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Diabetes Core Update
Diabetes Core Update – May 2025
00:30:34
Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association’s four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes...
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- [00:03]
A
We have another great issue this month, beginning with an article from the New England Journal of Medicine titled A long duration small interfering RNA targeting lipoprotein A, where we are discussing this with the first author, Dr. Stephen Nissen. Then we're going to talk about a very interesting article in Diabetes Care on on the relationship between diabetes and anemia, some surprising results here. Then another article from Diabetes Care on the efficacy and safety of phenurenon in type 2 diabetes. A pooled analysis of trials where we'll be discussing this with one of the authors of this study, followed by two articles. The first, cardiovascular and kidney outcomes and mortality with long acting, injectable and oral glucagon like peptide receptor antagonists and in individuals with type 2 diabetes. This is a systematic review and meta analysis of randomized trials published in Diabetes Care. And then a discussion of the CVOT of oral semaglutide looking at cardiovascular outcomes in high risk patients with type 2 diabetes published in the New England Journal. And we will be discussing these two articles with one of the authors of the trials, Dr. Darren McGuire. Our first article this month is from the New England Journal of Medicine titled A long duration small interfering RNA targeting lipoprotein A, the Alpaca Trial. Joining us to discuss this article, we're privileged to have Dr. Steven Nissen, who is Chief Academic Officer of the Heart and Vascular Institute at the Cleveland Clinic and Professor of Medicine at the Lerner College of Medicine. Welcome, Steve.
- [02:02]
B
Thank you, Neil.
- [02:03]
A
Steve, this is such an important topic and can you start by discussing the importance of lp, which I think many in our audience are not as on top of as they will be soon, as well as then why the study was undertaken.
- [02:20]
B
First of all, your initial question is absolutely important. Many studies have shown, including one that we did in 48,000 people globally who already had atherosclerotic cardiovascular disease, only 13.9% of them actually had a lipoprotein A drawn. Lipoprotein A is a lipid particle strongly associated with development of both atherosclerotic vascular disease and aortic stenosis. About 20% of the global population have this. It's not being tested even though the testing is inexpensive because people have felt there's no treatment, diet, lifestyle, statins, nothing was affecting levels. It's a genetic disorder. And so people weren't testing. That is in the process of changing. And that's why this topic is so.
- [03:17]
A
Important and it really is. And the idea of not testing for LP because currently we can't do anything about it. Makes as much sense as not asking about family history. Right. That there's a lot we do around other risk factors that are influenced by what we know about someone's risk. But now we're on the verge of actually having some treatments here. Can you tell us about the background for this particular study, the methods, and then we'll go over the results.
- [03:46]
B
As you point out, Neil, there are multiple drugs now in development and the only way you can beat a genetic disorder is to interfere with the messenger RNA or alter the gene, but interfere with the messenger RNA that codes for the protein that is needed to assemble lipoprotein A. Lepodycerin is being developed. It's a drug being developed by Eli Lilly. We've reported on phase one, which was very small and this was now a pretty good sized phase two trial, the ALPACA trial with 320 patients. We studied a variety of doses, but the really interesting dose was the one we expected to be the optimal dose, which is 400 milligrams. When we studied these people, and these are all people that had levels of lipoprotein a greater than 175 nanomoles per liter. Upper, limited normal for most laboratories is 75 nanomoles per liter. So these people were at least twice as high is the upper limits of normal. And they were administered a dose at baseline and at 180 days, essentially six months later. But those doses in some cases were drug and others were placebo is a randomized trial for the group that got 400 milligrams at baseline. And that's both those that were going to get placebo six months later and get a second dose of drug. We specified as the primary endpoint the time averaged reduction in lipoprotein a from day 60 to 180. And we got a rather remarkable 93.9% time average reduction in lipoprotein A all the way out to 180 days. And interestingly enough, from 30 to 360 days, reduction was 88.5%. So that's going up for a full year. In those that got a second dose, the time average reductions were 95%. Essentially levels of lipoprotein A were near to zero. In fact, many of the participants were below the lower limited detection for the assay. So a really effective interference with the message for apolipoprotein A, which is used in the assembly of lipoprotein A particles. Now, of course, safety is also very important and really there were no treatment related serious adverse effects. The major issue was Some injection site reactions and up to about 12% of patients at the highest dose, they were mild, they were transient. And when you have a drug given this infrequently, an injection site reaction really isn't much of a problem. This was about what you expect when you get a vaccine, COVID vaccine or whatever. Really very substantial effectiveness without substantial adverse effects.
