More Interesting Things About GLP-1 Receptor Agonists

For DiabetesJournals.org, Deborah Hinnen wrote, “Proper patient selection and education can assist in achieving positive treatment outcomes.” The writer is talking about the utility of the GLP-1 drugs in treating diabetes, but the same can be said of their use to fight obesity. Patient selection implies that some people, even if they could greatly benefit from any particular treatment, are just not suited to it for other reasons.

Education is paramount in any case. We hope that the patient will take any words that come directly from the physician’s mouth as gospel, and strive to obey “doctor’s orders” to the best of their understanding and ability.

But during office visits, patients are often not at their psychological best. They are worried about how to rearrange their lives to accommodate the new demands made upon them and their families. They are concerned about expenses, and thinking ahead to the possibility that today’s prescription might not help at all, and there will be rough times in store.

Sometimes they have what we used to quaintly call a “mental block” against absorbing certain items of information. An adult patient will sometimes bring along a friend to pay attention and take notes. For a minor individual, of course, there is a good chance that a parent will be present — which is not guaranteed to be a solution, as the attention span and comprehension depth of a parent or guardian can never be taken for granted, either.

Reinforcements

In an office setting, no matter what the doctor says or forgets to say, in the best-case scenario other staff members will make every effort to assure that the instructions and warnings are understood. They will ask if the patient has any questions, or needs clarification about anything. They might hand out a printed information sheet, or directions to a helpful online resource. Of course, even then, there is no guarantee that the helpful information will be pursued or assimilated.

The “I” word

Of more immediate interest is a recent report with the word “injury” in its title: “Acute Kidney and Liver Injury Associated With Low-Dose Liraglutide in an Obese Adolescent Patient.” This paper originates with four members of the Faculty of Medicine at the Hebrew University of Jerusalem. The complete work is accessible for a fee.

The brief summary version begins by recalling that liraglutide was approved in 2020 for people aged 12 through 18, as an adjunctive therapy for weight management “in combination with a reduced-calorie diet and increased physical activity.” It goes on to say,

Although reports in adults have suggested a link between liraglutide and adverse effects including hepatic injury and acute kidney injury (AKI), these effects have not previously been reported among adolescents treated with liraglutide for weight loss.

The cause for alarm was the experience of a 17-year-old boy afflicted with class III obesity, which is the more recent enlightened term for what used to be called morbid obesity. He had been using liraglutide (at its lowest recommended dose) for three months, and consequently experienced not only significant appetite loss, and weight loss, but a sensation of melancholy. By the standard of the Adverse Drug Reaction Probability Scale, it seemed clear that the liraglutide was also responsible for the injury to his liver and kidneys.

After being off the medication for a month, his kidney issue had settled down and his liver enzymes had reverted to normal, and there was an improvement in his mood. The authors note,

Our report highlights the importance of vigilance in monitoring for these potential adverse effects among adolescents treated for obesity with any dose of liraglutide.

Liraglutide had been approved in 2010 as antidiabetic therapy for adults. A document from that year states that some rodent study results were troubling, but there was no firm evidence of adverse effects on humans. Reports of several different conditions, like pancreatitis, appeared here and there, but in very small numbers, and the evidence to connect the cases with the drug was just not there.

Your responses and feedback are welcome!

Source: “Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes,” DiabetesJournals.org, 2017
Source: “Acute Kidney and Liver Injury Associated With Low-Dose Liraglutide in an Obese Adolescent Patient,” AAP.org, 06/12/24
Source: “Weighing Risks and Benefits of Liraglutide — The FDA’s Review of a New Antidiabetic Therapy,” NEJM.org, 03/04/10
Image by the healthy blog/Public Domain

Unlocking the Potential of GLP-1 Agonists Beyond Diabetes and Weight Loss

Initially developed for diabetes treatment, GLP-1 agonists have gained significant attention for their weight-loss benefits. The success of GLP-1 medications like Ozempic, Wegovy, Mounjaro, and Zepbound has spurred a wave of research exploring their potential beyond diabetes and weight loss.

Discovering secondary uses for GLP-1s

The headlines are coming at us fast and hard. Just in recent weeks, we’ve read that the GLP-1 agonists may help reduce sleep apnea, reduce pancreatitis risk in obese and diabetic patients, reduce rheumatoid arthritis symptoms, and potentially even boost fertility.

In other words, these medications are changing consumer habits and industry dynamics, and people just can’t get enough of them. While the pharmaceutical industry is eagerly investigating new applications for GLP-1 drugs, some think that the real opportunity lies in precision medicine. This approach promises to open numerous commercial pathways and significantly advance personalized patient care.

