Speaker 1 00:05 Lange, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin, University of Medicine and Science. Speaker 1 00:32 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 - Dr. Abel 00:47 And now on to the show. Dr. Sean Kane 00:51 Welcome to HelixTalk. Episode 16. I'm your co Speaker 2 00:53 host, Dr. Kane, I'm Dr. Schuman. I'm Dr. Patel, I'm Dr. Lahore. Dr. Sean Kane 00:57 See today we're talking about three of the newer agents FDA approved for diabetes. So we're going to review diabetes kind of as an overview, but really focus on some of these newer drug classes that have come out onto the market, Speaker 3 01:10 and I'm really excited to talk about them. So just briefly overviewing. So the two main accrediting bodies who produce guidelines are ADA American Diabetes Association and AAC E, which is the American Association of clinical endocrinologist as the guidelines don't get updated very often, but ADA is keeping up with this every year. So the most recent guidelines we have is 2014 Dr. Sean Kane 01:33 and that's pretty impressive, if you think about it, every year for an updated guideline that's pretty aggressive, but also very admirable. I think other guidelines could probably take note and do similar things. Speaker 3 01:43 Yeah, the changes are not very huge. However, I like the fact that they're reviewing new drugs, new clinical trials and things like that that are coming up. Speaker 2 01:52 I've been always taking a look at Preferred initial agents, second line agents, and where do some of these new, newer medications fit in? So as we know, Metformin is the preferred initial agent if the patient is able to use it. So that's the one we try to push, even if the patient is already on other agents, making sure that we have Metformin on board if the patient is able to use it. There is no specific agent recommended after Metformin failure at this point. That's pretty Dr. Sean Kane 02:18 surprising, if you think about it, diabetes has been around for a while, and we really just have one preferred therapy. Then beyond that, we don't really have a lot of firm recommendations in terms of comparative evidence of one drug class versus another, in terms of micro or macro, vascular complication prevention or treatment, anything like that. Speaker 3 02:34 Yeah, I think that that's the point where you have to kind of tailor the therapy to patient specific. You know, what's covered on the insurance? Can they afford it? Can they take it by mouth, or do they want to be taking an injectable medication, etc? So Dr Dr. Sean Kane 02:49 Patel, for any patient on a diabetic regimen, what are some of the therapeutic goals that we think about, and why do we pick those goals? Speaker 3 02:56 So first of all, the goals we think about is obviously your sugars, your fasting sugars, your postprandial sugars, and then the biggest goal is A and C, which is your three month average of blood sugar. And what we go for is less than 7% the reason this goal is set up because we have seen, if we keep people's A and C less than 7% we can actually prevent some of the microvascular and macro vascular complications, and again, this is not a cookie cutter go, either, you know, if your patients have more comorbidities, or they're a little bit advanced in their diabetes, have other complications and stuff, we can say they can stay at you know, 8% less than 8% or even less than 9% is okay, because we found out from some trials that too tight of A control it's not good for elderly patients either. Dr. Sean Kane 03:43 So not to breeze over the guidelines too much. And they're absolutely comprehensive guidelines covering everything from diet, physical activity, immunizations, blood pressure control, lipids, lots of different things. We could talk an entire podcast just on the guidelines, but today, we really want to focus on some of the newer drug therapies, so we'd encourage you, the listeners, to take a look at these yearly updates that Ada provides. And I think that the Infectious Disease Society of America guidelines could probably take note of the frequent updates that Ada provides as well. So one of the cool new agents is called Afrezza. That's the brand name, and it's actually an inhaled insulin, and that we used to have an inhaled insulin with the brand name of exubera, that was approved in 2006 but it actually got pulled from the market. So Afrezza is a newer inhaled insulin that is different than exubera was about a decade ago. And I think this Speaker 4 04:33 is interesting, because I know with with exubera, when it was pulled from the market, was actually due to limited use, and it wasn't actually due to any issues of the mechanism. It wasn't due to lack of efficacy, just that for we would think, okay, and a new mechanism inhaled, and that's obviously going to be a great boon to compliance, something that people don't have to take in a pill, or if