- [07:08]
A
Pretty amazing results. And from a practical point of view, if it eventually gets FDA approved, and I'm sure now it's moved on to phase three, which we'll mention in a minute, but it's sub Q given infrequently, it's something that could be given 20% of the population makes it a primary care medicine eventually. It's something that has to be addressed prior to broadly. It's something that doesn't require an infusion center and it enhances adherence with that interval.
- [07:40]
B
Absolutely. Now, we did something unusual here. We launched the phase three trial before we completed phase two, and we did that because phase two went out to 540 days. And we knew from phase one that this drug was really very effective and we didn't want patients to wait. So we started it with a proposed dose with the idea that when we completed phase two, we would determine whether or not to give the drug once or twice a year. But we started the trial and it's enrolled very quickly. And there's something else unusual about the trial. It's the first trial that includes primary prevention patients, not just secondary prevention patients.
- [08:24]
A
Patients.
- [08:24]
C
Wow.
- [08:25]
B
So we have a very large group of primary prevention patients in the trial. Our goal is to find out whether lowering lipoprotein A is effective in people, both in the primary prevention and the secondary prevention setting. Let me tell you why this is so important. There are 1.4 billion people on the planet that have this disorder and 64 million in the United States. We gotta find these people. We have the opportunity, we hope to be able to offer them a treatment. But FDA will not approve these drugs until we show that lowering lipoprotein A reduces cardiovascular morbidity mortality. And we're anxiously awaiting the first of these drugs, which is not Lepodiserin, it's a drug called Pelacarson. That trial will complete next year and we will have an answer as whether, like we saw with ldl, whether lowering lipoprotein A reduces cardiovascular events.
- [09:31]
A
This is such an exciting time.
- [09:34]
B
Yeah. I do want to add one more thing because of this is the ADA podcast. The combination of diabetes and an elevated lipoprotein A is particularly bad for Outcomes, we know that these two have additive effect cardiovascular events and other ascvd. So for the diabetes population, this is also really important.
- [10:03]
A
It's such an important issue. And I didn't know that you were looking at both primary prevention as well, which typically in trials we look at first an enhanced high risk cardiovascular population, maybe all with ascvd, and then move on from there. That's pretty remarkable.
- [10:20]
B
Yeah, we're excited to be able to do it. Obviously very expensive. It's a large trial, 12,500 patients, but it is enrolled incredibly quickly. I won't tell you how many people we enrolled, but we're making very rapid progress.
- [10:36]
A
Dr. Steve Nissen, thank you so much for joining us.
- [10:39]
B
And thank you, Neil, for having me.
- [10:44]
A
For our next article, we're going to talk about an article from Diabetes Care titled Association between Diabetes and Anemia Evidence from NHANES and the UK Biobank. The authors looked at the association between diabetes and anemia, which is not something honestly I've thought much about. They included over 9,000 people from NHANES and almost 400,000 people from the UK Biobank regression was used to examine the cross sectional association of diabetes and anemia. And what they found among people 40 to 69 years of age in both the US and the UK was that the adjusted odds of study participants with diagnosed diabetes also having anemia was two to four fold higher than those with normal glycemia. Over a median follow up of almost 14 years in the UK, 42,000 people, a little over 10% developed anemia. The adjusted hazard ratios for incident anemia that is developing anemia compared to diagnosed. Comparing diagnosed diabetes with normal glycemia was 3.05 for iron deficiency anemia, I.e. 3, 3 fold higher incidence of iron deficiency anemia, a threefold higher incidence for anemia of chronic disease and 4.8 and almost 5 fold times higher incidence for vitamin B12 deficiency anemia. John, your thoughts?
