Speaker 1 00:00 Alex, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University, College of Pharmacy. We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. 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 health care provider. And now Narrator - Dr. Abel 00:29 on to the show. Dr. Sean Kane 00:31 Welcome to Episode 35 of HelixTalk. I'm your co host, Dr. King. I'm Dr. Sherman and I'm Dr. Patel. Today we're talking about two updates regarding diabetes therapy. Speaker 2 00:42 And one of the update, it's not only an update to a new medication. We're talking about the same old our friend, empagliflozin. The brand name is Jardiance. We do know there are other two SGLT-2 inhibitors out in the market: canagliflozin, brand name is Invokana, and dapagliflozin, brand name is Farxiga. And these were covered in detail in Episode 16, but we are covering impalapozin once again because of the new trial and power reg outcome trial results that were published just very recently. Dr. Sean Kane 01:16 And just to give background again, Episode 16, we did cover these SGLT-2 inhibitors. But essentially they with the way that they work is they make you urinate out more glucose, so it decreases the threshold for when the kidney reabsorbs glucose. And that has some effects in terms of vital signs, some lab values and things like that. Speaker 3 01:34 And then we had mentioned there was, you know, some, some things to be concerned about, was a potential increased risk in urinary tract infections, because, again, bringing all that sugar through the ureters. And you know that can be problematic for outcomes. So remain to be seen how big of a problem that continues to be. Dr. Sean Kane 01:50 And when we're thinking about urinating glucose, some good things and some bad things happen. You mentioned a couple bad things. Some of the good things are that, because you're losing calories by peeing out calories, you can actually see a decrease in weight, both from loss of water, but also loss of, you know, energy, or calories. And oftentimes that also translates to a decrease in your blood pressure without really changing your heart rate, right? Speaker 2 02:14 And they, when you're talking about just surrogate endpoint reduction, again, they have seen some favorable effects on vascular parameter looking at the arterial stiffness, vascular resistance, visceral adiposity, albuminuria and plasma urate. But that being said, these agents currently do not have any microvascular benefits proven. Dr. Sean Kane 02:34 And then in terms of other surrogate endpoints that have been looked at, it does appear that these SGLT-2 inhibitors can increase your LDL and HDL. So really, from a surrogate endpoint point of view, no one really knows what to think of these agents. Because, you know, increasing LDL must be bad, but increasing HDL should be good. And then we have all of these endpoints related to vasculature and things like that. So when in doubt with surrogate endpoints, the gold standard to figure it out is to do a clinical trial. And that's exactly what happened with the EMPA-REG OUTCOME Speaker 2 03:07 trial, right? And we discussed in previous podcasts as well that now FDA requires any new anti diabetic medication to perform cardiovascular outcome study, and so EMPA-REG was a particular study that was done for empagliflozin improving this cardiovascular outcomes. Dr. Sean Kane 03:23 Dr. Patel, correct me if I'm wrong, but I would imagine this requirement by the FDA is partially due to the TZDs or thiazolidinediones outcomes that we've had in the past, where there is a question of increased risk of MIs or not, and heart failure and things like that. And that's kind of what has prompted some of this request from the FDA. Speaker 2 03:41 That is true. That was the biggest lesson learned with rosiglitazone. As we know currently, it's on REMS regulation. When FDA did put that regulation of performing a cardiovascular trial, people were not really happy about it. Other countries thought that FDA was unnecessarily being too strict about it, but now we saw this big example with rosiglitazone and I think it's our moral and ethical responsibility to make sure that we're also assessing cardiovascular benefits or harm as well. Speaker 3 04:14 Certainly so when we look at the study design, it included little over 7000 about 7020 patients with type two diabetes, and these patients specifically had to have a high risk of cardiovascular disease. So that was a history of coronary artery disease, history of MI, history of cerebrovascular accidents, history of peripheral artery disease, as well as an A1c specifically, seven to 9% without medications, or if they're on medications, anywhere between seven and 10% Dr. Sean Kane 04:44 so essentially, this is a very large trial that was recently published that included a lot of different kinds of patients, but specifically we're looking at those who are at very high risk for cardiovascular disease, and it turns out that if you've had some ASCVD in the past, that's one of the biggest predictors to get new ASCVD in the future. So they're really looking at a high risk group. So this isn't your 35 year old diabetic who's never had any problems in the past. And also, they're looking at fairly well controlled diabetics, anywhere from an A1C of seven to 10% as