A (5:42)

Neal John I love this trial. I've been waiting for this trial but before I tell you why, let's just get the name of the trial out of the way. Vesalius From Andreas Vesalius in Brussels in the early 1500s who wrote the book on the Fabric of the Human Body which is the book that ushered in modern anatomy. The book was Important because he also raised the issue of we need to question conventional knowledge by direct observation. Prior to this book and his work, everyone accepted what Galen from the first century CE had said about anatomy. But Galen got a lot wrong. Vesalius actually did human dissection. He wrote down in this book what he saw and essentially changed not just our understanding of anatomy, but our understanding of how to approach conventional knowledge and to look at it with honesty. And so it is not surprising that they named this trial after his name. Why do I love this trial? Well, we've known for years, since the Fourier trial and the Odyssey outcomes trial, that PCSK9s, when added to people who have existent ASCVD, who are already on stens, leads to a much improved outcome. My opinion, we underuse these medicines. They are recommended in the guidelines for high risk people to try to achieve an LDL for a long time. Less than 70 now, less than 55, and we underutilize them. That's in the highest risk group. But what the Vesalius trial did was it said, how about people who have not had a first event, who have not had an mi, who have not had a stroke, Is it still in addition to a statin? It's a PCSK9, in this case evolocumab, when added to that statin, going to have a benefit? Well, the first part of this trial, the main trial, which was published in the New England Journal, told us that yes, it is. Yes they do. And the benefit is large. Now, this sub analysis published in JAMA that you were just going over said, okay, in that large group, a lot of the people did have defined coronary disease. They had, as you mentioned, high calcium scores. How about the group that didn't even have defined underlying atherosclerotic disease, but were at high risk people with diabetes who had diabetes for a while, was the main group that we're looking at here. And, and sure enough, it's a big deal, big change in outcomes. When you add evolocumab, there was a 2.1% decrease in three point mace over five years, an absolute decrease, which translated to a 31% relative decrease. And when they further analyzed this, looking at the effect after you got that first year of treatment out of the way, that relative decrease was 41%. Is this going to affect our practice? I think it will. I think this is one of those major trials that's going to be, at some point in the near future included in the guidelines that for people with high risk diabetes, for people with high calcium scores, that will be having the ability to consider, based on what I believe the guidelines will say, based on this trial, the addition of the PCSK9 to achieve substantially better, better outcomes. Our next article from the New England Journal is on intensive LDL cholesterol lowering and atherosclerotic cardiovascular disease. This was an open label superiority trial conducted in South Korea where the authors randomly assigned patients with atherosclerotic cardiovascular disease in a 1, 1 ratio to target LDL cholesterol levels of less than 55 milligrams per deciliter. This is the intensive targeted group, or less than 70 per deciliter, called the conventional targeted group. The primary endpoint was a composite of death from cardiovascular causes, non fatal Michigan, non fatal stroke, any revascularization or hospitalization for unstable angina at up to three years. They also, of course, assessed safety. They looked at 3,048 patients who underwent randomization. The median follow up was three years. The median LDL cholesterol level during the trial was 56 milligrams per deciliter in the intensive group, 66 in the conventional targeted group. A primary endpoint event occurred in 100 patients. In the intensive targeted group, that is 6.6% and 147 patients, that is 9.7% in the conventional targeted group. That was a hazard ratio of 0.67, or to say it a different way, a 33% decrease in the primary endpoint with a p value of 0.002. Safety was equivalent in both groups.

B (11:24)

