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- [00:03]
A
We have another great month this month of articles starting with an article from the Lancet on semaglutide and cardiovascular outcomes looked at by baseline, adiposity and changes in adiposity. And this is a pre specified analysis of the SELECT trial. Then we're going to look at a trial from Diabetes Care on the impact of oral semaglutide on kidney outcomes in people with type 2 diabetes. This is from the SOL randomized trial. Then also from Diabetes Care, the Sodas trial, which is the effect of substituting water for artificially sweetened beverages on glycemic and weight measures in people with type 2 diabetes. And finally an article from the American Journal of Clinical Nutrition on something that boy if you or a friend hasn't tried, I don't know where you're hanging out. The effect of carbohydrate restricted diets and macronutrient replacements on cardiovascular health and body composition in adults. A meta analysis of randomized trials, hopefully addressing some questions that we have for patients and come up in casual conversations. John, do you want to start with the first trial?
- [01:28]
B
So our first article was from the Lancet and it looked at some magnetized in cardiovascular outcomes by baseline and changes in adiposity measurements. A pre specified analysis of the SELECT trial. So in this study the patients were at least 45 years of age and had a BMI of at least 27. They enrolled patients from 41 countries at 804 sites and they were randomized to 1 to 1 to weekly semaglutide, 2.4 milligrams or placebo. The primary outcome was time to first mace, so that was the composite of cardiovascular death, non fatal mi, non fatal stroke. Adiposity measures included weight and waist circumference. In this analysis, risk of mace occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and the separate analysis all in trial MACE were assessed between patients by adiposity changes over 104 weeks or two years. So what they found was semaglutide significantly reduced MACE incidence compared with placebo among over 17,000 patients enrolled in the SELECT trial. They found consistent benefits across all baseline weight and waist circumference categories in the semaglutide group. Analysis for linear trend showed lower baseline body weight and waist circumference were associated with a lower incidence of mace. So a 4% reduction in risk per 5 kilogram lower body weight with a hazard ratio of 0.96 and a per 5 centimeter smaller waist circumference also with a hazard ratio of 0. 96 in the placebo group, lower baseline waist circumference was associated with a lower risk of 0.96, but not body weight, which was really around 1 at 0.99. Lower mace risk and weight loss was paradoxically associated with increased MACE risk in those receiving semaglutide. There was no linear trend linking weight loss at 20 weeks to subsequent MACE risk, but greater waist Circumference reduction at 20 weeks was associated with lower MACE risk, and waist circumference reduction by 104 weeks was associated with lower in trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference with a hazard ratio of 0.86. Neil.
- [03:53]
A
John, this is absolutely fascinating, and you remember a few years ago when the select trial came out that was and remains an incredibly pivotal trial showing a 20% decrease in mace in people with overweight and obesity who also had established atherosclerotic disease and were treated with semaglutide. And that was over about three years. Now, the presumption at the time, or the question at the time was that entirely related to weight loss. Now, clearly some of it is, and that's what this trial shows, but the other thing that turns out is that there's something else going on. It's not just all about weight loss. This trial showed that about 30% of the decrease in cardiac outcomes could be attributable to weight loss, primarily to a decrease in waist circumference, which reflects visceral fat, which is most closely tied to cardiac outcomes. But the other study that came out recently that also suggests there's another pleiotrophic effect going on was presented at the European Congress of Obesity in May of this past year that showed that MACE began to be lowered temporally before there was significant weight loss. So that we see that semaglutide must be having other very important beneficial effects. We know it lowers ldl. We know it lowers triglycerides. We know it lowers blood pressure. But those effects, and maybe additional pleiotrophic effects are what actually, in addition to the weight that is lost, lead to the decrease in cardiac outcomes and the outcomes in mace. I'll say, clinically, this is an area where I think we really, as primary care clinicians, endocrinologists, we need to be thinking about in our patients who have either stroke or mi, because I see a lot of people that are seeing our subspecialty colleagues that are not put on a GLP1 specifically semaglutide with the goal of decreasing future mace and it gives us an opportunity to do so in people who have established ASCVD and also have overweight or obesity. Our next trial is from Diabetes Care titled the impact of oral Semaglutide on kidney outcomes in people with type 2 diabetes. Results from the sole randomized trial. The goal of this sub analysis was to examine the effects of oral semaglutide on kidney outcomes in people with type 2 diabetes and atherosclerotic cardiovascular disease and or kidney disease. The SOLE trial was a double blind randomized controlled trial that compared oral semaglutide with placebo in people with type 2 diabetes, ASCVD and or CKD and it showed a 14% reduction in the risk of major adverse cardiac events. That was a big deal that we all were very attentive to when it came out. Pre specified kidney outcomes that they then looked AT included a five point composite which was a greater than or equal to 50% decrease in EGFR, persistent EGFR that led to less than 15 initiation of dialysis or death from kidney or cardiovascular causes and a four point composite that excluded cardiovascular death. They also looked at estimated GFR decline among over 9,600 participants. The mean entry EGFR was 74 and follow up was 47 and a half months. The five point outcome occurred in 8.4% and 9% of participants taking oral semaglutide versus placebo respectively. That was not a significant difference. The four point outcome occurred in 2.3 versus 2.7%, again a not significant difference. The mean annual EGFR decline was less with the oral semaglutide than with placebo with a P value of less than 0.0001 and those effects were similar across all subgroups.
