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A cardiologist who helped set national cholesterol and weight targets for 40 years now says those numbers can mislead. Richard M. Fleming, a physician specializing in cardiovascular and inflammatory disease, argues that weight loss on a GLP-1 does not automatically mean a patient is getting healthier, and that some patients who never lose a pound are already metabolically well. This episode is based on his article “GLP-1 agonists and weight loss: Treating the disease, not the number,” published on KevinMD. You will hear why body mass index was never built to diagnose individuals, why inflammatory and thrombotic markers track disease more honestly than the scale, and how clinical trials from CAST to ACCORD have shown what happens when medicine treats the surrogate instead of the patient. He walks through which inflammation tests a primary care physician can run before, during, and after GLP-1 therapy, including high-sensitivity CRP, homocysteine, and fibrinogen. Hear why a 40-year insider says precision medicine requires precision measurement, not precision weighing.

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today we welcome Richard Fleming. He’s a physician specializing in cardiovascular disease and inflammatory disease. And today’s KevinMD article is “GLP-1 agonists and weight loss: Treating the disease, not the number.” Richard, welcome to the show.

Richard M. Fleming: My pleasure to be here. Thank you for the invitation, Kevin.

Kevin Pho: All right, so briefly introduce yourself and then tell us why you decided to write this article on KevinMD.

Richard M. Fleming: So originally I’m a physicist who then became also a cardiologist, nuclear preventive cardiologist, and later on I added an attorney to the repertoire to better understand some of the political aspects and patenting aspects. I’ve been involved with heart disease research with American Heart for 40, 45 years. And the work over that period of time is really focused on me trying to understand why people have the health problems they do, beginning with heart disease. But it evolved over the course of time in trying to understand how to measure that.

I remember when I was a medical student at Iowa, the second thing that the dean told us is that 90 percent of what we would be taught would eventually be proven to be wrong. And he encouraged those of us who were involved in research to go out there and add to the correction of those problems. And so the glycoprotein paper and weight loss was a natural evolution out of that.

As I’ve looked at these topics for decades now, where people use surrogate markers like weight or hemoglobin A1C or LDL cholesterol. In fact, part of the time with American Heart that I’ve had was I was one of the 12 that was involved in constantly refining those numbers and appreciating what those numbers really are. They are population surrogate markers. They’re not individual disease markers.

And so when I tell somebody as a cardiologist, you have a one in a thousand chance of having an MI or a CVA on the day of, or following my cardiac cath, that’s a population number. It’s a surrogate, but for you as a patient, it’s zero or one. It’s either you ended up with a problem or you didn’t. And too often, I think we look at these surrogate markers, including weight and the use of GLP-1 to help people lose weight, as the disease, when in fact it’s not the disease. It is simply a marker of something that could be problematic for the individual.

So my focus again is to try to find what causes disease, measure it, try to prevent it. When I see phenomenon, like the conversations with weight loss, once again come up, it reminds me of all the mistakes that we’ve made in cardiology, whether it was the CAST trial where our surrogate marker then was ventricular premature ectopics, right? And we treated that, but we ended up with more people dying than we expected. Or the ACCORD trial where hemoglobin A1C levels, the surrogate marker, was lowered. But again, there were consequences and people died. Or the Women’s Health Initiative trials where we tried to lower lipids, but as a result of some of the estrogen therapies we gave, they ended up with thrombotic disease. Or just the CANTOS trial reminding us that heart disease isn’t simply LDL cholesterol. It’s an inflammatory disease.

And so when I first presented all of this back in 1994 at American Heart, being a physicist, I defined it as a unified theory, and I initially called it the Fleming Unified Theory of Vascular Disease, but since then, we’ve learned it’s heart disease, it’s cerebrovascular disease, it’s cancer, it’s high blood pressure, it’s illnesses. And so the understanding is that what we have is an inflammatory, thrombotic, immunologic response that causes disease.

And it’s been a long time bringing that to the development because recognizing that 1994 is when I first started to explain that, that was 32 years ago. And it speaks to how slowly sometimes even new information that’s critical is challenged to get out there as we kind of reverberate back to what we were taught as medical students and hang onto that with a certain tenacity, which we don’t need to. That was our foundation training, and many physicians are eager to learn what the real problems are, so we take better care of the patients.

Kevin Pho: Now we talk about these surrogate markers, like these metrics that you mentioned. Why is it so tempting to use surrogate markers as a sign of progress whenever we initiate treatment?

Richard M. Fleming: Well, I think there’s several reasons for why that happens. First off is we’re all familiar with them. We’ve used them for many decades, and so we’re comfortable with them. Secondly, the system is really designed to reimburse our treating people by lowering them. You know, when we submit our DRG codes and CPT codes, it’s looking for something that has been approved. And so for many decades now, we’ve taken these population-level markers and been reimbursed and reinforced for following them and treating them.

