Review of the Cardiometabolic Effects of Low-Carbohydrate and Very-Low-Carbohydrate (Including Ketogenic) Diets

 

Hi, my name is Carol Kirkpatrick. I am the Wellness Center Director and a Clinical Associate Professor in the Kasiska Division of Health Sciences at Idaho State University, and I am talking to you today about the review of the cardiometabolic effects of low-carbohydrate and very-low-carbohydrate, including ketogenic diet, which is a National Lipid Association Scientific Statement. The full title of this statement is a review of current evidence and clinical recommendations on the effects of low-carbohydrate and very-low-carbohydrate, including ketogenic diet for the management of body weight and other cardiometabolic risk factors, and it was a scientific statement that we created as part of a nutrition and lifestyle task force. This scientific statement was published in September 2019 and our purpose for creating the scientific statement was that we realized that there was there were many health care professionals who were either talking to their patients about following specifically very-low-carbohydrate ketogenic diets or having their patients come in and ask questions or we did find that some clinicians were actually encouraging their patients to follow the ketogenic diet for the management of diabetes or for weight loss. And we felt as an association of the National Lipid Association, we really felt that there was a need to provide guidance to clinicians on really what the evidence is, what available evidence is available for clinicians on guiding you in having a conversation with your patients about whether really they need to be following a especially very-low-carbohydrate diet, but even a carbohydrate restricted diet. And if so, some of the benefits and possible risks that might occur. So that’s what I’ll share with you today as we go through our presentation. And hopefully that will provide some guidance to you as you talk with your patients about these types of dietary patterns. I have no disclosures, and my objective to the presentation today is listed on the slide. They’re quite extensive, so I won’t read through them all. But, you know, essentially our my goal for the presentation is that you will be aware of the evidence that we were able to identify by reviewing the scientific literature. We focused our review on systematic reviews and the analysis of randomized controlled trials, and then we developed key recommendation that hopefully by the end of this presentation, we’ll be able to identify and then utilize those key recommendations in your own clinical practice when you’re having a conversation with your patients who might be interested in low-carbohydrate and very-low-carbohydrate dietary patterns. So the concept of this current scientific statement is listed on this slide, but I am actually not going to talk about a couple of things that are available to you in the published articles. So the scientific statement is quite extensive, and as I speak with you today, I am going to cover these points on this slide, but I will not cover the evidence for the effect of low-carbohydrate and very-low-carbohydrate diet on emerging risk factors such as C-reactive protein, the gut microbiome and TMAO, as well as the gaps in knowledge. We do have some areas that we need more research on, but I will not be able to discuss those basically because of my allotted time with you today. So I encourage you to download the full text article. It is available on the Journal of Clinical Methodology’s website open access, and hopefully you’ll be able to download that and review that in full detail. So I do want to point out that when we were creating our key recommendations for the scientific statement, we used the ACC/AHA 2015 recommendation system methodology for reading the classic recommendations and the level of evidence. Diving in, I want to talk about the carbohydrate-restricted dietary patterns, including ketogenic diets, and discuss them in terms of the descriptions and definitions. So during the review of the literature, the task force identified that there is quite the variance in the definition or description of low and very-low-carbohydrate diets. So one of the things that we did with our scientific statement was we defined moving through our scientific statement what we felt were moderate, low and very-low-carbohydrate dietary patterns. But as you can see on the slide, a moderate dietary, moderate carbohydrate dietary pattern is 26 to 44% of total daily calories coming from carbohydrate, which ends up that you’re looking at a reference caloric intake of about 2000 calories a day, 130 to 220 grams of carbohydrates. So a low-carbohydrate diet then would be 10 to 25% of calories, total daily calories or 50 to 125 grams of carbohydrates in a day. And then very-low-carbohydrate or a ketogenic diet would be less than 10% of calories coming from carbohydrates, typically less than 20 to 50 grams of carbohydrates a day, so very-low-carbohydrate restriction. In some very-low-carbohydrate or ketogenic diets, the emphasis is also placed on glycemic index, so there is sometimes an encouragement for the carbohydrates that are chosen in a very-low-carbohydrate ketogenic diet to be less than 50 for the glycemic index. That is not always listed, though, or encouraged. The other aspect of looking at very-low-carbohydrate ketogenic dietary patterns is the content of fat and protein. The contemporary ketogenic diets that are being used for weight loss and diabetes management are not as high as the classic ketogenic diet that’s been used for epilepsy treatments. The classic ketogenic diets tend to be about 90% of total daily calories coming from fat, whereas the ketogenic dietary patterns that we see for weight loss or type 2 diabetes management tend to be more like 70 to 80% of total daily energy coming from fat. Still a very high amount, and unfortunately, many times it’s not discussed with a person following the diet to limit their intake of saturated