I am Sarah Thomas, an advisor on the American Diabetes Nutritional Science and Metabolism Interest Group. And I'm Ronnie Chatterjee. I'm chair of the interest group, and we're excited to welcome our expert panel and all of you to discuss the latest scoop on sugar substitutes and diabetes. Here's a brief look at today's agenda. I'll provide a few short announcements, and then we'll introduce the experts in a few moments. Each expert will provide a short presentation, and then we will have a panel discussion with questions and answers at the end. The panel will take questions from the audience. We don't want you to wait until the end of the presentation to enter your questions, so we would like you to use the Q&A box that's on your control panel to enter questions as you think of them. Do not use the chat box, because the ADA will be using the chat box to enter links during this announcement. Next, I wanted to thank other members and the whole leadership team of this interest group. It's been great to work with everybody, and I think we've come up with some nice webinar topics and activities, so I want to thank everybody. And then I wanted to encourage everybody who's attending today to join ADA. ADA has a lot of opportunities. You can join interest groups like this one, and you can join up to three of them. You can also join member-exclusive webinars and webinar recordings. Additionally, there are recognition opportunities and volunteer leadership positions available. And you can use the link in the chat to learn more about ADA membership. Another benefit of ADA membership is connecting with other members of your own interest groups and other interest groups on the Diabetes Pro Member Forum, and you can see the link in the chat now. Here's a preview of upcoming live webinars hosted by the ADA. To register for the upcoming webinars, please visit the link on your screen or in the chat. And then lastly, I wanted to direct you to ADA nutritional resources for both patients and professionals, and you can use the link on the screen and in the chat to look around the ADA shop. All right, so now I'd like to introduce today's presenters. We have Jotham Suez, PhD, who's an assistant professor at Johns Hopkins Bloomberg School of Public Health's Department of Molecular Microbiology and Immunology. He'll present the latest in basic science research related to non-nutritive sweeteners, including his own research on the impacts of different sugar substitutes on glucose metabolism in the microbiome, some of which was recently published in the journal called The Cell, and which heightened our excitement about having him come today. Maureen Chomko is a registered dietitian and certified diabetes care and education specialist. She practices at Neighbor Care Health in Seattle, Washington. She has also talked about this topic at various presentations, including last year's ADA scientific sessions. She'll review the latest clinical nutrition science on the use of different sugar substitutes for people with diabetes. And lastly, we have Judith Wiley-Rosette, who's Professor Emerita of the Departments of Epidemiology and Population Health and Medicine of Albert Einstein College of Medicine. She will summarize the two presentations before her, put them in context of current guidelines, and provide attendees with some key take-home points. And so we appreciate all of them joining us today. So I will hand it over to Jotham to start his first presentation. Thank you. Jotham, just a second. Sorry about that. Oh, here it is. So, hi everyone. Thank you for the introduction. Thank you for the invitation to talk about our work on non-nutritive sweeteners and put it in context of other works in the field. As he just said, I'm going to focus on the more basic sciences aspects of the impact of non-nutritive sweeteners both on metabolic health and specifically the mechanisms for which sweeteners can impact human metabolic health including the human microbiome. And I want to start with this statement or this recommendation published about half a year ago by the World Health Organization. So they have done a meta-analysis of cohort trials of cohort studies of neuronymized control trials. And based on that, which was published in last July they have published a following recommendation saying that the WHO suggests that non-nutritive sweeteners should not be used as a means of achieving weight control or reducing risk of non-communicable diseases. And based on this recommendation, we might as well ask why are we still meeting if that recommendation is out there and maybe one of the reasons to still continue researching and thinking about non-nutritive sweeteners is that that recommendation was considered a conditional recommendation. And the WHO have said that they are publishing this recommendation as a conditional recommendation because most of the evidence linking non-nutritive sweeteners to detrimental impacts on metabolic health are associative. Some of them are potentially underlied by reverse causality that I think we're going to hear more about later today. And the certainty of the evidence in the interventional studies in the randomized control drives was low and conflicting and heterogeneous. So I think a major question that many research groups including our own is trying to answer now is whether artificial sweeteners can actually cause metabolic derangements or basically everything we're seeing is just associations that might be confounded by multiple other factors. So for the question of whether non-nutritive sweeteners can cause metabolic derangements, one can turn into preclinical models, into animal models where you can have a very homogeneous population and just feed them artificial sweeteners. So I want to show results from a study we've published several years ago. It was a very simple study. I went to the supermarket. I purchased sachets of non-nutritive sweeteners, either saccharine, sucrose, or aspartame. And these sachets also contain glucose as the bulking agent. So we also had a group of mice that received glucose or a group of mice that received sucrose or a group of mice that was just drinking plain unsweetened water. So we gave the mice all of these sweeteners, caloric and non-caloric, in their drinking water, and we performed a glucose tolerance test. And what we were able to see is that the mice that received either water or caloric sweeteners in their drinking water had the normal glycemic response after 11 weeks of exposure, but all three groups of mice that were drinking non-caloric sweeteners, so saccharine, sucrose, and aspartame, actually developed glucose intolerance. So at least in preclinical models, we can say that non-nutritive sweeteners can in fact cause metabolic derangements. It's not just an association. And of course, many others have demonstrated