Transcript: HelixTalk #197 - Sweet Deal of Updates in Diabetes Pharmacotherapy from the ADA 2026 Standards of Care
Episode ID: 231
Generated: 2026-07-24 15:31:53
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[00:00] Voiceover 1: (Music)
Welcome to HelixTalk, an educational podcast for healthcare students and providers covering real-life clinical pearls, professional pharmacy topics, and drug therapy discussions. 

Voiceover 2: This podcast is provided by pharmacists and faculty members at Rosalind Franklin University College of Pharmacy. 

Voiceover 1: This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified healthcare provider. 

Voiceover 2: And now, on to the show.

Dr. Sean Kane: Welcome to HelixTalk episode 197. I'm your co-host, Dr. Kane.

Dr. Khyati Patel: And I'm Dr. Patel. And the title of today's episode is Sweet Deal of Updates in Diabetes Pharmacotherapy from the ADA, American Diabetes Association's, 2026 Standards of Care. So Dr. Kane, in this episode, we're going to discuss some of the important annual updates, as we know American Diabetes Association puts out their guidelines every year. So we're focusing on the 2026, but particularly focusing on some of the pharmacotherapy recommendation changes and supporting evidence. So we're going to kind of dive deeper into it.

Dr. Sean Kane: And Dr. Patel, again, we, whenever we do this episode, kudos to the ADA for like every year busting out a new set of guideline recommendations. I'm sure this is a massive amount of work to do that. There's always a lot of new evidence in the diabetes space, so it's really nice that they do this and even nicer that they do it every single year.

Dr. Khyati Patel: Yeah, I think the last time we kind of did a comprehensive sweeping updates from the Standards of Care was in 2023. That was our episode 164. So we have skipped a couple of years. Um, there are not new agents approved in the market, but there's some just evidence that's become available, um, and then that's how, you know, these guidelines are incorporating them and and weaving them into their recommendations.

Dr. Sean Kane: So Dr. Patel, I know digital health is a very hot topic in pharmacy education, and I know that there's some new diabetes technology updates that the new guidelines talk about. Why don't we start there?

Dr. Khyati Patel: Yeah, absolutely. CGMs and automated insulin deliveries. That's like the technology that we are talking about today. Um, CGMs, what's new in the CGM world is that we don't have those intermittently scanning CGMs anymore in the market. Everything is real-time CGM, so the RT-CGMs. We knew back in the day the evidence for RT-CGM was slightly better than the, uh, you know, intermittently scanning CGM anyways. Probably that was a good idea to sunset them, you know, out of the practice. Um, but the recommendation here for the CGM is that go ahead and use it at the start of the diagnosis, uh, in all patients using insulin therapy. So obviously all type 1 patient and some of your type 2 patients will also qualify for it. Growing evidence also has been coming out for CGM use in type 2 patients who are not on insulin therapy, and I've seen in my practice too more and more insurances are also covering CGMs for these patients. So Medicare still requires that one dose of insulin. Also there is another pathway for approval, which is if you're not on insulin therapy but are on other medications that can lower your glucose and you have like those level 2 type hypoglycemia, two events or more that are documented, you do get qualified for CGMs.

Dr. Sean Kane: So Dr. Patel, just to slow our roll a little bit, CGM is a continuous glucose monitor, and initially you said that we used to have two different kinds, the real-time CGM and then the intermittent scanning, and I heard real-time is better. And we did a CGM episode 162, but could you just review for the audience what the intermittent scanning meant and then why we've moved to this real-time instead?

Dr. Khyati Patel: Yeah, the intermittently scanning CGMs were also called as flash CGMs where we had to bring the reader device, whether it be your phone or your, um, separate reader that comes with it, near the sensor where you're wearing it and then scan it every few hours. For one that was available, it was every eight hours you must scan the data. With the real-time CGM, that's not the case. You put on a sensor and then it just kind of connects to your reader device via Bluetooth, automatically sends the data. So it takes away that remembering that I need to do this every eight hours, uh, or at least every eight hours to see my number. All they have to do with the real-time CGM is open up their app or look at their reader and the number is right there because it's checking every, you know, five minutes or so. The evidence was a little bit better with RT-CGM compared to the intermittently, uh, scanning CGM. A, because people were forgetting to scan, right? So you don't have enough data collection. If you don't have data collection, you're not seeing the numbers live, that also takes away from that instant action that you can make and change in your behaviors and stuff.

Dr. Sean Kane: Okay. So I understand that. And then what I heard is that current practice is that if you're on insulin, you should have a CGM. Like, full stop, right?

Dr. Khyati Patel: Yeah, they are recommending it. Even if it's just a basal and intense regimen.

[05:00] Dr. Sean Kane: So that means everyone with type 1, because that's what they get, and then type 2, people on insulin, but then I heard maybe if you're more prone or you've had hypoglycemic episodes, and I'm thinking sulfonylureas, is that the main patient group that might not be on insulin that has type 2 that might qualify?

Dr. Khyati Patel: Uh, yeah. They're not asking for a patient to be on a particular type of agents. They're just saying as long as they have two episodes of level 2 or more hypoglycemia that you can document where some sort of intervention was needed, whether you needed to change therapy, whether patient needed to come and see, whether you needed to prescribe glucagon and educate the patient, or patient ended up in the ER. Any of those count. Um, if you can document those and submit that for, uh, approval, um, patient may get qualified.

Dr. Sean Kane: Okay. And then the other piece of technology is automated insulin delivery. Um, is this new in the guidelines then?