fats. So a person who’s following a ketogenic diet may be consuming a high amount of saturated fat, as well as dietary cholesterol, because they are not encouraged to limit saturated fat intake and consume the higher amounts of fat from unsaturated fatty acids. The other aspect of the contemporary ketogenic dietary patterns is the amount of protein. These types of diets have an adequate amount of protein, but they aren’t high in protein. Typically, they’ll have a range of at least making sure a patient is consuming an adequate amount 3.8 to 1.0 grams of protein per kilogram body weight typically no more than 1.5 grams of protein per kilogram per day. The main reason for that is because protein, if it’s consumed in too high amounts in a person who’s trying to achieve ketosis, too high amounts of protein will actually kick them out of ketosis or not allow a patient to achieve ketosis. Because as many of us are aware, some of the amino acids are used for gluconeogenesis and they can actually stimulate insulin secretion and that can then reduce hepatic ketone production and prevent that person from achieving ketosis. So ketogenic, very-low-carbohydrate ketogenic dietary pattern is severely restricted in carbohydrate. It’s also limited in protein. So adequate protein, but not too much to prevent, so they can achieve ketosis or not be kicked out of ketosis, and then a very high amount of fat. The other thing people need to be aware of is that if they truly want to know that they’re in ketosis, then they need to be measuring ketones either in their blood or their urine. It’s easiest for people to check their level of ketones in their urine, but there is some evidence that that can actually be less accurate over time as the body adapts to ketosis, so using blood ketones to measure their level of ketones appears to be more accurate over time. Either way, there needs to be the presence of measurable ketones in the blood and urine to ensure that a person actually has achieved ketosis when they’re trying to follow a very-low-carbohydrate ketogenic diet. So moving on, in terms of the impact of nutritional ketosis on energy and cholesterol metabolism, the nutrition and lifestyle task force wanted to provide a little bit of an explanation, but not go into much detail because it can be quite complex in terms of understanding physiology. But we did want to provide a background on just how nutritional ketosis can impact energy and cholesterol metabolisms. So moving on and looking at the impact of nutritional ketosis on cholesterol metabolism, our review of the evidence found that low and very-low-carbohydrate ketogenic diet had a variable effect on low and very-low-density lipoprotein cholesterol levels or LDL-C. So some people had an increase in LDL-cholesterol levels and some people had a decrease in LDL-cholesterol levels, so we’ll talk about the mean way to difference when we discuss the data, but it is clear and we actually have patient cases that we’ve discussed as a group where some people actually did have low levels of LDL-C, whereas others had high. So clearly this whole mechanism is mediated by complex mechanisms and actually dietary intake without discussing the minutes, but we do know it is something that we need to pay attention to and really was one of the main reasons why we developed a scientific statement. So looking at nutritional ketosis and what might be happening with the LDL-cholesterol levels, again, when we consume adequate amount of carbohydrate, our insulin levels increase, and when insulin increases, that actually activates HMG-CoA reductase which is involved in the production of the L cholesterol and it promotes an increase in hepatic cholesterol synthesis and fatty acid storage are like the genesis. So then conversely, when we have a lower intake of carbohydrate, then our insulin levels decrease and that then inhibits HMG-CoA reductase and then activates HMG-CoA lyase which is involved in ketone production. And so therefore that’s going to promote a decrease in cholesterol synthesis and an increase in ketone production. So this theory, if we look at those basic metabolic pathways and if it works the way the theory goes, then that carbohydrate restriction that decreases insulin would then downstream decrease cholesterol synthesis. However, it’s not that simple. Again, there’s a lot of different mechanisms occurring that I won’t discuss as part of this presentation today. And we do know that some people have a genetic predisposition to LDL-cholesterol levels being influenced as well as an intake of saturated fatty acid intake and dietary cholesterol intake. So clearly saturated fatty acid intake will impact cholesterol levels in the blood. And so if a person is following a very-low-carbohydrate diet and keeping his or her saturated fat intake low, then hepatic cholesterol production may remain lower. Dietary cholesterol can influence LDL-cholesterol, but not to as high as an extent of saturated fat, But it can also play a role. So all of this really emphasizes the need for LDL-cholesterol levels to be evaluated in patients who choose to follow a especially a very-low-carbohydrate ketogenic diet. So then moving on in our discussion, the next few slides, several slides, I’m going to be discussing the evidence that we reviewed for the cardiometabolic effects of following low-carbohydrate and very-low-carbohydrate dietary patterns. So we’ll start with weight loss. And what this slide shows you is the data that we obtained from the various meta-analyses. The first table shows the meta-analyses of randomized controlled trials of adults with overweight or obesity and the impact of the carbohydrate restricted dietary patterns. As we move forward, I want to emphasize that the majority of the randomized controlled trials strive to include ketogenic diet, but many times if not, I think there was one study where study participants were able to adhere to a ketogenic diet until the study ends. So out of all of the randomized controlled trials, most of