similar impacts with other sweeteners, other doses, other animal models. So not all, but most of the studies in preclinical models would indeed say that non-nutritive sweeteners can detrimentally impact body weight or glucose tolerance. So this really raises an interesting question. We know that the sweeteners contain no or very few calories. We know that there's no acute post-prandial glycemic response to the sweetener. So the sweetener itself does not elicit any glycemic response. And this really raises the question of how can a sweetener, a non-nutritive sweetener, impact metabolic health? And the other question that we as basic scientists try to answer is whether there's any biological explanation to the heterogeneity that we're seeing in interventional studies in humans, or is it all just technical, just related to the protocol? So many research groups, including our own, is trying to think about the mechanisms through which sweeteners might impact metabolic health. And several of these mechanisms are related to the impact of non-nutritive sweeteners on sweet taste receptors, either found in the oral cavity or in extra-oral sites. And this cartoon here on the right demonstrates where sweet taste receptors can be found in the body. They can be found in many regions of the body, including our gut. So there have been several mechanisms that were proposed, including sweeteners being sensed by these sweet taste receptors, which then promotes higher production of insulin or intratins, GIP and GLP-1. However, this mechanism, although it was studied in humans, the results are conflicting between trials. Another mechanism that was proposed is that people that are habitual consumers of non-nutritive sweeteners then develop cross-adaptation to the sweetness of caloric sweeteners, which then reduces their sensitivity to sweeteners, basically causing them to desire more sweetness and then therefore increasing caloric intake. Again, the evidence for that in humans is mixed between trials. Another mechanism that receives a lot of attention, mostly in preclinical model, is that because the sweeteners provide a sweet taste, but they don't provide calories, this uncoupling of sweetness from energy disrupt the cephalic phase response and therefore causes increases in appetite and increases in energy intake. There have been studies demonstrating that in humans, however, they are very limited. Other impacts can be considered as behavioral or cognitive impacts. And we know that when a product is labeled a certain way, this can affect our perception and our intake of that product. And it has been demonstrated in some human studies, but not all of them, that when a food is labeled as low calorie, this would actually cause us to increase our intake. And there are evidence for that mechanism in humans. Again, they are mixed. And finally, the mechanism that I want to focus on today is a potential interaction between non-nutritive sweeteners and the gut microbiome. So rather than sweeteners directly impacting the human body, sweeteners are impacting the gut microbiome and through the impact on the microbiome, impacting our own metabolic health. And why do we think that the microbiome is such an interesting avenue of research in this specific context? So when we're thinking about the microbiome, of course, we're talking about the naturally occurring microorganisms in our body. And the interesting or the most important thing about the microbiome is that each one of us has a microbiome signature that is unique to that person. And that heterogeneity in microbiome actually can serve a purpose in personalized medicine in either predicting diseases or tailoring therapeutics and diets. And I wanted to quickly show some examples. So this is one study where they used three days of a diet rich in fiber, specifically barley kernel bread to improve glucose tolerance. And they saw that some individuals responded to the diet. Some individuals also had improvements in their glucose tolerance, but others did not respond. They were able to demonstrate that this was due to differences in their microbiome. Several years ago, we have published a study about personalized nutrition where we saw differences in post-cranial aggressive responses to identical foods. We were able to demonstrate that this can be predicted partly based on the microbiome signature of the individual. Based on that algorithm that we developed, we were able to design personalized diets. And this is a study where that group followed up on that algorithm and tried to apply that to individuals with prediabetes. And these individuals received either the standard of care, which in Israel means a Mediterranean diet here in red, or each individual received a diet that was tailored by the algorithm to their own microbiome. And you can see that the personalized diet actually had a superior impact on hyperglycemia and glycosylated hemoglobin A1C compared to the standard of care, which was the Mediterranean diet. Beyond the impact on metabolic health, the microbiome can serve as an important marker for responsiveness or non-responsiveness to anti-cancer immunotherapy, PD-1 checkpoint blockade, and also to therapeutics such as probiotics. We have recently demonstrated that when you give humans a probiotic product, the probiotics would either colonize or not colonize that individual, depending on their microbiome. And if they are not able to colonize, they will not produce an impact on the microbiome. So really the microbiome can mediate a lot of personalized differences, suggesting that maybe the microbiome also underlies some of the heterogeneity we're seeing in human studies related to non-nutritive sweeteners. And we do have evidence that sweeteners can interact with the microbiome, so I showed you before the study where we fed mice saccharine, sucralose, and aspartame, and here we profiled the microbiome of these mice that were drinking saccharine compared to each one of the three control groups. And we can see a bunch of microbes that either go up in their abundance here in red, or go down in their abundance when they're exposed to saccharine. In other trials, when we fed the mice sucralose or aspartame, we could see the microbiome is shifting compared to the microbiome of animals that were drinking just plain water. We can see that the diversity of the microbiome or how many unique species of bacteria in the sample goes down when the mice are exposed to sucralose or aspartame. And again, a list of microbes that their abundance changes as the mice are exposed to sucralose or aspartame. But really an important question in the microbiome field, even beyond non-nutritive sweeteners, is whether this means anything, whether these impacts on the microbiome are actually causing glucose intolerance or any impact on metabolic health. So