So I think that’s a lot of the rationale behind it. Plus it’s slow to educate people on recognizing that these surrogate markers, again, are population levels. We’ve depended upon them, and transitioning over to understanding that today in 2026, we’ve made advances in the way that we measure disease and we can actually get to the tissue level itself.

Kevin Pho: So as it relates to GLP-1s specifically, of course, we are measuring weight loss. So body mass index, of course, you wrote, would be a poor surrogate marker. What should we focus on instead?

Richard M. Fleming: We should really be trying to measure the inflammatory, thrombotic, immunologic responses. So whether there’s an inflammatory process going on, what is the function of the blood vessels, the endothelial function, what’s the metabolism, is there blood clotting going on. There is a number of ways to do that. We have, actually, part of what I’ve been working on is a method called FMTVDM, which actually measures or quantifies what’s going on that may not be available for everybody. But again, looking at these markers of inflammation, blood clotting, immunologic response, endothelial function, that’s happening at the tissue level for the person.

And the best thing about that is that we find the problems sooner than later. One of the issues behind these surrogate markers is I’ve explained to people it’s like water building up in a dam. Behind the dam, the tissue where the problem is, all of this is building up. And it’s not until it exceeds the level of the dam that it overflows the dam and gets into the bloodstream where we can measure the markers or we can measure things like weight. But that means we’ve waited until after the problem has actually happened. And now we’re dealing with disease versus trying to catch problems sooner, trying to prevent problems.

And so this is a transition period as we’ve shifted from surrogate population markers that have helped to guide us in the past, and we won’t throw those out, we’re not going to ignore those, but we’re going to combine those now with the ability to actually look at the tissue, find out what’s happening, and do a better job of providing precision medicine through precision measurement.

Kevin Pho: So if someone begins a GLP-1 agonist for the purpose of losing weight, tell us what is lost clinically if both the clinician and a patient is only solely focused on pounds loss or body mass index.

Richard M. Fleming: Right, so the problem with that is that just because you lose weight doesn’t mean the patient is actually getting healthier. We know people who have lost weight whose markers are still a problem, and they get that false sense of security that, “Well, I’m losing weight, I must be getting better.” And likewise, we all know individuals that are overweight. It’s not that they wouldn’t benefit from losing weight, but their inflammatory and thrombotic and immunologic markers are completely fine. So they’re not experiencing the disease problems.

So we run the risk of being misdirected, telling people they’re getting better just because they’re losing weight when they’re not, telling other people, not because they’re not losing weight, they’re at risk of a problem when in fact they’re not. So it misses the actual problem and can mislead us as well as the patient.

Kevin Pho: So I’m a primary care physician. If I am starting someone on a GLP-1, just tell us some of the easy tests that I can do to measure some of the metabolic improvements that are accessible to most primary care doctors.

Richard M. Fleming: Well, there’s several that we all know about. One is high-sensitivity CRP. It’s a marker of an inflammatory process going on. It doesn’t tell you where, but it tells you there’s something going on. You can look at clotting factors to see if they’re predisposed to clotting. We’ve all talked about D-dimer and other tests during the COVID-19 pandemic that showed markers of inflammatory processes going on.

We can look at interleukin-6 and tissue necrosis factor alpha. In fact, some of the pleiotropic benefit of the GLP-1 agonists is that we know that they affect both tissue necrosis factor alpha, they reduce it, as well as nuclear factor kappa beta, which is an inflammatory marker, which can also be measured. And that’s probably one of the more significant impacts of these GLP-1 agonists, is that they’re providing this decrease in inflammatory markers. And so we can measure those directly from the blood as well.

And then anything that we find. In addition to that, there’s several vascular flow reserve models that are available for people that are wondering whether there is a brachial flow-mediated problem, or whether it’s quantified nuclear imaging. Those are a little bit more advanced, but we certainly have those. Immune markers, interleukin-6, tissue necrosis factor alpha, homocysteine is a big marker for an increased inflammatory response in the immune system having issues, and a variety of like the CRP, high-sensitivity CRP.

Kevin Pho: Now, do you recommend screening or getting these markers before starting a GLP-1? Do you recommend a targeted approach? Because you did mention a lot of tests that are inflammatory and immunomodulatory markers. What do you recommend in terms of tests before starting a GLP-1?

Richard M. Fleming: Well, I think again, part of that depends upon the actual person you’re looking at. So there’s not a single one-size-fits-all phenomenon that I think we should be using. We should look at our patient who’s coming into us and seeing what types of health problems they may or may not be having to actually marker.