the studies were not able to ... study participants were not able to follow a very-low-carbohydrate ketogenic diet ‘til the study ends, and so I just want to have you keep that in mind as we talk through the data for the cardiometabolic aspects of low-carbohydrate and very-low-carbohydrate diet. If we do look at weight loss, then we do see that four of the meta-analyses that looked at adults with overweight or obesity, we find a significant difference between low-carbohydrate, high fat diets compared to high carb, low fat diets. So say participants in these four studies, that are bolded here, those are the significant difference ... data did find that low-carbohydrate, high fat diets did better in terms of weight loss compared to high fat, high carb, low fat diets. Now, both types of dietary patterns did achieve clinically meaningful weight loss. I think that’s important to keep in mind as well and these four meta-analyses that found that low carb diets fared a little bit better, were short term and essentially the RCTs and the meta-analyses here were less than one year in terms of study duration, and most of the RCTs were closer to 3 to 6 months. So it looked like short term, people did better with the low carb, high fat diet. If we look at people who have overweight or obesity and then also pre-diabetes or type 2 diabetes, there was actually no significant difference between a low carb, high fat and high carb, low fat dietary pattern in these meta-analyses. And so if you look at the data, we actually see that half of the meta-analyses found that even though there were no significant differences between the dietary patterns, some people actually gained a little bit of weight, whereas the other half lost a little bit of weight. So no significant difference in terms of weight in the difference, but it does send the message that sometimes people do better on a low carb, high fat diet and sometimes they do better on a high carb, low fat diet, even with pre-diabetes or type 2 diabetes. So I think it’s an important concept that we think about, you know, what’s going to work best for the patients that we’re working with and we’ll talk about that more in the presentation today. I do want to spend a moment to really kind of discuss the importance of looking at patients and how we can help them best achieve their goals if they’re needing to lose weight. For example, like our case study, John, he is a 54 year old nonsmoker. He was diagnosed with pre-diabetes, stage 1 hypertension, and his BMI was 31. And it was typical for the metabolic syndrome patient where it was mostly in his abdomen. He had a CACS score of zero, and in the conversation he had with his physician, who is Dr. Dan Soffer, a colleague of mine, he refused basically to take metformin. He did not want to start pharmacotherapy for his pre-diabetes and because of that, was fairly motivated to make some lifestyle changes that would help impact his lipids. And you can also notice his glucose levels clearly were elevated, his A1c was actually at a diabetes level in terms of diagnosis and his AST was elevated, so he most likely also had nonalcoholic fatty liver disease. So clearly in need of some changes to improve his lipids as well as his glucose and his liver function. So because he was so motivated, luckily John made some pretty significant lifestyle changes. He did not follow a ketogenic diet, so he did not restrict his carbohydrate intake to a level that caused ketosis, but he did make some changes that were pretty reasonable and pretty simple to do, that allowed him to reduce his carbohydrate intake and he also decreased his caloric intake overall as well. But simple changes like limiting his pasta intake, swapped out sandwiches for low-carbohydrate soups. I think probably most significantly, he cut out his sugar sweetened beverages and his alcohol, which clearly would have an impact on his glycemic control, triglycerides, as well as his liver function tests. He also started walking and if you’ll notice, quite a bit of walking. He was able to walk to work, so that’s how he was able to fit in 20,000 steps in a day, which clearly not everybody can do. But he could, so he did that and those changes achieved a 25 lb. weight loss for John. And so because of those changes, his labs improved dramatically and essentially he was able to reverse his diabetes and is basically back to normal and all of his liver function tests went back to normal and lipids are clearly acceptable. So the point I wanted to make with John is that he really made changes that were reasonable, that were things he could do long term. It wasn’t such a severe carbohydrate restriction that he cannot continue to follow this type of dietary pattern. And clearly the physical activity is helpful as well. And this is the type of conversation we should have with patients in terms of the person encouraging them to achieve their weight loss in ways that they can continue to do long term and not be short term difficulty with adherence that typically we see with ketogenic diets because of that severe carbohydrate restriction. So that brings us to the key point for evidence for the effect on weight loss. The key points that we identified in our scientific statement was that there is evidence that short term, selective six months, people following a low carb, high fat diet, especially if it’s hypocaloric compared to a hypocaloric high-CHO,. low-fat diet does tend to do better that maybe we have patients who want to do a short term stint of a very-low-carbohydrate diet to maybe kickstart their weight loss. Not that we necessarily encourage that, but it can be appropriate in that situation. Longer term, clearly the weight loss is basically equal between the low carb and very-low-carbohydrate and high carb, low fat dietary patterns. So that’s where our example of John helping a patient really identify what’s going to work best for them and fit within their lifestyle and encourage them to choose something that they can adhere to long term. Carbohydrate