- [08:25]
B
John Neil this one I think was interesting. I think if you're gonna look at what is gonna play out in primary care offices over the next 20 years, we're gonna spend a lot of our time and energy really trying to prevent the progression of kidney disease. And there's gonna be a lot more talk about cardiorenal metabolic syndrome, right? That as people's kidneys get worse, their cardiovascular disease gets worse. So in this study really didn't look at microalbumin. So you could really imagine a large healthcare system with just good primary care of patients with diabetes. You're going to have microalbumins and you're going to have GFRs and you're going to have a decent sized cohort of people who are on oral semaglutide. And you could look at this. So certainly I think this deserves its own study to really say is this one of the bullets we're going to have in our gun to decrease the progression? The injectable semaglutide has that indication. But I think this is kind of interesting and I would not reach for this medicine right now to say this is going to protect your kidneys. I think we have evidence now with this MACE trial that's going to protect people's heart, which in certain ways does protect their kidneys and, and kind of vice versa. So we're partway there. But I wouldn't say this would be the medicine for that patient who has micro macroalbuminoria that I'm trying to keep their kidney function getting worse. Our next article is from Diabetes Care and it looked at the effect of substituting water for artificially sweetened beverages on glycemic and weight measures in people with type 2 diabetes. The study of the drinks with artificial sweeteners aptly named the Sodas. A randomized trial. So this study, the Sodas trial was conducted at two academic health centers was a randomized two arm parallel trial with a two week running period and a 24 week active intervention period. Patients who had type 2 diabetes and there were 181 in total who had a 1Cs between 6.5 and 8.5 who were over 35 years of age who regularly consumed artificially sweetened beverages were randomized to receive and consume either 24 ounces daily for 24 weeks or either one a commercial artificial sweetened beverage of choice. That'd be the control. Or 2 an unflavored sparkling or still bottled or canned water of choice. In place of the artificial sweetened beverages. The outcome measures were collected at baseline 12 and 24 weeks. They included A1C. Secondary measures included fructosamine, fasting glucose, insulin, body weight and continuous glucose monitoring metrics. Of these patients, 179 provided complete data over 241 weeks from baseline to 24 weeks. The mean difference in A1C was 0.29. Statistically significant was higher than the water arm compared with the artificial sweetener arm. There were no significant effects on secondary clinical measures. Data were directionally consistent with the primary results.