the current gold standard in the microbiome field to attribute causality to impacts on the microbiome is to take a microbiome community and transplant that into germ-free mice. Germ-free mice are mice that don't have any microbiome, no bacteria, no viruses, no fungi. They live in these steroid isolators like we can see here, and we can conventionalize them with a microbiome of interest to see if they develop any phenotype, any health condition that we're interested in. So we've done this experiment many times. I'm showing here the results where we took the microbiome from mice drinking a combination of saccharine and glucose or mice just drinking glucose or from a different experiment. So we had mice drinking pure sucralose or pure aspartame or just plain water. We transplanted these microbiomes into groups of germ-free mice, and we performed a glucose tolerance test on these recipient mice. And you can see that in both of these examples, we can see that just by transferring the microbiome into germ-free mice that have never seen non-nutritive sweeteners, we can produce glucose intolerance in these recipient mice. So we can say that indeed the impacts of both saccharine, sucralose, and aspartame on the microbiome are sufficient to cause glucose intolerance, at least in mice. And this is an experiment where we were asking whether sweeteners can directly impact the microbiome to produce these effects. So this is an experiment that started in vitro, in a test tube. We just took a complex fecal microbiome community and we added sweeteners to that sample. And then we transplanted that sample into germ-free mice. And we've done this experiment twice with two distinct microbial communities. And we can see that when we transplant a community altered by saccharine or by saccharine and sucralose, mice that receive this community altered by sweeteners gain more weight compared to mice that receive the control microbiome community. They develop fasting hyperglycemia and they develop glucose intolerance all within a matter of a few days. So we can say that sweeteners directly interact with the microbiome and that interaction that leads to changes in the microbial community is sufficient to promote glucose intolerance and weight gain. And after we published those results back in 2014, there was a great interest in whether sweeteners can in fact impact the microbiome, at least in preclinical models. So several students in my research group have performed a literature review that we published last year, where we looked at all of the studies that reported an impact of sweeteners on the microbiome in preclinical models. And we looked at impacts of any sweetener in multiple animal models. And I just highlighted here the column of whether there was or wasn't an impact on the microbiome. And out of all the trials that we found, most of the trials have indeed found some impact of sweeteners on the microbiome and only a minority of the trials, only four out of the 28 that we found said that there was no impact of sweeteners on the microbiome. So at least if you're a mouse or a rat, we can say that sweeteners can impact your microbiome, which might underlie impacts on metabolic health. But really an open question is whether sweeteners can do the same in humans. So to answer that question, we started a randomized control trial in humans, where we asked them to drink for two days commercial sachets of either saccharin, sucralose, aspartame, or stevia. And you can see here the doses that they received, which for all of these sweeteners were below the acceptable daily intake. And it was for each one of these sweeteners, six sachets per day for a period of two weeks. Again, because these are commercial formulations, commercial sachets that contain glucose as a vehicle. We also had a group that was drinking an equivalent amount of glucose and a sixth group that performed the protocol without any supplementation. And we followed these individuals for one week before supplementation, two weeks of supplementation, and then an additional follow-up week after they stopped drinking the sweeteners. And we collected a lot of data and metadata from these individuals, including blood tests and the tropometrics and microbiome from both fecal samples and the oral cavity. And I want to focus on the impacts that we saw on glucose tolerance and on the microbiome. And we profiled glucose tolerance through nine glucose tolerance tests that were performed every week of the trial. So in terms of the impact on the microbiome, these are the results that we saw on the fecal microbiome. Each dot here represents the trajectory of the microbiome in a single individual, either in the control group in gray or in each one of the sweeteners groups, so the different colors. And we can see that each one of the sweeteners had an impact either on the composition of the microbiome, so which species of microbes are found in the sample, or on the function of the microbiome, so which functional pathways were enriched in the samples. Each one of the sweeteners that we studied, sucralose, saccharin, aspartame, and silica, all four sweeteners had an impact on the microbiome in humans. And when we looked at the impact on glucose tolerance, this is the incremental area under the curve of the glucose tolerance test for each individual. And we can see that individuals in the saccharin and the sucralose group already during the first week of supplementation, continuing to the second week of supplementation, had elevated glycemic responses in a standardized glucose tolerance test, but once they stopped drinking the sweetener, we can see that they start trending back towards their glycemic response at baseline. Interestingly, we do not see these impacts in the individuals that were supplemented with aspartame or with stevia, and importantly, we do not see these impacts in either of the control groups. So this really tells us that the impacts that we're seeing here are not because of the presence of glucose in the supplement, or not because they were performing nine glucose tolerance tests during that four-week period, but we can really attribute those impacts to saccharin and sucralose. But it's also interesting to note that although saccharin and sucralose had a significant impact as a group, if we ask what happened to each individual, we actually see considerable heterogeneity between individuals. So if you look, for example, what happened here in the second week of supplementation, each dot here represents the increase in glucose tolerance in that individual compared to their own baseline glucose tolerance test. And we can see that some had a very strong impact, negative impact on their glucose tolerance, others had a neutral impact, and very few of them even had what we would call improvement in their glucose tolerance. So as