restriction is difficult. That was definitely consistent throughout the meta-analyses that we reviewed. People have a very hard time adhering to such a severe restriction of the 20 to 50 grams of carbohydrates a day. And so that really does again, bring us back to that personal preference and what some people can really do fine and adhere to that severe carbohydrate restriction, but many people cannot. So having the conversation and hopefully prior to them initiating their weight loss efforts so that you can identify which is going to work best for them and hopefully encourage their success. So the key recommendations based on that evidence that we’ve discussed is that there really is not our first recommendations, key recommendations, but there’s not a specific distribution of carbohydrate, protein and fat that has been shown to be superior for weight loss. So because of that, it’s reasonable to achieve a calorie reduction by limiting the intake of multiple energy sources, so not having people just focus on limiting carbohydrate, but working with them on a macronutrient distribution of the carbohydrate protein and fat is going to work best for them and to limit their calories and achieve successful weight loss. The next key recommendation is that low-carbohydrate or very-low-carbohydrate ketogenic diet is reasonable for a limited amount of time, again, 2-6 months to induce that weight loss, maybe as a kick start, but over time, we know that it’s difficult to maintain, so our key recommendation is that a more moderate carbohydrate intake is reasonable for that longer term, which is greater than six months weight loss and maintenance. So moving on with the scientific statement content, I want to review the evidence for the effects of body composition, and I think many of us know that ketosis is associated with body water loss. When people decrease their carbohydrate intake, the body initially uses glycogen stores to provide glucose for fuel, and so when that glycogen is used, water is released. And then the initial weight loss that occurs, especially very-low-carbohydrate ketogenic diet, is primarily due to the loss of body water. So based on evidence that we reviewed for our scientific statement, we did see that carbohydrate restricted diets tend to result in greater loss in mean body mass versus a macronutrient balanced hypocaloric diet. So something with more adequate carbohydrates, moderate protein, moderate fats. We also saw that in the literature, a higher protein content is in the low-carbohydrate diets may result in less lean body mass loss during the weight loss. So those dietary patterns that were lowering carbohydrate but more moderate and protein tended to help people maintain their lean body mass as they were trying to lose weight. So because of that evidence that we reviewed, our key recommendation for body weight and composition is that with a carbohydrate restricted diet, it is reasonable to recommend a higher protein intake that’s 1.0 to 1.5 grams per kilogram per day to preserve lean body mass during a person’s weight loss effort. Moving on in our evidence review, I’m going to review the cardiometabolic risk factors, which is essentially looking at lipid levels, glycemic management and blood pressure. So looking at LDL-cholesterol first, the meta-analyses of adults with overweight or obesity who are following either low carb, high fat diet or a high carb, low fat diet. Basically the evidence showed that those following the low carb, high fat diet had a significantly greater LDL-cholesterol compared to those following the high carb, low fat diet. Again, if you notice, these are the same format analyses that found a significant difference with weight loss. So these were short term studies, typically for short less than one year, and then many of the randomized controlled trials in the meta-analyses were 3 to 6 months, so a shorter amount of time. That may have been that they were able to adhere to the low carb, high fat diet initially, and so that’s where their LDL-cholesterol levels were higher because they may have been - the participants - may have been consuming higher amounts of saturated fat. When we look at the evidence for people who have overweight or obesity and pre-diabetes and type 2 diabetes, interestingly, there was not a significant difference between the two diet groups in any of the meta-analyses. We were able to review the meta-analyses and some of the researchers who conducted the meta-analyses did identify that saturated fat intake did not increase from baseline in some of the randomized controlled trials or did not significantly differ between the diet groups in the randomized controlled trials or the carbohydrate was replaced with unsaturated fatty acids in the low carb, high fat diet. So that may be why there was not a significant difference for LDL-cholesterol levels between the diet group in these studies. Definitely interesting results with HDL cholesterol, this was pretty consistent in that people who were following low carb, high fat diets in the randomized controlled trials included in the meta-analyses tended to have frequently higher HDL cholesterol levels. As you can see with the slide with overweight or obesity, people with overweight or obesity similar with these people who had overweight and obesity or pre-diabetes and that and pre-diabetes and type 2 diabetes. So it may be that with the weight loss that occurred that helped to increase HDL, it may be that the level of triglycerides decrease also helps with HDL cholesterol, which I’ll talk about in just a few minutes. I do want to point out that the increase in HDL cholesterol tended to be short term as well. So in the randomized controlled trials or meta-analyses that went past the year by 1 to 2 years, there was no difference between HDL cholesterol in the study group. So the data on these slides are for one year and again, as the studies were not longer term, the significant difference between HDL cholesterol was no longer there, except for in