we'll talk about, the A1Cs were actually fairly reasonable as a mean. So we're looking at pretty well controlled type two diabetics who definitely have a history of ASCVD. Correct. Speaker 2 05:24 And the procedure of the study was there. There was a two week open label placebo run in period. Patients in this study were also on other anti diabetic medications, including insulin. But during this run in period, those background therapies or concomitant anti diabetic therapies were not Speaker 3 05:42 changed so they could be on whatever they were on previously when they came into the study, so long as they met the A1C goal, correct. Speaker 2 05:48 And then they were randomized between either placebo and empagliflozin, 10 milligram daily or 25 milligram daily. So they were looking at three different groups here. Dr. Sean Kane 05:58 And again, the brand name of empagliflozin is Jardiance, right? That is correct. Got it okay. So they randomized them. What kind of endpoints were they looking at in the trial? Speaker 3 06:07 On this one, the primary endpoints again, being as we were looking for cardiovascular disease. So looking at the composite of death from cardiovascular causes, myocardial infarction or even Speaker 2 06:17 stroke, and secondary outcome, was looking at the primary outcome, as well as looking at hospitalization for unstable angina. Speaker 3 06:25 And then we had some safety analyzes that we were doing too. So they looked for adverse drug reactions that occurred during treatment or even within seven days after the last dose of the study drug. Dr. Sean Kane 06:36 And when they designed the trial, it was actually a non inferiority as the primary analysis, meaning that they're trying to show non inferiority to placebo, which, as we've kind of talked about in the past, is kind of hysterical that we're treating diabetes in order to prevent these adverse outcomes. But then the FDA is requiring a safety analysis to show that your drug doesn't cause more harm than Speaker 2 06:57 placebo, absolutely. And then this study in particular, not only had non inferiority to the primary outcome or for primary outcome, they also looked at the non inferiority to the secondary outcome as well as superiority to both the primary and secondary outcome. Dr. Sean Kane 07:13 And honestly, from my point of view, it really should be a superiority study that the FDA should require, although I do understand with you know, a lot of different diabetic medications, it's very expensive for every single medication to show a cardiovascular benefit, and in reality, many, almost all the medications for diabetes haven't shown a cardiovascular benefit. So it would absolutely raise the bar and make it more difficult for new agents to come to market. So there's some balance there. So in this case, it's nice to see that they did do a non inferiority plus a superiority analysis, which is clinically what I'd like to see. So thinking about the kinds of patients that were included in the trial, they were in their mid 60s, almost three quarters of them were male, mostly were white, 20% Asian, about 20% Hispanic, mostly were European. This was actually only about 20% from North America, and most of these patients would be considered overweight, so the BMI was around 30 their A1c was actually pretty well controlled, around 8% and as we said, all of these patients had to have some history of ASCVD. So the majority had coronary artery disease, about 75% about half of them had a history of heart attack, about a quarter had a history of CABG. About a quarter of them had a history of stroke. So really, this emphasizes that this is not your typical 38 year old diabetic patient. This is someone in their mid 60s who's had diabetes for a while. And in fact, about just about 50% of the patients in the trial had had diabetes for more than 10 years. Speaker 2 08:39 And as we mentioned, you know, these patients were on concomitant other anti diabetic medications, but we were talking about improving cardiovascular benefits or not causing any harm, we want to make sure that these patients who already had cardiovascular risk were on other proper therapy. So like talking about proper dosing of statins, proper dosing of ACE inhibitors or ARBs or other medications, like Metoprolol that they qualify for it, and these patients were allowed to be on those medications as well. Dr. Sean Kane 09:06 So in looking at the primary endpoint, what kind of efficacy did we see in Speaker 3 09:10 the trial? What they found was the cardiovascular death, the non fatal MI, non fatal stroke. It was reduced versus placebo, 12.1% with empaglozin versus 10.5% with impact with flozin versus 12.1% with placebo, and that reached P value at point 04 so significant for superiority with the number needed to treat to see one significant change of 63 and that was a median duration of 2.6 years of therapy. So again, that's pretty long to, you know, make sure somebody's consistently on it. But yeah, we did see some benefit there. Dr. Sean Kane 09:45 And if we look at things like statin trials and things like that, oftentimes they even have a longer period than 2.6 years as a mean, some are closer to five years. So in thinking about a number needed to treat in the 60s to decrease this composite endpoint of clinically relevant. The