John Neil, pretty interesting thing and I think if you have to look to see what's going to change a lot in the care of cardiovascular disease for this year, I think it's going to be us reevaluating that. How low do you go? And you and I are old enough to remember that there were 130, 170 targets for LDL. And then some of the guidelines got away from that and just said someone should be on a high, a high intensity or medium, medium high intensity statin. And really we didn't have those numbers as targets. And I think for a lot of reasons, I think for those of us who are doing primary care, I think it's really nice to have that number as a goal. And so I think we're going to see that back. But kind of interestingly enough, the old gold standard of 70, you know, doesn't do as well as 55. And I think 55, I think, is going to be our new kind of target, really for our high risk patients. And I think that that's a good thing. Well, what, you know, can you go too low? We need, you know, we need LDL to kind of make a lot of the hormones and a lot of the things our body uses. Well, going back to the late 60s, there were studies of the Kalahari Bushmen or the now called the San people of Africa who have LDLs in the 40s and certainly don't have any kind of misadventures because of that. Our children have very low LDLs and their LDL rises. So there's not a whole lot of downside to that. Now, the study that you just talked about was one that someone was on their maximally dosed amount of statin that they could tolerate. And then you added on the PCSK9 to get down to this. So this is just looking at this number, a South Korean study. So I think what it should do is we really should be pushing that statin to the best point that we can get it to. And, you know, really, you know, rosuvastatin is our most potent statin. And then if, depending on how far away we are, maybe we are going to have to reach to a PCSK9 to make it down to 55, maybe we can just use ezetimod, which is about $20 a month if you look at some of the discounted kind of pay for yourself prescriptions. So if you can really max out your most potent statin and you could use Ezetimine, maybe you can reach that 55. I think the other thing that I think is going to be a big question is, you know, what do we do with the people who don't have a huge amount of kind of risk factors? Are we going to have even lower and lower thresholds to take someone who doesn't have these risks to put them on a statin? Because statistically the door, the exit door for most of us is going to be in the cardiovascular family. And when you look at soldiers who died during the Korean War who were in their early 20s, they had atherosclerosis on autopsy, some of them. So, you know, do we wait until the plaque has built up to a point? And not everyone tolerates a statin super duper. Well, when you look at the statins trials, somewhere in that 8 to 10% of people have myalgias from that. But we're not necessarily exclusively kind of left with only one family to get us where we need to go. So I think we really should be relooking at target numbers. And I think we should be using kind of the tools that we have, the many more tools that we have right now to help us get to that destination. Our next article is from JAMA Cardiology and it looked at cardiorenal outcomes with tirzepatide compared with dulaglutide in patients with diabetes and cardiovascular disease. This was a post hoc analysis of the surpass CVOT randomized clinical trial. So this was a parallel design double blind trial that enrolled patients with diabetes and pre existing cardiovascular disease between May of 2020 and June of 2022 at 640 centers in north and South America, Europe, Asia and Oceania. The data was analyzed between July 25 and February of 26. Participants were randomized to receive either subcutaneous tirzepatide up to 15 milligrams or a fixed dose of dulaglutide 1.5 milligrams administered weekly with roughly about 6,500 people in both arms. The main outcome was A primary efficacy measure was time from randomization to first occurrence of a six point composite of cardiorenal adverse outcomes including all cause mortality, myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure and a composite of adverse kidney outcomes among the over 13,000 patients enrolled. The medium age, the mean age was 64 years. There were 9,348 patients were male, 3,817 were female, 71% and 29% respectively. The mean standard deviation A1C was 8.4 after a median treatment duration of 46.9 months. The primary cardioretal endpoint occurred in 1559 tirzepatide treated patients or 23.7% and 1,803 of the dulaglutide treated patients 27.4 with a hazard ratio of 0.84. Sensitivity analysis showed similar hazard ratio for narrower five component endpoints without the kidney composite outcomes of a hazard ratio of 0.86 and the four point composite component composite that lacked both either the kidney or heart failure endpoint also had a hazard ratio of 0.86. GI adverse events were more common with tirzepatide 42.5% than dulaglutide 35.9%. Other adverse events were similar.

A (18:07)