one meta-analyses, and that was by Gjuladin-Hellon et al. So looking at triglycerides similar to HDL cholesterol, this is a consistent finding in that the study participants following the low carb, high fat diets tended to have significantly decreased triglycerides level compared to study participants following the high carb, low fat diet. And this was also the finding for people with overweight and obesity, as well as pre-diabetes or type 2 diabetes. So this may be associated with the weight loss that they achieved, but it’s not a surprise that when a person consumes less carbohydrate, they will have improved triglyceride levels is actually part of the medical nutrition therapy that we provide to patients who have elevated triglycerides to reduce their carbohydrate content in their diet. So it makes sense that if a person was following a lower carbohydrate dietary pattern, their triglyceride levels are going to improve. The other thing to consider, in terms of HDL, that we just saw in HDL cholesterol tends to follow triglycerides. So if triglyceride levels improve, we generally see HDL cholesterol levels rise. Many of us have seen patients with metabolic syndrome who come in and their triglyceride levels are very high, HDL levels are low. And as the triglyceride levels improve, the HDL cholesterol also improves. So that may be another reason why we see an increase in HDL cholesterol levels in patients who follow low carb, high fat diets. I do again want to point out, though, that that carbohydrate restriction wouldn’t be to a level to induce ketosis to achieve the benefits or triglycerides and HDL, and many of the study participants in these meta-analyses were actually not in ketosis or consuming carbohydrate that was at a ketogenic level. So I do want to take a minute to discuss another case that helps us understand the importance of the awareness that we have, how these two types of diets can impact a patient’s lipids. So Joan is a 48 year old smoker without clinical ASCVD or hypertension or diabetes management. Again, she’s a patient who was discussed with me by my colleague Dan Soffer. She was overweight and she did complain of menopausal symptoms. She was not taking any prescription medications, was taking dietary supplement fish oil, and primrose oil, most likely the primrose oil to help with menopausal symptoms. And she in the past has tried a variety of diets for weight management, and as you can see by her logs available on the slide, she has a variable lipid profile, nothing really concerning except for maybe her HDL in the past. So she started the ketogenic diet simply to help with treating her menopausal symptoms, which there is no evidence to support the use of that. But you’ll notice that when she did start the ketogenic diet and was not limiting her saturated fat intake, her levels of LDL-cholesterol increased significantly to the point where if you hadn’t had her previous lipids, this is a patient who I would think has familial hypercholesterolemia. So clearly Joan had a significant response to her saturated fat intake in the ketogenic diet that resulted in excessively elevated LDL-cholesterol. So this is a really great example of having a conversation with your patients, doing a baseline lipid test before they start following the ketogenic diet, educating them about consuming unsaturated fats instead of saturated fat, and then doing that follow up lipid profile to see how the ketogenic diet may be impacting, for sure, their lipid levels. So our key points for the evidence on the effects on blood lipids and lipoproteins, the meta-analyses really did show a variable effect of LDL-cholesterol response. It also showed a variable effect on total cholesterol, although I did not review that data for you today. Clearly a saturated fat content of the dietary pattern can play a role, as I just discussed with Joan. So paying attention to that and educating patients on limiting saturated fat, consuming unsaturated fat instead, genetic factors clearly play a role. I would guess that Joan has some genetic factors that influence her significant response to the higher intake of saturated fat when she was following a ketogenic diet. So that again really emphasizes the importance of baseline follow up lipid lipoprotein assessments as well in patients who are choosing to follow the very-low-carbohydrate ketogenic diet. So other key points for blood lipids and lipoproteins compared to high carb, low fat diets, low-carbohydrate diets do generally decrease triglyceride levels and generally have an increase in HCL cholesterol levels. Again, for sure, short term tends to wane over time and again emphasizing that these benefits that decrease triglyceride and increase HDL were achieved at low and moderate carbohydrate intakes versus very-low-carbohydrate intake. And so that may help patients be more adherent and able to follow carbohydrate restricted diets long-term. So moving on with our review of data, looking at HbA1c in meta-analyses of randomized controlled trials of adults with overweight or obesity, there was only one meta-analyses that looked at A1c and there was no significant difference in the meta-analyses that looked at people with pre-diabetes and type 2 diabetes. There were only two meta-analyses out of all of them that we reviewed that saw a significant difference in A1c long term. So if you looked at short term, less than six months, many of the meta-analyses did see a benefit between low carb, high fat and high carb, low fat dietary patterns. But by one year, essentially just these two meta-analyses showed that significant difference. And I do want to point out that the Meng et al. meta-analyses actually did not separate their analysis for studies that were shorter term. So their meta-analyses that did find a significant difference in A1c that favored the low carb, high fat group included four randomized controlled trials that were less than six months. So that may have influenced their results. So the key point, looking at glycemic control