you avoid that, we can do it inhale. But it didn't seem to really take off. So I'm excited about this, the second opportunity to see what this novel mechanism can do. Speaker 2 05:00 ... and I can tell already that providers and patients have already started asking about this Afrezza. So it's definitely, I don't know if the marketing is a little bit better than it was in the past with exubera, but it's definitely starting to get into the top news for diabetes management. Dr. Sean Kane 05:14 ... So Dr. Patel, what? Who is this approved for? And what is the PK profile of Afrezza, as in terms of how long does the insulin last once you inhale it and kind of what are some of the issues that we need to be concerned with. Speaker 3 05:25 Currently, it's approved for both type one and type two diabetic patients, obviously, because the route of administration is by mouth, it goes into your lungs, and that's how the insulin gets absorbed. It is not recommended for people who smoke because we know their lung capacity is a little compromised, or who have recently stopped smoking. But we also have to be careful patients who have breathing disorders such as asthma and COPD. Currently, this medication has a black box warning and it falls under a contraindication too, just so you know, Afrezza's profile of this insulin matches regular insulin and so patients still might have to use non-acting subcutaneous injection to get that overall control of their sugar as well. Speaker 2 06:11 Controlling sugars with this medication might be a little bit difficult too, because it comes in cartridges. So it comes in four unit cartridges and eight unit cartridges. So in order to kind of get really tight glycemic control without risking hypoglycemia, it might be a little bit difficult. Some patients in clinic, a four unit dose increase with a meal time regimen might be a huge dose increase. So it might really make it difficult, but it might be a good option for me, patients who are on higher doses of bolus insulin, Speaker 3 06:40 and if you look at the efficacy, you know, divided out to type one patient versus type two patient, what they found in type one patient is that they compared it to aspart, which is a rapid acting insulin. And they found patients with type one diabetes actually did better in aspart group compared to the Afrezza group. And so in aspart group, we were able to achieve that A1c goal of less than seven in 27% of the population, compared to only 13% of those patient in the Afrezza group. But to make a note that patient who were in the Afrezza group also needed higher basal insulin doses as well. Dr. Sean Kane 07:18 So you're telling me that Afrezza doesn't work as well in getting your A1c goal compared to a rapid ultrafast acting like aspart Speaker 3 07:26 in type one diabetes patients. Yeah, for type two diabetes patient, the study was done with Afrezza versus placebo, and so obviously we have better A1c reduction in the Afrezza group, which was, you know, difference of 0.82% versus 0.4% in the placebo and obviously more patients in the Afrezza group were able to reach that A1c goal of less than 7% Dr. Sean Kane 07:49 so why do you think the FDA approved it for both type one and type two? If it showed inferior efficacy for type one diabetes versus aspirated Speaker 3 07:58 it could be the marketing strategy too, but I guess also for type one patients, because they're taking lot of injections a day, you know, long acting as well as short acting. So maybe this was another way of offering them or minimizing the frequency of insulin injection. So I'm thinking that's why they did this study, and FDA did approve it. Like I said, it kind of falls into that regular insulin profile, Dr. Sean Kane 08:20 so I think the kinetics are kind of cool. So we talked earlier about how it's an inhaler with a cartridge on it, and there's two cartridges, either a four or an eight unit cartridge. You can't split it. It comes as a dry powder inhaler, and when you inhale it with all the capillaries in your lung, it gets rapidly absorbed well, which is pretty cool. So the peak effect is about a half hour, or an hour lasts about three hours, so a fairly short duration of action. And for patients who are on more than eight units per day with meals, you know, they're going to have to use more than one cartridge, because there's either a four or an eight unit cartridge, and it seems kind of like a pain to me. It's a single use cartridge. You have to carry around these, you know, somewhat bulky cartridges and have to calculate your dose and things like that. The packaging does do a really good job of describing, you know, how much to give, but at some point you're giving, like, 234, cartridges, maybe it's just easier to suck it up and take an injection. Speaker 4 09:12 And I think one of my concerns with it may be just that we could have the potential for a little bit of