Why What You Eat Still Matters on GLP-1 Drugs

0:00What if the best way to use a GLP-1 medication isn't to rely on it forever, but to use it as an opportunity to change how you eat? Here's why I believe GLP-1 medications and low-carbohydrate diets may work better together. GLP-1 drugs help reduce your appetite, so you naturally eat less, but they don't necessarily change what you eat. That's where a low-carbohydrate diet comes in. By cutting back on sugar and refined carbohydrates, you reduce the amount of insulin your body needs to produce, helping improve your metabolic health. In fact, my lab was involved in a small study where patients combined a ketogenic diet with low-dose semaglutide.

0:40Over six months, they lost an average of nearly 50 pounds, with most of that weight loss coming from fat. Now, we need larger studies to confirm these results, of course, but here's the bigger idea. Use the medications to help control your appetite while you build healthier eating habits that may help you maintain your progress. Because the goal shouldn't just be losing weight. It should be improving your metabolic health for the long term. This is Lecture 168 of The Metabolic Classroom.

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3:41Welcome back to The Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. No surprise, millions of people are now taking a GLP-1 medication, whether as a weekly injection or, even more recently, a daily pill. Many of them started because a doctor recommended it, and many have also started because they had a friend or a family member who did it and lost a striking amount of weight on one of these interventions. These drugs have become part of ordinary conversation in a way that very, very few prescription medications ever have. Along with that growth, a very familiar argument has formed.

4:20One side holds that the drug makes diet largely unnecessary since appetite falls and weight just comes off regardless of what a person eats. But the other side holds that the drugs are a shortcut and that anyone who changed their diet properly would not need them. So we have these kind of two polar opposite views. Both positions treat the medication and the diet as competing choices. If you're taking one of these drugs or you're thinking about it, the practical question I think is simpler. You want to know whether what you eat still matters while you are on it, and whether a low-carbohydrate diet in particular hurts or helps or makes no difference.

5:02GLP-1 medications and carbohydrate restriction are usually discussed as rival answers to the same problem, but I think they act on different parts of it. And the case for combining them comes from some good physiology, admittedly more than it does from head-to-head trials, which are still absent. My view is that these drugs work best as a temporary aid against the siren call of processed carbohydrate-rich food, but at a dose that is low enough that a person is still learning to eat well, indeed may still want to eat, and then eventually getting off the drug. All right, so let's get started. To get started, it helps to look at what each approach actually does in the body.

5:46GLP-1, as you know by now, is a hormone released by cells in the lining of the intestine when nutrients come through the gut. And its main effects relevant here are that it slows how fast the stomach empties into the intestine and it reduces appetite through signaling in the brain. The drugs that copy this hormone are engineered to last far longer than the natural version, which is cleared from the blood just within minutes. In controlled studies, weekly semaglutide reduced how much people chose to eat when they were allowed to eat freely. At the full obesity dose, calories that were eaten at a buffet when the study subjects could just eat as much as they wanted fell by about a third compared to those who are on placebo.

6:31At a lower dose of one milligram per week, total calories eaten across the day, once again with free access, fell by about a quarter. And people overall, no surprise, reported less hunger, they had fewer food cravings, and they had better control over their eating. The drug reduces how much a person eats, but it does not choose what goes on the plate. And whatever they do eat still produces its usual effect within the body, including hormone responses. Carbohydrate restriction acts on that second part of the problem. Dietary carbohydrates, especially those that are refined sugars and starches, are the main driver of a rise in glucose, but more importantly in this context, the rise in insulin, which has to be released to manage that glucose.

7:18If you remove a lot of the carbohydrates, you're going to lower the insulin that each meal requires, and then you're reducing the rise and fall of insulin and glucose across the day. A drug that reduces appetite and a diet that reduces the insulin load of each meal, I think then are really complementary. One governs how much we're eating, and the other governs what food does to the hormones that decide whether fat is stored or burned. Now, let's move on to the GLP-1 that the body makes for itself. People with obesity and insulin resistance often make less of their own GLP-1 in response to dietary carbohydrates.