and the effect of glucose, HbA1C, and insulin levels on which these dietary patterns, we found that compared to high carb, low fat dietary patterns, low carb dietary patterns did not reduce fasting glucose or insulin levels more in either overweight in patients with overweight or obesity or with those who have pre-diabetes or diabetes. There appears to be a greater shorter term, less than six months decrease in A1c in people with type 2 diabetes. But again, only one meta-analyses showed that significant difference past 12 months, but was consistent in the meta-analyses that is, that there was a reduced use of diabetes medication in patients who were following a carbohydrate restricted dietary pattern. So that’s definitely a win. We want patients to be able to use less diabetes medication in terms of just the health effects as well as the cost of that. So that was definitely a positive for the carbohydrate restricted dietary patterns. However, again, the carbohydrate restricted dietary patterns in the meta-analyses were generally not ketogenic. In some of the randomized controlled trials included in the meta-analyses, it was supposed to be a ketogenic diet, but by study end, they typically were not ketogenic. People could not adhere to the severe restriction of the ketogenic diet. A couple of the meta-analyses provided the average intake of carbohydrate by study end, and it was generally around 100 grams of carbohydrate a day. So still a reduced carbohydrate dietary pattern, but not ketogenic and probably one that people would be more likely to adhere to. And finally, in two recent meta-analyses the results show that the Mediterranean dietary pattern produced improvements in triglyceride levels, HDL, cholesterol and hemoglobin A1c levels in individuals with type 2 diabetes compared low-carbohydrate diet. So the Mediterranean dietary pattern did better in terms of these cardiometabolic risk factors compared to that low-carbohydrate diet. So that suggests that patients aren’t limited to just carbohydrate restricted dietary patterns in their efforts to improve their glycemic management. And that can be part of that conversation that you have with your patients. So in terms of blood pressure, basically the data on blood pressure showed inconsistency, essentially. So in adults with overweight or obesity, there was no statistically significant difference with systolic blood pressure between the low carb, high fat versus high carb, low fat diet groups and in patients who had diabetes or pre-diabetes, only two of the meta-analyses found a significant difference. Similarly, for diastolic blood pressure, only two of the four meta-analyses of adults with overweight or obesity found a significant difference for diastolic blood pressure in favor of the low carb, high fat diet dietary pattern and in patients with pre-diabetes or type 2 diabetes. One that analysis found a significant difference for diastolic blood pressure. So the key points for blood pressure based on that evidence is that essentially there’s inconsistent effects on blood pressures in adults with overweight obesity and with and without pre-diabetes, with type 2 diabetes. It may be that the carbohydrate restricted dietary pattern allowed or helps patients lose weight. And so that’s where the benefit for the blood pressure was seen is because of that weight loss. We do see that as people are able to lose weight, their blood pressure does improve, but maybe that more than the carbohydrate restriction itself. So summarizing the evidence that we have for cardiometabolic risk factors are key recommendations. The first is that to achieve an improvement in a patient’s cardiometabolic risk factor, weight reduction diet that achieves a clinically significant weight loss, which is typically 5 to 10% of their body weight is recommended. If a person needs to lose weight. The next key recommendation is that as part of a low carb and very-low-carbohydrate diet, it is reasonable for a patient to choose unsaturated fatty acids or saturated fatty acids. And we would emphasize this conversation with your patients again, that our example of Joan, our case studies showed that people do consume a high amount of saturated fat can then potentially impact their LDL-cholesterol levels to really increase to unhealthy levels. In patients with overweight or obesity with or without type 2 diabetes and with elevated triglycerides, the low-carbohydrate diet is reasonable for lowering triglyceride levels and also very low density lipoprotein cholesterol levels compared to a high carb, low fat diet. Again, helping a person reduce their carbohydrate intake is something we would do for their triglyceride levels, and that is typically part of medical nutrition therapy that we would provide. There is a substantial variation in lipid responses, as we discussed, so it is reasonable that you do a baseline and follow up with the profile with your patients who choose to follow carbohydrate dietary patterns. And in patients with type 2 diabetes, a low-carbohydrate diet may be reasonable to achieve improved glycemic control and a reduction in the diabetes medications. In the patients with overweight and obesity with hypertension, weight loss by following a low-carbohydrate or very-low-carbohydrate diet may be reasonable to help them manage their blood pressure better. Again, we didn’t find evidence that it was the low-carbohydrate that beneficially impacted the blood pressure, but it was probably more likely the weight loss that occurred that helped achieve better blood pressure. So moving on with the content of the scientific statement, I’m going to address the safety concerns, and adverse effects that we identified during our review of the literature. And really I’m going to summarize our evidence by sharing the key recommendations for you that we developed after our review of the evidence. So our first was that close medical supervision is recommended for patients who have various diseases or disorders that they’ve already been diagnosed