With GLP-1 Drugs, There Will Be Questions

As mentioned in a previous post, there are a lot of things about which nobody knows very much. The GLP-1 drugs have been around for a while, although mainly as a diabetes treatment. As weight-loss aids, however, they are relatively new and untried. When any discovery comes along, questions arise.

Which patients will or could be harmed? Which sufferers will receive the most benefit? Scientific American said,

Another unknown is who will respond to these drugs — and who won’t. It’s too early to tell now, but the drugs seem to be less effective for weight loss in people with type 2 diabetes than in those without. Conditions such as fatty liver disease and having fat around the organs, known as visceral body fat, might also affect how people respond to different drugs…

How much will the patients pay? How much would they be willing to pay if they had a lot more money to start with? Where will the funds come from instead? Can the team that wrote a particular paper continue to do meaningful work in this area? How about the pharmacology? What other drugs does this new thing clash with, causing an iatrogenic disaster?

Bloomberg journalist Lisa Jarvis raised several questions, such as:

[…] Why do some people on GLP-1s […] experience a total body transformation, while others lose only modest amounts of weight — or nothing at all?

[…] Is there a way to figure out who needs these drugs to avoid a heart attack or diabetes, and who is perfectly healthy in their larger body?

[…] Is constant therapy sustainable — or even required?

Jarvis states, “Some 44% of people taking Wegovy report nausea, and nearly a third experienced diarrhea.” People know this going in, and give it a chance anyway, and a very large number of them seem to stick with it despite the discomfort. The sickness seems to be a feature, not a bug. If that is what it takes to stop people from overeating, they seem willing to put up with it. But is it a life sentence? Or at least, will the necessity for periodic injections segue into discovery of how to make wider and more efficient use of alternate routes?

Time out?

Apparently, huge numbers of users want to know if they may self-prescribe a break from their medication regime. (The professional consensus on that is, “No.” But a certain number will do it anyway.) Resistance understandably crops up a lot, around holiday times. And reportedly, someone who stops their meds abruptly will become ravenously hungry, and prone to eat an enormous amount of barbecued ribs and hot fudge sundaes.

If a user does take a break, the next big issue seems to be whether they should pick up again with the dosage they previously used, or whether they need to fall back to a smaller dose and then crank it up again. Journalist Ross Woolen wrote,

It takes the body some time to adjust to these potent medications, and those infamous gastrointestinal side effects tend to be at their very worst in the first few days of a new higher dose. With longer pauses, the worry is that your body might lose some of the tolerance that originally allowed you to step up your dosage.

Starting over with the high dose that was typical before the break “could be more than your body is ready to handle, resulting in extremely uncomfortable side effects.” Medical professionals prefer to play it conservatively, recommending a cautious approach before escalating. This is not yet backed up by published studies apparently, but is the tactic preferred by doctors, who definitely prefer to be consulted rather than see patients tailoring their own medication schedules.

Patients who invent unauthorized dosage schedules might encounter surprises. They may not be aware that it takes at least a week for the last dose to clear their system. If someone wants to devour a big meal on a certain day, careful planning is needed. Even though they might have an enormous appetite, the mere ability to chew and swallow a large amount is no guarantee that the organs farther down the line will cooperate. There may still be “ugly gastrointestinal side effects.”

Your responses and feedback are welcome!

Source: “‘Breakthrough’ Obesity Drugs Are Effective but Raise Questions,” ScientificAmerican.com. 01/10/23
Source: “Do You Really Have to Take Wegovy Forever?,” WashingtonPost.com, 10/19/23
Source: “Is It Okay to Skip an Ozempic Shot Now and Then?,” EverydayHealth.com, 11/15/23
Image by Holly Lay/Attribution 2.0 Generic

The GLP-1 Meds vs. Muscle, Continued

The loss of muscle mass that inevitably accompanies fat loss is a hazard to teens who are prescribed a GLP-1 drug, as we have seen. Not surprisingly, seniors are also at risk.

According to the governmental branch that keeps track of these things, a leading cause of death among that age group is falling, and falling may be caused by what? Exactly — the loss of muscle mass, which holds the bones together and enables them to either move or remain still, as the situation requires.

That is on the physical side, and on the psychological/emotional side, older patients who successfully lost weight might feel they have been given a second chance, a new lease on life. Such a person might be tempted to try a dangerous or downright foolish activity, without the muscular ability to carry it through successfully.

When Madison Muller’s piece was written last year, it included these words about a trial of semaglutide that included 140 participants: “On average, participants lost about 15 pounds of lean muscle and 23 pounds of fat during the 68-week trial.” The mean age of those patients, however, was 52, which is pretty young for this era of ever-aging populations, and so it might reasonably be expected that older patients would not even do that well.

Meanwhile, Eli Lilly is developing the very inelegantly-named bimagrumab, which holds some promise to be a muscle-mass preserver, to be used in combination with the company’s tirzepatide.

Cautious optimism only

When clinical researcher Dr. Donna H. Ryan wrote about next-generation anti-obesity medications, her Introduction implied that in general, the ones in development were not quite meeting expectations:

The goal of medically supervised weight loss has been modest, or at most, moderate, weight loss — principally because that is all that could be regularly achieved.