variability in terms of technique of administration, because unique to this inhaler versus others is you're actually supposed to tilt the inhaler slightly downward before you inhale something that's not really because we talk about more remaining upright and holding it almost, you know, at an L shape with some of the other inhalers for COPD or or asthma. And so just that, that one little difference there, and again, a little bit of just variability in individuals that they do it, and whether or not that has an impact. Has an impact Speaker 2 09:43 on efficacy. Plus patients are going to have to come in for more clinic visits, because not only are you monitoring their technique, their blood sugar readings, they also have to do spirometry. So they have to do it before starting Afrezza six months later, and then annually. And they do mention in the package insert. That if the FEV1 decreases by more than 20% you're supposed to discontinue Afrezza as well. Yeah. Dr. Sean Kane 10:07 So going back to some of the patient populations, these are boxed warnings. So in someone who has COPD or asthma, they have a much higher risk of wheezing, so you have to be very cautious, even contraindicating that patient population, primarily because the studies didn't include those with underlying pulmonary disease. So we don't really know, you know what, what is the true incidence of bronchospasm and wheezing in that Speaker 3 10:28 patient population, or even for the efficacy of insulin in those patients? Dr. Sean Kane 10:32 Exactly, in addition to that, as we said, we need to be thinking about, you know, pulmonary function testing. And with that pulmonary function testing, at least in the clinical trials, we did see a decrease in FEV1, and this is basically how much you can expire from your lungs in one second of time. So how good you are at exhaling. To give you an idea, over a two year period, the FEV1 decreased by 40 milliliters. For you know, a typical 50 year old guy, his FEV1 is going to be about four liters. So that means that it's a very, very small reduction, but it was a statistically significant reduction, and one might presume that in certain patients, that would be more than you know, certain other patient populations, probably in those with underlying, undiagnosed COPD or asthma or something to that effect. Speaker 3 11:20 And then keep in mind, this is only studied for two years, so we don't know what's the effect on FEV1 for long term use, because patients are going to be needing this insulin for long term use. Speaker 2 11:32 So then, if you do have a patient who starts Afrezza, what do you want to counsel them on? So definitely adverse drug reactions of hypoglycemia, especially since we're titrating every four or eight units, so might be a little bit more aggressive than typically for some patients also cough. So pretty high incidence, 25% of incidents in patients using Afrezza may have cough, and it's the most common reason for discontinuation. It should improve after a month. So that's something to let them know that's going to take some time to kind of get used to throat irritation is another side effect that can occur. And then storage and handling is probably the most important thing with any insulin products. So they do say to replace the inhaler device every 15 days you want to store it in the fridge. And then when it's ready for use, you can store at room temperature, so just like our other insulins out there, so you have to use it within 10 days of an unopened cartridge at room temperature, and then within three days once you open it out of the packaging. So definitely, I think that's always an issue with insulin products, is storage and handling, Speaker 3 12:33 and you have to also remember to take out the cartridge out of the fridge 10 minutes before has to come to the room temperature. Dr. Sean Kane 12:40 We talked about how with type one diabetics, the A 1c was not improved, versus aspart type two diabetics, it was better. Is there any data in terms of quality of life or how satisfied the patients are with an inhaled insulin product, which to me, at least in my mind, would be the reason that you would go with an inhaled insulin to make the patient feel better about their diabetes, to make it easier for them to manage it. Speaker 3 13:01 Actually, those studies of quality of life actually showed that increased patient satisfaction and quality of life with the inhale insulin. So there you go. Like you said, you know, this was made to reduce the amount of injections, or number of injections the patient is taking, and it's replacing with the inhale therapy. And so definitely they're showing some improvement in quality of life. Just one caveat we need to worry about is insulin is actually the two goat therapy according to the American Diabetes Association for pregnant female However, currently this is a pregnancy category