a group, both switters were significant, but there is important heterogeneity between individuals that we need to consider. So we're then asking whether this can be related to the impact of switters on the microbiome, the extent to which switters impacted their microbiome. So in order to answer that question, we took the microbiome samples from the top four individuals in each group or the three bottom individuals in each group, and I'm focusing here on sucralose, and top and bottom refers to how strong or weak was the impact of sweetener on their glucose tolerance. And we compared the impact of the fecal microbiome taken from the last day of exposure, so day 21, to the impact of the microbiome from before the exposure, so the first day of the study. We can see that in each one of these top four individuals, the microbiome from the last day of the exposure that in the human was associated with a poor glycemic response. This also elicits a poor glycemic response in the recipient germ-free mice compared to the microbiome of the same individual, but from before they were taking the sweetener. But when we look at what happened to the bottom responders, we don't see any such impacts. So this really tells us that the microbiome shifts that we're seeing in the top responders are at least in part causing the impact that we're seeing on glucose tolerance. And we saw the same impacts in all four sweeteners, so not just in sucralose, but also in saccharin, and even in stevia and aspartame. The microbiome of the top four responders resulted in a strong impact on glucose tolerance compared to the microbiome of the same individuals, but before they started taking the sweetener. And again, importantly, we do not see these impacts in the two control groups. So to summarize, we saw that non-nutritive sweeteners can alter the gut microbiome, both in preclinical models, but also in humans. And these alterations in the microbiome can be causally linked to disrupted glycemic control. And in humans, as opposed to mice and rats, the impacts seem to be person-specific, and dependent on the microbiome. So I would just like to end by thanking my research group at the Johns Hopkins Bloomberg School of Public Health, and the research group of Eran Elinaf at the Weizmann Institute, where the randomized control trial was performed, and our collaborators, and thank you for your attention. And Maureen, we'll take you next. Okay, wonderful. Hi, so my name is Maureen, and I am a registered dietitian and certified diabetes care and education specialist at NeighborCare Health in Seattle, Washington. NeighborCare is a federally qualified health center, so we work with underserved, uninsured individuals. Okay, so if you are a clinician working with these individuals with diabetes, prediabetes, individuals with overweight or obesity, you probably have talked about artificial sweeteners, and you probably have heard individuals say, I read that it does this, I heard it causes tumors, I heard it causes dementia, x, y, and z. And this is because about every few days, every week, that there are more articles published on this online. And so, are these articles legitimate? This is what we're going to talk a little bit about, and how to communicate the research that is out there to our patients. And so, clearly, this is an issue among public perspective. This was a study done in the UK in 2021, but the results are very similar to the most recent study in the US, which was 2009. And this is perspectives about artificial sweeteners or non-nutritive sweeteners. And the blue lines represent the added totals of individuals who agree with these negative statements about the safety of artificial sweeteners, and individuals that either don't know or neither disagree or agree, which indicates that they probably don't have enough information to answer the question. And so, what we can see is about 60 to 70% of the UK population, but also the US population in 2009, did agree or were unsure if these artificial sweeteners can cause negative health effects, diabetes, weight gain, cancer. But overall, there is a large amount of concern for the safety. So, this is clearly the perception of many of our patients, of a lot of the public, but what is the reality of the situation? And so, I'm going to discuss a bit about cohort studies, which are following groups over time. And the important thing to talk about first is the differences between the people who drink non-nutritive sweetened beverages. They are very different groups, typically. So, more often, females, higher income individuals, white individuals, drink diet drinks, more likely drink by people who are already overweight or obese, and more likely drink by people with diabetes. And then on the other hand, people who drink these diet drinks less often are essentially the opposite. So, we have to do a lot of controls in these studies, because these groups are very different on a macro level. And additionally, with any nutrition study, it's very important to think about the micro level. Out of, you know, a study with an N of 4,000, that's 4,000 different people that have different backgrounds, and they have different reasons why they choose what they choose. So, why do people choose the foods they eat? Why does individual one choose a diet soda, and also individual two chooses a diet soda? Our cultural background, our personal environment, our social circles, our food environment are all altered, and it is very difficult to control for all these factors. Additionally, a lot of these studies were done when, say, aspartame was the most common non-nutritive sweetener used, and now we're looking more at stevia or monk fruit extract or sucralose. So, over time, the sweeteners that have been used are changing, and yet we are lumping in these groups as non-nutritive sweetener users. And so, there's a lot of difficulties in comparing this data, and yet we will look at what the data does say. So, as far as cohort study data, there's a lot out there. I've selected just a few we're going to talk about. This was a study done in 2014 showing that non-nutritive sweeteners were significantly associated with an increase in BMI. This is a common theme in a lot of cohort studies. We do see that users of non-nutritive sweeteners do tend to gain weight over time. This specific study did not show a significant increase in body weight or fat mass, which is a little unclear how the BMI increased. But moving on, there's a study in 2013 that non-nutritive sweetener intake had positive associations with obesity, metabolic syndrome, type 2 diabetes. Those associations were attenuated and non-significant after they adjusted for, as I mentioned, the higher BMI in individuals who use non-nutritive sweeteners. In 2017, there was a positive association between non-nutritive sweetener use and all sorts of metabolic sequelae. Unfortunately, as well, they said this might be potential reverse causation, as in individuals are drinking non-nutritive sweeteners for a reason. They're either overweight or obese. They're either already at risk for cardiovascular problems. They're at risk for diabetes. In 2015, a study said that one serving of non-nutritive sweetener per day increased risk of diabetes by 25%. This risk was attenuated down to 8% after they adjusted for the differences in adiposity between the two groups, which is important. 