with. So definitely a person who has a history of ASCVD already, a history of atrial fibrillation, or has the presence or history of heart failure, kidney disease, or liver disease, we aren’t sure how these changes, which are typically pretty severe if a person is choosing to follow, especially a very-low-carbohydrate ketogenic diet, we’re really aren’t sure how those significant dietary changes will impact the ability to manage these types of diseases. So close medical supervision is our recommendation for patients who choose to follow a very-low-carbohydrate diet after the conversations that you have with them and whether they should or not because of the potential harm that could occur, because of those severe dietary changes. In patients with type 2 diabetes, there is a risk for hypoglycemia, primarily because of the significant decrease in the carbohydrate intake that occurs especially with the very-low-carbohydrate dietary patterns. So they should be followed very closely to identify whether or not they’re having episodes of hypoglycemia and probably changing a diabetes medication. Same thing might occur with people who have hypertension as they’re making dietary changes, as they’re losing weight, they may have a risk of hypertension. And so being aware of that and following them closely. Similarly with vitamin K-dependent anticoagulation therapy, the dietary changes that may occur can impact the effectiveness of the vitamin K-dependent anticoagulation therapy. And so they should be monitored closely. In patients who have a history of genetic lipid disorders or elevated lipid disorders, essentially, our key recommendation is that they should not be following a very-low-carbohydrate ketogenic diet. Patients who have a history of hypertriglyceridemia-associated pancreatitis, people who have severe hypertriglyceridemia it may be genetic, it may be not. And then also patients with inherited causes of severe hypercholesterolemia, these patients are going to be more sensitive to some extent in terms of the saturated fat content that may occur with a very-low-carbohydrate ketogenic diet and which would then clearly result in a significant elevation in their triglycerides and or LDL-cholesterol. But because of that, we do not recommend patients with these diseases and disorders follow a very-low-carbohydrate ketogenic diet. In terms of the other key recommendations for safety, it is reasonable to monitor glycemic control and make adjustments in diabetes medication. As I just discussed, in patients who are taking an SGLT2 inhibitor, it should not be used in conjunction with a ketogenic diet. There is evidence that shows that the use of SGLT2 inhibitors with a ketogenic diet increases the risk of SGLT2 inhibitor-associated ketoacidosis. So typically what is done is that if a patient wants to follow a very-low-carbohydrate ketogenic diet, their SGLT2 inhibitor is discontinued before they initiate a ketogenic diet, and that is available and discussed in the literature as well as our scientific statement. Again, as I’ve mentioned on the previous slide, more frequent monitoring of vitamin K-dependent anticoagulation therapy may be reasonable to identify any changes that might occur with the following of a very-low-carbohydrate ketogenic diet, and we do have some observational studies that both low and high carbohydrate intake is associated with an increased risk of mortality. So really moderate consumption of carbohydrate is something that we would strongly encourage in our key recommendation for safety concerns is to avoid either very-low-carbohydrate intakes or very high carbohydrate intake because of the increased risk of mortality associated with those both ends of the spectrum that we see from our observational studies. And moving on with the scientific statement content, I’m going to cover the key recommendations for weight loss and weight maintenance, and these are recommendations that we did develop looking at the totality of the evidence and best practices essentially to help our patients be more successful for short term weight loss, weight loss, as well as long term weight maintenance. But I do want to talk about the key points for the discussion that you hopefully have with your patients before they start a carbohydrate restriction, especially a very-low-carbohydrate ketogenic diet. It is important to talk about the option for short term use for that initial weight loss that I have talked about previously. But discussing with your patient that what we see from evidence is that most people can only maintain a severe carbohydrate restriction for a short term and that over time it becomes more difficult. So that long term weight maintenance and cardiovascular health, we want to encourage gradually increasing carbohydrate intake and as people do increase their carbohydrate intake, have that consumption be more of a moderate level to improve adherence as well as really emphasizing the unprocessed carbohydrate foods that are rich in the nutrients and non-nutrients that we know are associated with improved health outcomes and associated with decreased cardiometabolic risk. We also know that we see from randomized controlled trials and clinical studies that when a person is referred to a comprehensive, multidisciplinary lifestyle intervention program, they do better with achieving weight loss and weight maintenance. So that comprehensive lifestyle intervention program typically includes interdisciplinary clinicians available. So primary provider, registered dietitian, nutritionist, a person who can help with physical activity like an exercise physiologist or a personal trainer or physical therapist, as well as behavioral therapists. Typically, people will reduce their calorie intake, they’ll increase their physical activity, they’ll address behavior changes that they need to make for long term success, and then eventually they’ll achieve reduced body weight. So that comprehensive, multidisciplinary lifestyle intervention is really important for long term