascular disease and where LDL-C targets are not met, despite taking medications such as statins and a second-line therapy such as ezetimibe (an inhibitor of intestinal cholesterol absorption). For adults heterozygous for FH, high-dose statin monotherapy will achieve a 55% to 60% LDL-C reduction. However, if after three months of compliant statin therapy the LDL-C target has not been reached, a second-line drug is generally needed. Options currently include either ezetimibe or a PCSK-9 inhibitor, or both. Ezetimibe, which is usually the preferred option, can lower LDL-C by an additional 20% to 30%. However, it may not be sufficient for patients with FH. For those with known cardiovascular disease where LDL-C targets need to be even lower (i.e., secondary prevention of cardiovascular disease). While no trials specifically for heterozygous FH patients have yet demonstrated improved clinical outcomes, in the FOURIER trial of a cohort without FH (detailed below), PCSK-9 inhibition, despite not decreasing the risk of CV death, lowered the risk of non-fatal myocardial infarction (MI) and non-fatal stroke sufficiently so that its use by inference can be recommended. In patients without FH, use is indicated: For those considered either high-risk (due to previous MI, angioplasty or stent, stroke, or history of heart disease, hospitalization for unstable angina, or peripheral arterial disease [PAD]) or very high risk (due to multiple episodes of listed high-risk events) and where LDL-C targets have not been met despite optimal first-line medical therapy. In the 10% to 20% of those who are statin intolerant, PCSK-9 inhibition may also be a treatment option.
PCSK-9 inhibitors are generally very well tolerated. Safety data is available for up to nearly five years. However, there are adverse effects, which can include flu-like symptoms with fatigue, back pain, and – rarely – myalgia. Elevated liver enzymes have not been seen. The most common side effect is redness, bruising, or pain at the injection site.
Several innovations regarding drug development for PCSK-9 inhibition exist, and more advances in gene-based therapies and delivery modes are being explored.2
Of interest as well, but outside of the scope of this article, as these are very uncommon, are third-line treatments for LDL-C reduction which include ileal bypass surgery, portacaval anastomosis, and liver transplantation.
Cutting-edge developments
PCSK-9 antibodies Monoclonal antibodies (mABs) are synthetic proteins (immunoglobulins) that have a defined specificity for a target antigen. This was the first type of PCSK-9 targeting therapeutic to be developed. These are administered through subcutaneous injections every two to four weeks. mABs have several advantages, including minimal drug interaction, as mABs bypass liver and kidney metabolism, as well as greater target specificity, which reduces potential off-site effects. Two mABs, alirocumab and evolocumab, are fully humanized mABs that bind free plasma PCSK-9, promoting PCSK-9 protein enzyme degradation. Early trials of both, which showed LDL reductions of approximately 50% to 60% compared with placebo, have been followed by Phase III cardiovascular outcome trials of FOURIER for evolocumab and ODYSSEY OUTCOMES for alirocumab.3, 4 The FOURIER trial involved participants with a history of MI, stroke, or symptomatic PAD, on maximum statin therapy followed up for 2.2 years, and showed a statistically significant reduction in cardiovascular events.3 A recently published 7.1-year follow-up study to FOURIER, FOURIER-OLE (participants were a subset of the FOURIER cohort), confirmed safety, tolerability, and a sustained 15% lower risk of major adverse cardiovascular events versus those who received a placebo.5 This is noteworthy, given concerns regarding possible harmful effects from very low LDL-C levels such as diabetes, stroke, cataracts, and neurocognitive impairment, and provides evidentiary support of the cumulative benefit of aggressive lowering of LDL-C. The ODYSSEY OUTCOMES trial involved participants with recent acute coronary syndrome (ACS) episodes who had been on maximum statin therapy. The trial tested efficacy of alirocumab versus placebo, and participants, who were followed up for 2.8 years, showed a statistically significant reduction in recurrent major adverse CV events.4 Additional benefits of PCSK-9 antibodies include a reduction in triglyceride levels by 12% to 31% and an approximately 7% increase in high-density lipoprotein (HDL) cholesterol. Interestingly, while the exact mechanism is not yet understood, sub-analysis of the above trials showed a lowering of lipoprotein(a) (Lp[a]) by approximately 25% and may explain some of the CV outcome benefits. Lp(a) is a genetically determined pro-inflammatory atherogenic LDL-like particle that is independently associated with atherosclerotic cardiovascular disease (ASCVD).6 As an aside, Lp(a) has also emerged as a potential additional new drug target due to recently published results of a phase 1 trial of muvalaplin, an oral formulation of a selective small molecule inhibitor of Lp(a). Muvalaplin has shown encouraging reduction in Lp(a) levels without modulating plasminogen activity.7 Another recent phase 1 safety and tolerability trial of lepodisiran, a small interfering RNA (siRNA) targeting Lp(a) production, showed positive results, supporting the need for further research.8
Small interfering RNA As mentioned above, another method of limiting PCSK-9 activity is to block its production, which is dependent on messenger RNA (mRNA). Inclisiran is an siRNA therapy which consists of a synthetic nucleotide sense strand as well as an antisense strand, which bind to and then degrade the PCSK-9 mRNA, silencing gene expression and preventing protein translation. Inclisiran, which is administered via subcutaneous injection, has been approved to treat individuals with primary hypercholesterolemia or mixed dyslipidemia as a second-line treatment when LDL-C goals are not met. The many ORION trials of inclisiran have shown its effectiveness, with an average 50% reduction in LDL-C across different participant groups.9 While cardiovascular outcome benefits have not yet been shown with inclisiran, two randomized controlled trials, ORION-4 and VICTORION-2 PREVENT, are underway, with results due in 2026 and 2027, respectively.