Dr. Khyati Patel: Um, the device or the word automated insulin delivery is, it's not new. We have the multiple daily injection, the MDI therapy, which is just the pen, you're using a a simple insulin pen injecting it multiple times a day. We have the insulin pumps, but the automated insulin delivery is a combination of a pump and a CGM. So the pump and the CGM have algorithms in the back and they kind of control the sugar, advise you if you need to inject a little bit more insulin or hold the insulin or suspend, we call it the insulin delivery. Um, so kind of work. Currently what we have in the market is called a hybrid closed loop technology. Quite not there with the closed loop, um, but that's what the guidelines are referring to as an automated insulin delivery. So they are recommending it that anybody who's using insulin, uh, we should be using this type of technology to support better insulin management.

Dr. Sean Kane: So in someone who takes multiple doses of different kinds of insulin throughout the day, um, they should be on this automated insulin delivery device as opposed to mealtime plus a basal insulin regimen.

Dr. Khyati Patel: Correct. And then once the insulin goes in the pump, it's just one kind of insulin. It's just delivered in a different fashion to give you both that basal and bolus coverage.

Dr. Sean Kane: It makes sense that this is easier, right? Like, I get that it's more technology, but it's easier from a patient perspective in terms of not having to inject yourself as many times, not having to remember the different kinds of insulin, and, uh, I'm sure that the devices are smart enough that they can kind of titrate your dose as needed based on your sugar, right?

Dr. Khyati Patel: Uh, yeah. There's some user interface still needed. It's not completely independent. But there are a lot of algorithms behind the scene that would provide, based on the patient's patterns of glucose and meal patterns, it can provide suggestions for, hey, you need this much of extra oomph to cover you with this hyperglycemia that's happening right now. Back in the day, in order to get the AID, you needed to have C-peptide levels and antibody testing, so you're making sure you're a type 1 patient. Um, that's no longer needed. Uh, and we know it's just not type 1 or type 2, there are some type 1.5, uh, patients who also need insulin therapy. So this is across the board for anybody who's on insulin, intense insulin regimen, who needs the, um, better control of sugars.

Dr. Sean Kane: Got it. Okay. Well, let's move on to the next uh section that you identified, and that was medication-induced hyperglycemia. So when I think medication-induced hyperglycemia, I'm thinking like, uh, atypical antipsychotics like Zyprexa or olanzapine, but that's like super old school. So we have some newer therapies out there on the market that, um, maybe we don't immediately associate with hyperglycemia, right?

Dr. Khyati Patel: Yeah, and I think we knew these therapies are not brand new, brand new, but I love the fact that the guidelines are bringing that discussion together and focusing on what do we do. Um, and so these are agents, obviously we know the steroids, right? Steroids increase, uh, the glucose and kind of really didn't know what was the management. So patients who are on recurrent or sort of like that long-term steroid therapy, they're going to face hyperglycemia. The recommendation actually is to use metformin to prevent that hyperglycemia in those high risk individuals and monitor a particular time of glucose, which is postprandial or random. So not fasting, but postprandial or random glucose. So that's that's kind of like the newish recommendations to manage hyperglycemia if patients are on steroid therapy.

Dr. Sean Kane: And I want to highlight the word prevent here. So is this a prophylactic regimen or you're monitoring postprandial glucose and based on that, if it's elevated, then you give metformin for the postprandial hyperglycemia?

Dr. Khyati Patel: Uh, that's correct. So they're saying don't wait for things to go bad, kind of ask the patients if they're on recurrent long-term steroid therapy, ask them to start monitoring that postprandial or random glucose. If those numbers are elevated, go ahead and start the metformin therapy.

[10:00] Dr. Sean Kane: So potentially these patients wouldn't necessarily have a diabetes diagnosis yet, but it's an elevated value that because they're on a steroid, because it's an elevated value, you're going to give them metformin to prevent them from getting to that diabetes diagnosis earlier than they might normally.

Dr. Khyati Patel: That is right.

Dr. Sean Kane: Okay. What about some other drug classes?

Dr. Khyati Patel: Yeah, um, immune checkpoint inhibitors. We talked about this in a previous episode of HelixTalk, 111. Um, these immune checkpoint inhibitors are our anti-PD-1 or anti-PD-ligand 1 therapies such as the nivolumab, uh, pembrolizumab. By the way, side fun fact, I love the PD and it really stands for programmed death, uh, which is really intense. Um, but in our previous episode we did discuss that, you know, a case of how these immune checkpoint inhibitors can cause DKA or HHS. Um, and so yes, that's the risk with these guys. Um, there is a high risk of DKA, uh, development. So the recommendation for the guideline is that every time patient is visiting, not just primary care, but even, you know, their, um, regular oncology appointments, glucose should be checked. And these patients may need to actually start on insulin therapy earlier, um, because of the high risk of DKA that's there. So they may not have true diagnosis of diabetes, but just to avoid that hyperglycemia that comes with it, insulin can be used in these patients.

Dr. Sean Kane: Okay. And then the uh second new drug class that's mentioned, I'm going to give it a shot. So, uh, there's a reason it's an acronym. So this is our PI3K alpha inhibitors. So uh that acronym stands for phosphoinositidylinositol 3-kinase alpha inhibitors. Dr. Patel, I don't know what crazy person thought that that was a good idea to come up with that, but I love that we have the PI3K alpha inhibitors out there on the market. Um, I don't even know what these are.

