Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 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. Narrator - ? 00:27 And now on to the show. Speaker 1 00:31 Welcome to HelixTalk episode 67 I'm your co host, Dr. Kane. I'm Dr Speaker 2 00:35 Sherman, and I'm Dr. Patel. And continuing the talk of diabetes, today, we're going to talk even further. The topic of our discussion today is diabetes. Does it cost a heart and a leg? So if you listen to our episode number 35 we discussed the cardiovascular outcomes of empagliflozin (brand name Jardiance) — that was the EMPA‑REG trial, and it showed that empagliflozin was superior to placebo. As a result, the 2017 ADA Standards of Care included empagliflozin for patients with diabetes who have established cardiovascular disease or are at high cardiovascular risk. Today we're going to talk about similar trials that have become available since the EMPA‑REG trial, and the first and foremost is the LEADER trial. Speaker 1 01:32 Now this was, as you would expect, a multicenter, double blind, placebo controlled trial done in a number of different countries. Included more than 9,000 patients with type 2 diabetes, all of whom had an A1c above 7%, and they were assigned to either liraglutide (1.8 mg or the maximum tolerated dose) or placebo. And they did this after a two week run in period, and then they followed them for 42 to 60 weeks. Speaker 2 01:59 And the run in period was just there to make sure patients were okay injecting the medication, and there was no issue that was going to arise because of the injection technique throughout the Speaker 3 02:12 study period, one thing they noted is they allowed other antidiabetic medications for A1c control, except they did not allow DPP‑4 inhibitors. So that's going to be medications like saxagliptin or sitagliptin and things like that. They did not allow pramlintide or other GLP‑1 agonists. So unlike many trials, the inclusion required either age ≥50 with established cardiovascular disease (or chronic heart failure, CKD stage 3 or greater) or age ≥60 with at least one cardiovascular risk factor. Speaker 1 02:49 And again, the whole point here is that they're trying to show a cardiovascular benefit. So they're going to pick the types of patients that are more likely to have a cardiovascular event. Yeah. Speaker 2 02:59 And if you think about the applicability of the results too. It makes more sense. We're using this medication in patients who have higher risk of cardiovascular conditions. Speaker 1 03:08 And of course, you know, the people who they excluded are type ones, because we're only looking at type twos. Those who were receiving the medications that we excluded, that we previously mentioned, that couldn't stop those medications. They also excluded those on rapid acting insulin, which I thought was interesting, and then also those who wouldn't be good candidates for a GLP one agonist, such as those with the specific type of thyroid cancer that we talked about in our previous episode. Speaker 2 03:35 Yeah, and I think the reason to exclude patients with rapid acting insulin is Because currently, the guidelines do not recommend doing both GLP one and rapid acting insulins together. GLP ones can be used along with the basal insulin, however, Speaker 1 03:51 and I think it's probably worth just talking about briefly. Dr. Patel, would you mind explaining why the DPP four inhibitors were an exclusion to the trial for this GLP one drug, absolutely. Speaker 2 04:02 So both GLP one agonist and DPP four inhibitors work on the same enzyme, which is GLP one in the incretin system. So having both medication doing the same thing, it's not necessary, but I can also put patient at a higher risk of side effects. Naming some of the side effects would be pancreatitis or nausea, vomiting, diarrhea, etc. So in your Speaker 1 04:23 experience, would this be consistent with clinical practice that you would not see a patient on those two medications at the same time? Speaker 2 04:29 Absolutely, just like they mentioned the example of rapid acting insulin, don't combine it with GLP one. That's the practice with the DPP four is do not combine them with GLP one agonist. So if I have somebody, let's say on Januvia. And if I'm wanting them to be switched to GLP one, I discontinue Januvia and then put them on GLP one. Speaker 1 04:47 So in terms of their endpoint, again, they were looking at cardiovascular endpoints. So the primary endpoint was the first occurrence of death from a cardiovascular cause, non fatal MI and non fatal stroke. So again, this is fairly consistent. In terms of a composite endpoint looking at cardiovascular endpoints, Speaker 2 05:03 yep, and the other endpoints that they looked at was the composite cardiovascular outcomes that from any cause, nephropathy, retinopathy. Those were some of the microvascular outcomes they looked at, in addition to macro and then neoplasm and pancreatitis, as we know, GLP ones are associated with increased cases of