7:57In the study of women with and without obesity, the GLP-1 response to an oral carbohydrate load was markedly smaller in the women with obesity, while their response to a fat load was pretty normal. In fact, to put a fine point on this, the GLP-1 response to carbohydrates was entirely absent in the women with obesity. Further, in non-diabetic men, a weaker early GLP-1 response after a mixed meal was associated with insulin resistance. And that association held independently of how much body fat the men carried. further in isolated intestinal cells and in mice insulin itself stimulates the cells that make glp1 but when those cells are made insulin resistant in fact in the models i just mentioned they were made insulin resistant through prolonged insulin exposure the glp1 secretion falls i think that the cell and animal work together offer a plausible mechanism and the human studies show an association rather than a cause and effect, as I admitted a moment ago.

9:04Regardless, I think it's reasonable to hypothesize that lowering chronically high insulin might, over time, allow the body's own GLP-1 response to recover. But again, that's not been established in people yet. Improving insulin sensitivity, of course, is worth pursuing for its own sake, whether or not the GLP-1 response recovers. Now, let's look at how cravings and dose fit together. The most usual effect of a GLP-1 drug, in my view, is the period during which the pull of highly palatable processed food is weaker. In the 1 mg semaglutide study, people felt less hunger and fewer cravings at a dose well below the maximum that is used for obesity.

9:48The change in food preference in that study was a reduced preference for high-fat, energy-dense foods. So the data do not always show that the drugs are selective with their targeting of carbohydrate cravings, but it still offers a window in which the highly rewarding processed foods will hold less sway. Processed foods work against the drug, of course. In an inpatient trial, adults were given either ultra-processed or unprocessed diets for two weeks each. The meals were matched for the calories that they offered. They were matched for sugar. They were matched for fat and fiber and sodium, and the people could eat as much or as little as they wanted.

10:27On the ultra-processed diet, they ate about 500 more calories per day, almost all of it as extra carbohydrate and fat. And no surprise, they gained weight while they lost weight on the unprocessed diet. Even a person who continues to eat this way while taking a GLP-1 drug is relying on the medication to overcome a food availability that is going to be designed to drive overeating. And the usual response is to just raise the dose of the GLP-1 until they can feel that reduced pull to those kinds of foods. The alternative to all of this is to use the lowest dose of the drug that meaningfully reduces cravings and to spend that time removing sugary drinks, the refined flours, the packaged snacks, while building habits around meals that are whole foods, especially protein heavy and the fat that comes with it.

11:24If cravings are lower because the food that provoked them is gone, the drug has less work to do and a higher dose is now, I think, going to be less required. As I've said now repeatedly, there's no large trial that's tested yet whether a low-carbohydrate diet works well deliberately with a low dose. So this does remain a clinical hypothesis. But having said that, we can turn to data from patients who combined the two. The most direct evidence that I'm aware of for this combination comes from a study that my own lab was a part of. And we conducted it with a metabolic clinic up in Meridian, Idaho, as well as some of the coaches within the Insulin IQ protocol.

12:08It's a retrospective case series, which means we looked back at the records of patients who had already gone through the clinic's six-month insulin resistance program, that is to say, Insulin IQ work. The program combined a whole food ketogenic diet with low-dose semaglutide. And patients were taught three principles, which were to limit carbohydrates, largely to focus on vegetables that grow above the ground, to include animal protein at every meal, and to include fat without deliberately adding more of it. Most patients started at a quarter milligram of semaglutide per week and settled at half a milligram.

12:47And one stayed at a quarter, one stayed at one milligram, and nobody went above one milligram. That is well below the 2.4 milligram dose that's used in the obesity trials. Eight patients completed the program, but only seven were analyzed because one had to be excluded due to switching to a different drug in the midst of the review. Six of them are women. One was a man. Over six months, average weight loss was about 22 kilograms. about 92 percent of the weight loss was estimated to be from fat and skeletal muscle fell by an average of only about one kilogram and one patient actually even gained lean tissue fasting insulin fell by an average of about 16 micro units per mil and then the clinic's visceral fat index that they use fell by about 37 percent triglycerides fell in six of the seven patients hdl cholesterol rose in all seven, and the marker of inflammation called C-reactive protein, CRP, fell in six of the seven.

