Naturally occurring metabolite that converts 'bad' fat to 'good' fat

 "Metabolism" describes the body's chemical changes that create the necessary materials for growth and overall health. Metabolites are the substances made and used during these metabolic processes -- or, as a new discovery out of Scripps Research and its drug development arm, Calibr, indicates, they could also be potent molecules for treating severe diseases.

In a study from Metabolites published in August 2022, the researchers used novel drug discovery technologies to uncover a metabolite that converts white fat cells ("bad" fat) to brown fat ("good" fat) cells. This discovery offers a potential way of addressing metabolic conditions like obesity, type 2 diabetes and cardiovascular disease. Even more, it speaks to the promise of using this creative drug discovery method to identify countless other potential therapeutics.

"The reason many types of molecules don't go to market is because of toxicity," says co-senior author Gary Siuzdak, PhD, the senior director of the Scripps Center for Metabolomics and professor of Chemistry, Molecular and Computational Biology at Scripps Research. "With our technology, we can pull out endogenous metabolites -- meaning the ones that the body makes on its own -- that can have the same impact as a drug with less side effects. The potential of this approach is even evidenced by the FDA's recent approval of Relyvrio, the combination of two endogenous metabolites for the treatment of amyotrophic lateral sclerosis (ALS)."

Metabolic diseases are often caused by an imbalance in energy homeostasis -- in other words, when the body takes in more energy than it expends. This is why certain therapeutic approaches have centered around converting white fat cells (known as adipocytes) into brown fat cells. White adipocytes store excess energy and can eventually result in metabolic diseases like obesity, while brown adipocytes dissolve this stored energy into heat -- ultimately increasing the body's energy expenditure and helping bring it back into balance.

To uncover a therapy that could stimulate the production of brown adipocytes, the researchers searched through Calibr's ReFRAME drug-repurposing collection -- a library of 14,000 known drug compounds that have been approved by the FDA for other diseases or have been extensively tested for human safety. Using high-throughput screening -- an automated drug discovery method for searching through large pools of information -- the scientists scanned ReFRAME for a drug with these specific capabilities.

This is how they uncovered zafirlukast, an FDA-approved drug used for treating asthma. Through a set of cell culture experiments, they found zafirlukast could turn adipocyte precursor cells (known as preadipocytes) into predominantly brown adipocytes, as well as convert white adipocytes into brown adipocytes.

While an encouraging find, zafirlukast is toxic when administered at higher doses, and it wasn't entirely clear how zafirlukast was converting the fat cells. This is when the researchers partnered with Siuzdak and his team of metabolite experts.

"We needed to use additional tools to break down the chemicals in zafirlukast's mechanism," says Kristen Johnson, PhD, co-senior author of the paper and a director in Translational Drug Discovery Research at Calibr. "Framed another way, could we find a metabolite that was providing the same functional effect that zafirlukast was, but without the side effects?"

Siuzdak and his team designed a novel set of experiments, known as drug-initiated activity metabolomics (DIAM) screening, to help answer Johnson's question. DIAM uses technologies such as liquid chromatography (a tool that separates components in a mixture) and mass spectrometry (an analytical technique that separates particles by weight and charge) to pool through thousands of molecules and identify specific metabolites. In this case, the researchers were searching through adipose tissue for metabolites that could lead to brown adipocyte cell production.

After reducing 30,000 metabolic features to just 17 metabolites, they found myristoylglycine -- an endogenous metabolite that prompted the creation of brown adipocytes, without harming the cell. Of the thousands of metabolic features measured in the analysis, only myristoylglycine had this special characteristic, even among nearly structurally identical metabolites.

"Identifying myristoylglycine among the thousands of other molecules speaks to the power of Siuzdak's approach and these technologies," adds Johnson. "Our findings illustrate what happens when an analytical chemistry team and a drug discovery group closely collaborate with each other."

In addition to Siuzdak and Johnson, authors of the study, "Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation" include Carolos Guijas, J. Rafael Montenegro-Burke, Xavier Domingo-Almenara, Bernard P. Kok and Enrique Saez of Scripps Research;and Andrew To, Zaida Alipio-Gloria and Nicole H. Alvarez of Calibr.

This research was partially funded by the National Institutes of Health and the NIH Cloud Credits Model Pilot.

