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. Narrator - ? 00:11 This podcast 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. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 66 I'm your co host, Dr. Kane. I'm Dr. Schuman, Speaker 1 00:35 and I'm Dr. Patel, and today I'm delighted to offer a little bit of an update in diabetes. We're going to call this session what's new in diabetes world, tapastyle, and what it means is we're going to talk a little bit about diabetes, bits and pieces of new Dr. Sean Kane 00:49 information before we jump into it. I just wanted to thank our listeners for letting us know that the audio quality wasn't coming through as clear as it could, and I hope that we fix the problem with the last episode in this episode as well. So Dr. Patel, why don't we go ahead and jump into what's new on the 2017 Ada, standards of care guidelines. And as I understand it, these are released every single year. Is that correct? Speaker 1 01:11 That is correct. It's a very active group of people who publish their updates every January. So this is a little bit late in our our time of updating our folks here, but the newest standards are as of 2017 of January, and one of the things that they focused on is care for gestational diabetes, so macrosomia, which is larger birth weight of a child defined as greater than nine pounds, is no longer an independent risk factor of having diabetes later in life, so this was considered one of the risk factors before, but the new studies show that this doesn't have any correlation anymore, so they're removing this as a risk factor. The other update in gestational diabetes was that instead of doing the postpartum assessment of blood glucose to check for development of diabetes at six to 12 weeks. They're doing it a little bit earlier, and this is just kind of cosmetic type of a change, just because they think that obstetric and gynecology appointment is usually at four weeks. So why not just do it earlier and let the results come and have the opportunity for the discussion to occur at the office. And last, but not the least, maybe a little bit more important change for us pharmacists is that insulin is ever more emphasized as the drug of choice over other oral agents such as metformin and glyburide, and that's because recent data that were done using concentration of these two oral medication in the cord blood, and the concentration was a little bit higher. And so yes, we're putting this information based on just pure concentration of the drug and then of the adverse side effects. But still, they're more comfortable in saying, let's just go with insulin as a drug of choice, rather than using this oral meds. Dr. Sean Kane 03:03 So Dr. Patel, prior to this standard of care change, was it common that a pregnant diabetic would be left on some oral agents, or were most of them already receiving insulin anyway? Speaker 1 03:15 It's very interesting that you ask that question, because in the last three years, I have heard different evidence become available regarding this oral drugs too. So couple years ago, glyburide was better than metformin. If you look at last year, metformin was better than glyburide, and now they're back to insulin again. Insulin is still the FDA approved drug of choice, and ADA still stands by that recommendation is just for some patients who didn't want to be on insulin therapy, or for some reason, couldn't be on insulin because of great hypoglycemia risk if clinicians wanted to consider or options. This is the data we have available now. Speaker 2 03:57 So look at the next piece of that they looked at is some more to the lifestyle modifications, the idea about really expanding beyond, I believe, the idea about carbohydrate counting, which is a basic tenet we recommend to all the patients that come to me, I know, but also, I guess, looking at protein and fat counting as well, specifically for patients on basal‑bolus regimens, is that correct? Speaker 1 04:16 That is correct. And this is just to emphasize the importance of multi disciplinary or interdisciplinary approach here that don't be afraid and teaching them about carb counting, but please send them to a dietitian so they can even micromanage their diets and define what are their protein count should be, what are their fat intake should be. Dr. Sean Kane 04:35 And I'm sure that something like that would assist in things like weight loss, which is a common recommendation for those type two patients as well. Speaker 2 04:42 That is correct, right? So then moving up beyond that is also the idea about interrupting prolonged sitting. So really, not just the amount of exercise, but really to try to get out of the sedentary state. So getting up, you know, for a 30 minute every 30 minutes, getting up with a short burst of physical activity, walking outside. Some, you know, it doesn't have to be running, you know, a couple miles real quick, but just some sort of physical activity, and then also balance and flexibility. Training, almost is more of a Speaker 1 05:07 holistic approach. That's absolutely right. They're just trying to cover all little bits and pieces and not leaving out any particular type of specific population. So they're including older adults over here and recommending, like Tai Chi type of treatment over here. And that, really, if you think about it, hypoglycemia can lead in those patients risk of falls. And so if you have, if they have better balance and stuff, you can avoid some of these fault type of injury. Dr. Sean Kane 05:33 And you know, a number of