parameters, that's a pretty good number, you know, all things considered, when you compare it to other therapies that we have. Speaker 2 10:06 And one good thing about what I like about this article, in particular, on the NEJM website, is that they have indicated a lot of things that are now part of the appendix, so you won't be able to see the charts and background information, unless you pull up the appendix. So the appendix has table S6 and it kind of talks about the secondary endpoints as well. So secondary endpoints were looking at the primary endpoint plus looking at hospitalization for unstable angina or CHF, and what they found was that this endpoint was occurring by 12.8% in empagliflozin either the 10 milligram or 25 milligram group versus 14.3% in the placebo group. And again, this was statistically significant for the non inferiority criteria. So the p value was less than 001, however, for superiority, the p value was point oh, 8% which Dr. Sean Kane 10:56 is still good. And as you said, they picked specific endpoints that were part of their composite primary endpoint, and the big one was a lower all-cause mortality, lower cardiovascular death, lower hospitalizations for heart failure. So all of those are really, really relevant endpoints for what we're interested in. It would have been one thing to have the composite endpoint, which sometimes can be inflated if you have kind of lesser end points that you kind of combine with a big endpoint like mortality. But in this case, in addition to the primary endpoint being significant, we also saw that these secondary individual endpoints like mortality were improved with empagliflozin. That's a really big deal. Speaker 3 11:36 That's not to say it hit a home run on everything. We just We didn't really find any difference when we were looking at myocardial infarction and comparing the drug to placebo, stroke either fatal or non fatal, comparing that active drug versus placebo. So yeah. And so the one difference there in stroke, interestingly, was with the two different doses the drug, 3.6 and 3.4% so Really 3.5% on average with the drug versus 3% with placebo. So an actually, a little bit of a slight increase Dr. Sean Kane 12:02 in stroke there. And this is super interesting, because almost always in trials like this, when we have a composite endpoint, usually the main driver is a non mortality driver, so like a decrease in heart attacks or decrease in strokes. In this case, it's actually the opposite of what we typically see, where the main driver of the composite was mortality and it wasn't some of these non fatal events like mis and strokes. So that usually doesn't happen. It's really interesting to kind of figure out, well, why did it happen like that? What was the mechanism of benefit, if it wasn't decreasing strokes and heart attacks? Why is it that people didn't die as often? And keep in mind that these were non fatal mis that were part of the secondary endpoint. So it could have been that it truly decreased fatal mis that were part of that overall benefit. But still, it leaves a couple questions that we want to know more about Absolutely. Speaker 2 12:50 And also, there were no differences when it when they looked at patients having transient ischemic attacks, or looking at patients hospitalized because of the anginal episodes. Dr. Sean Kane 13:01 So given that this decreases mortality and diabetes, it must have had a profound impact on the surrogate marker of a 1c right. Speaker 2 13:09 Actually, that was quite the opposite. So if they looked at they looked at the 94 week, they looked at the A1c reduction at 94 weeks, as well as the 206 week. And what they found that A1C was reduced by 0.42% in empagliflozin group, versus 0.47% in the placebo group, which is quite the opposite. But we have to also keep in mind that these patients were also on other diabetic medications. Dr. Sean Kane 13:35 So you're saying in the trial itself, obviously patients could be on whatever therapies they were on, and those could be titrated independent of the study drug, but the study drug itself had no impact on A1c Speaker 2 13:46 pretty much. This is what the study is telling us, and that really Dr. Sean Kane 13:50 throws the idea of A1c reduction through a loop a little bit, and that we don't see this difference in A1c yet, we see these pretty impressive clinical benefits from the study drug empagliflozin, right? Speaker 2 14:01 So it's a matter of, you know, when it comes to applying these study results to your patient population, you kind of have to be mindful here, you know, if you're looking at patients with A1C of 11 point whatever, or, you know, 16 point whatever, probably this drug won't be your first choice because it does not give us that major A1C reduction that we need? However, if they are already at high risk of cardiovascular condition, and you know, they meet one of those criteria for baseline patient characteristics, maybe we can apply this medication to reduce their risk of cardiovascular effects. Speaker 3 14:36 So I can kind of almost think about it in the way that we don't get a massive, massive A1c lowering for some of our DPP-4 inhibitors, however, you know. So you see them kind of as an extension once somebody's been established. And so maybe here we have an even lower, appreciable A1C