Why precision medicine?

Elliott Green, the co-founder and CEO of Dandelion Health, which collects and processes clinical data for the healthcare industry, is one of the believers. In a recent article he penned for Fast Company, he opined that, as the COVID-19 pandemic taught us, rapid innovation is crucial for saving and improving lives on a large scale. However, traditional clinical trials, while scientifically rigorous, are not designed for speed and cost-effectiveness.

In Green’s opinion, the challenge is accelerating precision medicine for GLP-1 drugs by applying lessons from the pandemic to achieve near-term, data-driven insights that lead to personalized treatments and care.

Learning from oncology

It’s complicated though. Green writes:

To understand just how “blackbox” GLP-1 drugs are today, one only needs to read or listen to the news. For example, early GLP-1 studies seem to appear daily, and they point to potential issues, such as unwanted side effects in some patients, like psychiatric issues, or opportunities — like GLP-1 agonists potentially being used to treat prostate cancer one day. The key word here? Potential.

With increasing access to data and advancements in AI, healthcare providers should be able to predict which patients will benefit most from specific weight loss drugs. Similarly, pharmaceutical companies should be able to identify new, effective uses for GLP-1 formulations. While progress is being made, it is not happening quickly enough to optimize patient outcomes or confirm new applications for these drugs.

Adopting a proactive approach from oncology, where precision medicine has had a significant impact, could be transformative. Oncologists select treatments based on the genetic profile of tumors. Similarly, GLP-1 drugs could be chosen based on a digital phenotype that predicts the best response with minimal side effects.

Addressing data gaps

The challenge in bringing precision medicine to GLP-1 drugs lies in the lack of real-world data. Although there is more real-world data (RWD) than ever before, much of it remains isolated and unreadable, locked in various systems within healthcare organizations.

RWD often comes from electronic health records (EHR), claims data, and disease-specific registries. However, the most valuable data — unstructured clinical data like waveforms (e.g., ECGs) and imaging data (e.g., MRIs, CT scans) — is typically outside the EHR. This data, which constitutes over 80% of healthcare data, holds immense potential for personalizing GLP-1 care and accelerating drug development. 

Leveraging AI for precision medicine

In Green’s words,

[W]e can take these broad generalizations and turn them into more precise hypotheses to be tested, like: demonstrating GLP-1’s therapeutic effects beyond current uses, including secondary benefits derived from exploratory use or demonstrated with additional data modalities; and developing precision-medicine tools to identify patients with uncontrolled symptoms or to match patients to the right treatment plans.

The bottom line

To advance personalized weight loss treatments, there must be stronger integration of both structured and unstructured health data, and a robust approach to vetting AI algorithms trained on rich, unbiased datasets. This will provide the necessary insights for personalized patient care and help pharmaceutical companies quickly and cost-effectively explore new uses for GLP-1 drugs.

By embracing these strategies, we can drive a more personalized approach to weight loss and unlock new therapeutic potentials for GLP-1 drugs, benefiting patients and the healthcare industry alike.

Your responses and feedback are welcome!

Source: “How AI can power GLP-1’s next frontier in medicine,” Fast Company, 6/7/24
Source: “Ozempic and Wegovy May Help Reduce Rheumatoid Arthritis Symptoms,” Healthline, 6/27/24
Image by lightfieldstudios/123RF

Interesting Things About GLP-1 Receptor Agonists

Most of the research on these drugs, over the years, has been performed with an eye to their usefulness in treating Type 2 diabetes. The findings are also, obviously, pertinent to their effects when prescribed for weight loss in non-diabetic patients.

And of course, it is not their effects alone that matter, but what happens when those effects combine with whatever else the patient is already taking? The professional with a prescription pad must be meticulously conscientious in recording a patient’s history, lest something important and potentially threatening slip through the net.

Regarding the currently existing GLP-1 RA meds, there are a few widely recognized contraindications. Except for oral semaglutide, the others are administered by subcutaneous injection. Some concerns do or may apply to all drugs in this class; others are so far known to only be relevant to one of them. Fortunately, many of the potential problems mainly apply to conditions that are relatively quite rare.

A very detailed report originated in 2006 and has been revised 11 times since then, now stating (among other things):

All GLP-1 agonists have been found to cause c-cell tumors in rodent models, but the human relevance has not been determined. All agents except for [two] have a black box warning for risk of thyroid C-cell tumors,

GLP-1 agonists have not been studied in patients with gastroparesis, and all drugs within this class, except for liraglutide and semaglutide, recommend against use in patients with preexisting gastroparesis.