different recommendations came out related to treatment and moderate nerve the treatment, one that I know is kind of a hotter topic recently is B 12 levels. So checking B 12 levels periodically and also potentially supplementing with B 12 and those who are deficient, especially if they're on Metformin therapy, which has been associated with low B 12 levels, and the potential for things like peripheral neuropathies and maybe even a macrocytic anemia. Speaker 1 05:58 Yeah, I think it was very well known of a fact that Metformin could lead to the, you know, deficiency in B 12 levels. But as a group, Ada just didn't have robust data, enough data to put it as a recommendation. And this year, they have enough data to put it in. So they have done so periodically. Is a very vague word. So as an institution, you may have your own guidelines. For an example, in my clinic, I do B 12 levels at least once a year. Now if they've been on chronic metformin therapy, the other recommendation that was incorporated directly looking at some of the randomized controlled trials that came out is empagliflozin and liraglutide. So empagliflozin is Jardiance, and liraglutide is Victoza. We know the EMPA‑REG trial we have covered previously in our episode, and liraglutide in the LEADER trial. Stay tuned for our next episode looking at the data from these two trials that they are recommending using these agents in patients who have diabetes but also have established cardiovascular disease. Dr. Sean Kane 07:05 And again, this is kind of the holy grail of diabetes therapy, that we're selecting agents that not only improve your glycemic control, but also improve long term outcomes of mostly macro vascular outcomes like strokes and heart attacks. And those two agents recently did show some good Speaker 1 07:19 benefit with that correct and they also show an improvement in mortality as well. Speaker 2 07:23 So and they kind of push in a different direction, is the idea that cost is not something to be considered so beyond just simply looking at efficacy, but understanding that, you know, again, there's going to be a wide span in terms of the the buying power and the cost can be a big issue. And then not everyone's gonna be able to afford some of these bigger agents. So to consider the these other ones that are somewhat more cost effective. Again, I think of our sulfonylureas, of being a Metformin, and even some of the different types of insulins, as well as the cost goes down, but those things may be more cost effective for a given individual. Speaker 1 07:54 And looking at the injectable medication therapy, you know, there was always a debate whether a basal bolus therapy is equivalent to maybe a basal injection and a GLP one. They had some non inferiority trials available comparing these kind of approaches. And what came out of that is that is a nice chart in ADA guidelines that says you can either do a basal bolus regimen, you can either do basal regimen plus a GLP one or a pre mixed injection, which is rapid acting and a longer acting insulin together twice a day. These all approaches yield pretty similar glucose control. Dr. Sean Kane 08:35 So to kind of put some brand names to it, what you're saying is, if I picked, let's say 7030 mix twice a day. That is equivalent, in the eyes of the guidelines, to Lantus with a Humalog, which is equivalent to Victoza with Adlyxin, correct. Speaker 1 08:52 And that's per available studies that are done. But as a clinician, I always, I may be biased towards it. I always prefer a basal and bolus regimen because it gives you a little bit more flexibility in dosing. Let's be honest. We tell patients to eat meals regularly, keep the carbs amount recommended, you know, and so your dose weren't weary, but that always doesn't happen. So the individual basal‑bolus approach, like Lantus and Humalog, may provide greater flexibility than a 70/30 mix. Dr. Sean Kane 09:24 You know, they also touch on kind of the whole diabetic patient, not just their glycemic control. So something like hypertension management, they're now in line with JNC 8 saying that if you don't have microalbuminuria, you can pick the four agents that are commonly recommended in JNC 8. So the ACEI/ARB, thiazide, or CCB, Speaker 1 09:43 correct, and this was just to make life easier and align with their J and Z partners. Speaker 2 09:48 And I think so, to go back to Dr. Kane were mentioning about pre mixed insulin. So one exception to the idea about being equally effective is that in an inpatient, non critical diabetes population, really there. Accommodation is basal only if patients are nothing by mouth NPO or basal plus a correctional insulin for patients with a normal meal allowance or even just sliding insulin, and they're really in this population, going to discourage the use of those pre mixed insulins, and they're specifically for the hypoglycemia risk. So again, in the general outpatient population, equally as efficacious and recommended, but in this inpatient population, maybe may want to be careful of it. Speaker 1 10:26 Yeah, we're basically just discouraging the use of sliding scale in this non critical hospitalized patient population, because they can still tolerate basal regimen, and then per how much meal they're completing, you know, and how much carbohydrate they ingested in that meal, we can calculate a bolus dose. And now we know a lot of bolus injections don't have to be always before a meal. They could be given either immediately after they finish a meal or within 15 to 20 minutes after the meal. Dr. Sean