Editing the PCSK-9 gene Experiments in mice followed by non-human primates using CRISPR/Cas-based treatment to precisely edit the PCSK-9 gene or specific nucleases (bases) have been carried out, the latter allowing for safer and even more precise gene silencing.10 This essentially results in a loss-of-function mutation that permanently silences hepatic PCSK-9 production. To date, initial results show durable LDL-C reductions.11 Advantages of using CRISPR/Cas include reduced usage of standard cholesterol-lowering medications and their associated side effects, thereby enhancing cardiovascular disease prevention. In mid-November 2022, Verve Therapeutics announced an exciting finding from its VERVE 101 trial, where CRISPR technology was used to turn off the PCSK-9 gene in people with heterozygous FH. The results showed successful and substantially lowered cholesterol in study participants and appears to be safe.12 Genetic alterations on somatic cells such as liver cells will not affect the next generation, but if germline cells are edited, the changes could pass to offspring. Notwithstanding the significant ethical considerations, safety, tolerability, and possible off-target effects of gene therapy that need to be assessed in longer-term studies, this development is certainly noteworthy. Not only in terms of using CRISPR technology as a potential “one and done” treatment for dyslipidemia, but also for the management of more common conditions.
Anti-PCSK-9 vaccines mABs can also provide immunity against PCSK-9, as they can act as passive vaccines. Active immunity in the form of a PCSK-9 vaccine, however, while technically challenging, has inherent appeal as a way to potentially reduce the overall cost of treatment and improve adherence. Early safely and efficacy trials of several PCSK-9 vaccine approaches are currently underway.
Oral therapies Several oral PCSK-9 inhibitors are currently in phase I and II clinical trials, which is exciting as, if successful, they would help reduce overall costs of therapy as well as the need for subcutaneous injections.
PCSK-9 inhibition is not usually a first-line cholesterol-lowering therapy. From an underwriting perspective, while laboratory results would be used to risk-assess an applicant, it is important to initially ensure a thorough understanding of the reasons and comorbidities associated with the need for PCSK-9 inhibition. There are also barriers to access to consider, and cost is certainly one of them. The cost of mABs has decreased significantly, to around USD 6,000 a year (from USD 14,000 per year). Cost-benefit studies have shown that mABs are cost-effective for those at greatest risk. The cost-effectiveness of inclisiran, for example, at around USD 6,500 a year, is yet to be established. Use and reimbursement would need to be managed according to recognized guidelines. But at the same time, insurance access could be broadened to those who would benefit most from using mABs or other approved therapies. The most significant question might be: What will the likely impact of PCSK-9 inhibition be on future mortality and morbidity trends? Substantial gains in longevity because of improvements in cardiovascular mortality, driven by better management of vascular risk factors and reduction in smoking rates, were seen in the latter half of the past century. But mortality improvements have slowed and lifestyle diseases such as diabetes and obesity have skyrocketed. The role of the insurer in enabling more proactive management of these lifestyle-related trends – and not just through access to medication – cannot be underestimated. Many factors drive future mortality trends, but PCSK-9 inhibition, through reducing cardiovascular events, could potentially generate improvements in the future. Although reported only at study-level and not patient-level, a meta-analysis of 24 randomized trials of PCSK-9 inhibitors across a diverse range of baseline cardiovascular disease risks and clinical profiles (as was seen with the benefits of statins), found a reduction in all-cause mortality of 55%, cardiovascular mortality of 50%, and MI of 51%.13
Consumption of ultra-processed foods (UPFs) has risen dramatically in recent decades, leading to increasing rates of overweight and obesity, cardiovascular disease (CVD), cancer, and depression. It may also increase future costs, to both consumers and insurers, for life insurance products. It is important insurers understand novel causes such as high UPF consumption that are behind rising rates of non-communicable diseases and their potential impacts. This article explains what UPFs are, details their ingredients and how they are classified, and discusses their impact on human health.
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
https://www.who.int/publications/i/item/9789290210672 https://pubmed.ncbi.nlm.nih.gov/31142457/ https://www.fao.org/fsnforum/index.php/resources/trainings -tools-and-databases/ultra-processed-foods-diet-quality-and-health-using-nova https://www.sciencedirect.com/science/article/pii/S0002916 522001253?via%3Dihub https://www.bhf.org.uk/what-we-do/news-from-the- bhf/news-archive/2023/august/ultra-processed-foods- linked-to-cardiovascular-risk https://pubmed.ncbi.nlm.nih.gov/34862518/ https://www.jacc.org/doi/10.1016/j.jacc.2021.01.047 https://ijbnpa.biomedcentral.com/articles/10.1186/s12966- 021-01081-3 https://ajcn.nutrition.org/article/S0002-9165(22)10524- 1/pdf#:~:text=Results%3A%20In%20this%20study%2C%209227% 20deaths%20and%207934,CI%3A%201.15%2C%201.42%3B%20P- trend%200.001%29%2C%20CV%20mortality%20%28HR%3A https://www.worldobesity.org/resources/resource- library/world-obesity-atlas-2023 https://pubmed.ncbi.nlm.nih.gov/31105044/ https://pubmed.ncbi.nlm.nih.gov/36944386/ https://gco.iarc.fr/tomorrow/en/dataviz/isotype https://www.thelancet.com/journals/eclinm/article/PIIS2589- 5370(23)00017-2/fulltext https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9527958/ https://www.medicalnewstoday.com/articles/ultra- processed-foods-may-increase-depression-risk-long-term- study-shows#1 https://jamanetwork.com/journals/jamanetworkopen/fullarti cle/2809727 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538973/ https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00190-4/fulltext
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.
Hilary Henly, FCII
Global Medical Researcher GAPR Global Research RGA
hhenly@rgare.com
UPFs are one of several novel factors changing incidence rates of many diseases
Ultra-processed foods (UPFs) are industrially produced foodstuffs. They are made mostly or wholly from additives as well as from ingredients derived from whole foods, and contain several items not usually found in home kitchens. These foods are designed specifically to have long shelf lives; to be extremely palatable, convenient, and affordable; and to be highly profitable. Nutrition is widely recognized as a crucial factor in health and longevity. As numerous UPFs are high in salt, sugar, and saturated fat, and low in nutrients such as fiber and vitamins, their consumption is increasingly resulting in poor nutritional health, which may lead to more morbidity and mortality claims due to non-communicable diseases.
Introduction
Harms to health
Overweight and obesity In 2020, an estimated 2.6 billion people worldwide were either overweight or obese (BMI >30kg/m2), and this figure is projected to rise to higher than 4 billion by 2035.10 Individuals who consume substantial amounts of UPFs have higher odds of obesity than those who consume lesser amounts.