But it is true that inexpensive tests like high-sensitivity CRP or homocysteine or fibrinogen are easy enough tests to look for those markers, and most people do. I recommend that people get those types of tests.

I definitely think that if you’re going to give somebody a drug or an intervention of any sort that can have a consequence, and you want to know what that consequence is, the best way to understand it is to get the measurements beforehand, do the treatment, and then follow that up to see if it’s actually produced any benefit. Because if you give these medications and they lose weight, but it hasn’t improved any of these inflammatory, body, immunologic responses, all you’ve done is changed the number on the bathroom scale. You haven’t helped your patient. And most physicians that I know really want to see our patients get better. That’s the reward at the end of the day when we see patients getting better as a result of what they and we do.

Kevin Pho: As far as you know, what are some clinical studies that show the beneficial effects of GLP-1s on these inflammatory markers, and is there data to show that there’s a positive clinical outcome for patients?

Richard M. Fleming: Well, I think right now we’re at the very beginning of that field where the data’s being collected, and every day you see something new about the GLP-1 drugs. I mean, that’s the surprise that every day on Medscape or a variety of other systems, you can see, here’s a new commentary or here’s a new concern that occurs.

What we know that GLP-1 drugs do by mechanism of action. As we know, they have an effect on the hypothalamus and eating appetite. We know that they have an effect on gastric motility, emptying of the stomach. We know they have an effect on insulin levels and glucose. We know that they have an effect on glucagon by inhibiting the breakdown of fatty acids into gluconeogenesis or new glucose. We know they have an effect on some of the tests that I mentioned earlier, the nuclear factor kappa beta, tissue necrosis factor alpha.

What we need to remember is that the mechanisms of action that I just described, that talk about why people lose weight, that’s also where the side effects occur. Side effects occur at the site of action. So endocrinologic, GI, liver, pancreas. Those are where we’re going to see the side effects. Because very much like the HMG CoA reductase inhibitors, or quote, statins, had their effect on HMG CoA to influence the rate-limiting step of lipid synthesis. That’s where we typically saw the problems, right, was in liver, or rhabdomyolysis in some instances with muscle, CK phenomenon.

And so as we watch these studies come out, we’re going to see more and more people talking about the side effects of all of those systems. And the clinician’s job, our job, is to take the information that we’re hearing, focus in on the patient, because it goes back to that cardiac catheterization example I gave earlier. For the patient, it’s all or nothing. Even though the numbers at the population level may be a certain number, for the patient, they either got better or they got worse. And that’s what we need to keep focused on.

Kevin Pho: So in the future, as more studies are being done, is it your hope that we would have some type of inflammatory-related objective number that we can treat with a GLP-1?

Richard M. Fleming: Absolutely it is. In fact, that’s the entire concept behind FMTVDM. The method that I developed was to allow us to collect the data. We have it on heart disease, we have it on breast cancer, we have it on infectious diseases. You’re going to see more of this in the published literature because there’s several research projects that we’ve completed, multiple studies that are being published, being accepted right now that are in press.

Where the goal is to find an approach that can look at an individual and find out what their total body health is, and then independent of what their treatment is, whether it’s GLP-1s or any other treatment, we can actually measure the impact for that person, allowing us to direct treatments and diagnostics and treatments to the patient. And be very specific. Because again, for them it’s all or nothing.

We’ve done this with other treatments in the past where there are interesting dichotomies in who gets better and who gets worse, and we’ve been able to sort that out. And the additional benefit that comes from that is by having groups who we know there’s a benefit, in groups where we know there’s a detriment, to allow other researchers then look at those groups very specifically and say, why is this? What are we missing? How can we add to our fund of knowledge and how can we better take care of patients?

Kevin Pho: We’re talking to Richard Fleming. He’s a cardiovascular and inflammatory disease physician, and we’re talking about his KevinMD article “GLP-1 agonists and weight loss: Treating the disease, not the number.” Richard, let’s end with some take-home messages that you want to leave with the KevinMD audience.

Richard M. Fleming: Well, I think the end is that we want to make sure that we’re treating the patient and not just some number. We want to, precision medicine means precision measurements, not simply using surrogates. We can use those, but they don’t tell us what the actual disease is, what’s going on in the patient.

So we want to remember that in the end it’s the patient and their health problem that we’re taking care of. Not to get caught up in the numbers that are easy to write down in a chart and to think that we’re doing something better. We want to make certain that the changes we’re making in people actually reflect an improvement in the overall health of the person, and not just some number that we’re adding to the patient’s chart.

Kevin Pho: Richard, thank you so much for sharing your perspective and insight. Thanks again for coming on the show.

Richard M. Fleming: My pleasure. Thank you very much.