Dr. Khyati Patel: These are rare therapies, uh, obviously for patients who have advanced stages of metastatic uh cancer, such as metastatic breast cancer. So the agents are alpelisib and um inavolisib. Again, these names are very tripping. Um, but I actually have a history of, uh, one patient who was on, um, alpelisib therapy, um, who ended up having hyperglycemia. So this patient did not have diabetes, but the glucose levels are high enough that they were flagging. Obviously we know sugar control is important in order to resolve underlying cancer process, right? Um, glucose is feeding these cancer cells, so we need to make sure that we are controlling the glucose. And then the guidelines are now recommending, um, to go ahead and use metformin as that first line for prevention of hyperglycemia in these high risk patients. So again, don't wait for them to have hyperglycemia. You could, if they have high risk factors, you could go ahead and start the metformin therapy right away.

Dr. Sean Kane: Okay. And then our last drug class that I'm way more familiar with are mTOR inhibitors. This is basically drugs that are used after organ transplant. So sirolimus, everolimus. These are well known for causing hyperglycemia. So similar, uh, the recommendation is fasting or random glucose at every visit. And then, uh, metformin just like, uh, the previous drug class can be used for prevention, um, before they get to that hyperglycemia point.

Dr. Khyati Patel: Yeah, and I think I want to kind of summarize why this this is a good step that ADA has taken to provide guidance as to how to approach hyperglycemia due to this medication use, um, because back in the day, if you look at randomized trials or small studies that are done, um, the recommendations are all over the place. Um, evidence was all over the place. So I'm glad that the, you know, the experts have come together and reviewed the evidence, especially with these, the PI3KA as well as the checkpoint inhibitors are kind of newer. So growing evidence has shown, um, how to approach the hyperglycemia better. So I'm glad that the guidelines kind of put it all together in one place.

Dr. Sean Kane: Yeah, absolutely. Well, why don't we move on to obesity? So this is specifically obesity management in patients with diabetes. What are some new recommendations here?

Dr. Khyati Patel: Yeah, so Dr. Kane, nothing different for patients with type 2 diabetes. Our GLP-1 receptor agonist and the combination GLP-1/GIP receptor agonist are still preferred therapy for weight management. The minimum weight loss of 5 to 7%, you know, recommended is still there. Um, what they're recommending is that just don't go after BMI alone, um, do consider another anthropometric measure such as like the waist to hip ratio, um, to consider that adiposity, um, issue that we are seeing, um, rather than just relying on BMI. We know BMI is not the best measure of adiposity, um, which is where all these obesity-related complications come from.

Dr. Sean Kane: Okay. And then, you know, Dr. Patel, you mentioned uh GLP-1s are our standard bearer for weight loss period, but then also among people with diabetes, which makes sense. Uh, I noticed that the guidelines made comments about people with type 1 diabetes using these, and most clinical trials they've been excluded from GLP-1 trials. So kind of blowing my mind here, what are we doing with GLP-1s among people with type 1 diabetes?

[15:00] Dr. Khyati Patel: Yeah, so that's kind of new. Um, and I think this is a big deal because, you know, we knew patients with type 1 diabetes had such limited use of anti-hyperglycemic agents, basically insulin, and then maybe amylin mimetic, but who knows if you use them at all, uh, if any. So we traditionally don't have the evidence for GLP-1 RA for hyperglycemia management. But people started using it. So we have some real world data looking at like that patient database type of cross-sectional study. Um, even though these therapies are not approved, we noted some benefit for weight loss, A1C improvement, and obviously because A1C is improved, we are using less insulin. So insulin sparing effect were seen. Based on that real world data, then there were a couple other randomized control trials that were done, ADJUNCT ONE and ADJUNCT TWO, uh, which used liraglutide. The brand name is Saxenda, liraglutide for 52 and 26 weeks, um, respectively in patients who were on type 1 diabetes. So this is that 1.8 milligram daily dose was used and it showed, uh, about 6% weight loss. So again, clinically significant weight loss is 5 to 10%, so 6% is meaningful weight loss across both the trials.

Dr. Sean Kane: I should just note that these are people who were obese that needed that wanted to lose weight. This isn't just to treat their type 1. This is for people who happen to have type 1 and whether it's kind of safe or not and do they end up losing weight. So weight loss was the main thing that we're looking at.

Dr. Khyati Patel: Absolutely. It did come with the extra benefit of, you know, blood glucose reduction, so we did see higher risk of hypoglycemia uh with the use of GLP-1, roughly like 20 to 30 percent, which is a big deal for a patient with type 1 diabetes. Um, and then on the other side, they also noted like double the risk of hyperglycemia with ketosis. Now ketosis by itself is not scary, but in type 1 patient, this could be a precursor to having a DKA. So real cases of DKA have not been noted, but because this patient population is already at a higher risk, um, we should be careful in how we approach the use of GLP-1. So good benefit, but a lot of monitoring and education needed.

Dr. Sean Kane: Yeah. So I'd say definitely it's not like every patient with type 1 who happens to be obese should be on it, but if they were to be on it for weight loss, the hypo-hyperglycemia risk, that's a pretty big deal that would need really close monitoring and a lot of patient education.

Dr. Khyati Patel: Yeah, and I think the guideline experts who worked on this recommendation went one step beyond and said, hey, there is this FDA approved indication, right, and the label and you start at a certain dose and you titrate for the weight loss purposes. That's all approved for type 2. Be cautious when you apply that to type 1 patient. You may not need to, um, titrate that aggressively or take your time in doing the titration with additional glucose monitoring because of these additional, um, risks that come with it.

Dr. Sean Kane: Mm-hmm. What about bariatric surgery? So is there some new evidence with type 1 patients um after bariatric surgery for weight loss?