UPF health impacts
Many studies indicate that high UPF consumption may be associated with early all-cause and cause-specific mortality. Individuals whose diets have higher percentages of UPFs are also more likely to smoke, have family histories of non-communicable diseases, and lead sedentary lifestyles, all of which may increase early mortality risk. The Seguimiento Universidad De Navarra (SUN) prospective cohort study in Spain, comprising 19,899 participants from 1999 to 2014, found that those with the highest quartile of UPF consumption had higher all-cause mortality (HR 1.62) than those in the lowest quartile. For each additional serving of UPF, all-cause mortality increased by 18%.18 A study of UK Biobank participants investigated the relationship between all-cause mortality and consumption of UPFs. Individuals in the highest quartile of consumption compared to the lowest had significantly higher all-cause mortality risk (HR 1.22).15 Analysis from the Prospective Urban Rural Epidemiology (PURE) study of 138,076 participants between ages 35 and 70 across 21 countries found that a diet high in UPFs was associated with a 28% increased risk of all-cause mortality, a 17% increased risk of cardiovascular mortality, and a 32% increased risk of non-cardiovascular mortality compared to those with a low intake of UPFs.9 In a multi-national cohort study by the European Prospective Investigation into Cancer and Nutrition (EPIC) of more than 250,000 participants, higher UPF consumption was associated with increased risk of cancer and cardiometabolic diseases, most notably for animal-based products and for artificially and sugar-sweetened drinks as well (HR 1.09).19
Impact on all-cause and cause-specific mortality
UPF consumption
Table 1: The NOVA Food Classification System3
Groups
Description
Examples
NOVA 1
NOVA 2
NOVA 3
NOVA 4
unprocessed or minimally processed foods
processed culinary ingredients
processed foods
UPFs (industrial formulations)
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
As a percentage of total calories in many countries, UPF consumption almost tripled from 1990 to 2010, rising from 11% to 32%.1 Recent surveys show that in Europe, the U.S., Canada, New Zealand, and Latin America, UPFs represent between 25% and 60% of total daily energy intake.2 Figures from the U.S. alone show that American adults are consuming more UPFs than ever before. From 2001 to 2002, UPFs accounted for 53.5% of calorie intake, and by 2017-2018, they comprised 57%.3 During roughly the same period (1999-2018), prevalence of obesity climbed from 27.5% to 43% among males and from 33.4% to 41.9% among females.4 According to the British Heart Foundation, more than half of the average British diet is made up of UPFs, higher than any country in Europe.5 Across 22 European countries, the energy share obtained from UPFs ranged from 14% to 44%, reflecting a daily average of 27.2% of total energy intake.6
UPFs often have poor nutritional content, as they are high in sodium, certain artificial sweeteners, additives such as emulsifiers and preservatives, and total and saturated fat. They are also low in potassium, fiber, and micronutrients such as vitamins and minerals. For example, sulfites – additives used widely as preservatives, stabilizers, and flavor enhancers – have been found to cause cardiovascular disease (CVD) in animal models. Artificial sweeteners and emulsifiers are thought to disrupt the gut microbiota, promoting inflammation and metabolic dysregulation.7 In addition, phosphates have been found to be a cardiovascular risk factor, and artificial sweeteners could also exacerbate atherosclerosis.2 UPFs also have been found to be contaminated by microplastics as well as by chemicals such as phthalates and bisphenol A (BPA), which are widely used in food packaging. Studies show a significant association between exposure to phthalates and BPAs and an increased risk of cardiometabolic disorders.2 Other contaminants due to UPF production methods are acrolein, which is formed during the heating of fat, and acrylamide, which is formed in heat-treated food products. Both of these can be toxic to cardiovascular tissue.8 Carcinogenic compounds such as heterocyclic amines and polycyclic aromatic hydrocarbons also have been identified in UPFs.2, 9 And even non-artificial additives such as the thickening agent carrageenan may be cause for concern, as its ingestion may lead to glucose intolerance and insulin resistance.
In a U.S. study of 20 inpatient adults given a diet high in either UPFs or unprocessed foods for 14 days, participants on the UPF diet gained an average of 0.9 kg (+/-0.3 kg) in weight, while participants eating an unprocessed diet lost an average of 0.9 kg (+/-0.3 kg). (Those on the UPF diet also consumed on average 508 kcal more per day.) Sodium intake also was significantly higher for those eating UPFs: 5.8 g/day versus 4.6 g/day in the unprocessed foods diet.11 A U.S. study of 9,640 adults ages 20 to 59 found that adults in the highest quintile of UPF consumption (>72.1% energy intake) had 1.6 times higher total body fat percentage compared to those in the lowest quintile (<39.4% energy intake).12
Cancer Global cancer incidence continues to rise. Cases are projected to increase from 19.3 million in 2020 to 30.2 million by 2040.13 Research shows that about half of cancer cases could potentially be avoided through diet modification and lower UPF consumption.14
In a study of 20,000 UK Biobank participants ages 40 to 69, mean UPF consumption was 22.9% of the diet. Participants with the highest consumption percentage compared to the lowest showed a 7% higher risk of any cancer, a 25% higher risk for lung cancer, a 52% higher risk for brain cancer, and a 63% higher risk for diffuse large B-cell lymphoma.14
Cardiovascular disease (CVD) CVD is the most common cause of death both worldwide and in the U.S., causing an estimated 17.9 million deaths worldwide and 840,000 U.S. deaths in 2016.8 Dietary factors play a crucial role in the development and prevention of CVD. High UPF consumption has been found to increase risk of high blood pressure, CVD, myocardial infarction, and stroke. In Europe in 2015, 56% of CVD deaths in men and 48% in women were related to dietary factors alone.2 In fact, a healthy and balanced diet can reduce risk of CVD by up to 50%.15
A meta-analysis of 10 studies by the Air Force Medical University in China of 325,000 individuals found that, compared with the lowest UPF consumption category, those who ate the highest amount of UPFs had a 24% higher risk of cardiovascular conditions such as myocardial infarction, stroke, and angina.5 The NutriNet-Santé study in France, composed of 105,159 participants, found that UPF consumption was associated with a higher risk of overall CVD (HR 1.12), coronary heart disease (HR 1.13), and cerebrovascular disease (HR 1.11).2
Mental health As UPFs are generally high in carbohydrates, saturated fat, and calories, and low in protein and fiber, the risk of inflammation and oxidative stress may be increased. They are also low in vitamins B12, D, E, and niacin (B6), as well as in a range of minerals (copper, iron, phosphorus, magnesium, selenium, and zinc) that are considered essential for optimal mental health16 and have been associated with alterations in the gut microbiome that are linked to the onset of depression.