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Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Carlos Guijas, Andrew To, J. Rafael Montenegro-Burke, Xavier Domingo-Almenara, Zaida Alipio-Gloria, Bernard P. Kok, Enrique Saez, Nicole H. Alvarez, Kristen A. Johnson, Gary Siuzdak. Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation. Metabolites, 2022; 12 (8): 749 DOI: 10.3390/metabo12080749

https://www.sciencedaily.com/releases/2022/10/221013194120.htm

New FDA Guidance Aims to Boost Access to Opioid-Reversal Drug Naloxone

 The US Food and Drug Administration (FDA) has issued guidance that will make it easier for harm reduction programs to distribute the opioid-reversal drug naloxone.

The new guidance exempts harm reduction programs from certain requirements of the drug supply chain security act for the distribution of FDA-approved naloxone products during the opioid public health crisis.

https://www.medscape.com/viewarticle/982472

Long COVID Can Make You Less Able to Exercise: Study

 Adults with persistent cases of long COVID lost some of their ability to exercise 3 months after getting COVID, according to a new study published in JAMA Network Open.

Researchers from the University of California San Francisco and Zuckerberg San Francisco General Hospital identified 38 previous studies that used cardiopulmonary exercise testing (CPET) to measure how well people with long COVID could exercise after recovering from COVID. CPET measured how much oxygen they used as they exercised on either a stationary bike or a treadmill to find out how well their heart and lungs were working.

Someone who used to play doubles tennis, for example, may find that they need to transition to a lower-impact sport like golf if they have long COVID symptoms, lead author and UCSF cardiologist Matthew Durstenfeld, MD, said in a news release.

"But it's important to note that this is an average," he said. "Some individuals experience a profound decrease in energy capacity and many others experience no decrease."

The team narrowed down their sample from 38 studies to 9, comparing exercise testing results from 359 people who recovered from COVID to that of 464 people who had symptoms consistent with long COVID. The age range of the people studied was 39 to 56 years old.

While the authors say they have some reservations about the results from their meta-analysis – mainly due to the studies' small sample sizes, oversampling of COVID patients who were hospitalized, and varying definitions of long COVID – their findings still "provided evidence of a clinically significant, mild to moderate decrease in exercise capacity among individuals with [long COVID] compared with infected individuals without symptoms despite different definitions of [long COVID]," they wrote.

Losing some ability to exercise because of long COVID symptoms isn't new information, but understanding the role of CPET results in long COVID patients may be a powerful measuring tool.

Among the study's limits, the researchers noted, was that their search plan was not peer-reviewed and the studies included in the analysis were not limited solely to peer-reviewed papers. Selection bias – that so many people in the study had been evaluated after recovering from severe COVID infections – also made it difficult to get a clear picture of how common reduced exercise capacity is.

"Further research should include long-term observational assessments to understand the trajectory of exercise capacity," says author Priscilla Hsue, MD. "Trials of potential therapies are urgently needed, including studies of rehabilitation to address deconditioning, as well as further investigation into dysfunctional breathing, damage to the nerves that control automatic body functions and the inability to increase the heart rate adequately during exercise."

Source

JAMA Network Open: "Use of Cardiopulmonary Exercise Testing to Evaluate Long Covid-19 Symptoms in Adults."

https://www.medscape.com/viewarticle/982483

Horizon: New Data on TEPEZZA and Thyroid Eye Disease at American Thyroid Association Annual Meeting

 Horizon Therapeutics plc (Nasdaq: HZNP) today announced new data will be presented at the 91st Annual Meeting of the American Thyroid Association (ATA 2022) in Montreal, October 19-23.

TEPEZZA is the first and only medicine approved by the FDA for the treatment of TED. It is only approved in the U.S.

'Our understanding of Thyroid Eye Disease is ever-evolving, and we are committed to ongoing research that reflects the experiences of those living with this debilitating disease,' said Jeffrey W. Sherman, M.D., FACP, executive vice president, chief medical officer, Horizon. 'We look forward to bringing these important data to the forefront to help physicians better understand the condition for their patients.'

https://www.marketscreener.com/quote/stock/HORIZON-THERAPEUTICS-PUBL-18100076/news/Horizon-Therapeutics-plc-to-Present-New-Data-on-TEPEZZA-and-Thyroid-Eye-Disease-at-the-American-Thyr-42009896/

Employers Target Expensive Surgeries to Cut Health-Care Costs

 Employers are trying to control rising health-care expenses without burdening workers with higher premiums and out-of-pocket costs as the 2023 open enrollment season starts.