change. But yes, those they doesn't look like we can just discount that cardiovascular benefit. So maybe even again, we're we're going to start getting less hung up. Some of these surrogate endpoints here, and start saying, Okay, this is a medication we're going to add on to your diabetes, not necessarily because it's magically going to make those numbers lower, but if you look at these long term outcomes, and again, I'm almost thinking sometimes individuals on statins, you know, we're not completely beholden to hitting those magic LDL numbers, but you have somebody that's pretty decent control, but they're at high risk, where we still talk about putting them on a hypothesis stack. So I'm kind of see those comparisons here, absolutely. Speaker 2 15:28 Yeah. And then, you know, they looked at two different doses here, 10 milligram versus 25 milligrams. So that becomes a big question, what dose do we put patients on? So if you look at the primary and secondary outcomes, there was actually no difference between the two active medication group patients. And if they looked at the A1C reduction at 12 weeks, they found pretty much no difference. It was 0.54% reduction in 10 milligram group versus 0.6% reduction in 25 milligrams group. Speaker 3 15:56 So I think another thing to start looking at, then is going to be some of the safety outcomes, right when we led off here we talked about the one of the issues with this class of medication have been some of the urinary tract infections. And so we see here, UTI wasn't really that different between treatment and placebo. Really a point 1%, 18.1 versus 18%, but genital infection itself. So we see a difference in terms of what we're looking at, lot more common with treatment 6.4 versus 1.8% Dr. Sean Kane 16:23 and if you actually divide that out by sex or gender, for women, it was 2.6 versus 10% number needed a harm of 14 or in other words, every 14 patients that take the drug for 2.6 years on average, one will have typically Mycotic, fungal kind of infection of the genital area, and then for men, it was 1.5 versus 5% number needed a harm of 29 so those are slightly different numbers than what we've seen in other trials. It could be from a lot of different reasons in terms of how they adjudicated the endpoint, or defined the endpoint. And as these trials get larger and larger, some of these endpoints are harder to capture, as they were in an earlier trial design. And really one of the questions here is, what is the mechanism of benefit? So clearly, it's not an A 1c reduction between the two groups that made it that much more superior. So what is it? Is there some pleiotropic effect that we're not aware of? Is it some of these vascular effects that we're still investigating. We don't really know for sure, and that's one of the question marks that we're we still have about the trial, right? Speaker 2 17:27 And some of the experts in the field are speculating that you know this effect might be coming from the diuretic effect of the drug itself. However, there are a couple other studies being conducted for canagliflozin as well as dapagliflozin, CANVAS, as well as DECLARE-TIMI 58 so we will have to see what the outcomes of those trials are. People are suspecting that it will be quite similar to the Impala frozen outcomes. However, they're also recommended not to stop the trial early, because, like we mentioned earlier, about the stroke and we discussed the stroke outcome that you know, if we if we treat them for a longer period of time, we might see that curve for stroke diverging in favor of placebo and not in flavor of the active drug. Dr. Sean Kane 18:12 And again, just to kind of reassess the available agents on the market, and this requirement by the FDA, this would show the mortality benefit, is in stark contrast to the Sitagliptin trial from the New England Journal of Medicine that was recently published, showing that it was no more harmful than placebo. So the concept of one trial for one drug class showing no harm versus placebo, and then this trial showing pretty impressive benefit versus placebo, I think that this is going to change our practice a lot in terms of our approach to diabetes management, not from an A1C point of view, but from a reduction of, you know, bad clinical outcomes Speaker 2 18:49 with you absolutely and we, I already discussed about the differences between the two doses, and they're saying that there is very minor A1C reduction or blood pressure reduction or even weight reduction that we have seen with the higher dose. So clinicians are favoring to keep patients on 10 milligram dose again, like we mentioned, A1C reduction is not going to be great, probably nothing compared to placebo. So here we are just trying to get that extra benefit of cardiovascular outcome, and they're saying 10 milligram dose would just suffice. Dr. Patel Dr. Sean Kane 19:20 correct me if I'm wrong, but is there only one other oral medication that has shown clinical benefit in terms of a clinical outcome benefit in diabetes? Speaker 2 19:29 That is correct, and I think you're talking about Metformin that has both the microvascular and macrovascular outcome benefit. Dr. Sean Kane 19:35 Wouldn't it be great if the manufacturers of Jardiance kind of combined Metformin with their product, just to make like a super clinical