- [12:25]
D
So I think this is an interesting study and it might change our workflow that perhaps the CBC should be part of our routine blood work when we're doing diabetes. And so a couple I think are the points to extrapolate. Certainly we worry about kidney disease and our patients with diabetes and kidney disease certainly can block hand in hand with anemia. So we're going to attend to taking good care of people's kidneys. B12 deficiency can travel with metformin. Metformin, the most common oral used medicine in diabetes. So certainly if we have people on metformin who have an anemia especially a macrocytic anemia, we might want to throw a B12 in there. The point that I think is worth thinking about is we really mark our control of diabetes based on A1Cs and A1C is kind of linked to red cells. And so how much does this correlate? How much should we be dampening or increasing or modifying our A1C based on hemoglobin, just like we might modify a sodium based on a very high sugar. And so there was a study in 2020 that was out of India. So India has a 40% prevalence of anemia in their population. So a pretty good place to look at anemia. And they actually looked at A1Cs and how it kind of links with anemias and how much. We can continue to base some of our information. Again, more of a homogeneous population before you want to expand it to everyone. But in this large study with a lot of anemia, they really found you needed to get down to hemoglobins about 5 before you start seeing these huge changes in A1C and other studies looking into that iron deficiency anemias might falsely elevate people's A1Cs. The anemias we probably need to be most cognizant of when we're using our A1Cs are people have hemolytic anemia. So in a hemolytic anemia, the red cell is going to live a shorter period of time, which it might not necessarily in a B12 deficiency or anemia chronic disease, but in a hemolytic anemia, we might really want to have a bit of a caveat in our interpretation of a 1C.
- [14:51]
A
For our next article, we're going to discuss an article that was published in Diabetes Care titled Efficacy and Safety of phenuronan in type 2 a pooled analysis of Trials of Heart Failure and Chronic Kidney Disease. Joining us to discuss this article is Dr. Muthu Vadaganatham, who is a cardiologist and co director, center for Cardiometabolic Implementation Science at Brigham and Women's Hospital and Harvard Medical School. School Mutu. Welcome back, Neil.
- [15:24]
C
Always a pleasure. Thank you for having me.
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A
Muthu, can you tell us a little bit about phenarinon and why this analysis was undertaken?
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C
Absolutely. Phenerinone is a non steroidal mineralocorticoid receptor antagonist. It's now been shown to be efficacious and safe in two primary populations. One is people living with type 2 diabetes and chronic kidney disease. That was based on the Fidelity program. And then more recently in patients with heart failure with mildly reduced preserved ejection fraction that's based on the Fine Arts Heart Failure trial. This particular analysis takes into account the totality of evidence of phenerinone in these related populations of cardioculin metabolism in a pooled analysis of the three phase 3 trials of phenerinone, totaling now about 18,000 patients. We particularly wanted to focus on the people living with type 2 diabetes because it is a common comorbidity across this CKM spectrum. And so we focused on about 15,000 individuals across these three phase 3 trials who had type 2 diabetes.
- [16:40]
A
And is there anything particular that we need to know about the pooled analysis? Anything about the way it was done before we jump into the results?
- [16:49]
C
The fine heart pooled analysis was entirely pre specified and pre registered prior to the unblinding of the Fine Heart Failure trial. And we published the primary results of the fine heart pooled analysis in Nature Medicine alongside the Fine Arts Heart Failure Primary publication. This showed across this broad population of these three trials that phenerinone not only influenced disease specific pathways, prevented heart failure hospitalizations, prevented kidney disease progression, but also influenced all cause events, reduced the risk of all cause mortality and all cause hospitalization. So really provided systematic protection for these individuals across the CKM spectrum. I think really importantly positioned phenerinon alongside some of the other pillars of care that we discuss in the management of CKM, such as RAS inhibitors, SGLT2 inhibitors and GLP1 receptors.
- [17:49]
A
So tell us now about the results of the current study and what that's added to our understanding.