8% is not zero. And in 2012, there was a study indicating that with one or more servings of non-nutritive sweetened drinks each day, there was an increase in the relative risk of stroke. But the risk was attenuated by adjustment for the prevalence of diabetes and hypertension in the group that was consuming non-nutritive sweeteners. So this is not to say that there is no association. It is just proving that it is difficult to identify the associations. And as Jotham was saying, why are these things happening? We don't have enough research at this time to understand. Jotham is clearly at the forefront of this, which is fantastic, but we don't necessarily have this straight line between the consumption of diet sodas and metabolic dysfunction. We cannot necessarily explain that pathway with the data that we have now. A theory that a lot of our guidelines promote and, or not promote, but question, is that do non-nutritive sweeteners increase the desire for and the consumption of other energy-dense or sugary foods? And therefore that is causing the weight gain that we see commonly in these studies. Is there something about non-nutritive sweeteners that disrupt our ability to accurately estimate how many more calories we need in that day? Or is it altering, as Jotham was saying, our perception of sweetness? And so instead of this direct line from diet soda to metabolic dysfunction, are we consuming more calories because of diet soda consumption? Is that leading to the increased body weight? And therefore is that leading to the metabolic dysfunction? Again, this is just a theory, is difficult to study. What information do we have so far? When individuals are put into randomized controlled trials, one group is drinking non-nutritive sweetener, one group is drinking soda. There is reduction of calories in the individuals who are drinking non-nutritive sweeteners. And this study was in 2019, and it was a systematic review and analysis of many randomized controlled trials. So they do see that there's less energy intake when individuals switch from a regular soda to a diet soda. But again, this is a randomized controlled trial, and we know, especially clinicians, that the randomized controlled trials are not the real world. And so it could be that once individuals are no longer being observed by a researcher, they're no longer in a trial, then maybe their behavior changes and they do consume extra calories. That's very difficult to study because we'd have to study it. We do see this increase in body weight. Individuals are more likely to gain weight over time, even after adjustment for the baseline BMI, when individuals started drinking non-nutritive sweeteners, even if they were overweight, obese, even if they were thin, both groups are more likely to gain weight. And then there's metabolic dysfunction. We certainly do see many positive associations between metabolic syndrome, increased risk of diabetes, increased risk of obesity, as individuals consume more non-nutritive sweeteners. As I mentioned previously, many studies do become non-significant after adjusting for BMI or accounting for reverse causality. So when these papers come out, it is important to know what did these people control for and are they discussing reverse causality as a potential for causing this metabolic dysfunction? But there's clearly something going on that we don't necessarily understand at this point. And so what are our guiding lights, the ADA and the AHA? The ADA in their consensus statement in 2019 put it really astutely, there's not enough evidence to determine whether the use of sugar substitutes definitively lead to long-term reduction in body weight. From the data that we have, it doesn't seem like it does lead to long-term reduction in body weight. It doesn't seem like it reduces cardiometabolic risk factors, including glycemia. Using sugar substitutes does not make an unhealthy choice healthy, rather it makes your drink choice less unhealthy. As we certainly know that sugar sweetened beverages lead to metabolic dysfunction, lead to hyperglycemia. And so therefore we would choose artificially sweetened drinks previously, but now we're not sure if those are great for our long-term health either. And the AHA says something similar, the use of these beverages, the non-nutritive sweetened beverages may be an effective strategy to help control energy intake and promote weight loss. But there is a dearth of evidence on the potential adverse effects of artificial sweeteners relative to the potential benefits. As in, we're not seeing clear benefits when individuals start drinking non-nutritive sweeteners or when individuals drink them over time. So it's not necessarily clear that we should be recommending them. And so how does all of this data soup that I've just presented help me when I'm sitting in front of a patient and my patient is saying, I've heard artificially sweetened drinks are worse than regular soda. I don't drink those because I'm worried that they're going to harm me. They're going to make my diabetes worse. So what do we tell these individuals? Importantly, the individual in front of us is always the one that's going to make the decision. We're never making the decision for them, but we want to present the evidence that we're aware of, present the evidence that's relevant to them, and then they are able to make the decision for themselves. So what we know, as I mentioned, the habitual consumption of sugar-sweetened beverages certainly is associated with metabolic disruptions, greater incidence of diabetes, no matter what a person's weight is. It's associated with cardiovascular disease, obesity, hypertension, hyperlipidemia, chronic inflammation. On the other end of the spectrum, replacing sugar-sweetened beverages with water, unsweetened coffee, tea is a great healthy choice for people with diabetes, for people at risk of diabetes. It would be great if everyone was drinking water, but there is a group in between of people who are not going to drink water or who really enjoy artificially sweetened drinks or don't want to stop drinking them. And so what do we tell these individuals? I mean, I tell them kind of, we don't know, but it's, it seems that people who do choose these drinks become less healthy over time. And we don't