A large Australian study of more than 23,000 people found that individuals with the highest percentage intake of UPFs (37% of the diet) had increased odds of elevated psychological distress compared to those with the lowest intake (15.9% of the diet) (OR 1.23).16 In a study of more than 31,000 women ages 42 to 62, those in the highest quintile of UPF consumption had a 49% increased risk of depression compared to those in the lowest quintile.17
Consumption of UPFs has risen significantly in recent decades, likely contributing to increased global incidence of cancer, CVD, mental health disorders, and overweight and obesity. These increases in non-communicable diseases could be directly impacting insurers, which may face rising claims costs and subsequently may need to adjust the cost of protection. UPFs are one of several novel factors of which insurers should be aware that are changing incidence rates of many diseases, and – over time – may alter the course of human health and longevity.
Conclusions
Table 2: Association Between UPF Consumption, Cancer Incidence, and Cancer-Related Mortality (reference = Quartile 1)
Cancer site
Cancer incidence Quartile 4 (Hazard Ratios)
All
Stomach
Colorectal
Lung
1.07
1.17
1.24
1.01
1.38
1.14
1.05
1.25
Kidney
Bladder
Brain/CNS
Leukemia
1.35
1.19
1.26
1.32
1.18
1.50
Breast
Ovary
Prostate
1.62
1.91
0.92
1.03
1.45
14
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Cancer-related mortality Quartile 4 (Hazard Ratios)
Non-Alzheimer’s dementias present with a broad spectrum of clinical features. Many overlap with psychiatric conditions such as mood disorders and schizophrenia and with neurological conditions such as autism spectrum disorder and motor neuron disease. This means diagnosis of these dementias may be delayed and arrived at only after long and complex clinical investigative processes.3, 4 This article, the first of two parts, explores frontotemporal dementia, an important cause of presenile dementia. Two other types of non-Alzheimer’s dementias, Lewy body dementia (LBD) and Parkinson’s disease dementia (PDD), will be covered in Part Two.
FTD is one of the leading causes of early-onset dementia, and it has a mortality rate higher than AD. Multiple studies from around the world estimate its prevalence at 3% to 26% among cohorts of people with early onset dementia, which means its main impact is on insured populations.5 The condition was first described by psychiatrist and neurologist Arnold Pick in 1892. A patient had presented to him with a constellation of symptoms, including aphasia (which can be disordered speech alone or dysfunction in writing or speaking), brain lobar atrophy, and presenile dementia. While it is sometimes referred to as Pick’s disease, FTD is the preferred term, based on its characteristic clinical and histopathological features.3 The observable pathology in FTD is a neurodegenerative process that initially affects the brain’s frontal and temporal lobes. The cause is abnormal intracellular aggregation of certain proteins, leading to neuronal loss, microvacuole formation, and fibrosis of neurons in the affected brain regions. This condition also spreads throughout the brain over time, destroying additional areas and causing progressive and extensive cognitive dysfunction. The extent and many sites of neuronal destruction in FTD give rise to the variations in its clinical presentation and its heterogeneity.
Frontotemporal dementia
https://www.who.int/news/item/02-09-2021-world-failing-to-address-dementia-challenge https://www.who.int/news-room/fact-sheets/detail/dementia https://www.ncbi.nlm.nih.gov/books/NBK559286/ https://pubmed.ncbi.nlm.nih.gov/26595642/ https://pubmed.ncbi.nlm.nih.gov/26595641/ https://pubmed.ncbi.nlm.nih.gov/34389969/ https://www.sciencedirect.com/science/article/pii/S26661 44623000059?via%3Dihub https://pubmed.ncbi.nlm.nih.gov/31119452/ https://www.frontiersin.org/articles/10.3389/fnins.2018.00473 /full https://doi.org/10.1038/s41582-020-0330-x https://link.springer.com/article/10.1007/s00415-020-10040-0
Dr. Karneen Tam is Regional Medical Director, Asia Markets, for RGA Reinsurance Company’s Asia Pacific region. Based on South Africa, she supports the regional team in product creation, underwriting, claims, and pricing for multiple markets. She is a diabetologist with an MBBCh from the University of the Witwatersrand, South Africa and an M.Sc. in diabetes from University of South Wales, Cardiff, Wales (U.K.). She also has a strong interest in non-communicable disease management, particularly in how that might extend healthy lifespans, and how novel digital tools may change the landscape of healthcare delivery.
Dr. Karneen Tam, MBBCh, M.Sc.
Regional Medical Director RGA Asia
Karneen.Tam@rgare.com
Currently, there is no single diagnostic test for FTD and its subtypes.
Part I: Frontotemporal Dementia
The World Health Organization (WHO) estimates that by the year 2030 – less than 10 years from now – about 78 million people will be living with dementia. This number is projected to nearly double, to 139 million, by 2050.1 Most people associate dementia with memory loss, which is the dominant symptom of early Alzheimer’s disease (AD). As AD is the cause of dementia in about 70% of affected people, it has become dementia’s archetype.2 Other dementia types, however, have different early symptoms that may not include memory loss but can include language dysfunction, loss of executive function, motor dysfunction, and even personality changes. Incidence of non-Alzheimer’s dementias, such as frontotemporal dementia (FTD), Lewy body dementia (LBD), and Parkinson’s disease dementia (PDD),3, 4 is on the rise. Non-Alzheimer’s dementias other than these three may be a consequence of other disorders, such as: vascular dementia, caused by impaired blood flow to the brain; secondary dementia occurring after traumatic brain injury; severe stroke; untreated HIV infection; and brain injury due to toxins such as alcohol. Non-Alzheimer’s dementias have a broad spectrum of clinical features that often overlap with psychiatric and neurological disorders. These dementias are more likely to affect a younger cohort (under age 65), and clinical diagnosis may be delayed due to atypical and complex symptoms and might be arrived at only after long and complex investigative processes.3, 4 These cases are challenging both to clinicians and insurers, as they can be difficult to understand and adjudicate. In recent years, many insurance markets have expanded living benefit coverage of a range of mental health and neurological disorders of varying severity levels, such as dementias and psychiatric, neurodegenerative, and neurodevelopmental conditions. It is more important than ever now that all such cases be recognized and correctly diagnosed, using available medical evidence, to facilitate appropriate adjudication and compensation.