theme, meaning it's not studied in that patient population, so you still want to go with traditional insulin therapy in your pregnant female patients, and even though it is approved for type one diabetic patients, who are most of our younger adolescents and as well as hit patient population, but the studies did not include any patient less than 18. So technically, even though it's approved, we don't know what the outcome could be, and we know that lot of young kids also come up with breathing issues such as asthma, so have to be wary of that. Dr. Sean Kane 14:09 So the next drug class is very, very new. It's one of my favorites because of how it works and some of the adverse effects that we get. There's three that are currently approved on the market. The first is called Invokana. The generic is canagliflozin. Speaker 3 14:22 Farxiga, the generic is dapagliflozin, Speaker 4 14:26 and then Jardiance is empagliflozin. Dr. Sean Kane 14:30 And these are all approved since May of 2013 and then Farxiga was 2014 in January, and then Jardiance was just a couple months ago. Speaker 3 14:40 And so how do these drugs work? Dr. lavori, so Speaker 2 14:44 they are sglt Two inhibitors. So sglt Two stands for sodium glucose co transporter two, which is a transporter and the proximal tubule that's responsible for reabsorption of glucose. So if you're inhibiting this, SGL. Two, then you're basically excreting all the glucose. So you are going to the restroom, getting rid of your glucose, then that way. So basically, at any doses that is prescribed, any blood sugar that's greater than 7090 will cause it to end up in the urine. Dr. Sean Kane 15:15 So you literally pee out excess sugar, correct? And it's not that, you know, diabetic patients normally do pee out sugar if they have a high enough blood sugar, so somewhere 180 to 200 of their blood sugar will start peeing out excess sugar. What these sglt Two inhibitors do is they lower that threshold from around 200 to more, like 70 to 90 instead. So are these approved for type one and that type two diabetes? No. Speaker 3 15:40 Currently the only approval status is for type two diabetes patient. These are available and pill forms, and so we're asking patients to take it once a day, which is good for the convenience and also for the compliance. And currently the dose adjustment is based on EGFR, not on creatinine clearance. They're trying to be a little bit fancy, and so they included that parameter when they did clinical trials, instead of Creatinine clearance. Dr. Sean Kane 16:07 And it should make sense that it's not for type one diabetes, right? So type one diabetes, they need insulin to open the key to get sugar in the cell. It's because they don't have enough insulin, as opposed to, we need to lower it using drug therapy that isn't related to Speaker 3 16:20 insulin, right. And this is definitely the pure insulin resistant mechanism. It fits it really well. Speaker 4 16:26 And then for those that have been on other medications for diabetes, some of the other issues with taking it are going to be similar, such as taking it before breakfast. Same thing you might see with the sulfonylureas or the insulins. Really want to have a good level of the drug in in place before you get to that first meal of the day, breakfast. Because hypothetically, what we want to do is avoid getting any kind of postprandial hyperglycemia, so that if you don't have it in there again, just with anything else you it's going to start piling up early Speaker 2 16:51 in the day. And then adverse effects are, as we call them, pretty special in this drug class category. So hyperkalemia, dehydration, which, if patients are presenting to you with low blood pressure, they're feeling dizzy, they have orthostasis. Maybe it is related to the medication, renal impairment. So definitely, still watching the EGFR and dose, adjusting appropriately if needed increased urination. That is going to happen, of course, because the mechanism of the medication is urinating the glucose. So patients might complain about that. And then the most interesting one is genitourinary infections, which are mostly fungal infections. So about 10% of women will get a yeast or fungal infection. And then men about three to 4% and normally this is rare for men to get, so they get an extra bonus with this medication. Dr. Sean Kane 17:40 But you know what the good news is, it doesn't really cause hypoglycemia. When used on its own or with metformin, we can see more hypoglycemia when we add things like a sulfonylurea on board. But based on the mechanism, you wouldn't expect that it does cause hypoglycemia, which would be true. I just want to pause for a second. So this is a medication that 10% of the patients, one out of every 10 women will get a yeast or a fungal infection from taking it, and three to four out of 100 men will get it by taking this medication. That's an