understand why exactly so that these may be associated with some sort of risk, but we can't really explain why at this point. Importantly, at the end of the day, the person asking that question, your patient in front of you is an individual. And we need to think about that individual's risks, that individual's background, that individual's preferences, and given this evidence, make the best decision for their health. And in the dream world, everyone would just drink water. We know it's the healthiest. We know it's great for diabetes. It's great for prevention of diabetes. It's wonderful. But if you are a clinician, you've probably heard lots of reasons that people don't drink water, whether it's not something they're used to, whether they hate the taste, whether they find it boring, they can't see themselves just drinking water for the rest of their lives. There are a lot of reasons that people will cite as to why they don't drink water, don't want to drink water. What is important, myself as a white provider counseling majority people of color, is that my interpretation and associations with tap water are very different with other groups. And so what we see in this NHANES data is with tap water, majority of white individuals drink tap water. And that number drops off when we're looking at Black individuals and Latino individuals in this country. And then this is one of the factors is that these individuals have had either unsafe drinking water or poor access to safe drinking water. And this is true. We've seen it in Flint, the Central Valley of California. So therefore, if you do not trust your drinking water or historically have not been able to access drinking water, then there's an additional economic burden. You need to purchase what you're going to be drinking, what your family's going to be drinking. And it's a choice between bottled water, sugar-sweetened beverages. And you know, a lot of people would prefer to get sugar-sweetened drinks. It's, you know, giving something delicious rather than just boring bottled water. And so this is something that we do have to be knowledgeable of when we are counseling individuals, particularly individuals that are not the same color as myself. And so what's important to recognize is we don't want our personal opinions or preferences to influence our recommendations. The individual sitting across from you has a completely different set of life experiences from you, completely different set of opinions and preferences. And we have to value those and we have to value what they believe to be true. And so if we do want to correct misinformation, if you do know, for example, Seattle's tap water is some of the healthiest water in the country. If I have a patient saying, I don't trust the water, I'm not just going to automatically say our water is safe, you should drink it. We want to ask for permission to correct misinformation. Similarly, if an individual is on TikTok and is watching a lot about artificial sweeteners, and they feel like they know a lot about artificial sweeteners, we want to be very delicate with that. And we want to ask for permission to correct that. If an individual is not willing to listen to us, they will tell us, and then we're saving time in that visit. And so our goal is to get people to drink less sugar sweetened beverages. We know for a fact that is an issue. And like I said, water is wonderful. If an individual wants to drink water, great. But our next step would be artificially sweetened drinks, because at this time, we're not sure if they contribute to metabolic issues, but we are sure that sugar sweetened beverages do. And so we can ask a variety of questions trying to elicit this information. Again, we want them to be open-ended. What other drinks have you tried besides soda? If individuals said, I would never drink a Diet Pop, eliciting why that is true, and discussing some people don't like the taste of water or diet drinks. Some people might be surprised how many people don't drink diet drinks, because as I hear a lot, the taste is nasty. I'm not going to put that in my mouth. So it could be that it's not even a problem with your patients. The patient would rather drink water because they hate the aftertaste of artificially sweetened drinks. And so if we are with a patient and we want to set a goal of changing what they're drinking, if a patient is ready to make a change, just basic, what do you think you could drink instead of pop? Once again, not a prescriptive, but you're rather asking them for ideas and what they think would be feasible for their life. For individuals who don't like the taste of water or diet drinks, can we brainstorm a few ideas of lower sugar drinks that you can try before we meet again? And then there are individuals that will not give up soda, will not give up artificially sweetened drinks. And so it would be useful to do an experiment, check your sugar before and after drinking, and then the patient can decide if it's worth it for them. And Jotham's research has me wondering if they can also do experiments drinking non-nutritive sweeteners for a week, checking their blood sugar regularly, not drinking it, drinking soda. There's a lot of data we can get, especially from continuous glucose monitors. And so to summarize, our best bet when we're trying to reduce sugary beverage intake is going to be water, flavored water, unsweetened tea, unsweetened coffee. We know these are the best for the patient. Number two, a little mixed. These are things that, you know, do we know if coffee with milk, coffee sweetened with one spoonful of sugar is going to cause problems in the longterm? That's very difficult to study. Flavored water, it's not great for your teeth in animal. That's why I put it as a number two. And then patients with a lot of resources, there's tons of low calorie drinks that are more natural, kombucha. One of my patients told me about hop water. I wouldn't drink it personally, but there are a lot of options out there that patients can explore. And then probably number three would be our diet drinks, which probably, you know, 10, 15 years ago, we wouldn't have said this. We would have said diet drinks are fantastic. Just switch over from soda to diet drinks. But now we're seeing that maybe there will be some issues with glucose tolerance. Maybe there's issues with weight gain in the longterm that we don't clearly understand at this point. And so thank you very much. We are going to turn it over to Judy. And as they said in the beginning, we'll have questions at the end. You've both given us a great deal to think about. And I'm going to be focusing on the perspective of your take-home messages and implications for care and research as we move forward. And if I can have the next slide. The takeaway message is basically what Kei-Heng has talked about, one of