Are Crucial Questions Being Addressed?

As of last month, the people who keep close track of these matters, namely ResearchAndMarkets.com, have identified more than 80 pharmaceutical firms that currently have more than 100 new anti-obesity drugs in the “pipeline,” the wide area that exists in between the gleam of inspiration and the marketing of a finished product. Naturally, the public expects that a medicine offered for sale has jumped through every possible hoop, and is as safe to use as human ingenuity can make it.

There are so many types of products, based on so many different molecules, with several possible routes of administration, and each one of them is in a different stage of development or testing. The test parameters will depend on whether the route of administration is oral, subcutaneous, parenteral, intravenous, topical, or other. And what about its type? Recombinant fusion proteins, small molecule, monoclonal antibody, peptide, polymer, or other?

There is clinical assessment, and then there is of course commercial assessment. What are the product’s “growth prospects”? This means, in business-speak, how soon can we get this product on the market and how much can we sell it for, and how much can we make off it every year going forward? And can our product become the top dog, the one undeniable and universally acknowledged winner that leaves all other contenders in the dust?

Between discovery and permission for unfettered sales, a hopeful drug faces many stages of trial and possible rejection. Concerning all of these 100+ hopeful entries in the anti-obesity sweepstakes, answers are anxiously awaited by financial officers of the companies, stockholders, the medical establishment, and the public.

And then, there’s this

What many people fail to understand, or choose to ignore, about the majority of products with strongly established market shares — products that have already been accepted, and that are used by millions of people — is that a distressing number of significant questions about them are equally unanswered. How can this be? As it turns out, it is because those questions have not been asked. The title of an article by Jonel Aleccia is a simple declarative sentence: “Drugs aren’t required to be tested in people who are obese.”

In the USA, somewhere around 40% of adults are filed in the obese category. And yet, an astonishing number of the familiar medications, both prescription and over-the-counter, have not been tested on officially obese human bodies. The writer states:

That’s because they are not required to be included in drug studies. And often, they’re explicitly excluded.

Many widely prescribed drugs and over-the-counter medications work differently in people who are obese, but exactly how and at what dose often isn’t clear.

At a workshop last year, FDA Commissioner Dr. Robert Califf acknowledged a “deficit of evidence” about how medicines act in patients who are obese. The NIH now encourages researchers to consider the impact of excluding obese people in their studies…

Aleccia cites work done by drug researcher Christina Chow, who recently reviewed over 200 new drug studies, of which almost two-thirds did not document the subjects’ weight or BMI. Apparently, most drugs of every kind that have ever made it to the market were tested primarily on Caucasian adult males. Sure, we don’t want the health or lives of vulnerable populations to be put in danger. Any kind of testing on children, expectant mothers, or anyone whose health is already compromised needs to be conducted with the utmost care.

But fat people get the flu too, and experience pain, and become accidentally pregnant, and suffer every malady that remedies have been devised for. Considering how many of them there are, medicines that work for them are definitely needed, along with definitive information on how to calculate the effective dose considering their body weight. Chow explains the dangers of not weight-relating certain specific drugs, including one that treats schizophrenia, the emergency conception prevention drug, and even ibuprofen:

Some drugs can become concentrated in fat tissues and not in the bloodstream. That means there will be less medication in the blood, leading to undertreatment… Other drugs remain in the body longer in the obese. That could result in harmful drug interactions if another medication is added too soon.

One group needs to be figured out quickly, considering its ever-growing number of members. More and more elderly people just hang in there and refuse to become extinct. How are scientists expected to use them as test subjects? But how can they not? And every day the senior citizen count increases, including a goodly number of obese senior citizens.

Your responses and feedback are welcome!

Source: “Obesity Pipeline Research 2024,” GlobeNewsWire.com, 06/26/24
Source: “Drugs aren’t required to be tested in people who are obese,” Archive.is, 11/07/23
Image by Aaaarrrrgggghhhh!/Attribution 2.0 Generic

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