benefit drug. Speaker 3 19:44 Have I got some news for you guys? All right? So it looks like Synjardy is now out yet, right? So we've got that Metformin, Dr. Sean Kane 19:51 so Metformin, with empagliflozin combination pill, absolutely. Speaker 2 19:55 And I don't know, I think the approval of this medication and the publication of this study. Is the timing is quite comical, but we won't be surprised. You know, once this is placed in practice, obviously based on the other two trials that I mentioned earlier, those results are to be coming out in about 2017 for one trial, and 2018 for the other trial. So people are really excited to see how this is going to shape up the new diabetes guidelines. But if it does, then, like you said, Dr. Schuman, we already have a product in mind since already it's a combination of metformin and empagliflozin. Dr. Sean Kane 20:31 Just to point out, in the New England trial of empagliflozin, about three quarters of the patients were on background Metformin therapy. So a true evidence based medicine person would say, well, we want a patient in clinical practice to be as similar as possible to the clinical trial patient population, and that would be true in this case, where the majority of the patients were on Metformin and then also received empagliflozin. On top of that, whether the benefit is present with or without Metformin, we don't really know the answer,er, but we do know that most of the patients in the trial were receiving Metformin. So it's probably still a very reasonable recommendation as a first line therapy for an oral therapy for a diabetic patient. Speaker 3 21:09 And then, just to clarify, we're still needing to prove some of those microvascular benefits with this medication. So again, that one-two punch with Metformin may not necessarily add to the microvascular benefit, but certainly that one-two punch is going to help by providing that benefit. Speaker 2 21:23 Yeah, and empagliflozin actually is doing a study looking at the diabetic nephropathy outcome. So we're hopeful to see what the results of those trials Dr. Sean Kane 21:33 are saying. And given the mechanism of this drug class, it makes sense it would be interested in some of the renal adverse effects or benefits of the drug itself, given that it works in the kidney, deals with receptors in the kidney, it would make sense that you would kind of want to investigate that, both from a safety and an efficacy standpoint, absolutely. Speaker 3 21:52 And be interesting too. Again, we do know some of the kidney issues with metformin as well, too, so that may be something, again, just to keep an eye on good or bad. Dr. Sean Kane 21:59 Switch gears a little bit. We wanted to mention another diabetic medication that was recently approved. We already talked about this drug class in Episode 16, but we wanted to just mention this new drug that's part of this drug class, Speaker 2 22:11 yeah, and the brand name of this drug is Trulicity, and the generic name is dulaglutide. And as we know, this is a long acting GLP-1 receptor agonist. So it was approved after Tanzeum, which is albiglutide, and exenatide ER, which is the Bydureon approval. Speaker 3 22:31 So this is one, again, it promotes that glucose dependent insulin secretion by increasing the intracellular cyclic AMP, so activating some of those beta cells. And so again, you start to get more insulin. It decreases glucagon secretion as well, and then, as a nice result, to slowing down gastric emptying. Dr. Sean Kane 22:47 And for the Trivia Buffs out there, if you recall, Byetta was actually derived from the saliva of a Gila monster, which is a form of lizard. So it's kind of neat to see that from inception of Byetta, all of these different drug molecules that have been approved to the market, and now we're even kind of playing around with the Connect profile to allow it to be weekly, or even less often than that, injections for the patient. Speaker 2 23:12 So dosing of this medication, like I mentioned, it's a long acting medication, so once a week, any time of the day, with or without food. It's okay. Most patients are started with 0.75 milligram dose, and then if need be, can be increased to 1.5 milligrams, because it's a one week duration. You know, the half life is about five days. They say that if you miss the dose, you can take it within 72 hours. But then if you know it's been more than 72 hours, they say, just wait for the next dose and don't double it up. Speaker 3 23:44 And again, looking at populations and adjusting amongst them, this one doesn't seem to have any kind of renal or hepatic dose adjustments, or really, any kind of special populations that we need to look for. However, there were more ADRs in patients who have renal impairment or renal failure. So you do want to keep aware of that, and it's not really recommended in pregnancy and lactation. And then the last thing is, if somebody is on a concomitant secretagogue, so again, if they're on a sulfonylurea, for example, or if they're on insulin, you probably do want to decrease the dose of those agents again, so we're not just getting an overall bigger effect on maybe leading to hypoglycemia. Dr. Sean Kane 24:21 These precautions are pretty similar to what we saw with our other GLP-1 agonist, in that you get more nausea and GI adverse