his studies looking at the mouse model and the human model together, and he's also given us the ability to characterize for epidemiological studies what someone has eaten so we can have a valid measure of their intake of various sweeteners which we had not had, and Maureen had talked about how we made a shift so we could have a wide variety, and he hinted at we have the possibility of looking at machine learning, and with the advent of continuous blood glucose monitoring I can see research like this moving forward fairly rapidly, and Maureen looked at the ADA statements and the Heart Association statements, and basically another quote from the Evers statement was replacing sugar-sweetened beverages with water as often as possible and to avoid compensation with food from other sources of calories, and raises the questions that Maureen talked about in terms of looking at hunger appetite, and she clearly drove home the message that it's the person's decision, and if I could have the next slide please. The ADA and AHA statement from 2019, basically some of the key decision in terms of promoting water in that, because that was the first time water had been promoted as the beverage of choice as a policy statement, and that coincided with what WHO, they didn't focus so much on water as a beverage, but the avoidance of non-nutritive sweeteners, and basically that association with unhealthy lifestyle and a cardiometabolic risk, and it actually turns out it's a very low proportion of the large cohort studies, and the intake of non-nutritive sweeteners has been looked at in very large cohort studies of over 100,000 per study, and the first one to do that is the Framingham study, which showed a two and a half to three-fold higher increase in stroke and cognitive impairment in people who consumed high over a 20-year time period, but that still was a very small number of people, but it raises questions, so the relative risk was higher, but the absolute risk was still relatively low, and basically in adjusting for confounders, one of the issues comes up, if you adjust for calories, do you adjust for BMI, do you adjust for waist to height ratio, waist to hip ratio, there are, when do we have we overcompensated in terms of adjusting. If I can have the next slide, please. The guidelines that came out last month basically have taken a perspective that use of non-nutritive sweeteners can, again, it can be used as long as there's no evidence that they can be a viable alternative to water, and they should be counseled in terms of calories, so that we've had very few studies that have done a head-to-head comparison to water, and if I could have the next slide. There have been three meta-analyses, and I'm using this one as an example. They looked at three, they looked at 17 randomized trials, but they looked at three intervention modes. They looked at comparison of non-nutritive sweetener beverages to water and sugar to each as a comparison, and basically, they used the LNCB for low-calorie sweetened beverages, and basically, their findings showed that there was a higher proportion of body fat and intercellular lipids with the use of the non-nutritive sweetener, so this raises the questions that Maureen talked about from a clinician's perspective, and the strength, so these are some of the problems with trying to look at these studies, and one of the strengths is we're now coming up with new statistical methods for doing what is considered network meta-analysis, and network meta-analysis allows comparisons, not paired non-nutritive sweeteners versus sugared beverages, but making those three-way comparisons, and the limitations are that there was a lot of inconsistency in terms of the findings, and very few of the studies were judged as high quality. The next slide will show us, basically, if you look at the far right column, only two of the studies were considered to be of high quality out of 17, and if you look at the next to the far right, in terms of comparing the non-nutritive sweetened beverage to water, you can see it goes back and forth in terms of body weight, look like the diet soda was better, BMI, but if you notice that the lines, basically, are insignificant because they all cost zero, with very few exceptions, so salt and blood pressure being one example of favorite non-nutritive sweeteners, which there's no biological explanation for that, but this method will be moving things forward, I think, in the future, in terms of looking at these studies, and if I could have the next slide, please. In terms of care and research, I think we're all asking questions in terms of bringing the decision, as Maureen pointed out, to the patient, and looking at tailoring that advice, and in terms of research, the omics research that we looked at earlier, and making availability of large data sets, like the Women's Health Initiative, and studies like the MESA study, and so forth, offer a lot of possibility, and again, the machine learning and statistical methods will advance this over the future, and our next slide brings us to some of the questions and answers that you may have in your discussion. All right, great. Thanks for summarizing the body of evidence, Judith. We'll move on to the Q&A. We've received a few questions here. The first one I have from Rita Miller. This might be more for you, Jotham, but I'll open it up to everyone. What about natural non-nutritive sweeteners, such as stevia or monk fruit? So, I know you addressed stevia, but their question is related to monk fruit. Yeah, that's a really interesting question. So, if we just go by our study, the impact of sucrose and saccharin on glucose tolerance was significantly poorer than the impact of stevia or aspartame. We do know, and that predates our work on sweeteners in the microbiome by several recent years, that stevia is known to alter the microbiome, but what are the functional consequences of that on metabolic health? That's still an open question. At least in our study, we saw that only in a subset of the participants and not in all of them. I don't think that it matters much whether the sweetener is artificial or natural in terms of its potential ability to impact the microbiome. However, we do currently see more evidence that showed that some of the artificial ones can have poor impacts on our microbiome and health compared to stevia. As for monk fruit, I think the research is just at its beginning. All right. Thank you for that. Another question here that's come in from Natalie Brenneman. What do you recommend for people with diabetes who undergo bariatric surgery? Most of the protein supplements contain non-nutritive sweeteners. Any thoughts from the panelists or the speakers? I would say since I do patient care, I am in a primary care clinic, so I do not specialize in patient's bariatric surgery. It also