Over time, FTD patients show personality changes as well as continuous declines in self-control, communication, and decision-making and problem-solving abilities. In advanced stages, memory loss and motor dysfunction also develop, resulting in a loss of independence and necessitating intense physical, financial, and social support. As about 70% of FTD cases are in people younger than 65 years of age, the disease can decimate what would have been the patient’s most productive years, with significant financial as well as physical impacts. Receiving a timely and accurate diagnosis and having adequate risk cover may help ease a patient and family’s transition into care.
Progressive negative impacts
The presenting symptoms of FTD are complex, making these cases challenging both to diagnose and to adjudicate. Onset generally occurs in individuals ages 40 to 65, but it has been seen in people as young as age 17. As its symptoms often overlap with other psychiatric and neurological disorders, misdiagnosis can be frequent. The diagnostic process may require longer observation of its symptomatic evolution before confirmation. In addition, some who display many of the symptomatic criteria for FTD may later be diagnosed with bipolar disorder or autism spectrum disorder. Medical researchers are working continuously to gain a better understanding of this disease group. Insights into FTD’s genetic-molecular and histopathological characteristics have added more assessment tools and biomarkers to improve the diagnostic process. However, diagnosis remains complex, as FTD continues to lack a definitive diagnostic test and requires clinical vigilance from attending physicians.
Diagnostic challenges
Genetics FTD is characterized by neurodegeneration in the frontotemporal lobes, caused mainly by abnormal aggregations of three proteins: tau protein, TAR DNA-binding protein 43 (TDP-43), and fused-in-sarcoma protein (FUS). More than 20 genetic mutations have already been identified that correlate to these and related proteins, which are involved in various synthetic steps of the intracellular structures of neurons, such as microtubules and the cytoskeleton. These mutations are implicated in both familial and sporadic FTD.3, 8 Up to 40% of FTD cases are known as familial, as these patients may have family histories implying a strong genetic component with some individuals showing an autosomal dominance inheritance pattern.9 At least 10 genetic mutations have shown association with these heritable FTDs. The three most frequent pathogenic gene mutations are in the progranulin (GRN), microtubule-associated protein tau (MAPT), and C9orf72 genes. In cases with symptoms and histories suggestive of FTD, genetic testing may be a useful aid for differentiating FTD from psychiatric disorders.8 Next-generation sequencing allows multiple genes to be tested simultaneously and may in the future be incorporated in diagnosing early-stage cases. Some of the understanding of disease-causing molecular pathways involved in FTD is also offering potential intervention targets for research directions. No effective pharmacological intervention has yet emerged, but some groundbreaking clinical trials are underway investigating therapies that target some of the genetic mechanisms.10
Underlying genetics, disease mechanisms, biomarkers, diagnostic tools
FTD variants
FTD is grouped into two main variant categories: a behavioral variant (bvFTD) and at least two language variants.6, 7 bvFTD is by far the most common subtype of FTD, accounting for about 50% of cases.5 The earliest presentations of bvFTD can mimic certain psychiatric disorders, as symptoms can include personality changes with altered social behavior, disinhibition with impulsiveness, apathy with loss of social insight, aggression, inappropriate sexual remarks or behavior, personal hygiene neglect, and dysfunctions in abstract thinking and executive function. The degree of the resulting dysfunctions may lead to unemployment and social isolation, with dire consequences. The language variants of FTD manifest as primary progressive aphasia (PPA). This form has two main subtypes: semantic variant (svFTD) and non-fluent variant FTD (nfvFTD).3, 5 Individuals with the svFTD subtype lose vocabulary, have difficulty naming objects and faces, and experience impaired comprehension of verbal language over time. Written communication may be initially preserved but also declines as the disease progresses. Those with the nfvFTD subtype, although they may have trouble understanding complex sentences and speak with disjointed speech and scrambled words, selectively retain certain cognitive functions intact, such as abstract thinking and calculation abilities, until the disease reaches later stages.3, 5, 7 In all FTD variants, memory remains adequate in the early stage of the disease. A small number of affected people may experience abnormal motor symptoms such as spasticity, exaggerated reflexes, muscle weakness, atrophy, and fasciculations (which can resemble motor neuron disease). While not the focus of this article, it is also worth noting that amyotrophic lateral sclerosis (ALS) has been linked to some FTD syndromes, as it shares with it a pathogenic mutation on the chromosome 9 open reading frame 72 (C9orf72) gene.3, 5, 7
Research is providing a better understanding of FTD – its complexities, its syndromes, and its variants. Revelations about its underlying genetic-molecular mechanisms have also opened up understanding of the many biological pathways involved in FTD, thus helping to expedite and hopefully simplify the diagnostic process, and also to discover effective medical treatment. People affected by FTD have historically had challenging clinical experiences, with symptoms and delays in diagnosis often leading to social isolation, unemployment, and early mortality. As the disease progresses, affected individuals lose their independence and require intense social and physical support. Risk products can make a critical difference: These are the very types of health impairments the insurance industry looks to help so as to ease some of their devastating support needs. By being vigilant and by applying fresh and updated knowledge, insurers can provide meaningful help for these serious conditions.