- [17:55]
C
Absolutely. So we wanted to focus on people living with type 2 diabetes because of the medical complexity of their care and because these patients are at enhanced risk for clinical events and clinical disease progression. We focused on the 15,000 individuals with type 2 diabetes. These were patients who were commonly seen in clinical practice. Their average age was 66. About a third of individuals were women and the average A1C at baseline was 7.6%. They had a varied background use of glucose lowering therapies. A number of individuals, about 17% were on insulin or another 13% were on insulin and metformin. Many individuals were on metformin alone or metformin in combination with sulfonyl. But most importantly, the treatment effects of phenerinone were entirely consistent, irrespective of not only background use of these therapies, the background glycemic regimens, but Also background hemoglobin A1c across a broad spectrum of hemoglobin A1c in these trials, the treatment effects of phenerinone was entirely consistent, meaning phenerinone can really be layered or added alongside existing regimens in a safe and effective way and not only again showed prevention of disease specific pathways, but also prevention of overall events entirely consistent. Based on that background, use of medicines and glycemic profile, and that's so important.
- [19:35]
A
Was it also true on top of SGLT2s and or GLT1s?
- [19:42]
C
Very important point and part of the reason we undertook this is because the use of SGLT2 inhibitors in GLP1 receptor ant agonists have of course been accelerating across these disease populations. And with the addition of the more recent fine arts heart failure population, we had a sufficient number of people now treated at baseline with one or both of these therapies. And reassuringly, the treatment effect on key endpoints and the safety profile of pheneurinone was entirely consistent, irrespective of people were pretreated already on an SGLT2 inhibitor or GLP1 receptor agonist or not. And so that again provides reassurance that these are additive approaches to care and that they can be incorporated in a complementary manner in treatment regimens in people with type 2 diabetes, especially who face high risks of clinical disease progression.
- [20:40]
A
And that's so important because very few of our people with diabetes are in just one or even two medicines. And we really have moved from a glucocentric approach to a risk based approach, a more personalized approach. What do you see as the clinical implications of this analysis?
- [20:59]
C
I think treatment guidelines have often been in individual disease specific silos. We've often had diabetes guidelines, heart failure guidelines, kidney disease guidelines. I think now we're understanding these therapies have really broad implications to people and that extend maybe well beyond the disease that was intended to focus on. I think these data, especially this fine heart pooled analysis, which takes into account all the varied effects of phenerinone, may influence multiple guidelines and including emerging guidelines like cardio, kidney metabolic guidelines that bring these disease states together under a single umbrella. And we expect that in upcoming years that many different societies may actually include and incorporate multimorbid patients and how to best management manage them in care. I think these data will be tremendously informative for those types of guidance.
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A
Dr. Muthu Vadagunatham, thank you so much for joining us.
- [22:06]
C
Absolute pleasure. Thank you so much.
- [22:10]
A
For our final discussion this month we're going to look at two articles. The first was published in the New England Journal of Medicine titled Oral Semaglutide and Cardiovascular Outcomes in high risk type 2 diabetes. This is the long awaited CVOT. The second is from Diabetes Care entitled Cardiovascular and Kidney Outcomes and Mortality with Long Acting, injectable and oral GLP1 receptor agonists in individuals with type 2 diabetes. A systematic Review and Meta Analysis of Randomized Trials. To discuss these two articles and their clinical implications, we really are privileged to have Darren McGuire joining us. Dr. McGuire is an author on both studies and is first author of the Oral Semaglutide trial. He is a cardiologist and a clinical trialist. He is the Distinguished Teaching professor of Internal Medicine at the University of Texas Southwestern Medical center in the Division of Cardiology. He is the director of the Parkland Hospital Health Systems Outpatient Cardiology Clinics. He is deputy editor of the journal Circulation and a whole bunch of other titles as well. And frankly, just an all around good guy. Darren, it is such a pleasure to have you joining us again. Welcome back to our podcast.
- [23:34]
E
Hey, thanks so much, Neil. It's always great to hang out with you.
- [23:36]
A
Let's start with the first article. The CVOT for oral semaglutide. What should we understand about how it was done and what did it show?
- [23:46]
E
Yeah, so we, we randomized almost 10,000 people to oral semaglutide versus placebo. These are patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease and or kidney disease. And we randomized them to once daily oral semaglutide versus placebo. Our primary outcome was cardiovascular death, MI or stroke. And we succeeded. We showed 14% relative risk reduction, statistically significant. And, and this is on the backdrop of really excellent medical care that they were getting back on the background. It's a real win. It shows us that oral semaglutide plots perfectly on the meta analysis of the pulled data from the injectables. So we now have an oral option for patients.