Neil John, I just want to remind people about how important the surpass CVOT trial was and then we'll talk about today's analysis and surpass had a dilemma when it was being designed because the original CVOT trials, remember were all based on non inferiority and so you can compare the active drug, either SGLT2s, GLP1s to standard of care and you wanted to make sure that they weren't hurting anybody. But now it wouldn't be ethical to not use one of those medicines which have been shown to be superior to not using them in high risk groups. So you can't run a new trial on a GLP1 using a placebo comparator. So this was actually the first trial that addressed that dilemma using an active comparator. So tirzepatide was compared to dulaglutide because remember, dulaglutide had been shown in the rewind trial to have beneficial cardiovascular outcomes. And so one, this was really a groundbreaking trial in that respect. And the term imputed placebo, which most of us had not heard about before, came up with this trial because one could impute if tirzepatide is just as good non inferior dulaglutide, then it too was better than placebo, as was dulaglutide. There was a lot of complexity and it was done and, and the trial was organized around three point mace because that's what is needed for regulatory approval and showing that it has cardiovascular benefit. But the reality of clinical care and what we've learned over the last few years is this interrelationship between cardiac and kidney and metabolic outcomes. So about two and a half years ago there was an American Heart association presidential advisory called Cardio Kidney Metabolic Disease. A call to action reminding us of what we already know, but giving it a name that all these different parts are actually closely linked in a cohesive whole. So what this analysis sought to do was look at that broader set of outcomes that included cardiac outcomes as well as kidney outcomes. And sure enough, when you look at that broad set of outcomes, Tirzepatide was significantly better, as you said, a 16% improvement on that, on that multiport point mace outcome when compared to dulaglutide with a P value that was very significant less than 0.001. So how do we think about this? Well, on that six component cardiorenal endpoint analysis, there was an absolute risk reduction of 3.7% in the tirzepatide group compared to dulaglutide. And that turns out to equate to a number needed to treat to prevent one event of number needed to treat of 1 to 27, one event is prevented for every 27 people treated. That's considered an excellent NNT. So what do we find from this trial? That on the broad array of endpoints that dual agonist GIP, GLP1 antagonism tirzepatide performs better than dulaglutide. For our next article from Diabetes Care are going to look at the association between GLP1 and ischemic optic neuropathy. This is a meta analysis. Now we've been talking about this a bit over the last year because this has come up as a bit of a surprise I think to many people and it's important to be able to get the solid data and perspective on it. The objective of the authors was to investigate the association between GLP1 receptor agonists and a non arteretic ischemic optic neuropathy. That is a form of optic neuropathy where there is sudden onset of visual loss in one eye and it is not due to something like temporal arteritis, a art heretic cause of it. The authors looked at PubMed, Embase and Cochrane Library databases. They calculated odds ratios and absolute risk for non arteritic ischemic optic neuropathy. Naion how I'll refer to it as we move on. They pulled those results. They also looked at any ocular event as a secondary outcome. They looked at 15 longitudinal studies. That was eight trials with over 1.5 million patients included. GLP1 use was associated with higher incidence of naion risk with an odds ratio of 1.7 and that was fairly consistent across randomized trials. An odds ratio of 2.36 and non randomized studies. An odds ratio of 1.6. Absolute NAION risk in the GLP1 group was 0.09%. So even though we have that high odds ratios, the absolute risk was 0.09% corresponding to a 0.037 risk difference or number needed to harm of 2,700. There was no association with overall ocular events.

B (24:28)

So Neil, we've done some similar articles like this that have come to about the same conclusion. And you know, overall if you look at the study, the amount of ocular events turned out to not be a whole lot different. But for our patients who are on GLP1s who have diabetes, one can argue that that would lead to better glycemic control. Better glycemic control can decrease microvascular disease. So really a lot of the things that we're going to do to improve someone's, the care of someone's diabetes, especially if it's early on, can have some implication in decreasing their, their vision loss from, from diabetes. So this is occurring in about 1 in 2700 patients kind of the number needed to harm in my reading for people who are not on a GLP one somewhere in that one to 10,000 in the general population. But you know my concern for this is not necessarily our patients that we're trying to achieve better glycemic control or really the patients who are obese enough to be on one of these class of medicines for weight loss. You know, I am worried that there are industries out there that are prescribing these medicines as almost cosmesis type things and if, you know, if I'm having a side effect that I lose vision from something for medicine I probably really didn't need except for whatever reason that I went on to one of these online sites, that's a little bit worrisome and I think that probably that needs to be in a bit of the disclosure because that person with diabetes has a much higher rate of that of losing vision if their diabetes is not in good control. But that person who doesn't have that risk and is just doing it for some cosmesis related thing, I am worried a little bit about this as a side effect that is not intuitively obvious. Our next article is from Diabetes Care and it looked at comparative effectiveness of tirzepatide versus dulagotide or Semanga nilatide on major cardiovascular events in type 2 diabetes and cardiovascular disease. Insights from two TARGET trial emulations so the two TARGET trial emulations included commercially insured adults between June of 2022 and December of 2024 who had type 2 diabetes and atherosclerotic cardiovascular disease. The patients initiated subcutaneous tirzepatide, dulaglutide or semaglutide. The primary outcome was mace defined as a composite of non fatal mi, non fatal stroke and all cause death. First, new users of tirzepatide and dulaglutide were propensity score matched 1 to 1. Second, new users of tirzepatide and semaglutide were propensity score matched 1 to 1. Incident rates per thousand patient years and hazard ratios were estimated. After the matching, 9233 pairs of tirzepatide or dulaglutide initiators and 25,206 pairs of tirzepatide or semaglutide initiators were identified. The tirzepatide initiators experienced a lower rate of modified mace versus dulaglutide, an incident rate of 31.3 versus 39.4 respectively or a hazard ratio of 0.8 which seemed to be driven by lower all cause mortality among tirzepatide versus dulaglutide initiators with a hazard ratio of 0.6. In the post hoc analysis, Tirzepatide was associated with lower rates of pneumonia related hospitalization when compared with dulagutide. Rates of modified MACE were similar among tirzepatide and semaglutide initiators 23.7 versus 23.2 with a hazard ratio of 1.03.