However, their rep is mostly positive:

There is no basis for limiting the duration of treatment for GLP-1 agonists in patients using this medication for chronic weight management if it remains beneficial for weight loss and is not causing intolerable side effects.

Here are some of the caveats and cautions applicable to either the whole class, or various individual drugs. All of them are, of course, contraindicated in patients who are hypersensitive to the particular substance. All should be warned that since the drugs increase the sensation of satiety, it is quite possible that continuing to eat past the point of feeling full can cause nausea and/or vomiting.

Individual drugs are warned against for patients with existing or incipient pancreatitis, gastroparesis or inflammatory bowel disorders, renal disease, or Multiple Endocrine Neoplasia syndrome type 2. Likewise, for those who have a family history of medullary thyroid cancer.

They probably should be avoided for patients who are on tricyclic antidepressants. It should be noted that the GLP-1 receptor agonists, which are therapeutic peptides, could potentially cause the development of drug antibodies.

Another article, titled “Glucagon-like Peptide-1 (GLP-1) Receptor Agonists,” offers a very thorough comparison of the various available meds of this type. For starters, their efficacy and safety “primarily differ by their frequency of administration.” They all delay gastric emptying and increase satiety, and “There is no significant [clinically meaningful] difference in weight loss effect among the agents in the class.”

Here are other details that could be very disappointing, because none of these things match up with what their various manufacturers would have us believe:

Semaglutide is the only GLP-1 receptor agonist that is available as a once-daily oral tablet. Unlike semaglutide injection, the evidence of CV benefit using the oral route has not been definitively established. Compared to placebo, all agents, except albiglutide, significantly reduced weight and increased the risk of hypoglycemia and GI side effects. There were no clinically meaningful differences in weight loss effects, blood pressure reduction, or hypoglycemia risk among the drugs.

Your responses and feedback are welcome!

Source: “Drug Use Criteria: Glucagon-Like Peptide 1 Receptor Agonists,” Texas.gov, October 2022
Source: “Compare and Contrast the Glucagon-Like Peptide-1 Receptor Agonists (GLP1RAs),” NIH.gov, 03/27/23
Source: “Glucagon-like Peptide-1 (GLP-1) Receptor Agonists,” Elsevier.health, 04/11/22
Image by Consumerist Dot Com/ATTRIBUTION 2.0 GENERIC

More Vagus Nerve Knowledge

The previous post listed some activities of the vagus nerve as having to do with…

[…] stomach expansion, stomach contraction, gastric acid release, stomach content release into the small intestine, digestive pancreatic enzyme secretion and the sensations of both hunger and fullness.

Who is in charge of those departments? Who tells the vagus nerve what messages to convey? It now appears that the directives carried from this area of the body originate with the gut microbiome (as differentiated from, for instance, the skin microbiome).

The notion does seem rather radical, and it feels appropriate to resist the idea that just about everything we are, and do, is fundamentally determined by our colonies of gut bugs. Although we may diligently seek help from various treatment modalities, it is very likely that, where mood and behavior are concerned, the little critters are running the show.

Not surprisingly, the same cluster of functions performed by and related to the stomach, is heavily influenced by bariatric surgery, which causes a faction of professionals to wonder: Rather than subject children to the ordeal of surgery, if the same benefits can be achieved by somehow controlling the vagus nerve, why not concentrate on that? How can it be done?

The vagus nerve has been compared to an “information superhighway” that conveys messages from the gut to the brain. It seems that if we could influence the microbiota in regard to the messages they dispatch through the vagus nerve, that might help. It has even been suggested that “probiotic bacteria could be tailored to treat specific psychological diseases.”

This sounds like a great idea when the potential benefit for autistic children, for one example, is considered. They tend to become obese, because that is a side effect of the only drugs that are approved to treat their condition. This is also true of the drugs used against anxiety, epilepsy, and depression. If the body could be induced to manufacture its own meds to deal with those conditions, the results would be pretty spectacular… and apparently, thanks to the efforts of its microscopic tenants, it can.

The gut-brain axis is a thing

For DiscoverMagazine.com, Carla Delgado described how ultra-processed foods can cause inflammation in the gut, as well as in other parts of the body, and how the inflammation connects with mental symptoms of anxiety and depression. This information comes from Dr. Uma Naidoo of Massachusetts General Hospital, who is credentialed as not only a psychiatrist and nutrition specialist but also a professional chef.