pancreatitis. Speaker 3 05:24 One interesting thing to note from the statistics side is the study, at the outset, hypothesized that liraglutide would be noninferior to placebo. So this was not out. It's outside a superiority study. There was subsequent superiority testing, but again, a priority, they established non inferiority and Speaker 1 05:40 this is something that the FDA requires for all new diabetic medications on the heels of, kind of the TZD thing that happened, where we thought for a while that maybe it increased your risk of MI, as opposed to decreasing it. So, you know, it's very standard to have these non inferiority studies to just say that it doesn't cause harm, which is an ironic thing that we have to study. Speaker 2 06:00 Yeah, and I think these subsequent superiority testing is what's led to proving fact that, oh, some of these medications are actually better than placebo when it comes to cardiovascular outcome, amazing. Speaker 1 06:12 So terms of the results of the trial, the median drug exposure was about three and a half years, and the median dose was about 1.78 mg of liraglutide. To give the audience an idea of who was included, about 80% had established cardiovascular disease. So again, we're looking at those at a higher risk. These are not 30‑year‑olds with diabetes — these are patients with established cardiovascular risk. About a quarter of them had CKD stage 3 or higher, and about 15% had both established CV disease and CKD. Median diabetes duration was almost 13 years, and their A1c was poorly controlled (mean 8.7%). Speaker 3 06:56 for their A1c and just to go back to that number. So there were a total of 9340 patients that were enrolled in the study. And so again, that meets the number we needed to enroll to be able to obtain our outcomes. Speaker 2 07:07 Yeah. And then one thing to also notice, you know, comparing this with trials like EMPA‑REG, which enrolled many patients with established cardiovascular disease; the LEADER trial had almost 81% with established cardiovascular disease. I mean, you can relate that to the clinical applicability of the outcomes. Speaker 1 07:25 So Dr. Patel, what did they actually show in the trial in terms of that primary endpoint? Speaker 2 07:29 So what they found that the primary outcome of cardiovascular events — the composite outcome — occurred in 13% of patients in the liraglutide group versus 14.9% in the placebo group (608 vs. 694 patients). So when they looked at the non inferiority marker, this was statistically significant, with the P value of less than point 001, and then, like we said, there was a subsequent superiority testing occurred as well, and that was the p value of point 01, so it not only was non inferior to placebo, it actually proved superiority to placebo, and the number needed to treat for this outcome was 52 right? Speaker 3 08:19 I think that's an important thing to focus on, because we can sometimes get lost in the numbers here and what they're statistically significant versus clinically. And so what we have here, then is to prevent one of these outcomes, we would be able to 52 individuals. So where does that fit within, I guess, a general study as far as what's what's good? Speaker 1 08:35 Putting that into perspective, if you consider something like a PPI for GERD, your number needed to treat is going to be in the very low single digits in terms of patient‑reported symptom improvement. But if you consider something like statins, we're looking at a couple percentage points of improvement depending on your baseline risk. Or in heart failure trials, we're looking at between, let's say, three and 5% absolute benefit. So this is not nothing. It's on the lower end of what we would expect to see from some of the other cardiovascular drugs that we use. But a number needed to treat a 50 is definitely not something that we can ignore in terms of potentially impacting our impaired therapy for these high risk diabetic patients. Speaker 3 09:15 Ryan, you also keep in mind this is going to be in addition to, you know, one other added thing in terms of preventing further outcomes. We're adding it on to what we're already considering about you. Considering about, you said, statins or aspirins or different other Speaker 2 09:25 types of treatments too. Yeah. And then we will talk about, you know, how much a 1c reduction occurred with using lirabotide versus placebo. There was a 0.40‑percentage‑point difference in A1c between the two groups, with liraglutide being lower. But this was not statistically significant or even clinically significant looking at it, but we do know that any reduction in A and C eventually would lead to reduction in cardiovascular outcomes, Speaker 3 09:49 and I think, a couple of other outcomes to note. Death from cardiovascular causes was 4.7% in the liraglutide group versus 6.0% in placebo (statistically significant). And again, our number needed to treat here of 77 so we're moving kind of in a direction, you know, of it is significant, but