Dr. Khyati Patel: Yeah, so um patients who meet the BMI requirements in type 1 were also looked at benefits of bariatric or metabolic surgery. They looked at about 17 different retrospective analysis trials. Um, total not that large, 107 patients who had type 1 diabetes. Um, their BMI went from 41 to 31, uh, over year and a half to five years of duration they were followed after the metabolic surgery. So still not complete resolution of obesity, but coming down from that stage 3 obesity to stage 1 obesity. Um, this did come with additional risk, obviously. 15 to 20% of the patient had DKA in first few weeks after surgery. Uh, the impact on A1C was sort of inconsistent, so not beneficial for sort of diabetes management, but you could say by dropping that BMI, you could avoid some of these obesity-related complications that come from.

Dr. Sean Kane: So definitely it's not a slam dunk then for really either GLP-1s or bariatric surgery, and if you were to pursue either route, there's a ton of patient education about the risks in particular to think about then.

Dr. Khyati Patel: Yeah, absolutely.

Dr. Sean Kane: Um, and then just to re-emphasize, we already mentioned it, GLP-1s or GLP-GIP receptor agonists, these are preferred for people with diabetes, primarily for type 2. Um, we just talked about type 1. And then in terms of titration, did the guidelines talk about uh the titration of those GLP-1s in particular?

Dr. Khyati Patel: Yeah, and I think this is important, um, Dr. Kane, because a lot of insurances will make sure you're following that FDA label titration. Um, and if you don't, they'll say, okay, you don't need the therapy. So these experts are coming out and say, please don't treat everybody the same. Um, some of these patients need individualized approach and titration. Please don't always look at the efficacy, also look at the safety. Um, and then you don't have to push to that max dose of what what is in the FDA approved label.

[20:00] Dr. Sean Kane: Intuitively makes sense that if you're having good efficacy at a lower dose, why would you push the dose higher, get more side effects, and potentially lose more weight at a quicker pace than what would be appropriate for that patient, right?

Dr. Khyati Patel: Yeah, that makes sense. So I think this was just a nice way of experts to say to insurance company, you you don't have to adhere uh to that and patient individualization should come first.

Dr. Sean Kane: For sure. Um, why don't we talk about type 2 patients and some of the recommendations about preferred therapies?

Dr. Khyati Patel: Yeah, this is chapter nine is the chapter that focuses on all pharmacotherapy recommendations, forward focused on obviously um lowering the glucose, but also some of the comorbidities of the diabetes. Um, so if you look at that image, um, 9.2, it's not any different, Dr. Kane, just tiny bit difference and that's what we want to talk about today. A lot of that revolves around our GLP, so incretin agents. Um, we have those three main comorbidity arms. We have the ASCVD or high risk for ASCVD, we have the CKD, and then the heart failure arm.

Dr. Sean Kane: Let's focus on the ASCVD and high risk ASCVD.

Dr. Khyati Patel: The recommendation is still use either GLP-1 RA. However, there used to be a a big OR in the middle and that's no longer there. If you look at the fine print in the recommendation, it says GLP-1 RA and/or uh an SGLT2i. And this is important. In patients who have very high A1C levels, they probably will need dual therapy and not just monotherapy. Traditionally we have done add one, see what the response is, go to the other. This and/or recommendation is interesting because they are saying in higher ASCVD risk patients, you could start both the therapies at the same time. Again, there is not any particular studies that the guidelines are citing, but I'm thinking this is probably somewhat apparent in the SOUL study, which was the oral semaglutide and the CVOT in the high risk patients. 26% of the patients in this study were already on an SGLT2i at baseline.

Dr. Sean Kane: So really what you're saying is that it's not like we have a trial of combining them both versus one versus the other, but in the trials, especially some of the newer trials, because these are somewhat newer therapies, we are seeing background therapy of both at the same time. So it and they work differently, right? So like intuitively it makes sense that they both have cardiovascular benefit. Um, it's not like you have to do one and then the other, like you could potentially do both at the same time.

Dr. Khyati Patel: Yeah, absolutely.

Dr. Sean Kane: Well, well let's talk about the SOUL study. So uh that was oral semaglutide or uh the brand name is Rybelsus. Was there a new trial with that then?

Dr. Khyati Patel: Yeah, this was a new trial. So as part of the semaglutide uh trial group, which was all the PIONEER trials, trial six, so PIONEER 6 uh was that uh CVOT trial. And it actually did not show additional uh cardiovascular risk reduction benefit. That was not, it was shown to be non-inferior to placebo. So what they did in the SOUL study is that they looked at high risk patient. It was a double blind placebo controlled superiority trial in type 2 diabetes patients, and they call them high risk diabetes patients. So these patients had A1C, baseline A1C ranging from 6.5 to 10%, had actual ASCVD, CKD, or both, and that's what the high risk was defined as. And total follow-up in this study was about 49.5 months. So pretty, pretty long trial.

Dr. Sean Kane: Okay. So then they looked at major adverse cardiac events. Um, 12% versus uh almost 14% with placebo. So there was a uh roughly like 14% reduction, number needed to treat of 56. That's a pretty big deal in terms of still observing a reduction in cardiovascular outcomes.

Dr. Khyati Patel: Yeah, and then secondary outcome was looking at the major kidney disease events. There was no significant difference there, but when it came to that primary event of MACE, that was definitely better.

Dr. Sean Kane: And then as you might expect because it is a GLP-1, even though you're taking it orally, we we still saw the typical GI side effects of semaglutide versus placebo, which would be nausea, anorexia, maybe changes in your bowel pattern, things like that.