insane amount of adverse effects, not even just like orthostasis, where it's a troublesome adverse effect. This is an actual like, genital infection that the patients are going to get from this medication. That's a big Speaker 3 18:19 deal, absolutely and in your older patient who have urinary retention issues and stuff, you have to be really careful before you give this medication to them. In fact, I had an incident in the clinic where a lady came to see the provider for UTI. She comes next week in the clinic and sees me and she's inquiring about one of these agents. And I said, Well, you just had a UTI. And she goes, Oh, no, I don't want this medication because, you know, it's painful to go through UTI episode. Dr. Sean Kane 18:45 So like pretty much all of our other newer oral diabetic medications, the core problem that many evidence based medicine people come up with is that these are approved on the basis of a 1c reduction or pre or postprandial glucose reduction, as opposed to looking at clinical endpoints, so you know, micro and macro vascular complications. So we don't have data showing that this, or many of our other oral hypoglycemic agents, can improve some of the complications of diabetes. All we see is the surrogate markers associated with diabetes. Speaker 3 19:18 So if you look at those surrogate markers, I know there has been shown to decrease fasting plasma glucose as well as postprandial glucose. We have seen even seed reduction up to 1.2% in some of the trials, because people, you know, pee out a lot of water. There has been some minor weight loss, about two three kilogram has been seen. And blood pressure obviously depends on that. You know, water attainment as well. And so basically, by getting rid of extra water, will also improve your blood pressure a little bit as well. One thing to notice is one of the monitoring parameters is to check patients cholesterol levels, because it does actually increase the LDL. Well. So technically, for diabetes patients, we want to decrease their LDL and control that better. However, this medication can does the opposite. Dr. Sean Kane 20:08 So this is literally like a battle of the surrogate in points here. So we see improvements in glycemic control, which is good, we see weight loss which is good for diabetes and for cardiovascular complications, but then we see this paradoxical increase in LDL that may not be the best thing for a diabetic patient, that we're trying to prevent macrovascular complications. Speaker 3 20:28 Yeah, and I mean, looking at the clinical trials too, the LDL increases not just significant. Most of our diabetic patients, as we know of the HACCP guidelines, should be on some sort of statin. So if that happens to be an issue, we can always titrate the statin dose up. Dr. Sean Kane 20:44 So what did the guidelines say about these new sglt Two inhibitors, given that they came out, you know, basically in 2013 and we're seeing more of them now, and there's some pretty important patient issues that we need to think about. Speaker 2 20:56 So the ADA actually doesn't recommend them right now. They don't mention them the guidelines. So probably because the most recent one just came out, and we're still kind of looking into them. Long term data, the AAC E does say that we can consider them, but with caution. So they say we can use it as mono therapy if they're a 1c is less than 7.5% or as dual triple therapy in those with 7.5 to 9% a 1c but again, with caution. Dr. Sean Kane 21:22 So our next drug class is actually a number of different drugs, but they're all under the umbrella of GLP. One agonists Speaker 3 21:29 and various different agents have come in the market. The oldest one to begin is Byetta, which is generic exenatide. Shortly after Byetta was introduced, Victoza (liraglutide) came out in the market. And then slowly, they figured that it's time to make something new out of the existing products. So they made an extended release version of Byetta called Bydureon. And then recently, just this April, Tanzeum came out. Generic name is albiglutide. Once again, these are all GLP-1 agonists. So how are Dr. Sean Kane 22:07 these given to a patient? Speaker 2 22:09 So these are injections. Byetta that's been around is a twice-daily injection. Bydureon that just came out is a once-weekly injection, so that for some patients can be very appealing. And what they found is that this extended-release Bydureon, which is extended-release exenatide, is actually decreasing A1c better than the twice-daily one. So it can decrease A1c 1.5 to 1.9% versus 0.5 to 1% for the twice-daily Byetta. Dr. Sean Kane 22:37 Do you guys like the brand name Bydureon (durable or longer duration)? Speaker 3 22:41 product, yeah, it's very smart brand name. So we said that all Dr. Sean Kane 22:45 of these are GLP one receptor agonists. GLP one is one of those in cretin hormones. This is the same