Nutritional Psychiatry does not insist that correlation equals causation — however, the evidence against ultra-processed foods is quite damning. By all indications, the brain is tightly bound to the gut microbiome because of the vagus nerve connection, which is compared again to a “fast two-way highway sending signals and chemicals back and forth.” Dr. Naidoo is quoted:

We produce over 90 percent of our body’s serotonin — as well as other neurotransmitters which govern mood — outside the brain, in the gut where our food is digested and broken down into vitamins, minerals and other nutrients. This enables a natural symbiosis between food and the body’s brain chemistry.

Do emotional and mental disorders cause overeating? Obviously. Does overeating cause mental and emotional disorders? Undoubtedly. And right there in the middle of everything, facilitating the two-way communication, is the vagus nerve.

Your responses and feedback are welcome!

Source: “How Ultra-Processed Foods Can Affect Your Mental Health,” DiscoverMagazine.com, 10/24/22
Image by NIH Image Gallery/ATTRIBUTION 2.0 GENERIC

Why Is the Most Recommended Childhood Obesity Treatment Not Readily Available?

For many U.S. parents seeking help for a child with obesity, the most widely endorsed treatment is out of reach — and it’s not the popular GLP-1 agonists like Wegovy, used for weight loss and managing diabetes.

What is the recommended childhood obesity treatment?

Leading medical groups recommend intensive behavioral counseling, spanning 26 hours within one year, to teach children and their families practical ways to eat healthier and be more active. Sounds good, right? A recent Reuters article digs into the reasons these touted programs aren’t easy to find.

And why is not widely available?

These programs are not widely accessible, with wait lists often stretching for several months. They are frequently not covered by health insurance and require a time commitment that many families find challenging, according to interviews with over a dozen doctors and parents.

No treatment option improvement is expected

Consequently, fewer than 1% of the nearly 15 million U.S. children with obesity receive this type of structured care, the U.S. Centers for Disease Control and Prevention (CDC) told Reuters. Efforts by the CDC and other organizations to expand insurance coverage have stalled, doctors involved in the process also told Reuters.

“The coverage for these programs was never good, and we’re not seeing any movement toward improvement,” said Dr. Joseph Skelton, a professor of pediatrics and obesity medicine specialist at Wake Forest University School of Medicine.

No end in sight for curbing childhood obesity

The prevalence of obesity among U.S. children has steadily increased, from 5% in 1980 to nearly 20% now, according to the CDC. It’s also a global issue. New research published by JAMA Pediatrics and based on a review of global studies revealed that the prevalence of obesity increased by 150% in the period covering 2012–2023 compared to 2000–2011, indicating that pediatric obesity and overweight conditions are increasingly common. The problem is getting worse.

This is where the GLP-1 drugs come in

According to new research, the number of young people in the US prescribed GLP-1 agonist drugs, such as Wegovy and Ozempic, for weight loss and diabetes increased by 594.4% over the past three years. The most notable increase in prescriptions was observed among young women and adolescent girls.

Last year, the American Academy of Pediatrics updated its obesity management guidelines, recommending that in addition to behavior and lifestyle interventions for the entire family, weight loss medications are suitable for children aged 12 and older.

Clinical trials involving intensive behavioral programs for children and found that, on average, children lost 5.7 pounds. In contrast, Wegovy and similar drugs have resulted in a more dramatic weight loss — 15% or more of body weight in clinical trials. This significant weight loss, coupled with a lack of insurance coverage for counseling, may lead more families to consider these medications in the future.

Are GLP-1 medications safe for children?

In short, more research is needed. Many doctors and parents are cautious about using the medication due to the lack of data on its potential impact on a child’s development and other long-term risks.

Some doctors argue that increased use of Wegovy among youth will make it even more critical for children to learn healthy eating habits for the long term. They are concerned that relying solely on the drugs could lead to nutritional deficiencies or eating disorders.

Dr. Thomas Robinson, a professor of pediatrics and director of the Center for Healthy Weight at Stanford Medicine Children’s Health in Palo Alto, California, said:

Many of us believe it would make sense to offer behavioral counseling along with the drug. These drugs are very effective at reducing weight and health risks, but you don’t all of a sudden adopt a healthy diet or become more physically active.

Your responses and feedback are welcome!

Source: “Weight-loss options for children are hard to come by,” Reuters, 6/17/24
Source: “Prescriptions for weight loss, diabetes drugs for young people leaped 600% since 2020, study says,” CNN, 5/23/24
Image by Omar Lopez on Unsplash