- [24:35]
A
Yeah, which is so important. And we've had that oral option for a while, but now we know that it does what we hoped it would with regard to outcomes on mace. And that brings us right into our next article that we're going to discuss. The meta analysis and systematic review of both injectable and and oral GLP1s. What should we understand about how that meta analysis was done and what did that show?
- [25:01]
E
Yeah, it was remarkable. When we first saw the data, when we first got the result from the sole trial, it was amazing that the 14% relative risk reduction mapped perfectly onto the class effect that had been seen before in the Meta analysis of the injectable we went into the trial hoping to see if we can demonstrate efficacy and it might perfectly to the thousandth decimal point. It's amazing. And when we did this updated meta analysis we didn't move the needle at all because the needle was already there. And we just put this squarely into the, into the, into the domains. The oral option is as good as the injectables.
- [25:42]
A
Yeah. And the consistency across the board in all of these trials for decreasing MACE was really amazing. That 14%. Now can you share with us what was the number needed to treat? That's often a good way to view. Is it? How important is the intervention?
- [26:01]
E
Yeah. So we pre specified a number needed to treat analysis at three years. We knew we would have, it was an event driven trial. We needed to collect over 1225 events and we wanted to collect number needed to treat when we had the most robust data. And so we knew we would have a median follow up of four and a half to five years. And we established that three years. We analyzed the absolute risk difference which was 2%, which yields a number needed to treat of 50. So 50 people treated for three years yields a clinical benefit. People look at that number and they say that means 49 people didn't achieve the benefit. But you have to realize this, this is squarely in the context of the effect of aspirin for secondary prevention, moderate dose statins, good blood pressure control. So although it's everybody doesn't benefit but we think over time they would. It's really. This puts us right in step with all of the cardiovascular therapies we use for ascvd.
- [27:09]
A
Yeah, I've often had heard people minimize what really are very good NNTs. And the thing that we always need to remember is that we don't give these medicines just for three years. People are on them for 10, 15, 20 years and one expects as those curves diverge, the number needed to treat for a longer period of time diminishes. If it's 50 for three years, perhaps more likely it's 25 when you look at six years. So it's a way of viewing real absolute benefit. But we should be careful not to minimize the effect as you alluded to. Now I was fascinated in the meta analysis, in the discussion section you compared the effect of GLP1s to that of statins. Can you share a little bit of that those thoughts with our listeners?
- [28:07]
E
Yeah, I think this, we are so comfortable with the efficacy of statins and their benefits and I want to put that straight into context. These are not endocrinology drugs. These are not diabetes drugs. These are cardiovascular risk reducing medications. And they're squarely in the wheelhouse now of cardiologists, of primary care providers. We brought the nephrologists on board and this is an add on benefit to aspirin, statin, blood pressure control. These are. We're not treating glucose, we're not treating glycometabolic stuff per se. We're treating risk of the patient. And it's reduced with these medications.
- [28:50]
A
Yeah. And it's impressive. And I love the way in the discussion you also alluded to the fact that statins are only cardiovascular benefits. Really? And the GLP1s also have very well demonstrated effects on decreasing progression of chronic kidney disease, the flow study and heart failure. And really robust.
- [29:13]
E
And weight. Good point.
- [29:15]
A
Yeah, yeah. And so really robust effects across many different organ systems. So Darren, if we were to summarize this, what do you feel are the take home points for our audience?
- [29:27]
E
The take home point from our study is there are a lot of people who have eligibility indication for a GLP1 receptor agonist, even access to the medications, but don't want to take an injection. These the take on point is if you can get your patient to take the injection. I would choose that every time. But for whatever reason, if they don't want to do the injection, we now have an oral option once daily tablet and. And it maps right on the efficacy of the outcomes we've seen from everything else so important.
- [30:03]
A
Dr. Darren McGuire, thank you so much for joining us.
- [30:06]
E
All right, thanks so much, Neil. It's great seeing you. Always.
- [30:09]
A
You too. For more information and links to the articles that we discussed in this issue, just go to diabetesjournal.org until next month.
- [30:23]
D
Keep listening and keep learning.
- [30:27]
A
SA.