Kane 10:53 And they also touch on the critical care diabetic patient, or just a critical care patient with hyperglycemia. And really, if you're meaningfully trying to safely give the patient glycemic control, an insulin drip of insulin regular IV, is the recommendation, both by the ADA and also by the SCCM. If you have a patient who this is barely above their goal of about 150 to 180 potentially, you could get away with, let's say, a sliding scale. But really, if they have true hyperglycemia, the treatment of choice for that critically ill patient, because they can be so labile in their blood glucose is an insulin drip, Speaker 1 11:28 and I think that's where your expertise in the ICU comes in place. Dr. Kane, if I'm not wrong, then every institution has a protocol on what the drip rate should be based on the glucose levels. Correct. Dr. Sean Kane 11:39 Yeah. So for a patient on an insulin drip. You're checking the blood glucose every one maybe every two hours, if they're very stable, but this is frequent assessments. They have to be in a critical care environment if they're going to have an insulin drip, because it's so easy to overdo it or underdo it, and there's so much monitoring associated with it. Speaker 2 11:57 So the other way they went is to look specifically at management of diabetic peripheral neuropathy. So one of the things they mentioned is the use of pregabalin, duloxetine as first line agents, which makes sense, being the two that are FDA approved for that indication. But they also acknowledge that there's a lot of other medications, so with similar mechanisms, tricyclic antidepressants, so your amitriptyline, nortriptyline, gabapentin (structurally related to pregabalin), then venlafaxine (analogous to duloxetine), and then other agents like carbamazepine, Tramadol, even topical capsaicin, can be used for a lot of neuropathies, specifically here for diabetic neuropathy. Yeah. Speaker 1 12:34 And then the difference here in this guideline is that they actually run in and looked at the outcomes for these two agents that they're strongly recommending. Another FDA approved agent for treatment of DPN is an opioid, actually, and they do not recommend for obviously good reasons, because of opioid dependency and things like that. Plus, it hasn't really shown any good efficacy in pain reduction. So pregabalin and duloxetine, if your patient can try it, if not, some of the other options Dr. Schuman mentioned are valid as well. Dr. Sean Kane 13:04 So if we just take one second to kind of touch on that Dr. Schuman, pregabalin or Lyrica, duloxetine or Cymbalta, granted like if a patient has depression or anxiety, it's pretty clear that you should pick duloxetine because it also carries those indications as well. But in a patient who doesn't have those that just has diabetic peripheral neuropathy. Are there pros and cons to one agent over the other, in your view? Speaker 2 13:27 So it's gonna be one. It's a lot of it does depend if they don't have depression or anxiety. Again, if there is another diagnosis, they're concerned. One of the ones that commonly comes up with us is if somebody has bipolar disorder, for example, and we're concerned not about depression, they're about to switch to mania. So that's the case. I'll consider more of the pregabalin other, you know, if, again, if there's something like seizure history, or anything like that, to where we may be more evidence to say, all right, switch over to a strong seizure medication, and otherwise, again, talking to the patient about it, because sometimes there's a negative stigma. The other day of pay, talking with a couple patients about why I don't want to be on the oxygen that's a that's a psych med or, you know, happen. So we have to kind of push against that stigma and explaining to him that even though, you know, you've heard from people, oh, you know, that's a certain other type of med, it really does work in this indication, even though you don't have depression, the medication is still going to work. And we still discuss, kind of the changes in mood, things like that. But I have no problem using either one of those medications again, as long as you sometimes have to push against some of those barriers or stigmas. Dr. Sean Kane 14:25 I think also thinking about side effect profile. So pregabalin, I always think of like lower extremity edema. Duloxetine, I think about sexual dysfunction in men especially, and, you know, a host of other adverse effects that come to mind that may be incredibly relevant to the patient, but maybe isn't at the forefront of our mind too. Speaker 2 14:42 Yeah, again, that's another one that comes with that shared decision making idea about laying cards out on the table. What are the deal breakers or deal makers for the individual, and then that way they can make an informed decision to guide their own therapy. Speaker 1 14:53 Yeah, we can take a look at all these clinical factors, but sometimes it's come down to patient wanting to have yet another. Medication on their list of meds they're already taking. So if they have neuropathies that are on and off, doesn't really bother them. Do not limit their daily activity. Most patients do not want this type of medication. It's really when it becomes painful, it becomes it comes in their way of finishing their functions and chores of the day. It's when they would like to go for an approach like this, really, Dr. Sean Kane 15:23 to build on that also the efficacy isn't like night and day difference, right? So this is fairly subtle in the efficacy of treating