13:49LDL cholesterol varied across all of them. In the paper, we described that the findings are preliminary, and we know that we need to do more controlled prospective trials, of course. But with all that having been said, not only does it prove the concept here, but let's just reason and think through this a little bit. And let's specifically consider muscle for a moment. A low-carbohydrate diet may help here through the ketone beta-hydroxybutyrate, which the liver makes from fat when carbohydrates and insulin are low, or a person is just taking an exogenous BHB, exogenous ketones. In healthy adults, infusing BHB into the blood has been shown to lower the breakdown of amino acids from the muscle by an average of about 30%.

14:35So that's pretty meaningful. In fact, in one very interesting study in healthy individuals, they gave them a very low dose of a bacterial toxin to induce some inflammation. And the infusion of BHB cut the muscle breakdown in their body by about 70%. So this indicates that muscle protein breakdown fell significantly. Now, both of these were very short-term infusion studies in a lab with ketone levels that were pretty high but still capable of what a ketogenic diet produces. but nevertheless they show what a ketone can do here in protecting muscle my lab actually has also contributed to this we tested the question during a weight loss protocol and this was not glp1 related but in a randomized double blind trial 51 adults with overweight or obesity were put on to a generally kind of lower calorie moderate carb diet so that they wouldn't necessarily be making a lot of ketones on their own, but then they took an exogenous BHB supplement, just simple BHB salts.

15:38We measured body composition with the scanning method, and only the ketone group lost a significant amount of fat compared to where it started, and the ratio of lean mass to fat mass improved. Lean mass was preserved in both groups, though, and the difference between the ketone and placebo groups was not statistically significant, so the trial was maybe a little underpowered, but it does indicate a favorable direction of defending muscle.

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17:57Next, we come to side effects in this mini lecture and how the meals can affect them. In the step one trial of semaglutide, nausea and diarrhea were the most common adverse events with semaglutide. And about four and a half percent of people stopped the drug because of GI problems compared with less than one percent on placebo. These effects do rise as the dose rises. So a diet that also allows a lower dose would help with tolerability. Even here, I think a low carbohydrate diet can help by changing what a meal contains in ways that I think help with these side effects. Built around, of course, protein and non-starchy vegetables, it removes the large servings of the processed carbs like breads and pastas and sweets and cereals that are very easy to overeat on a stomach that is already emptying in a changed way.

18:49It's emptying more slowly. Fat also, fat and protein will slow stomach emptying. So the most tolerable version includes fat with the protein without piling on extra fat by all means, but don't avoid the fat that comes with those proteins. Non-starchy vegetables, of course, are going to help with just normal bowel movement habits. The fat also in a low-carbohydrate diet is going to play another role when it comes to gut health and indeed problems that have been implicated with GLP-1 use, which is the gallbladder. A meta-analysis of 76 randomized trials found that GLP-1 drugs increase the risk of gallbladder and bile duct disease by about a third overall, more than double in the weight loss trials, and it even goes up as the dose goes up.

19:35The gallbladder, as you've heard me articulate before, it empties when fat is eaten. In an older randomized study of rapid weight loss on liquid diets. Gallstones formed in four of six people on a nearly fat-free diet, and in none of seven whose diet included even a modest amount of fat. Fat is what empties the gallbladder. If you're not eating fat, then the gallbladder stays full, the bile starts to crystallize, and you have the formation of stones. Now, that study I mentioned earlier didn't look at GLP-1, but I'm just trying to once again make a physiological connection here, that with GLP-1 use, I don't think it's a direct effect of the drug.