- [11:39]
A
Neil John, I love this study and I know that you do too, judging from that cherry Coke Zero that I often see you with. You know, this was absolutely fascinating. There has been so much research and so much Controversy with regard to artificial sweetened beverages. All of the randomized trials that have compared artificially sweetened beverages to sugar sweetened beverages show that it is positive outcomes. You lose weight a little bit on an artificially sweetened beverage when looked at prospectively and it improves other parameters. And this is contradicted actually by the large observational cohort studies that have shown that people who drink artificially sweetened beverages have a higher incidence of things like obesity and diabetes. And a number of authors, and in fact the American Heart association guidelines on this topic, have felt that as I do, that most likely those observational trials are the result of reverse causality, meaning that people who struggle with their weight tend to be the ones who pick artificially sweetened beverages. And so therefore you might see a higher incidence of things like obesity and diabetes in that group. This trial looked at that question in a different way, in a prospective randomized way, and said, hey, let's substitute either an artificially sweetened beverage or water, right? Water is what we all should be drinking. That's ideal. And what they found was there's essentially, I mean, not much difference. Yeah, the A1C looked a little bit better with an artificially sweetened beverage. Whether or not that's true or not. It was in this study. But I think the important take home point is that there isn't a downside here of an artificially sweetened beverage. And this is consistent with other trials that have looked at this. There was a meta analysis of nine randomized trials in Frontiers in Nutrition this past year. There was one in Diabetes Care about three years ago. And they say the same thing, that when looked at prospectively, when you compare artificially sweetened beverages to sugar sweetened beverages, you are much better off with the low and no calorie beverages. When you compare prospectively low and no calorie beverages with water, they look about the same. So, John, I think you can feel comfortable and so can I. I'll opt in here too in continuing to both drink, in my case water with a squeeze of lemon, but also sometimes that cola with, with that's artificially sweetened and feel comfortable that we're, we're having a healthy approach. For our last article, we are going to look at an article from the American Journal of Clinical Nutrition titled the effect of Carbohydrate Restricted diets and Macronutrient replacements on Cardiovascular Health and Body Composition. In a meta analysis of randomized trials here, the background was that carbohydrate restricted diets are widely promoted for improving cardiovascular and body composition outcomes. Yet the evidence remains mixed across different dietary patterns, populations and study designs. So the authors did a Meta analysis of 174 randomized trials that encompassed over 11,000 individuals from 27 countries. Eligible studies compared carbohydrate restricted diets. Now this was defined as less than or equal to 45% of energy from carbohydrates to higher carbohydrate containing diets in adults. They also looked at different types of carbohydrate restriction, different degrees. Ketogenic diets, low carb, moderate carb. So carbohydrate restricted diets significantly reduced triglycerides by about 15 systolic, blood pressure by 2 points, diastolic blood pressure by about 1 1/4 points. Various lipid profiles and inflammatory markers including C reactive protein though there and there was an increase in high density lipoprotein by about 3, low density lipoprotein and cholesterol though did increase modestly by about 4,4 points. All measured body composition markers showed significant reductions on carbohydrate restricted diets. Moderate carb diets offered balanced benefits, whereas ketogenic diets produced greater weight loss but also greater increase in LDL and total cholesterol.
- [17:05]
B
John, you know, I'm very excited by this topic. So we have to go back to 1863, Banting and Dr. Harvey, but it wasn't that Dr. Harvey. It was a different Dr. Harvey in England who was an ENT. And it wasn't the banting we think about for insulin, Although this patient Banting is a distant relative of Frederick Banding who discovers insulin 60 years later. So this guy Banting is having trouble with his hearing. He is an undertaker, he's a heavy guy. He goes to his doctor, Dr. Harvey, who tells him he's having trouble hearing because he's too fat, and recommends a diet that stays away from potatoes, that stays away from beer, that stays away from sugar and butter. And he goes on this diet. And Dr. Harvey had heard some whisperings of a diet like this. He was somehow at a conference that was talking about diabetes somewhere in Europe. So banting goes on this diet and loses a lot of weight and he writes the first diet book called Letters on Corpulence. And it becomes kind of a big hit. The term banting was synonymous with diet, going on a diet, dieting was banting. And that really kind of struck this off and that lived for about 60 years. We get into the 1920s and a couple different things happen in the 1920s. The people who take care of epilepsy kind of found that low carbohydrate diets decreased the recurrence of seizures. Boy, that's something I've not heard about in my career. But if you would go to the American Epilepsy association right now, they would talk about low carbohydrate diets may be effective in children only, who might have seizure disorders that are