At the same time, she named two “interesting and unique” examples as “generating much interest.” Specifically, they are the GLP-1 dual agonist tirzepatide (weekly injection) and the “new agent with a unique mechanism of action,” bimagrumab, which not only eliminates fat mass but preserves and promotes the gain of lean mass.

Apparently, although only needed once a month, it must be administered intravenously in the hospital. Still, bimagrumab “gives the first evidence that we might succeed in targeting improved quality of weight loss for our patients.” In the “Conclusions” section of the piece, Dr. Ryan waxes poetic:

Of course, it would be better to live in a world where healthy eating and active living were the default behaviors and where those behaviors were reinforced in a world without undue emotional and financial stress. All of us need to work toward creating that world…

We are, however, not quite there yet. According to one report, although bimagrumab can increase muscle weight in mice and cultured myotubes, it has no demonstrable effect on increasing muscle strength:

On this background, a large controlled study was performed with 251 patients randomized to receiving monthly bimagrumab or placebo for 52 weeks. No change in the study’s primary end-point was noted compared to placebo; all enrolled patients continued to worsen with further deterioration in quantitative muscle strength testing, with more falls, and worsening swallowing.

The Canadian company 35Pharma developed a molecule called HS235 which sounds very promising. Last October, they announced that lab mice who only got tirzepatide “lost 46 percent of their fat mass.” The ones who received a tirzepatide and HS235 combo “lost 64 percent of their fat mass” without, apparently, losing any muscle mass.

Journalist Sumi Sukanya Dutta explained the importance of not losing too much weight, too fast:

Good muscle mass is vital for resting metabolic rate, which, simply put, means the ability of the body to burn calories even while resting… Less muscle is lost with less aggressive weight loss programmes.

Your responses and feedback are welcome!

Source: “Weight-loss drugs pose risks for people over 65, experts say,” BusinessMirror.com, 10/21/23
Source: “Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?,” NIH.gov, 09/30/21
Source: “Motor System Disorders, Part I: Normal Physiology and Function and Neuromuscular Disorders,” ScienceDirect.com, 2023
Source: “Move over semaglutide, new drug on the horizon promises to melt only fat, not muscle,” ThePrint.in/health, 10/22/23
Image by GreenFlames09/ATTRIBUTION 2.0 GENERIC

The GLP-1 Meds vs. Muscle

Muscle mass is a large and rather frightening issue, overall. As previously mentioned, any legitimate weight-loss regime must aim to shed the greatest possible amount of fat, while retaining the largest possible amount of muscle, because a healthy balance of the two is paramount — and as it turns out, very difficult to achieve.

The whole point of these meds is to help the patient eat less, which in itself could be a problem if it leads to an insufficient intake of protein. To maintain and build muscle, several macronutrients from other sources are also important:

Alongside resistance training, research suggests consuming 1.4–2 grams (g) of protein for each kilogram of body weight per day to maximize muscle building. However, it’s important to consume a well-balanced diet that includes healthy carbohydrates and fats.

The Healthline article quoted above, like many similar guides, goes on to recommend a plethora of excellent protein sources.

The necessary

On the most practical level, long-term weight loss is almost impossible to maintain unless dietary caution is accompanied by plenty of exercise for the muscles. In addition, the older a person becomes, the more the body must struggle to maintain muscle while shedding fat. Some doctors who prescribe the GLP-1 meds have become alarmed by the disproportionate loss of muscle mass in their older patients.

In any case, it is unwise to measure only overall weight loss, without distinguishing between fat and muscle — which is the strongest objection to the near-universal use of Body Mass Index as the official measurement tool.

Among other outcomes, this ongoing source of unease within the community has led to the creation of a new category, of which plenty of people are members:

In simple terms, ‘skinny fat’ refers to someone who looks fit and healthy from the outside, but who is actually carrying excess visceral fat internally… But the reality is that this hidden belly fat can lead to some serious health problems.

The medical term for this is Metabolically Obese Normal Weight (MONW).

“Intention to Treat” is a podcast produced by the New England Journal of Medicine, hosted by Rachel Gotbaum, and one of this summer’s episodes discussed the recent approval of GLP-1 drugs for children. Guest Dr. Ali Ibrahim first establishes that with or without medication, any kind of slimming endeavor will inevitably involve the loss of not only fat tissue, but lean muscle mass as well.

That loss cannot be eliminated, but it can be limited, maybe… probably… eventually. This is especially important when the patient is a child or teen, because “we’re putting them through a catabolic state, a state of breakdown, whether it’s adipose-tissue breakdown, whether it’s lean-muscle breakdown…”

Dr. Ibrahim is one of many who ask some version of the question, “What is going to happen to them in the future, especially if they continue being on this medication for decades?” He goes on to say,

These are chronic medications. They’re not meant for use for short-term use. Once we start them, for most people, they will have to continue on these medications for the rest of their lives.

Your responses and feedback are welcome!

Source: “26 Foods to Eat to Gain Muscle,” Healthline.com, 02/15/24
Source: “What is skinny fat? Causes, risks and how to fix it,” GoodTo.com, 07/20/22
Source: “Treating Obesity in Kids — ITT Episode 31,” NEJM.org, 06/05/24
Image by Aidan Jones/ATTRIBUTION-SHAREALIKE 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

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