as far as what it means clinically, or maybe maybe a little bit less so here, and then no difference between groups in terms of non fatal mi or stroke. Speaker 1 10:15 And as we would expect based on GLP‑1 agonists, we saw modest weight loss — about 2.3 kg more with the liraglutide group versus placebo. Speaker 2 10:29 Yeah, and then couple other outcomes that they tested was more related to microvascular outcomes of nephropathy and retinopathy, and as we described earlier, about quarter of the patient population had stage three CKD. So they looked at nephropathy outcomes and found these occurred less often in the liraglutide group versus placebo (268 vs. 337 patients; P = 0.003). Now, again, the study was not primarily powered for this secondary endpoint, but the result noted that liraglutide had a favorable effect on nephropathy outcomes. Speaker 1 11:22 they also looked at retinopathy. It was no different between the two groups, although numerically liraglutide actually did a little worse (106 vs. 92 patients). But again, it wasn't statistically significant. It was a fairly rare outcome and a study of something like 9000 patients. Speaker 3 11:39 So then another thing to look at, as mentioned before, is some of the safety outcomes we knew a little bit going into the study about some of the concerns of medication, and just to see if those held consistent. So one of the things they noticed was there were 13 cases of pancreatic cancer in the liraglutide group versus five in placebo. There were no cases of medullary thyroid carcinoma in the liraglutide group (one case occurred in placebo). So again, that may have been incidental; fewer prostate and leukemia cases were observed in the liraglutide group versus placebo. And of Speaker 1 12:10 course, pancreatitis is something that we always think about with the GLP one agonists. It's definitely a warning that we would want to advise our patients on that if they have, you know, abdominal pain that seems very severe and doesn't go away that they should have that investigated, and in this study it was really, numerically no different and very rare. So acute pancreatitis occurred in 18 patients in the liraglutide group versus 23 in placebo — very rare in a study of ~9,000. Speaker 2 12:36 However, acute gallstone disease occurred more frequently in the liraglutide group compared with placebo (145 vs. 90 patients). Cholecystitis incidence was 36 vs. 21 patients (liraglutide vs. placebo). Speaker 3 13:11 group, and Dr. Patel. Is that something that, from what we knew before about the medication was expected, or is that something that's kind of a new finding? Speaker 2 13:18 I would have to say this is more of a new finding we knew pancreatitis or maybe pancreatic cancer. It's still being researched, you know, more globally, but cholecystis and acute gallstone disease is something of a new finding for a GLP one agonist. Yeah, so I Speaker 3 13:34 imagine that's going to be something that will continue to be just observed, you know, whether from the FDA or just in further prospective studies, yeah, absolutely. Speaker 1 13:43 And given that we have a diabetic drug, we're always worried about hypoglycemic events. And what we found was numerically and statistically better with liraglutide versus placebo — keeping in mind placebo patients may have needed other therapies to reach the A1c goal. Severe hypoglycemia occurred in 114 patients with liraglutide versus 153 with placebo (about a 30% relative reduction). Speaker 2 14:15 yeah, and I think you caught that absolutely correctly. In order to reach the A1c goal during the trial, the placebo patients had to be on sulfonylureas and insulin more often than those in the liraglutide group; both insulin and sulfonylureas can increase hypoglycemia risk. Speaker 1 14:33 And as expected with GLP‑1 agonists, injection‑site reactions and GI adverse effects (nausea, vomiting, diarrhea) were more common with liraglutide and contributed to study dropouts. Speaker 3 14:47 Are there any others? Is this really the landmark one? Are there any other studies out there looking at this class of medication, the cardiovascular risk? Speaker 2 14:53 Yeah. So we have a few shorter acting GLP one agonists available. We have a few longer acting GLP one. Agonist available. The ELIXA trial (lixisenatide) showed noninferiority to placebo. The EXSCEL trial (Bydureon/exenatide once‑weekly) showed noninferiority — full results were to be released in Sept 2017. The REWIND trial (dulaglutide) was ongoing; dulaglutide is one of the longer‑acting GLP‑1 agonists. Speaker 1 15:41 doing so, to kind of summarize what we've seen in this trial, this is a great addition trial to what we've already seen with what we discussed previously, way back in episode 35 with Jardiance, that we have now another diabetic agent that has shown macrovascular benefit, microvascular benefit, a fairly favorable side effect profile, and most interestingly, a minimal effect that anyone Speaker 2 16:03 see that is