20:16People are experiencing more frequent gallbladder problems just because they're eating so much less, especially they may be deliberately trying to avoid low-calorie fat foods, which is going to make the gallbladder even more reluctant to empty. Gallstone risk is just going to go up. Now, as we're nearing the end, let's turn to what happens when people stop the drug. In the extension of the step one trial that I mentioned earlier, people who had lost about 17 % of their body weight stopped both semaglutide and the lifestyle counseling. And within a year, they'd regained about two-thirds of what they had lost with pretty much all of the cardiometabolic improvements moving back right to where they started.

21:01In a different trial called the SIRMOUT4 trial, people who lost about 21 % on terzepatide and were then switched to placebo regained about 14 % of their body weight over the following year. And of course, unfortunately, those numbers were continuing to go up. In the step one extension that I referred to earlier, nothing deliberate replaced the drug when it was withdrawn. And in the surmount four, the lifestyle counseling that continued was the same general advice people had received all along. A low carbohydrate diet may help maintenance of the weight loss in two ways. In a feeding trial of adults who had already lost about 12 % of their body weight, those assigned to a low carbohydrate diet for 20 weeks burned roughly 200 more calories per day, just as a cost of living because they were on that low-carb diet compared with those on the high-carb diet.

21:58With the largest difference in people who secreted the most insulin before their weight loss, and their levels of the hunger hormone ghrelin were also lower. Lower insulin also allows stored fat to be released between the meals, which is the same metabolic state that the drug helps create. And no surprise that exercise offers the best post-treatment data that we know of so far in large trials. One year after treatment ended, people who had received exercise and a GLP-1 together weighed about five kilograms less than those who had received the GLP-1 alone. And those who had exercised only also had maintained the weight that they had lost.

22:40Now, no trial has tested the same question with a low-carbohydrate diet, as I've said before. So a lot of what I'm talking about here is speculation based on associative studies as well as reasonable speculation on the physiology.

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25:00Now, from there, with all of these points in mind, it is worth comparing this approach with the way the drugs are usually used. The major obesity trials paired a high dose with the reduced calorie diet of about 500 fewer calories per day and advice to just be more active, but they give no guidance on carbohydrate or food quality. A participant could meet the calorie target while eating largely the same foods as before with insulin still rising after each meal. And as insulin goes up, of course, hunger is going to go up and metabolic rate is going to go down. That is not a great combination. The low-carbohydrate diet's role in this comparison is to change what's eaten so that the insulin falls because of the food rather than only because less of it is eaten.

25:47And so the lower dose, I think, can do a little more work. You can get by with a little less. The weight loss may be a little slower, but the point is a change in food choices. Insulin, it's a change in habits. and the post-treatment exercise data suggests that changes built during treatment can outlast it. So to really bring that idea home, use that window of time on the drug. Use the lowest possible dose and define that based on how well you're able to control your cravings for carbohydrates. Finally, let's look at how a person comes off the drug. A low starting dose leaves less distance to come down.

26:32The diet's role at this stage is to already be in place, so that when the drug's effect on appetite fades, the sweetened drinks, the refined flours, the sugary snacks, that provoked cravings have been out of the kitchen for months. Insulin remains low because of what's eaten, and meals are built on protein and fat, and that's going to satisfy the person a lot better. A reasonable plan, of course, made with a physician who's doing your prescribing. I'm not your clinician, remember. I'm just your friendly neighborhood scientist. But a reasonable plan from a metabolic scientist is to reduce the dose gradually only after eating habits have been stable for a sustained period.

27:13Of course, during this time, you're watching weight. You're watching your waist in particular. but also as appetite continues to be controlled, you are engaging in resistance training and you're just controlling your cravings for the foods that are the hardest to control. And that's always going to be refined carbs that come in bags and boxes with barcodes. Now, none of these taper steps have been tested in a randomized trial. So the plan should be adjusted. It should be open minded. It should be accepted as just a speculative idea at this point. The trial that would settle the larger question comparing a low-dose GLP-1 plus carbohydrate restriction with the drug alone has not been done, but I would sure love to see it.

27:57Class dismissed. Until next time, more knowledge, better health.

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