Dr. Khyati Patel: Yeah, so it's important to note up until now, you know, we didn't recommend PO semaglutide for that ASCVD risk reduction, but with the result of SOUL trial, it's kind of opened up the boundary. Those who don't want to inject, uh, you know, PO version is okay. Just to remind, this is supposed to be taken a particular way, you know, first thing in the morning with just like that four ounce, they call it the quote-unquote sip of water, 30 minutes of no food, no drink, no other medication. So you still have to take it properly to maintain that good bioavailability. So patient education is important.

[25:00] Dr. Sean Kane: Um, then why don't we transition to the GLP-GIP receptor agonist. So this would be tirzepatide. Um, it's one of the newer ones, so it's not surprising that compared to some of the older GLP-1s like semaglutide, we don't have as much data for cardiovascular outcomes, but we did have an interesting trial called the SURPASS-CVOT trial. Why don't we talk about that a little bit?

Dr. Khyati Patel: Yeah, so Dr. Kane, usually when a drug's CVOT trial is needed, FDA recommendation is to do it against placebo. With case of tirzepatide, they did actually an active comparator in this trial and they used uh dulaglutide instead. So this was a double blind, um, active comparator trial, non-inferiority, um, trial that included about 13,000 patients and it was looked at over four years. And then mind you, both of these products are Lilly products. So they're kind of just comparing their own products with each other. Maybe that was another reason why they didn't go with the placebo and they just try to, you know, compare their own products.

Dr. Sean Kane: And then uh we've mentioned it a couple times. Dr. Patel, can you just explain what does CVOT stand for?

Dr. Khyati Patel: Yeah, cardiovascular outcomes trials. And this is the trial um that is required for all anti-hyperglycemics that are approved by FDA. Um, this happened with the whole Avandia, you know, debacle that happened back in 2008. And so any new drug that is approved by FDA, they need to have CVOT data to prove that it's not causing additional cardiovascular risk.

Dr. Sean Kane: So then they compared tirzepatide 15 milligrams versus dulaglutide 1.5 milligrams, and we'll talk about that dose in a little bit. Primary outcome was major adverse cardiac events, and it was about 12 versus 13 percent, um, so an 8 percent reduction, which proved non-inferiority but failed to show superiority difference. So, um, that's okay though. So they're looking to prove against, in this case, an active comparator that tirzepatide was just as good as dulaglutide in terms of reducing cardiovascular risk.

Dr. Khyati Patel: Right. And in terms of the secondary endpoints, it did show lower rate of death from any cause and composite death from any CV causes or hospitalization for heart failure in the tirzepatide group. And this is where that heart failure uh data for tirzepatide also comes in play. We're going to talk about another trial in a bit too.

Dr. Sean Kane: And they they did look at a number of other markers. So the the main thing was that they wanted to prove the CVOT, right, that their drug was just as good as, in this case, an active comparator, um, which is an FDA requirement. But they did look at some other stuff, and it shouldn't surprise you that much that they ended up picking like a pretty high dose of tirzepatide versus a not high dose of dulaglutide. But we saw better A1C reduction with tirzepatide, about 1.7 versus 0.9 percent reduction. We saw more weight loss, so a percent weight loss of almost 12% weight loss versus about 5% um in favor of tirzepatide. What else did we see?

Dr. Khyati Patel: Um, they also looked at other, you know, uh surrogate markers like triglyceride levels. Um, kind of focusing on that obesity metabolic syndrome route, and they found the reduction in triglyceride was 24% uh versus 10% from the placebo. They also looked at systolic blood pressure reduction. I don't think the difference was a whole lot, you know, um reduction of six uh in SBP versus four millimeter per mercury with the placebo. So they looked at also the eGFR loss over 36 months and it was not clinically significant, like six versus nine, not not a big deal.

Dr. Sean Kane: And then side effects, uh, as you might expect with the the more aggressive tirzepatide dose, they did see a little bit more of the GI side effects with tirzepatide versus dulaglutide, which is kind of what you'd expect.

Dr. Khyati Patel: Yeah. So Dr. Kane, you mentioned something about, hey, we're going to talk about that 1.5 milligram dulaglutide dose. And that was probably my biggest critique that they did not compare it to that 4.5 milligram dulaglutide dose, which is the max dose. So you always want to, when you're looking at active comparator trial, you want to make sure that both the groups receive comparable doses of the medication. Tirzepatide 15 milligram is the top tier, that's the max dose. So why not use dulaglutide 4.5, which is the max dose of dulaglutide?

Dr. Sean Kane: So it turns out that it's kind of a timing problem, and I'm sure that if Eli Lilly could rewind the clock, they might do it differently, but it is what it is. So at the time that they designed the SURPASS-CVOT trial, the trial we're talking about, at the time that they planned that, 1.5 milligrams was the max dose of dulaglutide. Several months later, the FDA approved the higher dose, but the trial had already been planned, it was already running, you just can't change it midstream. So that makes sense that they picked the lower dose, but it's still a limitation of the trial because now we have the higher dose on the market that wasn't actually compared to the higher dose.

[30:00] Dr. Khyati Patel: Right. And then if you rewind back, pun intended, um, the dulaglutide CVOT trial, which was the REWIND trial, also ended up using that 1.5 again because FDA approval for max dose was 1.5 at that time that was published in 2019.

Dr. Sean Kane: Um, and then do we have uh tirzepatide versus placebo trial then, or is this kind of what we've got?