Employers increasingly are turning to hospitals that have good track records for quality and value to cover high-cost surgeries. They are also steering their employees to lower-cost providers that offer good quality care.

Open enrollment at companies, when plan participants can make changes or enroll in coverage, typically is held in late October and November.

Health-care costs borne by employers are expected to rise sharply in 2023 due to hospital and specialty drug price inflation and treatments for people who deferred care during the pandemic. Employers should expect per-employee increases of about 8% unless they make plan changes or shift costs to employees, according to Edward Kaplan, national health practice leader of employee benefits consulting firm Segal Group Inc.

“That’s the highest it’s been in over a decade,” he said. For plan sponsors that are making changes, net cost increases are expected to be 5% to 6%, he said.

Mix of Changes

The mix of changes will depend on a company’s situation, Kaplan said. Many hospital systems, trying to keep their staff, are absorbing all the increases instead of passing them on to employees, while high-turnover retail employers, which tend to have low profit margins, are asking employees to pay 5% to 15% more, he said.

Kaplan expects employees to pay average annual increases of $350 to $600 on top of the $70 to $100 a month they now pay for single coverage, while employers will end up paying about $600 a year more per employee than the $7,000 average they now pay for single coverage, based on the sample of employers Segal monitors.

Annual premiums for employer-sponsored family health coverage reached $22,221 in 2021 with workers paying $5,969 on average toward the cost of their coverage, according to Kaiser Family Foundation.

Centers of Excellence

Carrum Health, which provides a software platform to connect self-insured employers with hospital centers of excellence, expects its revenue to double or triple in 2023, CEO Sach Jain said in an interview. The company works with 300 employer groups, he said.

Centers of excellence provide high-value health-care, often at lower prices than other medical centers.

Employers face recessionary pressure in 2023, while costs are increasing, Jain said. At the same time, the labor market remains tight, limiting employers’ ability to reduce benefits, he said.

“The cost pressure on employers and demanding more value for every dollar is obviously playing in the favor of what we offer,” Jain said. “Employers are also tired of implementing solutions that promise savings three years down the road, five years down the road,” he said.

Using centers of excellence for surgical procedures results in immediate savings, Jain said. Carrum, which works with centers that cover 90% of the US population, provides “bundled” prices that cover the procedure and related care. Jain said Carrum’s centers cut employers’ spending for covered services by about half by reducing the cost of surgeries, reducing hospital readmissions, and avoiding some procedures. The savings amount to about $16,000 per procedure for employers, and another $1,000 to $2,000 in employee out-of-pocket costs, he said.

In 2023, employers are particularly interested in including oncology services in the centers Carrum contracts with. “It is the No. 1 or No. 2 priority of every single employer meeting that we’re having,” Brook West, Carrum’s chief commercial officer, said.

A Business Group on Health survey released in August found that, as care has been deferred during the pandemic, cancer is the top driver of large companies’ health-care costs.

Tiered Networks

Rice Lake Weighing Systems, a family-owned manufacturing company based in Rice Lake, Wis., will keep employee-only contributions for the approximately 500 employees and dependents it covers at $20 a week in 2023, the eighth year at that level, Jake Nolin, vice president of human resources, said in an interview.

Rice Lake has done that by using its own primary care clinic and a tiered system of contracted coverage under which employees save money by using the most economical health systems, Nolin said.

“The track record of eight consecutive years without increasing employee contributions, especially in the environment that we’re in this year with inflation doing what it is—that would be adding insult to injury to put a price increase on top of everything else that’s going on, so we’re going to hold our contribution steady,” Nolin said.

The primary care clinic, used by about 750 members in Wisconsin, saves enough money that the company doesn’t need to increase prices at other locations that don’t have a clinic, Nolin said.

The company spent about $4 million on health care in 2021, Nolin said. Rice Lake expects costs to go down at least 10% in both 2022 and 2023, he said.

https://news.bloomberglaw.com/health-law-and-business/employers-target-expensive-surgeries-to-cut-health-care-costs

A Deeper Look at Hollywood's Newest Weight Loss Drug

 Zhaoping Li, MD, PhD, of the UCLA School of Medicine in Los Angeles, breaks down the newest weight loss drug for the stars, semaglutide (branded as Ozempic for type 2 diabetes treatment and Wegovy for weight managment).

