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A key focus of her presentation was chronic suppression of interleukin-6 (IL-6) with GLP-1 receptor agonists, which Loh said could have health implications beyond weight loss, such as muscle growth and brain development.<\/p>\n
Healio spoke with Loh to learn more about the mechanisms behind GLP-1 receptor agonists and their potential trade-offs.<\/p>\n
Healio: GLP-1 receptor agonists are often discussed in terms of weight loss. Can you discuss the deeper immune and neuroendocrine mechanisms that drive their efficacy?<\/b> <\/p>\n
Loh:<\/b> We often think of GLP-1 as a gut-produced hormone. It is formed in the gut, but its effect systemically may not be as big as we think because it gets degraded very quickly; it has a half-life of 2.5 minutes; and only 10% to 15% (on a really good day) of that will get into the bloodstream. But it turns out we can also make GLP-1 in our brain. This is where the weight loss effect is most important.<\/p>\n
We have areas in the brain that have GLP-1 receptor and can pick up this signal. It turns out that the areas in the brain that have the GLP-1 receptor are involved with metabolic regulation, energy expenditure and sickness behaviors, for example, and also motivational circuits that are involved in salience and cravings. So, when those areas of the brain are impacted by the influence of GLP-1, I think that is what is causing the effects that we see primarily with weight loss, but also with some behavioral changes.<\/p>\n
Healio: What are the potential trade-offs of chronically suppressing IL-6?<\/b> <\/p>\n
Loh: <\/b>We think of IL-6 as bad, and so we want very low levels of IL-6 in the body. What we don\u2019t realize is that IL-6 is very nuanced and has different signaling modes. In some modes, it is absolutely necessary because it is signaling repair and proliferation. And in some modes, it\u2019s inflammatory; its telling cells there\u2019s damage in this area and we need to go after the bad pathogens. But just looking at a number and saying, \u201cHigh is bad, low is good,\u201d is really not the way to approach it. In the future, we need to actually look at specific aspects of IL-6.<\/p>\n
When you\u2019re on a GLP-1, you\u2019re going to change the IL-6 tone. Whether it is lower in the bloodstream is one thing, but what about in tissue? We can\u2019t measure that. We don\u2019t even try. We don\u2019t even try to do that in many animal studies. So, even if there\u2019s less of it in the bloodstream, maybe we have an activation in the brain that we\u2019re not able to pick up. So, again, it\u2019s complex.<\/p>\n
When we look at any kind of metabolic intervention, we have to keep in mind the immune impact of that and vice versa. Our research needs to move toward understanding the implications of different aspects of IL-6 in the body before we can make a metabolic intervention, and that we affect IL-6 in a particular way so that it signals in the appropriate fashion and we have a good effect.<\/p>\n
If you have very low IL-6, that could actually be bad for muscle growth. It could also be bad for a developing brain because we depend on IL-6 in the developing brain for neurogenesis and to prune certain synaptic circuits. If you have too little of it, you might actually have miswiring in the brain as a result. Those are just two examples, but we can look at different tissues and come up with very similar scenarios.<\/p>\n
Healio: Can you explain the difference between <\/b>physiologic<\/b> and supraphysiologic GLP-1 activity? Why is it important for clinicians who prescribe GLP-1s to know this?<\/b> <\/p>\n
Loh:<\/b> Because we often tell patients that this is a natural hormone. Your body makes it, so it\u2019s fine for you to take it. Now, physiologically, the levels of GLP-1 that we have are dependent on time. So, when you\u2019re fasting, you pretty much have none. But after you eat a meal, it starts to rise and then it peaks before it drops down again. The levels that we see are in picomoles \u2014 very tiny levels, even at the peak. When we give the medication, we are not reproducing a physiologic state. What we\u2019re doing is overriding it. We\u2019re slamming the body with a very high dose. Even if we just look at the unbound bioactive portion, it\u2019s seven to 40 times the peak physiologic dose. That\u2019s what I call a supraphysiologic dose. And we have no staggering in terms of time. There\u2019s no fasting level, there\u2019s no after-meal level. It\u2019s just on all the time and it overrides everything. And in the body, GLP-1 works physiologically with other hormones. There\u2019s a coordinated synchrony that happens. We don\u2019t see that with the drug. Even when they try to do combination drugs, it\u2019s a distorted architecture. That\u2019s the main difference between physiologic, which is what your body does under normal circumstances, and supraphysiologic, which is when we try to override a system and impose a signal on it, regardless of what else is going on in the body.<\/p>\n
