Neil (4:03)

John the first thing I'll say is, wow, this is exciting. Another medicine that we are now seeing that has over 20% weight loss on the average by by the end of the trial. It's interesting. The inputs to satiety and appetite are complex, so it is not surprising that when we combine different mechanisms, we see more effectiveness with regard to weight loss. Here we're seeing a combination of an Amlin agonist along with semaglutide, a GLP one we've seen in other studies, a glucagon agonist. We've seen GIP, both agonists and antagonism, all when combined with the GLP1s yielding greater weight loss than the GLP1 alone. So what is amylin? We remember it from way back in medical school and it is a satiety hormone that's released from the pancreas in response to nutrient intake and it works in the hypothalamus to dampen appetite. So it makes sense and in fact is what we see, that along with the GLP1 semaglutide, it has greater weight loss than the GLP1 alone. What is fascinating here though as well, and there were two articles, this is Redefine 1, the other is named Redefine 2. This is in people with obesity without diabetes. The other is in people with obesity with diabetes. That was in the same issue of the New England Journal. What we see is enormous metabolic benefits as well. So in this trial, over 87% of the individuals who are obese with prediabetes had normoglycemia by the end of the trial. Pretty phenomenal blood pressure reduction. We saw a mean blood pressure reduction in this trial of 9.9 millimeters of mercury in systolic, about 5 in diastolic. That's about what we get with the use of our usual blood pressure medicines. In the Redefine 2 trial, the other trial in the New England Journal that was people with obesity with diabetes given CagroseMA. The baseline A1C on entry was 8%. They had 13.7% weight loss, always less in people with diabetes than in people without. But what was amazing here is that they looked at a secondary endpoint of an A1C less than 6.5% and that was achieved in 73% 3/4 of the people in the cagrosema group. So what we're going to see now is if this gets FDA approved. An expanding array of options for powerful outcomes in both the obesity space and the diabetes space. Our next article from Lancet Diabetes and Endocrinology could not be more exciting. Once weekly icocema versus multiple daily insulin injections and type 2 diabetes management the combined 3 trial is a once weekly combination of basal insulin, weekly icodec and weakly semaglutide, which of course is a GLP1 receptor agonist and the ICOSMA combination has been developed for treatment of type 2 diabetes. The authors aim to evaluate the efficacy and safety of ICOSAMA versus basal bolus therapy in adults with type 2 diabetes who were not adequately controlled on a single daily basal insulin dose. This was the combined three trial which was a 52 week open label treat to target non inferiority randomized phase three a trial enrolling individuals 18 years or older with type 2 diabetes receiving daily basal insulin 20 to 80 units a day who are randomly assigned one to one to receive once weekly icosimma using a pen or basal bolus insulin. That's once daily insulin glargine with two to four daily insulin aspart injections as well. The primary endpoint was a change in a 1C from baseline to week 52 and it was tested for non inferiority using a 0.3 percentage point margin to be considered non inferior and they had secondary endpoints that were very relevant, that was change in body weight from baseline in week 52 and weekly total insulin dose during weeks 50 to 52 as well as clinically significant hypoglycemia episodes. There were over 670 individuals in the trial with a mean age of about 60 59% males randomly assigned to icosimma or basal bolus insulin and john at week 52. The estimated mean change in a 1C was minus 1.47 percentage points with ICOSMA and negative 1.40 percentage points with basal bolus therapy confirming non inferiority. Pretty amazing with and I'm sure you'll talk about less shots per week. Superiority was confirmed for icosema versus basal bolus therapy for change in body weight. In fact, There was about 15 pound difference in body weight with icosimma having less body weight weekly. Total insulin dose during weeks 50 to 52 was less with ICOSMA and overall rate of clinically significant or severe hypoglycemia from baseline to week 57 was 0.21 versus 2.23 episodes per person. Year of exposure with a P value is less than.0001. John, what do you think?