the peripheral neuropathy. So it's another medication that doesn't work incredibly well. So you know, if you're going to start it, I think counseling about what is the actual intended efficacy going to be that is also really important. Dr. Kane, Speaker 2 15:43 that's a whole other tangent. But as far as just pain in general, that's a huge tenant of it is, what is the expected benefit relative to the perceived side effects, and where does the individual fall? As far as what's again, what's that plan was to say, I've had enough. Yeah. Speaker 1 15:56 And kind of continuing with their holistic approach and treating diabetes patients is looking at sleep pattern and duration of sleep, because now we know that the quality of sleep has a lot to do with how their blood glucose is controlled, yes. Speaker 2 16:10 And so this is one where I always try to make my little soapbox about being careful with meds like quetiapine, a medication often used (unfortunately) for sleep management, but which also has the ability to cause weight gain and insulin resistance. And so again, just another plug for if you're going to use a medication to address sleep, make sure it's one that will not worsen the blood sugar control. Dr. Sean Kane 16:31 Then finally, you know, within the guideline update, they mentioned a number of comorbidities that are somewhat associated with diabetics, so autoimmune disorders, HIV, anxiety, depression, eating disorders, serious mental illness, all of these have to be taken into account when considering a diabetic patient, Speaker 1 16:48 kind of goes vice versa. You know, they have depression, they're more likely to be inactive. Some of the medications they're taking for depression could make them have metabolic changes, and even could lead to diabetes. So it really goes hand in Speaker 2 17:02 hand, and then it just goes to the idea about the whole patient approach, and so that you're working with a number of other providers, so that everyone is on the same page. And then when you're seeing the patient for your diabetes and metabolic monitoring, you're also getting idea about the mental status, and the psychiatry is seeing them and discussing their medications, and they're getting a feel for their compliance with their oral anti diabetic medications that whole team Dr. Sean Kane 17:22 approach there. So, you know, moving on to one of the big updates, which is a new drug, as I understand it, this is actually really relevant to one of the new recommendations and the guidelines that GLP one and basal insulin is a very valid approach to the diabetic patient. So, Dr. Patel, why don't you kick us off with this first big update. Speaker 1 17:42 So thank you for that introduction. And like I said, it's a combination of basal insulin and GLP one. So as the guidelines say, you know, you try the oral agent, first, mainly being Metformin, and then you advance to dual therapy, triple therapy. And after triple oral therapy, if the patient has still not control, you advance to basal therapy, and then, usually before we have we had all these evidence for GLP one. We used to add bolus insulins for prandial control, but now we have this now, GLP one class, even some of them are once a week injections. They studied heavily whether control overall control of A and C and blood glucose is similar in basal bolus regimen versus basal plus GLP one, and now we know that it is so. So they came up with this new, novel option. Obviously, they're not newer molecules or newer agents. It's just a newer combination here, Dr. Sean Kane 18:40 and before we kind of talk about the actual agents, I just want to emphasize that for a second, because when I think of a diabetic on insulin, I think of basal plus or minus the bolus dosing. What you're saying then is that these patients, instead of having that meal time insulin, they could potentially just have a GLP one to cover their meals, even though it doesn't have to be coordinated with the meals and multiple injections per day, Speaker 1 19:04 correct, and so it does reduce the frequency of injections for the day. But as we know, GLP one is only approved for use in type two diabetes, so this combination is also limited for its use in type two diabetes only. Dr. Sean Kane 19:19 So what are the fun names of these new medications are that are available. Speaker 1 19:23 So first agent we have available is Xultophy. It's a combination of ultra long‑acting basal insulin, degludec and liraglutide, and it's available in a 100‑3.6 mg/mL combination. It comes in a box of five pens. Speaker 2 19:43 So the other one is Soliqua, this combination of insulin glargine and lixisenatide. It is a 100‑33 µg/mL combination. Dr. Sean Kane 19:55 So this lixenatide Is that a new GLP one that's not been on. Market before, or is that something that has already been on the market? Speaker 1 20:03 So it has been on the market recently under the brand Adlyxin. It's a once‑daily GLP‑1 injection, just like Victoza or Adlyxin. Dr. Sean Kane 20:15 sounds like both of these were approved at the end of 2016 and they should be available this year, 2017 and as you mentioned, Dr. Patel, these are only for type two diabetics who are inadequately controlled using a basal insulin or a GLP one, agonist alone. Correct. So how are these dosed? Then, given that we have kind of the inflexibility, if you will, of having the long acting insulin combined with the GLP one, how do you how do you work that with a patient? Speaker 1 20:42 So interestingly enough, you want to go to this dual combination if patient was already