hormone that we're trying to not break down when we give a DPP four inhibitor like Januvia or sitagliptin. So we have an enzyme, DPP four, that breaks down, increasing hormones. This is one of those incretin hormones that is in the body. Speaker 3 23:05 So then why do we want to not have the GLP one broken down? Speaker 2 23:11 So GLP one is useful for the body, so it allows the body to produce more insulin, it decreases glucagon production, and it slows gastric emptying. So in that regards, you're going to be reducing the fasting blood sugar and postprandial blood sugars as well. Speaker 4 23:25 And one thing that I always think is really cool about some of these medications are those that are synthesized from animal products. And this is one that actually came from the Hila monster, which is a reptile living in the kind of the desert of the south southwest. But anyway, so they use the the salivary gland venom, and then they use that to synthesize this. And it's only about 53% homologous, so there's a little bit of structural differences between the GLP, one of the Hilo monster, and the human, but it's so it seems that that one's much more potent the human version never. Nevertheless, they've synthesized the drug out of it, and so we've been able to mimic the general effect in it, but it's always cool to see where in the world we're going to find some of these drugs Dr. Sean Kane 24:05 out of so by far, the biggest adverse effect that a patient will experience with any of the GLP one agonists is nausea and vomiting, and it's dose dependent, so the bigger the dose, the more they're going to get. And many of these are also renally eliminated. So if they have renal impairment and they're getting a standard dose, they're going to have more nausea and vomiting, right? Speaker 3 24:23 The GLP, one agonist are associated with some weight loss, not clinically significant, but some, and they're saying that the weight loss comes from the side effect of nausea and vomiting, because patient doesn't want to eat anything. So it's about 40% if you look at your regular release, Exenatide, versus about 11 to 27% with the extended release, which makes sense, the body is not getting all the GLP one at the same time with the extended release, so the incidence of nausea is a little bit lower. Speaker 4 24:51 And as we said, this medication works by helping the body to produce more insulin. So there is a risk of hypoglycemia, though it's primarily going to be the combination therapy. Speaker 2 25:00 In regards to pancreatitis, there has been reports that this is a potential, but the reports are rare, and the FDA is still investigating this, so we don't really know too much. In regards to this, there are the potential for injection site reactions, so kind of getting itchy or having hard nodules underneath the skin is also a possibility, Speaker 3 25:20 and the skin reactions are noted a little bit more with the extended release products versus the daily injections. So kind of have to take, you know, weigh out the benefits and risk of using extended versus the regular release Dr. Sean Kane 25:34 at least one box warning that's worth mentioning. I don't know that I've mentioned it to a patient, per se, but the warning is that in rat models of the drug, they saw an increased risk of a very specific type of thyroid cancer called medullary thyroid cancer, or MTC. So in anyone who has a family history of this, they shouldn't receive the drug. If someone asks about cancer risk with it, certainly you can talk to them about it's a very, very specific type of cancer that was only seen in animal models. But again, I think it is rare enough and only seen in animals that it's probably not something I'd include in a everyday encounter with a patient newly on Byetta or exenatide. Speaker 3 26:12 This type of cancer in itself, is very limited in population, so you're not going to see whole lot of patients being contraindicated to these agents. Speaker 4 26:19 There is a little bit of a potential, I believe, for drug drug interaction, but part of that may be theoretical. Since we know the medication seems to slow the gastric emptying time, we could see some change in the absorption from your medication. So there's some theory that we may just want to be aware of before looking at medications. I do have very narrow therapeutic windows. One example would be to be careful that it could potentially increase the INR when used with warfarin. Speaker 2 26:42 In terms of contraceptives, they have found that it might decrease the efficacy of contraceptives, so they recommend taking the oral contraceptive at least one hour before the exenatide. And also, to keep in mind for our female patients, this is pregnancy Speaker 3 26:54 category C, yeah. And then you just kind of have to look at the physiology and the action of this medication, you know, essentially they slow down the gastric