John (10:26)

So Neil, thinking about gold standards, right? So you know, basal bolus insulin is the gold standard. I mean that most mirrors physiology. That's what you should be aspiring to, right? And we taught that to scores of residents over many, many, many years. And now looking at studies like this, it becomes really hard to argue and I think you and I have both argued that that weekly GLP1 with a daily basal insulin. Wow, what a revolution that is to get down to eight shots a week from 28 shots a week. Right? So you're saving over a thousand shots a year. So in this case, you know, the, the Delta is about 1400 shots different per year. And, and I also kind of think in thinking how this has evolved, you know, we use so much CGMs anymore that we're not necessarily apologizing for people about all the finger sticks and things like that because the people who are checking their sugar so often, often have the ability to use this great technology and you know, will people, if you said to someone you could do 1400 shots a year versus 50 shots a year and you would get the same outcome.

Aaron Skolnick (11:58)

Wow.

John (11:58)

Well, you're not just getting the same outcome, right? You're, you're losing 15 pounds at the back end, you're having less hypoglycemia, which is something in starting to read this article, kind of worried about, because you really can't get that genie back in the bottle if there is a problem. So I find this to be fascinating. This can be a really exciting way to get our patients kind of back to being euglycemic and maybe much earlier. And I find this to be something that I might think about for that poorly controlled patient with diabetes a little bit earlier than I otherwise might.

Neil (12:41)

Next we're going to discuss a joint advis from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine association and the Obesity Society titled Nutritional priorities to support GLP1 therapy for obesity. This is important information for us. And joining us to discuss this is Aaron Skolnick, who is a personal trainer and physical therapy assistant from Naples, Florida. Welcome, Aaron.

Aaron Skolnick (13:08)

Thank you for having me.

Neil (13:10)

This is an important paper because clear guidance in this area is helpful for clinicians, dietitians, personal trainers. As more and more people are taking GLP1s and thinking that they can leave lifestyle behind, but they shouldn't, do you see a lot of people coming in who are on GLP1s?

Aaron Skolnick (13:31)

Yeah, I would say about 20 to 30% of my training clients are on a GLP1. Especially if you're shifting towards an older population.

Neil (13:40)

You know, that's interesting and that that makes sense. And those are people who would be attentive to their health. So from your perspective as a personal trainer, what are the important issues that this advisory talks about?

Aaron Skolnick (13:53)

So one of the things is nutrient deficiencies, right? And a lot of people will take the injection and not address their core nutritional needs. We know in America, generally people are kind of low on the protein intake to begin with. So once you start to reduce calories, you're reducing total protein intake even more. And when you're in a caloric reduction, this is going to lead to even more severe muscle loss.

Neil (14:16)

That's. Those are really good points. And as important as protein is in general for all of us, it's probably even more important for the group that you see who are older. Right?

Aaron Skolnick (14:27)

100%. Most of my elderly patients both don't get enough protein. And as you age, you tend to experience some sarcopenia, some muscle loss, sarin.

Neil (14:37)

It's interesting, in a place like Naples, Florida, you probably see a lot of older people for whom preservation of muscle is particularly important. Is that right?

Aaron Skolnick (14:49)

Yes, that is true. I see a lot of people that the preservation of muscle is important. A lot of people lose strength as they begin to age. So being able to maintain that muscle mass and strength is vital.

Neil (15:00)

It really is critical. As a geriatrician, I see this all the time as well. So the advisor gives helpful advice about how to mitigate short term side effects of GLP1s. But for the sake of our discussion, I'm going to leave that behind because I want to focus on what they say about prevention and mitigation of nutritional deficiencies and loss of muscle mass first. What do they say about nutritional deficiencies?

Aaron Skolnick (15:24)

Well, as you're reducing your total caloric intake, reducing your total food intake, you're going to come across some deficiencies. Now, these deficiencies can range from vitamins, minerals, all the way up to your macronutrients, proteins, fats and carbs. Now, in America, the likelihood of you not eating the amount of carbohydrates or fats that you need is very low. But a lot of people do lack their protein intake that is necessary to maintain muscle mass, especially in a caloric deficit.

Neil (15:51)

Excellent. And are there any recommendations when we talk about micronutrients for vitamins or particular foods that might be helpful?

Aaron Skolnick (16:01)

Everybody pretty much knows what to eat, let's be honest, right? Everybody knows dark leafy greens, eat the rainbow, cut out the processed foods. If you just eat those from a basic framework, you're good. A lot of people get lost in the dogmatism that has become nutrition nowadays. And the truth is, to get you 90% of the way to where you want to go, all you need to do is just eat smart. Just veggies, fruits, variety colors, enough protein, that's helpful.