correct, and thanks for summarizing this. As a result of this trial, the ADA has included liraglutide as a treatment option for patients with established cardiovascular disease or high cardiovascular risk. Very briefly, we covered Tresiba (insulin degludec). Tresiba underwent a MACE outcome trial called DEVOTE, with insulin glargine as the comparator. The primary composite outcome (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) showed Tresiba was noninferior to glargine (8.5% vs. 9.3%). Speaker 1 17:04 Again, the whole point of doing the study, as you mentioned earlier, Dr. Patel, is that all new diabetic meds have to go through this kind of a study to show that they don't increase your risk of cardiovascular disease. Again, the irony is that now we have drugs that are improving cardiovascular outcomes, yet we still have this requirement that in order to be a diabetic drug, you have to show that it doesn't harm, as opposed to doesn't help. That is correct. Speaker 3 17:27 So just to move on from here, going back to another class. Looking at the SGLT2 inhibitors — canagliflozin was studied in the CANVAS program (combined CANVAS and CANVAS‑R). The program included a little over 10,000 people with an average diabetes duration of ~13.5 years; about 65% had established cardiovascular disease. Speaker 2 17:51 find there? So just to clarify the canvas and Canvas two, which was the canvas renal outcome trial, so the first Canvas trial looked at the cardiovascular outcomes, the canvas two which was the R arm, which looked at the renal outcomes. And combined results were published under the canvas program and total number of patients with about 10,000 patients who had diabetes of anywhere between 13 to 13.5 years. And what was noted in this trial is that out of all patient enrolled, only 65% of the patient had established cardiovascular disease. So we mentioned for a leader trial, this number was around 80% in here there was 65% so if you compare results with EMPA‑REG (Jardiance/empagliflozin) and CANVAS (canagliflozin), there are some differences in enrolled populations to keep in mind. And this was a study that was extended for 188 weeks against placebo, and what we found as a primary outcome, which was the cardiovascular death, or death from any cardiovascular causes such as MI or stroke, the difference was 26.9 participant per 1000 patient years, versus 31.5 of that in the placebo group. And this result was statistically significant for the non inferiority as well as for superiority, which was established later on. Speaker 1 19:24 So again, just to highlight that now we have two drugs in the SGLT2 category — empagliflozin (EMPA‑REG) and canagliflozin (CANVAS) — both showing improvements in cardiovascular outcomes and mortality. Speaker 2 19:38 That is correct. And just like the leader trial, they also looked at, focused on one of the particular outcome of nephropathy. There was the progression of albuminuria. Now they looked at, you know, what was the regression of the EGFR? What was the regression in proteinuria? But they looked at the composite. Nephropathy outcome, and they found 40% sustained reduction in EGFR rate need for any renal replacement, replacement therapy or any death from the renal causes. And this outcome was in favor of using canagliflozin rather than placebo. And that's very interesting, because we always say, you know, patients who are on sglt, two inhibitors, we have to monitor the renal function, because in those with poor renal functions, we cannot use this drug. So this was one of the favorable outcome compared to placebo. Speaker 3 20:29 And then speaking of safety and monitoring outcomes. So again, is before we jump on board to medication with its efficacy, we have to look at safety. And so one of the big things I know that came up in the past was risk of amputations? They noticed amputations occurred about twice as often in those on canagliflozin treatment (6.3 vs. 3.4 per 1,000 patient‑years in placebo). And that was statistically significant, yeah. Speaker 2 20:53 And then they this was more of a combined Canvas program outcome. They kind of broke this result down into what happened in the cardiovascular outcome arm versus the renal outcome arm, and the results were pretty similar to what the combined results presented. We noticed the amputation rate in the Canvas trial, which was the cardiovascular outcome, was 5.9 per 1000 patients, versus 2.8 in the placebo arm; 3.3% in the canagliflozin group versus 1.5% in placebo — about twice the risk in the drug group. Speaker 1 21:30 And when we say amputations, does this count toe amputations equally to like a leg amputation, or are these kind of the more relevant kinds of amputations. Speaker 2 21:41 Yeah, so the majority of the amputations were toe and mid‑foot. There were a small number of below‑knee and above‑knee amputations included. The FDA warning focuses on toe and mid‑foot amputations. Speaker 1 22:02 As you both mentioned, this warning was issued by