Dr. Khyati Patel: There is. Um, they are looking at tirzepatide uh versus placebo CVOT trial for superiority. Um, and that's SURMOUNT-MMO trial. However, this one's mainly in patients who are obese or overweight. That's ongoing trial that's expected to show results in 2027. So not not necessarily diabetes patient, but looking at does patients with obesity and overweightness have higher risk of cardiovascular disease and whether tirzepatide makes a dent in it or not.

Dr. Sean Kane: Okay. And then I know you said we had three categories on that figure in chapter nine, and we just covered the category of high risk cardiovascular disease patients. Um, and then you mentioned that another category was patients with heart failure. Um, and we've had some heart failure stuff in this area specifically with SGLT2 inhibitors. So what's new in that area?

Dr. Khyati Patel: Right. So SGLT2 inhibitors are still recommended for patients with heart failure. But a couple other incretin therapies are now making its way. So there is an additional box added in the image to show if patients need additional benefit or additional use, um, you could add semaglutide or tirzepatide. And we're going to talk about the evidence where where this recommendation is coming from.

Dr. Sean Kane: So for tirzepatide, that's coming from the SUMMIT trial. And this was um a little more than 700 patients with preserved EF heart failure, um which was defined as an ejection fraction of 50% or more, and then they were obese, had a BMI of 30 or more. Uh, it was tirzepatide up to 15 milligrams versus placebo for at least a year, but the median duration was actually closer uh to two years. So the primary endpoint was a composite of cardiovascular death and then uh a worsening heart failure event. Uh, so basically did your heart failure get worse or did you die? And then they had a secondary endpoint that was quality of life uh or functional outcome, which was the Kansas City uh Cardiovascular Questionnaire, which is a questionnaire that patients fill out about their functional status with heart failure.

Dr. Khyati Patel: Yeah, it goes kind of like the scale of zero to 100, and higher number means better quality of life. And then a change of like five uh on that scale, it's considered clinically significant. So they found in terms of their primary endpoints that death uh death from um cardiovascular cause was 9.9% in the tirzepatide group versus 15.3% in placebo group. So they kind of looked at a good 38% reduction in that, with NNT of 19, so that's impressive.

Dr. Sean Kane: That's very impressive. And then uh in terms of worsening heart failure events, which was a pretty soft measure, so hospitalized, going to a clinic where you get IV diuresis, or even if they just have to modify your oral diuretics, so just generally like worsening heart failure, but not all of these would be hospitalization for heart failure. So the outcome was about 8% with tirzepatide versus 14% incidence rate with placebo. So almost a 50% reduction in having these worsening heart failure events, that's a really big deal.

Dr. Khyati Patel: Right. And then in terms of that quality of life score, the KCCQ-CSS score, um, they found that that was also better in tirzepatide group versus in the placebo group. The difference was 6.9. Again, that change in five points is considered clinically significant.

Dr. Sean Kane: Um, and then as you might expect, it is versus placebo. People who got tirzepatide tend to have more of those GI side effects, and sometimes that led to discontinuation.

Dr. Khyati Patel: So then another article that is relevant in this space are the STEP-HFpEF or STEP heart failure with preserved ejection fraction trials. There's a main trial and then one in patients with diabetes. Um, and this is for injectable or subcutaneous semaglutide versus placebo.

Dr. Sean Kane: So they kind of basically have same study design. It's just that one population didn't have diabetes and the other population had diabetes. Population was also similar to the SUMMIT trial where we talked about tirzepatide in patients who have preserved heart failure and diabetes. And in the non-diabetes trial, the endpoints were again change in that quality of life score from baseline, change in body weight versus placebo. So not those long-term, you know, clinical markers, but we we did some quality of life changes and that change in the KCCQ-CSS score was 7.8 points better in the semaglutide arm versus the placebo arm, and this was statistically significant as well.

[35:00] Dr. Sean Kane: And then for percent weight loss, we're looking at about 11% more body weight loss with semaglutide. 

Dr. Khyati Patel: So again, Dr. Kane, even though these are not your hard like mortality endpoints, from a patient perspective, some patients would actually be more excited about these measures in terms of your quality of life is going to get better in a fairly short term and your body weight is going to get a lot better. And these are patients with obesity that might want to lose that weight and as they lose weight, their um ability to walk farther is better, things like that. Like these are important endpoints even though they're not our typical like heart failure type endpoints.

Dr. Sean Kane: Right. And then in that diabetes arm, again, they looked at similar endpoints and they found the quality of life score was 7.3 points better in the semaglutide arm. Again, a statistically significant difference. And the weight loss was 6.4% more um in the semaglutide arm compared to placebo. But again, this is still a clinically significant weight loss, but it was also statistically significant too.

Dr. Khyati Patel: And again, just to highlight, these are people with preserved ejection fraction heart failure, so their EF is at least 50%. We don't have these trials for reduced ejection heart failure, and we actually don't think it would be helpful based on the pathophysiology for those patients. So I just want to highlight these are uh with or without diabetes among people with preserved EF heart failure.

Dr. Sean Kane: Right. And up until now, if you look at that uh guideline directed therapy for preserved heart failure, we had SGLT2i. And now we have another therapy, especially in patients who cannot be on SGLT2i. So if their eGFR is below 20, what do we do? At least we have something to use.

Dr. Sean Kane: Absolutely. Speaking of that, so among people with diabetes that do have lower eGFRs, like less than 30 let's say, or are on dialysis, what is the preferred therapy for those people?

Dr. Khyati Patel: Yeah, so now they're recommending um GLP-1 RA for lower risk of hypoglycemia and reduction in the cardiovascular events. So again, these patients may not get the same benefit of using the SGLT2i to reduce the hypoglycemia because obviously those drugs work in the kidneys and if there is not good perfusion, you know, it don't work really well. Um, so that's where the GLP-1 RA preference comes from.