Neil (16:32)

And I know the, the advisory also mentions that one can also add just a multivitamin. It's an easy way to get things like vitamin D, calcium, B12, et cetera.

Aaron Skolnick (16:44)

Definitely supplements are good, but I want people to remember that they are indeed supplements.

Neil (16:49)

That's really a good point. So that brings us to preservation of muscle mass, which you as a personal trainer are very involved in. One of the things they talk a is making sure that people eat enough protein. The recommended daily allowance for protein is 0.8 grams per kilogram per day. But higher amounts of protein they emphasize may be helpful during active weight reduction. They actually discussed the imprecision of the current recommendations and say that an absolute protein target of 80 to 120 grams per day is a reasonable target for for most people. And they go on to emphasize that for many people this will require a thoughtful approach with emphasis on nutrient dense, high protein foods. Things like fish, eggs, Greek yogurt, cottage cheese, nuts and seeds, peanut or almond butter spreads. I've also found that it's helpful for people to use protein supplements, either protein powder or protein Shakespeare or bars. But protein alone isn't sufficient to preserve muscle mass. What else is important for preservation of muscle mass?

Aaron Skolnick (18:06)

So the number one thing for preservation of muscle mass is going to be resistance training. And one of the things I see with a lot of new clients that come in is they come to me saying they exercise and they're doing enough to maintain muscle mass. But when they actually explain to me what it is they're doing. It isn't really true resistance training. A lot of people say, oh, they do aqua aerobics so many times a week, and that's great that you're moving and all, but that's not going to help you maintain muscle mass. When you're looking to maintain muscle mass, you're looking to work in a repetition range and effort range that is going to have you getting quite fatigued, somewhere between six and 10 repetitions.

Neil (18:49)

That's so helpful. And I'm guessing that this is new ground for a lot of the people that you see, is that right?

Aaron Skolnick (18:55)

Yeah, a lot of the people I see haven't worked out in a while, so they're not very used to any sort of resistance training or moving in general. And one of the hardest things to teach people is effort indeed. You know, I. It was a blessing and a curse for me personally to have injured my back and not been able to work out for a little while. But that also gave me that perspective to see how hard it is to get back into the gym when you have been laid off for a while. So it's being able to integrate effort back into any kind of training program that they have.

Neil (19:29)

That's insightful. So it's so helpful for people like myself as physicians to be able to refer our patients to personal trainers in order to learn how to do exercise properly. Now, you said one of the challenges is motivating people and getting them to move when they haven't in a while. Any hints about how you do that before we're done with our podcast?

Aaron Skolnick (19:54)

Copious amounts of caffeine, they will not be able to sit still. But on a serious note, motivational interviewing. Getting down to the why, that's really the biggest thing that's so helpful.

Neil (20:05)

Aaron Skolnick, thank you so much for joining us.

Aaron Skolnick (20:08)

Thank you.

Neil (20:09)

Our next article from Diabetes Care is on gradual titration of semaglutide, resulting in better treatment adherence and fewer adverse events. This is a randomized, controlled, open label pilot study where the author sought to determine whether a slower, more flexible titration regimen of semaglutide would improve adherence and reduce GI side effects compared to the label recommended regimen in people with type 2 diabetes. There were a total of 104 patients with type 2 diabetes who were randomized to the label recommended titration, and that is beginning at at a dose of 0.25mg, then go into 0.5, then 1mg at 4 week intervals or a flexible titration that started at a much lower dose, 0.0675 milligrams, which the authors explain was measured as five clicks made by the dose selector dial. And again, I do want to remind people this is not an FDA approved dosing, with gradual increases by 0.0675 milligrams per week and delays if someone had undue GI adverse effects. And they did this for a total of 26 weeks. While the final doses, interestingly were similar between groups, only 2% of the patients in the flexible arm withdrew due to GI side effects versus 19% in the label dosage arm. And that's a P value that was equal to 0.005. The flexible arm reported less nausea, 45% versus 64% and less weakness. A1C and BMI changes were similar between the two groups. John, your thoughts on this?