Conclusion
Imaging Advances in imaging techniques can tap into knowledge of proteinopathies and certain lobar degeneration patterns. Structural MRI and CT scans, for example, can effectively detect FTD’s characteristic regional atrophy, even in pre-symptomatic stages. As the disease progresses, larger areas of the brain are involved, and certain characteristic patterns of atrophy, volumetric loss, and white matter hyperintensities have been observed to correlate with certain FTD molecular subtypes. At this point, however, these patterns still lack specificity.8 Functional MRI, fluorodeoxyglucose PET, and single-photon-emission CT are three types of neuroimaging scans that can detect abnormal lobar blood flow and metabolic activity. These findings align with and strengthen the changes seen on structural imaging tests and aid in diagnosis. Neuroimaging findings are not specific to FTD, but both structural and functional imaging modalities are becoming helpful tools in consolidating and correlating clinical findings.6 During the past two decades, clinical understanding of AD has advanced due to molecular scanning, a procedure in which a molecule of radioactive material (i.e., a radiotracer) is used to detect any abnormal buildup in the brain of proteins such as amyloid or tau.11 In FTD, amyloid positivity is low, so its presence either may indicate the coexistence of AD or be an incidental finding. Detection of pathological tau and TDP-43 have also shown potential in FTD assessments, but clinically applicable utility is not yet available.7, 8 Current investigations into these proteins as they relate to FTD are still largely confined to specialized research facilities. Other researchers are exploring possibilities that measurements such as volumetric change rates, structural connectivity by diffuse tensor imaging, and functional connectivity by resting-state MRI could serve as biometrics. Future research may also yield additional suitable and useful imaging biomarkers for FTD detection and monitoring.
Fluid biomarkers Research during the past few decades has led to the discovery of novel cerebrospinal fluid (CSF) and blood biomarkers for AD evaluation. Fluid biomarkers are also an area of intense research in the effort to develop a useful test that can reliably detect, differentiate, and prognosticate FTD. One such biomarker is neurofilament light chain (Nfl), a protein which is released into the CSF and blood in response to axonal injury in AD, FTD, multiple sclerosis, and atypical Parkinson’s disease. In all forms of FTD, Nfl levels may be a few-fold higher than is seen in healthy people and is observable in the condition’s pre-symptomatic phase. Its level of fluctuation has been predictive of the progression into the symptomatic stage and longitudinally correlates with severity of the disease, irrespective of the FTD subtype. Although presence of Nfl is not specific to FTD, it can rule out psychiatric disorders and consolidate the FTD diagnosis in conjunction with other means of assessment.8 In contrast to CSF testing that is obtained invasively with potential risks, accessibility of Nfl via blood means it may be a more useful and affordable biomarker. Other blood proteins such as tau, TDP 43, and miRNA have been investigated for their potential as biomarkers, but to date they have not shown sufficient clinical utility as they lack specificity to FTD. The blood-brain barrier also blocks passage of many intracranial proteins into the blood, hence CSF protein levels may be more reflective of the proteinopathy and neuronal flux in FTD and other dementias. Similar disease-marking proteins in CSF were the primary candidates investigated, and they have shown some diagnostic potentials. However, the invasive nature of lumbar puncture and its cost have restricted utilization of CSF biomarkers to research.7
Currently, there is no single diagnostic test for FTD and its subtypes. Assessment and diagnosis continue to rely on symptomatology with established neurocognitive decline, and imaging investigation looks for structural and functional alterations. Where appropriate and available, genetic testing and fluid biomarkers have added much value to the diagnostic process.
Click here to read Part II: Lewy body dementia
What’s New?
Photoplethysmography (PPG) Technology Update
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Article Update from Past ReFlections: More Text for Lengthy Titles
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 provide a possible explanation for the associated neurocognitive symptoms of Long COVID. The findings may also extend to other post-viral syndromes and offer actionable therapeutic insights.
Serotonin reduction in post-acute sequelae of viral infection
Jouven X, et al. American Heart Association Resuscitation Science Symposium 2023, Abstract 347.
Artificial intelligence may help predict - possibly prevent - sudden cardiac death
Publications relevant to insurance medicine appearing recently in research literature.
Research Watch
Health View Part 1
Health View Part 2
Drug Watch
RGA Thought Leadership
Ref: https://www.ferring.com/new-data-show-durable-response-following-treatment-with-adstiladrin-nadofaragene-firadenovec-vncg/ Ref: https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-us-fda-approval On the Knowledge Center: https://www.rgare.com/knowledge-center/article/what-lies-beneath-photoplethysmography-(ppg)-solutions-for-insurance https://www.rgare.com/knowledge-center/article/new-therapies-take-giant-steps-toward-treating-sickle-cell-disease
PPG signals have also been used to study mental stress. One vendor in the EU has obtained the CE mark for a solution that can detect post-traumatic stress disorder in cancer patients, which is enabling early intervention. This capability has the potential to be expanded to other impaired life populations or even the general population, to ascertain susceptibility to mental stress. Lastly, PPG can capture heart rate variability (HRV), a parameter associated with autonomic function and closely correlated to cardiovascular diseases and diabetes mellitus. Numerous studies have also found HRV to be independently associated with all-cause mortality. With PPG technology now providing the means to collect HRV information, it could become a parameter for underwriting related risks.
Commercial vendors of devices and software programs utilizing photoplethysmography (PPG) technology (a non-invasive, optical method of measuring volumetric variations of blood flow and obtaining biometric data) are actively pursuing medical device certifications and quality assurance credentials in response to the clinical-grade data they have thus far captured. With approvals and certifications successfully earned from authorities such as the U.S. Food and Drug Administration (FDA), the European Union (EU) (which grants the CE mark), and the International Organization of Standardization (ISO), users can be increasingly confident that PPG devices are at least as good as any clinical-grade devices. However, even with approvals and certifications, one of the most concerning issues around using PPG signals is “noise”, i.e., random, unwanted variations or fluctuations that interfere with signals. For devices that gather their data via contact with skin, such as smart watches or rings, user movement is the main contributor to noisy signals. For devices utilizing remote PPG, e.g., cameras on mobile devices, lighting conditions also add noise. The impact of noise on data can be mitigated by controlling the conditions while signals are being collected. For example, when using a mobile phone camera, ensure the subject is facing a light source, and use wearable devices during sleep to minimize noise from physical movements.
The latest 36-month follow-up study showed that more than half the patients receiving Adstiladrin® avoided cystectomy, 90% of patients survived at the end of the three-year study period, and complete response was reported for 34% of the patients in the study’s treatment arm. This data is likely to increase take-up rates of the therapy. The improved mortality rates, as well as the potential for complete remission may also have implications for insurance products other than health. In another milestone for gene therapies, Casgevy, the world’s first CRISPR-based gene edited therapy, has been approved in the U.S. and the U.K.to treat the hereditary blood disorders sickle-cell disease and β-thalassemia. This one-time therapy is highly likely to pave the way for more CRISPR-based therapies, and with an estimated wholesale acquisition cost of U.S. $2.2 million per treatment, will also add to the small but rapidly growing list of multimillion dollar gene therapies insurance payors will need to monitor.