resistant to medications. How about that? Also in the 1920s, there is a paper in 1926, 100 years ago in Jama, someone travels to Alaska and observes the Inuit population who eat mostly fish and meat, about 90% of their diet. And really kind of how well they do. And really the evidence out of that diet, that study has never been refuted. So 100 year old study on diet in JAMA on the Inuit population in Alaska and other parts, in kind of North America, in the Iceland, Greenland kind of area, did not show that. Also then that leads to the dupont company. So the dupont company had noticed that their executives were getting heavy. So they put a doctor on that and he found some of this data from Banting, and he saw some of this other data and he started putting the executives who worked for the Dupont company on low carbohydrate diets. Became known as the Dupont trial, the Dupont diet. And then kind of 40 years passes and then a Dr. Atkins, Dr. Atkins was a cardiologist, a lifestyle doctor who was having trouble with his practice in the 60s, got a little depressed, did what most of us do when we're a little depressed, we eat some of the wrong stuff. Found himself being heavy and really discovered some of this stuff and started the Atkins diet, which was published in 1972. So that's this long history that predates the end of the Civil War of people trying to do this for diets. And certainly it can have some success. We've certainly seen that. If we haven't experienced that personally, we've certainly seen it in patients. And I think it has many fathers and I think there is something to be said about staying away from certain things. Also, if you and I walk by the coffee machine in our office, the stuff that people bring in to snack on tends to be a lot of carbohydrates. No one's bringing in bologna to put by the coffee machine and things like that. But certainly it's had some efficacy. So how about some of the stuff they found in this particular trial with that as a background? Well, certainly weight loss can be associated with lowering triglycerides. Right? And if you look, if you dig into the data they showed better kind of cardiovascular responses in women. Well, if you look at the Framingham trial, the data in the Framingham trial, the people who had lowering triglycerides had the biggest impact on mortality were women with a low HDL and a triglyceride in that 150 to 300 range. So women triglycerides is a little bit more of a risk factor than it would be in a male population. And even some of those people who have very high triglycerides color micro anemia isn't completely associated with cardiovascular disease. Lots of other stuff. So lowering triglycerides certainly could help. You saw a little bit. So raising hdl, and if you look at the, the, you know, the WHO trial, a different trial for every point you raise someone's hdl, and this was a gemfibrizil trial, but for every point you raise someone's HL, you decrease cardiovascular mortality by about 6%. So it raised HDL, it lowered all the inflammatory markers. Well, what about this LDL rising? Are we, you know, fixing one thing and causing another? Well, if you look at some of the trials of fish oils, fish oils often can be used if you use high enough doses to lower triglycerides. And they have been known to low to increase ldl, but, you know, not all the LDL are the same. So if you have little teeny atherogenic LDL that you kind of convert into normal, more fluffy, less atherogenic ldl, you might have an increase in ldl. So I think this is something that we can talk about with people. I think, you know, I think one of the things with looking at the world through a lower carbohydrate lens, I think is really how portion sizes have changed with regard to carbohydrates in our life. You know, if you, you know, ate a fast food hamburger, it certainly doesn't seem any bigger than it did in 1972. But the size of the soda has gotten bigger and bigger. When McDonald's opened, the smallest soda was 10 ounces. Now the smallest soda is 22 ounces. If you look at the size of fries or the size of Mac and cheese or the size of anything, we are so supersizing carbohydrates. And, and if you look at kind of ADA guidelines, they don't really say that people should have no carbohydrates. And probably people need to have a little bit. And if we looked in this study, the people who had a modest amount of carbohydrate probably did best on all the different metrics. But, you know, maybe we can avoid that sweetened soda as we heard about earlier. Maybe we could split a fry with the family and have a couple of fries. Maybe we could put a lot more vegetables on our plates. Maybe we could have some lean pieces of protein. And I think as we look at kind of what is happening in the diet world, there certainly are more voices that are talking about us having more lean sources of protein at every meal. And certainly some of that is in keeping with some of the newer guidelines that we're seeing from the government, really talking about making sure we're getting enough protein and not as much stuff in the middle of the grocery store. So. So I think there's some interesting stuff here. I love thank you for giving me this article so I could kind of take that dive back in history, but. So it can be helpful to patients. But I think having a little bit of moderation in everything makes some sense. But we do need protein, and having some lean sources of protein, possibly at every meal, especially as you and I get older, might make a whole lot of sense.
- [25:42]
A
For more information and links to the articles that we discussed in this issue, just go to diabetesjournal.org until next month.
- [25:54]
B
Keep listening and keep learning. Sam.