John (22:04)

You know, if we're starting someone on a glp, one is there that rush and certainly oftentimes it's easier to underdose a medicine and kind of work it up before someone has that side effect that we all kind of learn of and that's the one that we match with that particular drug. So I find this to be really innovative. And why not, right? Because we want someone to stick on these medicines and you know, if we say cheese, I can give you this laundry list of all these great things that go along with the GLP1s and I really want you to stay on it. And then I give you something that really makes you feel lousy. You're going to forget all those good things I said. But if you can slowly kind of put your foot in the ocean a little bit, if it's kind of cold down the Jersey shore, you're going to have maybe a better time than jumping right in. So I find this to be innovative and hopefully this is something that we can start using a little bit because I think it is very patient centered and I love thinking about locus of control. So when you and I prescribe a medicine at a certain dose as the prescriber, we have the locus of control. When you give the patient a little bit of an ability to adjust their own dosing, they have a little bit more locus of control themselves. And people feel better when they have more control over what's happening to their body. So our last articles from the New England Journal of Medicine looked at tirzepatide as compared with semaglutide for the treatment of obesity. This was a Phase 3B open label controlled trial that had adult participants who had obesity without type 2 diabetes. They were randomly assigned in a one to one ratio to receive a maximal tolerated dose of tirzepatide, which would be 10 milligram or 15 milligram or the maximal tolerated dose of semaglutide 1.7 milligram or 2.4 milligrams subcutaneously once a week for a 72 week period. The primary endpoint was a percentage change in weight from baseline to the week 72. Reading key secondary endpoints including weight reduction of at least 10, 15, 20 and 25% and a change in waist circumference from baseline to week 72. A total of 751 participants underwent randomization. The least square means change in weight at week 72 was 20.2% with tirzepatide versus 13.7 with semaglutide. The least squares mean change in waist circumference was a decrease in 18.7 cm with tirzepatide and 13 cm with semaglutide. Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10, 15, 20 and 25%. The most common adverse events in both treatments groups were GI and most were mild to moderate in severity and occurred primarily during dose escalation.

Neil (25:07)

Neil John, I love head to head trials and we don't see enough of them because there's always a risk to companies when they do that. I remember years ago I think it was a Prava versus a Torva trial where the authors thought they knew what was going to happen, the end point didn't result and a lot of people probably lost their jobs. But here they looked at tirzepatide versus Semaglutide and you went over the results and I just want to reflect on what an amazing journey it has been. We're actually comparing two medicines that are both far more powerful at weight loss than we ever would have thought we would see just a decade ago. Clearly consistent with the results of the original trials, the step one trial, the surmount one trial, tirzepatide showed up to be about 50% more effective with regard to weight loss. We need to see head to head trials because when we don't we risk comparing different populations and taking the wrong conclusions from separate trials. One of the things interesting in that vein was this trial had a little less weight loss than the comparator trials, the step one and surmount one trials because Those trials enrolled more women. And one of the things that we saw in this trial was that women on the average had about 6% more weight loss than men. So we learn all sorts of things with every trial that we do. Knowledge is always important. I think both of these medicines offer really remarkable benefits. And it's worth reflecting as we have this continued evolution of our knowledge in the field of obesity that we saw just this past week. Semaglutide approved for the treatment of MASH with moderate to advanced fibrosis. You and I discussed that trial when it came out not long ago. Semaglutide also is approved by the FDA for treatment of people with obese or overweight who have coronary artery disease. Based on the select trial we see with tirzepatide that it was approved about eight months ago for treatment of osa, in addition, of course, to treatment in diabetes and obesity. And we know that more studies are in the pipeline for tirzepatide for mash as well as cardiovascular risk reduction. We're going to be seeing a lot of endpoints over the next few years with all sorts of medicines we saw earlier in this podcast. Another medicine that has amazing effects on weight and other metabolic endpoints. We live in an exciting age for both us as clinicians and for our patients. John before we close, I want to share some important news with our listeners. As you know, in addition to diabetes, we've been covering the full range of cardiometabolic conditions. And so our name is going to be changing to meet that consistent mission. Our podcast will be rebranded as Diabetes, Obesity and Cardiometabolic Update. I know, I know. You're already thinking and you're right. The new name is doc. Diabetes, Obesity and Cardiometabolic Update. You'll notice this when the change is made on your subscriber feed will have a new title and branding. Same great information. For more information and links to the articles that we discussed in this issue, just go to diabetesjournal.org until next month. Keep listening and keep learning.

John (29:17)

Sam.