Dr. Sean Kane: And just to be clear, this is a preferred therapy among those types of people with diabetes. So instead of let's say reaching for a sulfonylurea, the guidelines are saying for those people with that more advanced uh kidney disease, GLP-1 RA would be the preferred therapy.

Dr. Khyati Patel: Right. They might experience the GI side effects a little bit more, so closer monitoring, education on how to mitigate them is also important, um, but definitely better than sulfonylureas.

Dr. Sean Kane: Um, what about patients that have chronic kidney disease, specifically patients that are spilling protein into their urine where they have that uh albumin to creatinine ratio of more than 100, which is kind of the normal criteria for albuminuria. If they're already on RAS inhibition, so they're already on let's say an ACE inhibitor, what is the recommendation for those patients with diabetes?

Dr. Khyati Patel: Yeah, uh the recommendation is obviously to use the SGLT2i and actually not just itself, but in combination with the finerenone, which is our non-steroidal MRA. Um, so they're recommending to start both SGLT2i and the finerenone therapy together.

Dr. Sean Kane: And, you know, Dr. Patel, just to wrap up this section, what I really like about chapter nine with the ADA guidelines, as an example, the heart failure guidelines have not been updated for the use of GLP-1 in people who have preserved EF heart failure. But because the ADA guidelines encompass all of these different disease states and they're updated every year, I like that that you can go to a guideline and you can see like what is the latest and greatest among people with diabetes who have certain types of heart failure, CKD, things like that, where those other guidelines might lag behind a little bit with the evidence. So it's a really nice one-stop shop.

[38:00] Dr. Khyati Patel: Yeah, and that image is great. So print it, you know, use it as your pocket guide. Um, there is table 9.2 as well. It's a little extended table, but kind of breaks down the evidence pretty well per the agent.

Dr. Sean Kane: So Dr. Patel, another section I believe that got updated was about systolic blood pressure goals. What can you tell us about that?

Dr. Khyati Patel: Right. So in the high risk patient, so high cardiovascular or kidney risk patient, the guidelines are recommending the systolic blood pressure goal of less than 120. Again, quote unquote, should be considered. Uh, it's not a newest recommendation, but they're saying in these high risk patient, if tolerated, you should aim to achieve that goal. Dr. Kane, do you remember we did an episode for the SPRINT trial? That was older people who weren't in nursing homes and it showed a cardiovascular benefit aiming for a target less than 120 for blood pressure.

Dr. Sean Kane: But those patients didn't have diabetes.

Dr. Khyati Patel: Correct. So since then, there were two other trials that were done with the similar blood pressure goal in mind, less than 120, in patients with diabetes who had uh elevated cardiovascular risk. Um, that is the BORD trial and ESPRIT trial. They both compared the intense blood pressure control less than 120 millimeter per mercury versus that standard of care which is less than 140 millimeter per mercury.

[40:00] Dr. Sean Kane: So we'll start with the BORD trial. This was an open label trial, which makes sense because you have to kind of know what their blood pressure is and then be able to titrate down more aggressively. Uh, 13,000 patients-ish with diabetes and were at a higher cardiovascular risk. And what they showed was that by achieving a lower blood pressure, the mean blood pressures were about 122 versus 133. So about a 10 millimeter difference, right? Um, and it showed a 21% reduction in basically cardiovascular outcomes. Definitely there in terms of benefit. At the risk though that those that uh were at the lower blood pressure goal had more hypotension, more hyperkalemia because some of our drugs cause hyperkalemia. Uh, so there were harms associated with the benefit that you get from that uh more intensive blood pressure reduction.

Dr. Khyati Patel: Yeah, and the ESPRIT trial was similar, about 11,000 patients. However, 39% of these had type 2 diabetes, so it wasn't just type 2 diabetes patients. And they saw about 12% reduction in this composite outcome of MI, revascularization, hospitalization for heart failure, stroke, or CV death. Not as strong as BORD, but there was 12% reduction. And again, similar in the intense control group, more side effects including syncopal episodes were noted.

Dr. Sean Kane: And then in terms of side effects, including syncopal episodes were noted.

Dr. Khyati Patel: And that's a big deal, right? So again, thinking about what what would be a patient-oriented outcome, right? Obviously patients don't want to have any of these items in the composite of having a heart attack, stroke, things like that. But the chances that a patient will benefit and not have those events by having that lower blood pressure goal, it's fairly rare, right? So like if it's a 12% reduction, if not that many people have the event anyway, there's not that much opportunity for improvement. But if a good portion of patients are having syncopal events and things like that, the patients feel immediately, right? Like, hey, I'm having trouble like standing up because when I get up too quickly, I literally feel like I'm going to fall over or worse, I fell over and I hit my head. Those are like very clinically relevant things for patients. I think shared decision making to some degree plays a role here to say like, how are you tolerating your blood pressure medication? Your current blood pressure is 128, we don't need to push it down to less than 120 if you're already having some of these issues, right?

[42:00] Dr. Sean Kane: Right. So again, as long as you can achieve that goal without that undue burden, um, that's what I think what the guidelines are recommending here.

Dr. Khyati Patel: Yeah. Dr. Kane, not groundbreaking, however, there is more of a stronger collective statement in regards to the dyslipidemia therapy from this guideline group. Um, they're recommending against the fibrate, niacin, or the dietary supplement versions of the omega-3 fatty acids. These are the ones that you find over the counter, um, if patient is already on statin therapy. Now I'll tell you what, it's not groundbreaking, it's not new. These recommendations were kind of dispersed throughout, they kind of just brought it together and say, don't use any of these therapies if patients already on statin therapy.