effects because the drug half-life is longer if you have renal impairment, and also it will decrease your insulin requirements, whether it's from a sulfonylurea or from insulin itself that you may need an adjustment on that Speaker 2 24:38 absolutely and subcutaneous injection is required in the either abdomen, thigh or upper arm area. This has two different formulations available, pre filled syringes as well as the pen. Syringes obviously would expose the needle, but the pens are pretty neat formulation from what I've seen in the clinic, the samples that the reps have provided to me, it's basically a needleless system. It has a needle inside the device itself, but it's not visible to the patient. Once it goes in, or once it retracts itself, you never really get to see the needle itself. So somebody has a visible needle phobia. This medication is really good. The second factor is the reconstitution. When we reviewed Tanzeum and Bydureon, we made sure that you understand how important all these steps are in reconstitution and properly mixing the medication and waiting for so long of a period. Trulicity, take it out of the fridge. Don't need to reconstitute it, sterilize the site and inject the medication, and the entire pen device then goes into the sharps container. It's that simple. Dr. Sean Kane 25:43 This is really interesting in terms of the progression of the GLP-1 agonist market at first, you know, we just had a couple agents that were kind of more immediate release formulations, and then they went to extended release. And now they're even playing with the way that it's delivered to the patient. So every drug company that's iterated on the market is not just trying to find better efficacy, but they're focusing on things like convenience in terms of how frequently you inject and how you inject and whether you reconstitute or not. So a lot of this is more marketing and convenience for the patient, as opposed to efficacy for the patient. But given that it is an injectable product, it makes sense that those things probably matter to a patient, right? Speaker 2 26:23 Yeah, absolutely. And we, as a pharmacist, our main job is to make sure that the medication is being utilized the way it's supposed to. They're gonna get the big bang for their buck. They're paying the insurance companies, right? So if the patient's not reconstituting it properly, they're wasting the money, but they're not getting any benefit. At the same time, versus Trulicity, they have made it a little bit easier. It's a kind of like a fool-proof type of administration, where you just have to sterilize the area and inject the medication, no need to reconstitute. Speaker 3 26:56 But at the same time, you know we were talking about these medications may have some better for patient specific factors, easier to administer, longer half lives. But one thing want to make sure is that we're not worsening outcomes, coming up with any kind of surprise ADRs and so I think we mentioned about you got some of the GI effects, nausea, vomiting, diarrhea, abdominal pain, decreased appetite, probably due to the change in gastric emptying, constipation, probably due to the same but then we also have fatigue, hypoglycemia, and then maybe some interesting effects on the heart. Dr. Sean Kane 27:27 So in terms of changes to the conduction system of the heart, we saw a very small increase in heart rate, somewhere between two and four beats per minute, or a slightly increased risk of sinus tachycardia, which would be defined as greater than 15 beats per minute over baseline, and then also in prolongation of the PR interval. So didn't have QTC prolongation, but we saw prolongation of PR which means a higher risk for AV nodal blockade, so different heart blocks for patients, right? Speaker 2 27:58 And then comparing to the other agents. So because you're injecting this longer acting medication, once a week, there were higher incidences of injection site reaction. If you remember the exenatide ER or the albiglutide, which is Tanzeum, versus this medication, is very interesting. They only noted about point 5% injection site reaction. So this makes the this drug particularly different from the other two long acting GLP-1 agonists, the hypersensitivity reaction is still there, just like the other agents. It's still less than 1% this drug do develop immunogenicity. So they found anti drug antibodies as well as the anti GLP, anti human GLP antibodies as well. Dr. Sean Kane 28:45 So to kind of summarize or compare and contrast other GLP-1s versus this one, we see similarities with regard to some of the GI side effects. We see fairly similar adverse reactions in terms of the risk of bad allergic reactions and things like that. There are some unique things that the other GLP-1s didn't have, that this one has right Speaker 2 29:06 correct, which is the injection site reaction. It's only point 5% versus up to 18% with the long acting Exenatide, Dr. Sean Kane 29:15 and then also the cardiovascular changes that we saw with respect to the EKG changes in heart rate, but really no bad outcomes as a result of that. It's something that probably should deserve monitoring, though, Speaker 2 29:26 absolutely they haven't done long term studying up to show the, you know, cardiovascular benefits, like we just discussed, for