Healio: <\/b>What emerging concerns<\/b> <\/b>around GLP-1s should clinicians be aware of?<\/b> <\/p>\n
Loh:<\/b> Muscle mass preservation is one of the biggest challenges. Now, a lot of times you put someone on GLP-1 because you want to regulate their blood sugar levels. They\u2019re diabetic and they have obesity. But if you keep this person on for 10 years and they lose significant muscle mass beyond already what you lose from normal aging, then you might find that 10 years, 15 years down the line, suddenly they become diabetic again. But this time it\u2019s because they have such a small muscle mass that there\u2019s not enough \u201csink\u201d for the glucose to go into, and now it\u2019s spilling out into the blood. So, we just created the problem 15 years later. But we\u2019re not looking at that, and we\u2019re not even aware that it might be a problem. That\u2019s one challenge. We don\u2019t know long-term how it changes the immune tone in the body. And I talked about how the body isn\u2019t a perfectly reversible system. Given this, when you change something, you have to understand that you\u2019re not likely to 100% reverse some of the changes. We have to keep this in mind. So, you put someone on a drug, but you also have to be asking for how long? Is this really appropriate? Are the trade-offs worth it? Do we keep this person on for life? If we\u2019re trying to wean, what are we going to do when they regain weight? How are we going to manage that situation? All these clinical questions start to come up.<\/p>\n
Healio: How can clinicians mitigate risks like muscle loss while patients are on GLP-1 therapy?<\/b> <\/p>\n
Loh:<\/b> Well, again, knowing the different factors that are involved, there\u2019s not just one thing that they have to do. Being very much more nuanced in their approach. Bolusing the protein appropriately. I usually do three to four protein boluses per day, and I regulate that. So, my patients are seeing their meals like a prescription. They have a dose, they have a frequency, and I make them do that in conjunction with any medication that they\u2019re on, so that by the time we get to the point where we may even start to talk about discontinuing the drugs, they are dosing their protein on schedule. That\u2019s a habit that\u2019s already ingrained. And when we start to wean down the medication, we have a lot of structure that we built up that will help protect them. They\u2019re doing their resistance training. That should not be optional. We\u2019re really going to have to try to get the patient on a structured program to preserve muscle even before we talk about weaning.<\/p>\n
Healio: Is there anything else you\u2019d like to add?<\/b> <\/p>\n
Loh:<\/b> My secret objective today was to generate many questions. One of the things I was so happy about was to get people coming up to me with a trillion questions. That made me really happy. Physicians are some of the brightest people. We have great talent in the room. And yet, we kind of reduce the job of being a doctor to following algorithms. When you see X, do Y. When you see this, do that. Give this, give that. We take away the thinking process. AI is very good at giving answers. What they\u2019re not good at is asking human-centric questions. I want physicians to remember that is our value, and that we\u2019re here to ask the hard questions and to have judgment on what to do and also importantly what not to do.<\/p>\nFor more information:<\/h2>\n
Vyvyane Loh, MD<\/b>, <\/b>can be reached at primarycare@healio.com.<\/p>\n\n
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Sources\/Disclosures<\/h3>\n Source: <\/h2>\n Healio Interviews<\/p>\n
Reference:<\/h2>\n\nLoh V. GLP1-1 receptor agonists: What we know, what we don\u2019t and what comes next. Presented at: Obesity Medicine 2026. April 10-12, 2026; San Diego.<\/li>\n<\/ul>\n\n
Disclosures: <\/strong>
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