Dr. Sean Kane: And what I like about this is that patients are pretty commonly on a lot of these therapies, right? So if we just look at the fibrates for example, we already had the ACCORD trial from forever ago that showed that there was no benefit to adding a fibrate in people with diabetes. Um, but then we had a newish trial called the PROMINENT trial that looked at a different fibrate called pemafibrate, and that was in people with high triglycerides who had diabetes, and it did reduce their triglycerides, but it didn't change any cardiovascular outcomes.

Dr. Khyati Patel: Yeah, so results were very similar to the ACCORD results. Again, not showing any additional benefit, don't add it. Um, when it comes to niacin, we still have that AIM-HIGH trial that did not show any additional benefit, but after that we had the HPS2-THRIVE trial, again, showed to capture that cardiovascular risk reduction when niacin was added to the statin therapy. In fact, in both of these trials, when niacin was added, it showed that the patients had harder time regulating their glucose. So there were some disruptions in glucose uh control, which we know niacin does cause hyperglycemia. And so if you're going to get in trouble there and not have any cardiovascular benefit, why add this agent?

Dr. Sean Kane: And then we had the REDUCE-IT trial that looked at EPA-only prescription fish oil that did have a cardiovascular benefit, but basically the rest of the landscape more or less for fish oil has not shown cardiovascular benefit. So the guideline recommendation is if you're going to use fish oil for whatever reason, use the EPA one, don't use these over the counter um or mixed DHA EPA fish oils because they haven't shown that cardiovascular benefit.

Dr. Khyati Patel: Right. And then to round this kind of recommendation up for what to do in patients who have cardiovascular risk, recommendation of the guideline is put them on statin and max tolerated statin. If that's not sufficient, you can add the ezetimibe, which is Zetia, or the anti-PCSK9 therapy that has shown to decrease cardiovascular risk. Um, in patients who are statin intolerant, you could extend um the agents to maybe bempedoic acid or use that inclisiran, which is that anti-PCSK9 therapy or PCSK9 inhibitors, which has proven ASCVD risk reduction. Um, this is kind of like a a sneak peek preview of our next episode. We're going to dive into AHA/ACC uh lipid guidelines that came out recently, but these guidelines did a good job of summarizing that too.

[45:00] Dr. Sean Kane: This is kind of like a a sneak peek preview of our next episode. We're going to dive into AHA/ACC uh lipid guidelines that came out recently. And then the last section that kind of was on our radar from the ADA update was perioperative glucose goals. And there's two numbers that they threw out there.

Dr. Khyati Patel: Yeah, and this is kind of pertaining to the inpatient management goal, but um, you know, I see this a lot in patients who are going for surgery and they come for the pre-op visit and we have to adjust their insulin dose the day of the uh the procedure itself. So what they're recommending for any type of elective surgery in that three month period of elective surgery, A1C goal of less than 8% improves uh outcomes of the surgery as well as diabetes. And then when it comes to blood glucose, 100 to uh 180 in that perioperative period. So that bottom threshold of 100 is interesting because normally, you know, we can go up to 70, usually 70 to 180 is that range in your CGM uh monitors. So not an intense lowering, uh kind of giving a little bit of freedom there. So 100 to 180 when it comes to the blood glucose goal.

Dr. Sean Kane: So Dr. Patel, why don't we wrap up again some of the key concepts that stood out to us? So one is that a few existing agents now have ASCVD risk reduction, and that specifically was oral semaglutide and then tirzepatide. So new data that these are good therapies if you're at a higher risk that you should be favoring those as uh preferred therapies for diabetes management.

Dr. Khyati Patel: Right. Previously these agents did not have that evidence, so now we do. Uh, kind of going along the line with this incretin therapy, your uh SGLT2is are still that first line in patients who have diabetes and heart failure, including that preserved ejection fraction heart failure, but we have evidence from the subcutaneous semaglutide and tirzepatide that could be recommended in patients who have symptomatic preserved ejection fraction heart failure and obesity uh because we do have benefit in this population.

Dr. Sean Kane: And then in terms of weight management among patients with diabetes, no change, GLP-1 or uh GLP-1/GIP receptor agonists are still recommended definitely for type 2 patients. What's new though is these therapies can be considered for weight management in patients with type 1. We went through that there's uh potentially a higher risk of some side effects and um more monitoring is definitely appropriate for those patients.

Dr. Khyati Patel: Right, but it opens up another avenue for the patients who did not have weight loss option before. And then last but not the least, I think guidelines are better defining recommendations for medication-induced hyperglycemia for agents such as the immune checkpoint inhibitors, the PI3K alpha inhibitors, mTOR inhibitors, and steroids as to what glucose to monitor and what preventative therapies to consider.

Dr. Sean Kane: So Dr. Patel, we covered a ton of trial names, the guidelines, things like that. So in our show notes at helixtalk.com, again this is episode 197, we have links to those ADA guidelines, but also links to a lot of these really new exciting trials that are shaping these guidelines. Um, so for the listeners, if you want to take a look at that, it's at helixtalk.com. We also have a mailing list, so if you want to get an email when new episodes come out, you know, highlighting we're going to get uh an episode soon on the 2026 lipid guidelines. If you want to know as soon as that is out, then make sure that you subscribe too. So with that, I'm Dr. Kane.

Dr. Khyati Patel: And I'm Dr. Patel, and as always, study hard.

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