Amid a surge in demand for the GLP-1 agonist, Li discusses a supply shortage, weight-loss misconceptions, and an NIH study that could change the way we think about dieting.

The following is a transcript of her remarks:

Ozempic, or Wegovy, is a new class of medication that belongs to GLP-1 agonists. It was first developed as a medication to treat type 2 diabetes, and now we know it also has an indication for weight loss.

GLP-1 agonist is actually an endogenous hormone. When we eat, particularly with protein-rich food, the level of our endogenous GLP-1 goes up, it creates satiation or fullness, and that is the reason we're giving ourselves additional injections -- to enhance the effect of endogenous hormones.

With that being said, it is a higher dose of our own hormones. It has been shown to be safe from all the experience we have treating type 2 diabetes. As to using it as a weight loss drug, it has been on the market for over 2 years, and it has been generally safe as well.

Requests for GLP-1 agonists as weight loss drugs have significantly increased. That's because over 70% of us have a weight problem, and we all also struggle to find an easy solution. So, this is just another tool in the box. We have seen this kind of enthusiasm in the past for any new drug that can be potentially helpful for weight management. There's no exception for GLP-1 agonists.

With the supply chain issues together with the new indication [for weight loss], there has been a shortage of this class of drug across the board on the market. That is just fanning the issue of people really trying very hard to get this drug. It may also make people feel that this is more of a miracle than anything else.

My passion is to help everyone not only manage weight, but have a better life and feel better about themselves. We all need to invest in our own health, and the one-size-fits-all approach in the last 20 or 30 years has proven to be not effective. We are all different, it's not just that we have different genetic background, cultural background, different height, different weight, but we are truly dynamically different, even when we compare ourselves today from yesterday, from 1 week ago.

That's the reason NIH this year in January launched a first-ever discovery study called Nutrition for Precision Health. The goal actually is testing 12,000 people with one standard meal to see who you are and what your body's response is. After that, everyone will be on three different diets, and we will check metabolically which diet fits you and your body.

In a sense, there are people who may be better off with the Mediterranean diet or the best diet we think is healthy, but meanwhile there are people who would benefit from a ketogenic diet, or there are also those of us who are just okay with what we are doing day in, day out.

So, that is just a new beginning of discovery and science. Hopefully in five or 10 years, instead of me telling you that you've got to do portion control or go on the keto diet or do intermittent fasting, we can really do a test and to see at this time what your body's best reaction is to it. It could be nothing to do with diet, [maybe] you just need to simply sleep better or go to bed today, not until tomorrow (meaning early morning at 2 o'clock in the morning).

So, it is a rapidly evolving field, and we are really at the spearhead in trying to get a better answer.

https://www.medpagetoday.com/popmedicine/popmedicine/101225

Brokers Earn More to Steer New Beneficiaries to Medicare Advantage

 One reason why enrollment in Medicare Advantage (MA) plans has been growing as fast as it has -- with 2.2 million new enrollees between 2021 and 2022 -- is the complicated broker commission structure.

In a nutshell, because CMS sets agents' MA commission rates, they tend to be much more favorable to those selling MA plans to first-time enrollees than to the agents who would put those beneficiaries in traditional Medicare with a supplemental plan, known as a Medigap plan.

That's the take from Christopher Westfall, an extremely vocal insurance broker who runs Senior Savings Network, who is licensed to sell health plans in 47 states. Westfall told MedPage Today that he's paid roughly twice as much in commissions -- depending on the state and the plan -- for enrolling a new beneficiary into an MA plan for 2023 compared with a Medigap plan.

For example, if Westfall enrolls a newly eligible 65-year-old client from California or New Jersey into an MA plan, he'll earn a $750 commission for that year. But if he enrolls that same client into a Medigap Plan N policy, an increasingly popular choice, he receives 22% of the plan's premium, or $259.80, for the year.

In fairness, he gets another $92 in commission for selling the traditional Medicare client a separate Part D plan for drug coverage (which many clients refuse, although there's a penalty if one does enroll in Part D later), but still, that's $398 more in his pocket for getting a new beneficiary into an MA plan instead of a Medigap plan.

Incentive to Push MA

"It's a huge financial incentive for agents to push nothing but the positive [in MA plans] and leave out all the potential negatives," Westfall said. "Ironically, this is what all of the big call centers are recruiting for and selling, exclusively through their television commercials."