am thinking, so if your medications are being absorbed in the stomach, you know, you kind of have to worry about those kind of absorption related drug interactions too. Dr. Sean Kane 27:10 No, I've never seen exenatide or Byetta or Bydureon given, but I've been told you're supposed to shake it like a Polaroid picture. Speaker 2 27:19 My favorite part from the package insert for Bydureon is shake hard, like you would shake a bottle of oil and vinegar salad dressing. And they actually have a picture of oil and vinegar salad dressing in there. Dr. Sean Kane 27:28 Interesting. So is it a reconstituted product that the patient has to combine two elements together? Speaker 2 27:34 There's very many parts to the product, and so they have to pretty much go step by step, putting everything together. And it does involve a constitution, yeah. Speaker 3 27:42 So what we recommend, and I've done this in my clinic as well, is that if we are sending a patient, it's best that we start them in the clinic. We explain them how to reconstitute the product, have the patient show the ability to do this on their own, inject it on their own. Once they feel comfortable, that's when we should let them walk out of the clinic with a new prescription that they can get it from the pharmacy. Dr. Sean Kane 28:04 So Dr. tell me help me understand kind of the place in therapy for a drug like exenatide or Byetta or Bydureon. It seems like you know, you have the hassle of an injectable just like you would with, let's say, glargine or Lantus, but you have potentially a worse adverse effect profile with the nausea and vomiting, some very strange adverse effects, like pancreatitis, you have to reconstitute it, as opposed to drawing it out of a vial. Who is going to be a good candidate for a drug like this, given that we seemingly would have other drugs that, in my mind, don't seem as bad as this Speaker 3 28:36 drug, absolutely. And you know, the bidarion, yes, there is an extra step of, you know, rigorous shaking and reconstitution process. But if you were to prescribe Exenatide, those are already made available pens. The pain is that they have to take it twice a day, you know, around the meal time and stuff. One advantage of using this medication is that it kills two birds with one stone. You're controlling your fasting glucose as well as postprandial control. Keep that in mind, though, it gives us a and c reduction. In the clinical trials we have seen up to about 1.5 to 1.9 for the extended release and about 1% for the regular release. So you kind of have to look at your patient, where the patient is standing. Obviously, if they're at 10.2 you're not going to reduce their agency to their goal by just using one of these agents. Keep in mind the AAC e guidelines, which is the American Association of clinical endocrinologists. They actually recommend GLP, one agonist, as actually second line after starting Metformin earlier, we mentioned that, you know, there is not really a second line recommended agent. The first line therapy is definitely Metformin, and then you pick whatever based on patient factors AAC E, which is the American Association of clinical endocrinologists tend to weigh a little bit more on the GLP, one agonist side. They want that to be the second line, preferred agent over the other. However, know that you still want to go with, you know, looking at other patient factors and figure out, you know, what the hypoglycemia risk is. Speaker 2 30:00 So it depends on the person as well. So there are a lot of patients who are resistant to starting insulin. They're concerned about maybe they've had significant others or family members who didn't do well with insulin. They have a fear of it, and this provides just an additional medication that was overall pretty effective and pretty safe to use. So I've had a few patients who, for example, cannot use insulin because they drive trucks between states. And so in that case, the their truck driving license won't allow that. So we have to get a little bit more creative. And so, you know, we've had quite a few patients who do pretty well in Dr. Sean Kane 30:36 Exenatide, actually. So truck drivers cannot take insulin. Speaker 2 30:39 Well, if they're driving between state lines. If they're within state lines, Speaker 3 30:42 they're okay. And some of the school districts do not allow the school bus drivers to be taking insulin either. So for them, this becomes an alternative option. Dr. Sean Kane 30:51 So it seems like we've got the trucker market cornered with these GLP one agonists. And beautiful so I know that there's an at least two other GLP one agonists in the market. Are there any fun factoids that we should know about either of those? Speaker 3 31:05 The Victoza, liraglutide, has been out in the market since 2010 and you know, it was another kind of me-too product after exenatide had come out or Byetta had come