depends on, does the patient with bariatric surgery also have diabetes? Is a regular sweetener going to increase their blood sugar? Or is it going to cause dumping syndrome? Or are any of these problems going to cause any gastrointestinal effects? Because certainly after bariatric surgery, lots of foods can cause gastrointestinal distress. My guess is, unfortunately, it would be based on the individual and trying to determine how they're feeling with each and reducing their risk in whichever way. If the patient is gaining weight afterwards, then maybe we don't want to use regular sweeteners. If the patient does have some GI side effects from any of these sweeteners, then they're going to have to find what works best for them. Pretty disappointing answer. Sorry. Just got to work with the patient. Great. Thanks for that answer. Any other comments from the presenters? One, do people basically try out and again, as Maureen pointed out, testing themselves? Yeah. Okay. The next question from Molly Osgood. What opinions do you have about water flavor enhancers like Sercule? I don't know if I pronounced that right. It must be a type of flavor enhancer. It's spelled C-I-R-K-U-L. I'm not familiar with it. But any insights on water flavor enhancers? No. I'm also not aware of that specific one. If it has any artificial or natural ingredients, my guess is similar to the answer Jonathan gave about Monk Fruit is we probably don't have the data on new ingredients and new formulations. But as anything, checking the list of ingredients and seeing what it has in it. I would say we can only speculate because I'm not familiar with any research about this specific product. But some of the mechanisms that are currently being researched, we're not doing a lot of work about that because we are focused on the microbiome, but are related to the uncoupling of sweetness from energy. And if it provides any sweetness, but without the energy, then potentially it can impact caloric intake, appetite, our glucose tolerance through any of the same mechanisms that are currently being studied. And I see that we have the ingredients. Oh. Okay, great. And the next question we have is from Zink Liu. Is there any evidence of gender differences in terms of metabolic responses to non-nutritive sweeteners? So any gender differences? In our study, there were no differences between males and females. And maybe Maureen or Julian can comment further on the other trials that are out there. But as far as I know, in RCTs, there was no detectable differences between males and females. But correct me if I'm wrong. I think where we see the difference is in the frequency of consumption. And so in your observational studies, there will be differences just because the proportion of the sample. But I'm not aware of any analysis that suggests that there's a biological difference in response. Okay. And then a question that just came in. Do you have any different recommendations for patients with CKD or chronic kidney disease? Maybe not. Yeah, that really makes me think. I don't think so. I certainly haven't done the literature review to answer the question if there have been studies specifically done in that population. So I would have to go back and do a literature review. But it wasn't a frequently occurring concern in any of the meta-analysis, systematic reviews that were done. It was not mentioned as a concern. I agree with Maureen. I have not seen any literature on that. And even in the very large cohorts studies that have been followed for 20 years or more, I don't remember seeing anything about renal function. But hypertension, on the other hand, is one of the predictors of doing more poorly so that they ultimately may end up with kidney disease because they have a lot of the cardiometabolic risk. All right. Great discussion. Now, a question to Dr. Suez. You showed the effects of the sweeteners on blood glucose. Did you look at levels of insulin or C-peptide? Yeah. So in the recent human study, we have looked at insulin as well as GLP-1. However, this was not done in fasting. So this was random fed insulin, random fed GLP-1 because this was during visits to the clinic and we couldn't control their fasting time. So this was just non-fasting. We interestingly saw some signature or some signal of actually blunting of insulin, both in people that took saccharin or sucralose. We also found that in people that took sucralose, which we were a bit confused about. But again, this was not fasting, so I cannot say much more about that. When we've done the mouse studies, we have not seen any significant impact either on fasting insulin or when we performed insulin tolerance tests, we have not seen an impact on that. All right. And then next, we have a question from Larry Brown. Are there any controlled planned studies comparing water consumption only versus cohorts drinking artificial sweetened drinks? Any that you're aware of? I looked in clinicaltrials.gov and my search didn't yield very much. There were some on water, but it wasn't the head-to-head comparison that I was anticipating. So I do know that there are some studies that are underway. I have not seen if they are already registered on clinical trials, so maybe they haven't even started. But there are studies that are planning to compare just water to artificially sweetened beverages, including looking at the microbiome in several countries. So hopefully we'll have more data soon. All right. We have quite a few more coming in, so I'm just trying to keep up here. Okay. So one comment or question. So as a conclusion, could we say that even stevia is not better than other artificial sweeteners? Maureen? It's a great question. I think Jotham's research and other research will prove that stevia has become more popular recently, as everyone knows. So there isn't this huge amount of data that we have like the other sweeteners. Unfortunately, I think it would be an individual, as Jotham's research showed, that there are individual responses to this. Stevia might be a good candidate for, or people might be good candidates for stevia if they hate the taste of artificial sweeteners and they need to change from regular sweeteners to artificial sweeteners or nothing based on their blood sugars or their risk for disease. So, you know, look at the individual and decide what would be best for them. But it is intriguing that stevia does alter the microbiome, and we don't know really what to say at this point. All right. Well, thank you all. We're a minute over, so we'll go ahead and end for now. Thank you to all the presenters. And that concludes our session. Thank you. Thank you. Thank you all.

sugar substitutes

diabetes

metabolic health

non-nutritive sweeteners

glucose metabolism

microbiome

clinical nutrition science

artificial sweeteners

personalized care

research