A (28:40)

Neil John, it's pretty amazing. We live in this time of enormous data sets and this data set was from the Optum data set. Optum is essentially a company that aggregates information from multiple electronic health records from multiple, multiple, from extremely large numbers of health systems and Medicare databases. And what it allows us to do is make comparisons like this which really are needed between different medicines which otherwise could only be done by an actual randomized trial. Randomized trials of course, taking years and years and years and often hundreds of millions of dollars to carry out. What this one shows is it confirms in a way what we would suspect, which is that people on Tirzepatide, Tirzepatide being the dual agonist compared to dulaglutide, Tirzepatide having Both more powerful A1C reduction, larger metabolic benefits and much greater weight loss than one would see with dulaglutide that we see a lower incidence of MACE with tirzepatide versus dulaglutide. It's what we would expect to be the case and it's nice to see that confirmed that lower all cause mortality. I'm not sure I would have assumed and this was 40% lower. That's a big deal. And given that this is the best data on this issue out there and it fits with what one logically would believe and there are no obvious confounders that would otherwise explain this if all other things were equal. I think I would lean toward tirzepatide in that comparison if I were to pick a medicine for my patient. All things aren't always equal, we know that. The other thing of course that the trial showed is that tirzepatide and semaglutide came out about the same again here. That is fascinating. These are both second generation long acting GLP1s one of course a dual agonist, one of course, a single agonist. Differences in Both have excellent A1C reduction, excellent weight loss. Yes, there are differences in potency. This is what the data Shows and again, fascinating and the best data out there on the comparison. Our next article, John, is actually not an article, as we mentioned in the introduction, but this was a study that was presented at the American College of Cardiology's annual scientific sessions, and it looked at over 246,000 US adults with underlying atherosclerotic heart disease. And its findings were so remarkable that we thought we would share this, even though it's not out yet. In an article, researchers used the Trinext database. Again, we've talked about these enormous data sets that we have out there. The previous one was from Optum. This is from Trinex. This is data set that includes health records of millions of Americans. And they looked at, in this case, to assess the rate of serious cardiac events in people over age 50 with atherosclerotic disease between 2018 and 2025. The study included 123,000 people who had received at least one dose of either the Shingrix or Zostavax shingles vaccine, and the same number of people who had not received any doses of shingles vaccine. Demographic and other health conditions were similar between the two groups. When the researchers examined cardiac events occurring between one month and a year after shingles vaccination, and of course, the same time period for unvaccinated individuals, they found that vaccination was associated with a lower risk. Across all outcomes studied, vaccinated individuals were 46% less likely to suffer any major adverse cardiac event and 66% less likely to die from any cause. They were also 32% less likely to suffer a heart attack, 25% less likely to suffer a stroke, and 25% less likely to develop heart failure. John.

B (33:24)

So, Neil, I think this is a very interesting study during these very interesting times when it comes to vaccines. So, you know, I think when our patients are hearing all these kind of varying, different opinions, you know, often not as rooted in science as the ACIP is kind of struggling to kind of find out what they are right now. Pretty powerful study. You know, it's one of the interesting things that this study just really looked at a year. There was a study last year that really looked at up to eight years and really found this kind of same thing. How do you put this together? Well, if you look at influenza and you look at the Three Days After Developing Influenza, a study by McIntyre in the British Journal of Cardiology found that people have a tenfold chance of having a repeat someone who's already had cardiovascular disease, a tenfold chance of having another mi worth sevenfold chance of having a stroke. So really that acute inflammation is a really kind of big thing on this. And really shingles is an inflammatory response kind of more local, but I think it's kind of fascinating. So there's, you know, one out of three people over a certain age, over probably over 60 are going to have shingles at least one time in their life. There's only about a hundred deaths. The shingles vaccine itself, kind of a tougher vaccine in that it's very reactionary and that people can, you know, and it's a two dose series there. The Zostavax really wasn't, was really kind of phased out before this trial really started. It really has mostly been the recombinant shingles vaccine but it's only 100 people die from shingles. We're also starting to see studies with regard to decreasing dementia. Big study out of Kaiser Permanenti, a big study out of Australia and we're also starting to see things from some of the other adult vaccines that having less inflammation might be certainly as tethered to cardiovascular disease. So the anti inflammatory certainly is tethered to cardiovascular disease, but we might find it tethered to a whole lot of diseases. And I think as we are struggling in the din of information to talk with our patients about getting some vaccines, I think this might be a potent one to talk about, hey, you are at risk for cardiovascular events. We probably all are over a certain age. That might be another reason to get the shingles vaccine or the flu vaccine. So I view this as a win for science.

A (36:27)

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.

B (36:46)

Sam.