out. The only difference with Victoza is that it's once a day subcutaneous injection versus exenatide is twice a day, so you're minimizing the number of injections, but otherwise, you know, looking at the side effects or contraindications, it's pretty much similar to exenatide. Dr. Sean Kane 31:32 Do either of you see any favor for one agent over the other in your clinical practice, Speaker 2 31:37 for the most part, I have seen exenatide more so, but it also depends on the formulary options, and that plays a big role in regards to where you do work. Speaker 4 31:46 The big one, other agent that can be a little bit newer, is tanzyme, or ambiglitide. And this one was launched around May of 2014 and like a zenotide, this is another one that's GOP one agonist, and can be given weekly injection 30 or 50 milligrams. Speaker 2 32:01 And the nice thing with this one is that you don't have to go through the hard process of, you know, reconstituting this medication. It's not as time consuming as the other medication you just talked about. So this one, you still have to mix it. So for the 30 milligram pen you have to wait 15 minutes after you mix it. And then for the 50 milligram pen you have to wait 30 minutes. So with this one, you still have some time restrictions to it, but it's not as complex maybe as the by jury on in regards to Speaker 3 32:29 mixing it up. Yeah. And keep in mind, even though there is this wait period, it's once a week, so most of the patients can't schedule that on a Saturday or a Sunday when they're home, so they're not taking all that time out during their weekdays. Dr. Sean Kane 32:41 And I assume it's 110 is good for one use for that one week. Then right? That is correct, just like the other agents, it does have the boxed warning for that very specific type of thyroid cancer. But they were actually unable to study this particular drug in the case of Tanzania more albiglatide because of the animal model they were using, the animals actually formed antibodies against the drug, so they couldn't study it in the rat model that they saw with biata or Exenatide, but they still gave it the same boxed warning for the potential of this very specific type of thyroid cancer. And I Speaker 4 33:13 think we're dealing with some of the similar ADRs as well compared to some of the other GLP one agonists, we've got pancreatitis, small amount, point 3% and there's some nausea and vomiting that doesn't seem to be as bad as exenatide. Again, based upon those phase three studies, there's not really any comparative data, since it's such a new age, and we don't have any head to head comparative of two of these branded agents, one against another just Dr. Sean Kane 33:35 yet, and just like what we saw with Exenatide, because it's a really eliminated drug, just to give you an example. If you have a credit clearance of 60 to 90, which is kind of normal or maybe mild renal impairment, the incidence of nausea was 3% versus 16% if you had pretty severe impairment. So clearance of 15 to 30, so that again, exemplifies a dose dependent effect on nausea that is often related to the patient's renal function or renal dysfunction, Speaker 3 34:03 and shortly, hopefully, if FDA approves another me too. Drug Victoza, manufacturer is also working on producing a longer acting version of it. So don't be surprised if you see another once a weekly exactly more expensive and hard to reconstitute medication out in the market, Dr. Sean Kane 34:21 let's be honest, there's a lot of trackers in America that I think would benefit from another drug. All right, so to review, we've talked about a few newer diabetic agents. The first one was Afrezza, which was essentially an inhaled insulin that mimics regular insulin in the body. Speaker 3 34:38 The second category of agents we talked about were the SGLT2 inhibitors, the sodium glucose co-transporter-2 inhibitors. And we talked about three different agents that are recently approved: Invokana (generic canagliflozin), Farxiga (generic dapagliflozin), and Jardiance (generic empagliflozin). Speaker 2 35:00 And then we also discussed our long-acting Byetta/Bydureon class — specifically Bydureon, and Tanzeum (albiglutide). And both of those are GLP-1 agonists, so they allow our bodies to produce more insulin, decrease glucagon production and then slow gastric emptying. Dr. Sean Kane 35:16 So with that, we'll go ahead and conclude, if you want to visit us online, we're at HelixTalk.com if you have no idea what a podcast is or how to download it, we have instructions at HelixTalk.com to tell you how you can become a subscriber and get our every two week podcast. We really appreciate a five star review on iTunes with that, I'm Dr. King, I'm Dr Speaker 3 35:36 Shuma, I'm Dr. Patel, and I'm Dr. lavorsi. And as always, study hard. Narrator - Dr. Abel 35:44 Thank you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com. You.