success. So based on those key point are key recommendations for long term weight off and maintenance. We do think it’s reasonable to refer patients who are interested in achieving weight loss, to refer them to a comprehensive lifestyle intervention program with that multidisciplinary team. And as part of that, whether or not a person is able to go to a comprehensive lifestyle modification therapy, addressing behavioral family, cultural and social dynamics and accommodating their ethnic or economic influences can be useful to promote their long term success. It really essentially this key recommendation is that we consider where people are in their efforts with weight loss and individualize the recommendations and the assistance that we provide to them to help with their long term success. A moderate carbohydrate intake, so about 130 to 225 grams a day with that emphasis on including foods known to be associated with improved cardiometabolic health may be a reasonable long term strategy for weight loss and weight maintenance. Next recommendation is that it is recommended that all patients receive counseling on reducing sedentary activity and increasing physical activity, and that should include both aerobic physical activity as well as strength and resistance activities. And for long-term weight maintenance, it could be that some people may need a higher amount of activity to achieve that long-term success. So it’s reasonable to encourage higher levels of physical activity, which may be about 200 to 300 minutes per week for that long-term success. So conclusions or summary statements for the scientific statement, and based on the evidence that we reviewed, we do know that one macronutrient distribution is not superior for weight loss or type 2 diabetes management. Based on the evidence that we have available to us right now, it really is about working with your patients to identify which one is going to work best in their own life. A carbohydrate restrictive diet may improve triglyceride levels, HDL cholesterol, glycemic control, and reduce the need for diabetes medication. But again, it is not necessary to have our patients decrease their carbohydrate intake to a level that induces ketogenesis. And if it can be found without that severe restriction, carbohydrate restrictive diets have a variable effect on LDL-cholesterol as well as total cholesterol. And that, again has is impacted by the intake of saturated fats as well as potentially genetic factors. And adherence to severe carbohydrate restriction is challenging, as I’ve mentioned throughout the presentation today. But it’s important to work with patients and help them understand that lower amounts of carbohydrate or moderate carbohydrate intake can help them achieve benefit without having to achieve the severe restriction that’s associated with ketogenic diets. And we do not have long term studies for how ketogenic diets affect ASCVD outcomes. We do see that short term, there may be some improvements with ketogenic diets, although LDL-cholesterol, as we’ve seen, does increase. So it really is important that in the context of when we’re making these recommendations for our patients, we have longer term evidence that shows moderate carbohydrate consumption can help with health outcomes. We don’t have evidence that shows the same for severe carbohydrate restriction, and we need to pay attention to that in the context of our conversations with our patients. As I’ve discussed previously, the clinician-patient conversations should happen hopefully before a patient starts a carbohydrate restricted dietary pattern, although I’m aware and many others have patients who come in who are already following a carbohydrate restricted dietary pattern. But again, hopefully you’re able to have the conversation before they start the carbohydrate restrictive dietary pattern and can discuss the pros and cons and individualize the recommendation for your patients. And ideally, if a patient chooses to follow a lower carbohydrate or a very-low-carbohydrate ketogenic dietary pattern after that conversation, then it is encouraged and recommended that medical supervision occur for the patients, especially those who may have health problems or diseases or disorders previous to following the ketogenic diet, it is recommended that a baseline and follow up with lipid proteins occur and that a referral to a multidisciplinary lifestyle intervention program, if it’s available, also occurs. If a multidisciplinary intervention is not available, at least a referral to a registered dietitian nutritionist, if one is available and feasible. A registered dietitian nutritionist can help patients facilitate them following a carbohydrate restrictive diet and transition them to a dietary pattern that is the best fit for them and allows a consumption of an appropriate amount of carbohydrate that provides the consumption of vegetables, fruits, nuts, seeds, legumes, and whole grains that have been associated with positive health outcomes. And finally, long-term, we strongly encourage patients to follow a cardioprotective dietary pattern that they will be able to adhere to and again include the consumption of the high quality carbohydrates that are unprocessed and provides the nutrients and non-nutrients that will promote their cardiovascular health as well as their health in general, and physical activity is always something that should be the foundation of a healthy lifestyle. In closing, I would like to say thank you to the writing group team who worked with me on the scientific statements, as well as a special thanks to Terry Jacobson, who was our NLA Scientific Statements Committee Chair, and also provided his insight and editing, and Vivian Grifantini, who helped with all of the small details to help with the publication of the scientific statement. Thank you for your time today and I hope this was beneficial for you and provided guidance to you as you work with your patients who may be interested in carbohydrate restricted dietary patterns.