Gene therapies have always been a concern for health insurance payors, largely due to their multimillion-dollar price tags. As these therapies were targeting rare genetic diseases, low exposures, availability and accessibility issues, as well as policy exclusions for congenital and hereditary diseases, have limited the financial impact on the majority of payors worldwide. This is now starting to change, with the recent introduction of Adstiladrin® (nadofaragene firadenovec-vncg), which targets low-grade bladder cancer high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors (±Ta/T1). With a higher prevalence than rare genetic diseases (about five In 100,000 for males and one in 100,000 for females) and being neither a congenital nor hereditary disease, the financial exposure of low-grade bladder cancer in any health insurance portfolio can be significant. While not priced at the kind of multimillion dollar levels as single-dose gene therapies for genetic diseases, Adstiladrin®, which is given every three months for a year, can cost as much as U.S. $240,000 per patient annually.
Gene Therapies
https://www.ferring.com/new-data-show-durable-response-following-treatment-with-adstiladrin-nadofaragene-firadenovec-vncg/ https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-us-fda-approval
Read more about this topic on RGA’s Knowledge Center
Editor’s note: The increasing ubiquity of mental health diseases worldwide makes identifying their risks essential, especially when these risks are behavioral and easily adjustable.
Consumption of ultra-processed food and risk of depression
Editor’s note: AI could help to identify and address individual risks prior to cardiac arrest and may prevent deaths. This would have major significance for risk stratification in the insurance industry.
Wong AC, et al. Cell. 2023 Oct 26. 186; 22: 4851-67 https://doi.org/10.1016/j.cell.2023.09.013
Samuthpongtorn C, et al. JAMA. 2023;6(9): e2334770 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2809727
Despite the reduction in overall cardiac disease mortality in the past 30 years, sudden cardiac arrest continues to be a major public health challenge, representing 10% to 20% of all mortality in industrialized countries. Predicting it has always been difficult, and the usual approaches fail to identify high-risk people. Preliminary research which analyzed electronic health records from 25,000 people who died suddenly and 70,000 people hospitalized for cardiac arrest who did not die, is showing that predicting sudden cardiac death may be possible using artificial intelligence (AI). The data, which represented more than 1 million hospital diagnoses and 10 million medication prescriptions, was gathered from medical records up to 10 years prior to each death. Using AI to analyze the data, researchers built nearly 25,000 equations with personalized health factors used to identify people who were at very high risk (more than 90%) of sudden cardiac death. Additionally, they developed a customized risk profile for each of the individuals in the study.
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.
Post-acute sequelae of COVID-19, also known as PASC or Long COVID, pose a significant global health challenge. Several hypotheses have been formulated to explain its etiology, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. However the pathophysiology is still unknown, and no effective treatments have been found to date. Scientists at the University of Pennsylvania performed a metabolomics investigation and found that serotonin levels are a possible discriminator between recovered individuals and Long COVID patients. Using a combination of human cohort studies, animal models of viral infection, and organoid cultures, they determined that the presence of viral RNA and downstream interferon responses cause a decrease in serotonin. One important consequence of peripheral serotonin deficiency is reduced activity of the vagus nerve, which in turn is associated with hippocampal dysfunction and memory loss, both of which are associated with Long COVID.
Extensive data now links ultra-processed foods (UPF) – i.e., energy-dense, palatable, and ready-to-eat items – with human disease. This cohort study investigated the prospective association between UPF and its components with incident depression. Researchers used a sample cohort of 31,712 females ages 42 to 62, who were free of depression at baseline, from the Nurses’ Health Study II ,and conducted a long-term study between 2003 and 2017. Their diets were assessed using validated food frequency questionnaires (FFQs) every four years, and UPF intake was estimated using the NOVA classification system, which groups foods according to the degree of their processing. A range of known and suspected risk factors for depression were also adjusted, including age, total caloric intake, BMI, physical activity, smoking status, menopausal hormone therapy, total energy intake, alcohol, comorbidities, median family income, social network levels, marital status, sleep duration, and pain. This exploratory analysis then examined the association between changes in UPF consumption, updated every four years, with incident depression. The findings suggest that greater UPF intake, particularly of artificial sweeteners and artificially sweetened beverages, is associated with increased risk of depression. A reduction in UPF intake by three servings per day, however, was able to reduce depression risk. Although the mechanism associating UPF with depression is unknown, recent experimental data suggests that artificial sweeteners elicit purinergic transmission (a form of extracellular signaling mediated by purine nucleotides and nucleosides such as adenosine and ATP) in the brain, which may be involved in the etiopathogenesis of depression.
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
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Bridging the Mental Health Gap in Asia: Challenges and Opportunities
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PFAS: Forever Chemicals, Forever Trouble?
Navigating Troubled Waters: World Food Day 2023
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Wegovy, Trulicity, Ozempic… Oh My!
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Accelerated Underwriting Analysis: Examining today’s accelerated underwriting and its bright future
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In hac habitasse platea dictumst
A Pinch of Accelerated Underwriting and a Dash of Simplified Issue: Could it be the perfect recipe for risk?
5 Obstacles to Implementing Automated Underwriting and How to Overcome Them
Please click the articles below to see some of RGA's recently published thought leadership on underwriting topics.
Underwriting has always been a profession requiring an extensive breadth and depth of risk related knowledge and research as well as the ability to apply what we know to real-world situations. RGA’s Global Underwriting Manual (GUM) team is committed to providing our clients with up-to-date resources and information about the broad range of conditions and impairments that underwriters and their teams of experts might encounter. For this reason, we have created a new section of ReFlections – Underwriting Update – which will provide information about the manual’s most recent updates. We look forward to providing you with details about this information in future issues of ReFlections.
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WATCH NEXT: Case Clinic Claims Video
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ABOUT
Underwriting Video Title
Thyroid Cancer
A brief look at a complex case
Dr. Sheetal Salgaonkar, MBBS, DBIM
Vice President and Director Global Medical, RGA India
ssalgaonkar@rgare.com
The Challenge
No malignant thyroid tumor
Ultrasound did not show any thyroid tumor
Only Fine Needle Aspiration, no histopathology
FNAC - the study of individual cells HP - examination of sampled part of tissue Histopathological verification is more accurate
Is the information enough to diagnose thyroid cancer?