Jardiance, but these surrogate endpoints have been noted, and they probably are doing a long term study to prove that this medication has no cardiovascular issues or harm now, Speaker 3 29:44 Dr. Patel, it's my understanding that there is a black box warning with this medication for medullary C-cell tumors or medullary thyroid carcinomas or MTC that they saw in rats, and that, as a result, they've actually said the medications contraindicated in patients with those thyroid carcinomas, or any that have something called MEN2 or multiple endocrine neoplasia syndrome. Now, is that something that's unique to this medication within the class or is that a class effect? Speaker 2 30:09 It's it's more so of the class effect, and that's why the black box warning is there. Another class effect is looking at pancreatitis. You know, none of the patients who had a history of pancreatitis were allowed to be on this medication or in this study, so we don't know what the outcomes would be. And then, just to keep in mind, there are no macrovascular outcomes that have been proven yet. Dr. Sean Kane 30:29 So Dr. Patel, when I think of any, basically any diabetic medication, I think of roughly around a 1% a 1c reduction, depending on the agent, and things like that. But I think that's a fair mean assessment of benefit. What kind of benefit did we see in this, in this drug, with the different clinical trials that were Speaker 2 30:45 done, so with different clinical trials that were done, you know, we have noticed that the longer acting GLP-1 agonist have shown a little bit more than 1% reduction in A1C, which is a good thing. And dulaglutide in particular, has been anywhere between 0.7 to 1.6% reduction. And if you compare this to the other long acting GLP-1s, you know, albiglutide is anywhere from 0.7 to 1% and exenatide ER is from anywhere from 0.8 to 1.9% reduction. So it's somewhere in between albiglutide and exenatide as far as the A1C reduction goes, but when it comes to maybe side effect profile like injection site reaction and the ease of administration, Trulicity is a little bit better than the other two agents. Dr. Sean Kane 31:32 So we were saying it's pretty similar efficacy, but there's certain convenience factors that can't be captured in a clinical trial that should be applied at the patient level, correct, correct. So the other thing that I think about very commonly with diabetics is that oftentimes they need multiple medications. And ideally you want to study any given drug that's a new drug on the market. You want to study it how you would use it in clinical practice with, you know, multiple different anti diabetic therapies. So was this studied in more than just monotherapy for a diabetic, absolutely. Speaker 2 32:04 So obviously they did a monotherapy trial, head-to-head comparison with metformin. And then they also did add on trials, so patients were on Metformin, Trulicity, and then they compared it with sitagliptin, they compared it with pioglitazone. They also compared it with basal insulin, insulin glargine to be particular, and that's where the conglomerate of A1C reduction between 0.7 to 1.6% comes from. Dr. Sean Kane 32:26 So you're saying that this medication would be safe to be combined with oral agents and insulin. Speaker 2 32:31 Absolutely, that's correct when you when you talk about insulin. Currently, the trials have been done for basal insulin only enough for the bolus. Dr. Sean Kane 32:39 So to summarize, we talked about two anti diabetic medications today. The first was empagliflozin or Jardiance, specifically with the newest New England Journal of Medicine trial that came out called EMPA-REG OUTCOME, which surprisingly showed an all-cause mortality benefit and also benefit in the primary endpoint of mortality, MI and stroke. Speaker 3 32:58 And even more surprising again, that it didn't have that robust A and C reduction that we were expecting, right? Speaker 2 33:04 So we are waiting to see, you know, how this would impact the guidelines. There are other two studies in line. They're going to publish their results sometimes in couple years, next couple years. So it will be interesting to see how this will alter the whole world of diabetes guidelines. Speaker 3 33:18 And then as our second agent, we had trulicity or diracite, and this is a little bit of a longer acting formulation of our GOP one agonist that overall seems to maybe have a little bit more of patient compliance factors due to the long acting, due to maybe having that kind of hidden, unexposed needle. And really a side effect profile that seems to be fairly favorable in comparison to the other agents in the class, right? Speaker 2 33:41 And particularly that injection site reaction is more favorable, and as we look at the A1C reduction, we're getting anywhere from 0.7 Dr. Sean Kane 33:48 to 1.6% reduction. So for those of you who haven't already left us the five star review on iTunes, we'd really appreciate it. It helps other listeners discover the podcast in iTunes. If you want to visit us online, we're at HelixTalk.com with that, I'm Dr. King, I'm Dr. Schuman, Unknown Speaker 34:05 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 34:08 Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science. For more information about the show, please visit us at HelixTalk.com, you.