the FDA in March 2017 regarding the risk of amputations with canagliflozin. Speaker 2 22:14 Canagliflozin has been studied in other trials, but the amputation signal was most prominent in the CANVAS program. The amputation findings are specific to canagliflozin (Invokana); the FDA warning applies to canagliflozin. Speaker 1 22:51 At this point, granted that it's easy to either not report data extensively, or there may be kind of funny business going on that makes different trials hard to compare each other, but if you were to pick an SGLT2 inhibitor between empagliflozin and canagliflozin — given they both improve cardiovascular endpoints — you might favor empagliflozin because the amputation signal has been reported with canagliflozin. Speaker 2 23:24 The CANVAS program reported about double the risk of amputations (mostly toe/mid‑foot), although not all canagliflozin studies have shown the same signal. If I were to choose between empagliflozin and canagliflozin, I would probably choose empagliflozin (EMPA‑REG), since EMPA‑REG enrolled a higher proportion of patients with established cardiovascular disease. Speaker 3 23:59 And so to turn it back to, you know, for those clinicians who are looking at using canagliflozin in practice, one of the recommendations, then is to evaluate underlying risk factors. So you know, thing of peripheral vascular disease, any other things that may impact the ability of that circulation to the extremities? So peripheral vascular disease, neuropathy, history of amputations, foot ulcers. And then if you do notice things like infection, new pain or tenderness, sores or ulcers involving the lower limbs, at that point, recommend to discontinue the medication. Speaker 1 24:28 And of course, hopefully these are things that we're talking to diabetic patients about anyway, but certainly someone who's on canagliflozin should receive extra emphasis on foot care. Speaker 2 24:38 Until we study these SGLT2s further, additional data will be informative. Speaker 3 24:46 But as Dr. Kane said, again, this is the standard of practice, is to do this monitoring. So as long as you're continuing to do your standard of practice monitoring, again, I think then that's the best case here. Speaker 1 24:56 I think it's important not to miss the trees in the forest. Yes, and that yes, this is something that we have to worry about in terms of a side effect. But there's this other side effect of all sglt twos that I think would be remiss if we didn't talk about, yeah. Speaker 2 25:10 So again, looking at the outcomes from the canvas program, we found that mycotic (vulvovaginal) infections were more common in women, genital infections in men, volume depletion and osmotic diuresis were more common in patients who received canagliflozin versus placebo; these results were statistically significant. Speaker 1 25:32 We've seen this in other trials, but we didn't see a difference in urinary tract infection risk. So the kinds of infections that we're seeing are more of the fungal infections in the in the genital area, as opposed to urinary tract infections. With that said, I almost don't believe it, because it seems so obvious that UTI should be more common, although this is another trial that does not demonstrate that that is Speaker 2 25:55 correct, and some of these side effects that we mentioned later, we're also responsible for dropouts from the from the canvas program to both, both the canvas trials. So just to summarize, you know, our episode today, we would like to present some key concepts. We talked about the LEADER trial showing liraglutide reduced cardiovascular morbidity and mortality and had favorable nephropathy outcomes — liraglutide is now included in ADA recommendations for patients with established cardiovascular disease or high cardiovascular risk. Speaker 3 26:39 We also briefly discussed the DEVOTE trial of Tresiba (insulin degludec), which was noninferior to insulin glargine for cardiovascular outcomes. Speaker 1 26:52 Then we covered the CANVAS program — canagliflozin improved cardiovascular endpoints, similar to empagliflozin (EMPA‑REG). However, the trials enrolled different patient populations, so they aren't directly comparable. Speaker 2 27:15 There was cardiovascular benefit in CANVAS, but the same trial results prompted an FDA warning specific to canagliflozin (Invokana) for increased risk of toe/mid‑foot amputations in type 2 diabetes patients. Speaker 1 27:36 So with that, that wraps us up. If you'd like to see the references for Canvas. Canvas are things like that. You can visit us at HelixTalk.com to view the show notes and the references for this episode. We're also available on Twitter at HelixTalk with that. I'm Dr. Kane, I'm Dr. Schuman, and Unknown Speaker 27:53 I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 27:56 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store, search for HelixTalk and place your review there to Narrator - ? 28:07 suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.