Critical Illness Claims
Q
Dr. Michael T. Osterholm, Ph.D., MPH
What is (are) the greatest or most important lesson(s) we have learned from the COVID-19 pandemic?
Dr. Osterholm: I think there are two. The first is that no matter what technology is brought to the table, if the public doesn’t trust it or buy into it, we’re really challenged. We’re seeing this with vaccines and drug therapies. We have to understand the power of science is greatly limited if we can’t get the public to use the technology. The second is the importance and power of trust. We live in a difficult world – one in which trust in science and public health has lessened. The old ways, of providing recommendations and then the public following through, are seriously compromised, and this new lack of trust in public health will be a major challenge moving forward.
Are we now in a better position to deal with future pandemics?
Dr. Osterholm: Unfortunately, I think we’re in worse shape. Not only because there is such a high level of distrust of public health, but also, we never conducted a lessons-learned study to prepare for the future. We will need new and additional technologies for a future pandemic. Current vaccines are good, but not great. Work is proceeding on that research but still, little investment is going into it. Depending on political outcomes in the U.S., there could be a 50% reduction in CDC and NIH budgets as well as efforts to sideline those leading future pandemic responses. I can’t image what the impact of these actions would be. Additionally, disease surveillance may be more compromised now than at any time in the past. Despite wastewater surveillance technology, we are still not quite sure how to interpret those results, plus funds are being cut to support this technology. We have also seen the gutting of public health institutions and a significant number of people have left those institutions. Globally, we are also seeing funding for surveillance being cut.
What is currently keeping you up at night?
Dr. Osterholm: I worry based on this week, this year, and this decade. They all have different implications. As mentioned, I don’t believe we’re at all prepared for the next pandemic. Our group has been very actively involved in developing influenza and coronavirus vaccine roadmaps and we’re making progress, but we have a long way to go. We don’t yet have correlative protection testing in the lab for these vaccines. My immediate near-future worry is the potential for funding cuts to our public health institutions such as the CDC and NIH. I also worry about the elimination of PEPFAR (President’s Emergency Plan for AIDS Relief). This worry is real.
What is the current state of technology when it comes to the development of a universal flu vaccine?
Dr. Osterholm: The technology is clearly moving forward. Part of the challenge we have right now is that Operation Warp Speed (to develop COVID vaccines) gave people the perception that in one year we can come up with magic. mRNA vaccines were already in development for two decades. All the money in the world can’t accelerate development. Also, we are not seeing significant private sector investing at this point. Thus, it will mostly be supported by government investment. We are still five to ten years from having these game-changing vaccines that would provide broad protection with efficacy over an extended period of time.
How concerned should we be with the current global avian influenza outbreak? Is its risk of jumping to humans still low?
Dr. Osterholm: I have been involved with H5N1 since the late 1990s in Hong Kong. At that time, it posed substantial risk to humans, but we’ve seen it change over time. In 2015 it spread to Africa, the Nile River valley, and we saw a concerning level of human transmission. However, the receptor sites on the current circulating virus have changed substantially. This is why the WHO and CDC list it as a low risk for humans, but high risk for birds. I feel more comfortable that we are at lower risk for humans at this point, but clearly the impact on animal species around the world will be dramatic.
From a public health standpoint, I’d like to see prevention of chronic disease and expansion of the healthspan.
To what extent will climate change drive changes in the patterns of transmission and distribution of infectious diseases?
Dr. Osterholm: I think it’s going be huge, in two areas in particular. One is the availability of safe, potable water for people to drink around the world. Climate change is affecting water availability. Glacier and snowmelt are rapidly being depleted as well as ground water. The other is on vector-borne diseases. For example, temperature and precipitation patterns are changing to favor certain mosquito species in areas that never had this as an issue. In parts of South America, we are also seeing mosquito habitat gaining almost 2,000 feet in elevation.
How concerned should we be about the potential of bioterrorism, in general, and viral gain-of-function research, specifically?
Dr. Osterholm: This has been an area of great interest to me, especially since 9/11. Since then, it’s become easier for those not part of an organized government effort to conduct research on bioterror agents. How do we regulate this area while not holding back on potential positive scientific gains from this research? We don’t have a good handle on this yet. Gain-of-function research will be a challenge, but there is an appropriate role for it. For example, it could be applied in learning how Ebola could be modified to lead to airborne transmission. However, this research must be done in the most secure laboratory location possible with redundancies in the system to limit inadvertent escape or release.
What value does CIDRAP provide for its leadership forum members such as RGA?
Dr. Osterholm: We offer daily information few other sources can. By 8 a.m. each weekday we have prepared a comprehensive summary of what’s going on around the world, which is made available to our members. Second, we can bring together multiple groups which can share and learn from each other. We operate in a Chatham House rules forum which creates an optimal environment. CIDRAP also offers members a “front row” seat, as we did in the very early days of the pandemic, with examples of actionable information.
What is your hope for the future?
Dr. Osterholm: I’ve been in this business for 50 years. I can’t imagine retiring right now. I have six grandchildren and they’re coming into a challenged world. I do believe we can do better. I believe the improved technologies will be reality one day. We have more vaccines than we’ve ever had. From a public health standpoint, I’d like to see prevention of chronic disease and expansion of the healthspan. Quality of life is very important.
Are there any other points you would like to make which you feel are important but were not addressed thus far?
Dr. Osterholm: I think we covered a lot, but as I look back on our conversation, I see clear challenges in science and technology, in policy and politics, and in public acceptance of recommendations and technology tools.
Globally recognized epidemiologist Dr. Michael T. Osterholm is Regents Professor at the University of Minnesota School of Public Health and founder and director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota. He has long been a knowledgeable and influential voice in the highly complex field of public health. He recently sat down with Dr. Daniel D. Zimmerman, Senior Vice President and Chief Science Advisor, RGA, and co-editor, ReFlections, to offer his perspective on several key issues impacting the world and our industry.
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 November 2023 newsletter, which discusses the foundation’s many recent activities, including the funding of nine new research grants and the creation of a commemorative video featuring several members of LLF’s leadership as well as alumni researchers. 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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