Clients don't have to sign any disclosures -- although he thinks they should be required to sign something that states the following: "I understand I or my doctor is going to have to get prior authorization for procedures, and they may be denied altogether by the Advantage plan. I will have a limitation of my provider network. My doctor may change and leave my network anytime he wants. But I can't leave the MA plan whenever I want. And I may forever give up my opportunity for a Medigap plan if I later go back to original Medicare."

"When the incentive is for agents to get clients off of traditional Medicare, none of those things are disclosed," he explained. "And there's double the pay for me for the first year, and paid all at once. Agents are always concerned about one thing -- getting the first-year MA commission because it is paid all at once."

Westfall is obviously open about his disdain for MA plans and his preference for original Medicare with supplemental plans, despite the fact that MA sales earn him more money. He's posted numerous YouTube videos explaining his reasons for this.

"Sometimes I think I'm the single voice in the industry telling both sides of the coin," he said in one video in which he refuted the claim that MA plans cost less than traditional Medicare with a supplement, adding that they may cost more in deductibles and co-pays if one gets sick.

The differences in commissions between MA and Medigap supplemental plans in most other states are similar. For example, in South Carolina, where Westfall lives, he receives around $189.52 for selling a new beneficiary a Medigap Plan N the first year, but $601 for selling them an MA plan.

"Here's the part where my agent friends are going to completely lose their minds over. This is what brokers make working on their own," he said in another video, showing a document with the maximum broker compensation for 2023 MA plans, which showed about a 5% raise over 2022.

Westfall pointed to the HHS Office of Inspector General report from April that concluded, "a central concern about the capitated payment model used in MA is the potential incentive for Medicare Advantage Organizations (MAOs) to deny beneficiary access to services and deny payments to providers in an attempt to increase profits."

"The MA plans are good for some people. There's not one plan good for everybody, and we do represent those plans. But we do it in a different way. We do it with full transparency by telling everybody what they're getting involved in," he said. "There are some huge pitfalls, which if your agent is not honest enough to tell you about, can leave you very poor, with paying out all of your bank account and possibly denials when you seek care."

The Plan That Keeps Paying

When a health insurance agent enrolls a beneficiary, it's not just a one-time commission for that year, Westfall noted, as his sample commission schedule shows.

Brokers reap payments for subsequent years if their client stays in the same plan, but the disparity between MA and supplemental plan commissions is evident here as well.

Although rates vary depending on the region and the plan, a common commission for each renewing MA enrollee is about $375 per year, which continues annually as long as the beneficiary stays in that plan, Westfall explained.

The renewal commission for each Medigap plan enrollee is a percent of the enrollee's premium, usually around 22% to 26%, but that drops after the sixth year to 1% or 2%, and zero after the 10th policy year. An agent, consciously or unconsciously, may pivot the client to a plan that brings back a revenue stream that will continue at a healthy pace as long as the client stays in the same plan.

Commission rates for Medigap plans also drop precipitously for clients above age 80, from 22% to 11% within the initial 6 years in California, further disincentivizing brokers to enroll older beneficiaries.

Westfall pointed out that if an unhappy enrollee wants to switch to traditional Medicare with a supplemental plan after the first 12 months of being in an MA plan, plans in all but four states are allowed to reject high-risk, unhealthy would-be transfers. This means that beneficiaries who have had common conditions or illnesses including knee replacement, diabetes, cancer, or even high cholesterol and high blood pressure with other conditions will likely be rejected after answering a health questionnaire, a process called underwriting.

Westfall said that he recently spoke with a client with wet macular degeneration and another with atrial fibrillation and high blood pressure, noting that they can't get approved through underwriting.

"When they go with a Medicare Advantage plan, they forego their opportunity, possibly forever, to go back to original Medicare with a supplemental plan that they could have had with no health question screening when they were new to Medicare," he explained.

Westfall is willing to earn lower commissions selling Medigap plans instead of MA plans because he thinks his honesty, and his YouTube videos, draw more informed consumers and he has made back the money with more volume. And unlike other brokers who get complaints about delays and denials, "we have no complaints," he noted.

He will still enroll clients in MA plans if they insist, but he first makes sure they understand all the downsides. "We tell them the truth," he said.

https://www.medpagetoday.com/special-reports/exclusives/101229