on one of the agents and and did not have proper blood glucose control. So keep in mind that most of your patients will either already be on a basal insulin or already be on a GLP‑1 alone, and because that glucose control wasn't enough, now you're trying to add something else and to reduce the number of injection you're going with this combination therapy. Now, because this is designed in a very fixed dose fashion, you may have to kind of step back a little bit and dose it according to the manufacturer's recommendation. So Xultophy, for example, starts at 16 units. And what it means is that it's a combination of 16 units of degludec and 0.58 mg of liraglutide. You can titrate this every 3–4 days by 2 units. So in the trial, they picked Monday and Thursday as their titration day for this particular drug, the maximum dose is, and that's a catch over here is 50 units only. So if you can imagine, if somebody needs higher doses of basal insulin, there is a cap on how much higher you can go on here, and that's because there is a liraglutide component tied to it. So if they go more than 50 units, they're going over the 1.8 mg limit (the approved maximum liraglutide dose in this combination). So there is some limitation that comes along with the with the dosing, because you can't max out on one of the agents in the in the combination. So Dr Speaker 2 22:20 Patel, what you're saying is, so if somebody was on, let's say, 20 units of insulin degludec, they will then be back down to 16 units in combination with 0.58 mg of liraglutide. And they'll be able to, fairly rapidly, though, get them back up to 20 if they're if they still Speaker 1 22:34 need the high levels correct. But I mean, how many times are you going to suggest the patient go from 20 units of basal insulin to a combination, where we can see there's an opportunity to titrate that insulin. So most of these patients are going to be on a fairly high dose, which will have to be back down. But on slightly positive note, you can gain some insulin sparing effect over here, because there is another drug involved that can help lower blood glucose. Dr. Sean Kane 23:01 And I think that that is more than just saying you get less insulin, that probably also means your hypoglycemia risk is a little bit less, but more importantly, your weight gain is going to be less because you're getting less insulin in your body, right? Speaker 1 23:14 Just stay tuned, Dr. Kane, we're going to talk about some safety issues, and I think that will blow my mind Dr. Sean Kane 23:19 with Xultophy, unfortunately, they don't provide any renal dosing adjustments, but we already know from many of the GLP ones, already if you have renal impairment, you will accumulate it, and your risk of getting the side effects like nausea, vomiting, anorexia, which we use to our advantage with saxenda, which is the brand of liraglutide for weight management. So if you have renal impairment, you're going to accumulate more. You'll have more side effects related to, you know, this, nausea and Speaker 1 23:44 vomiting, yeah — if you look at the individual labeling of Victoza, there's no particular down‑titration recommended, but they do say that, as you know, renal impairment or renal function worsens, the risk of these side effects are higher. So you kind of just have to titrate based on patient side effects. Speaker 2 24:01 The other interesting kind of side note is the idea of the shelf life is fairly short relative to a lot of other medications. So despite Victoza itself having a 30‑day shelf life, and degludec up to eight weeks when used separately, Xultophy has a 21‑day shelf life for the combination product. So you know, those, those individual doses, you know, we'll need to be careful of that. Dr. Sean Kane 24:22 Of course, that's after your first use, so once you've kind of already used the pen once. But at this point, you might be asking yourself, Xultophy — is that fewer injections per day worth it as a combination product, or is it better to have these separate products that you can titrate the doses separately, but you have another injection? And I don't know the answer to that. It's probably fairly patient specific and insurance specific, but it's a question that I think is worth having absolutely. Speaker 2 24:48 Yeah, I think they were just like the licentivoral hydrochlorothiaz. That combination is kind of a textbook. One is for some innovators who know I've got to have just maybe one thing tablet, and they're okay with that, with a little bit of that rigidity, though, as Dr. Sean Kane 24:59 far as those. Situation. So the next agent is so liquid, why don't you tell us a little bit more about that? Dr. Patel, Speaker 1 25:04 so that one is also a fixed dose combination, and the initial dose depends on what basal insulin dose you were on. So if you your basal insulin dose was less than 30 and you're switching to soliqua, you will start at 15 units. Or if your basal insulin dose was 30 units or above, then you will start at 30 units with Soliqua. The titration here is a little bit slower. They did it once a week, by two to four units in the study, and the max dose cut off is 60 units. As far as the dosing in renal insufficiency, they're saying it's contraindicated in GFR less than 15. And that's comparable to the Adlyxin label, but there is no specific dose‑reduction recommendation. If the GFR varies between 50 to 90. Again, there could be a dosing, you know, dose accumulation in those with lower renal clearance. Dr. Sean Kane 25:56 And for those patients, would we see the same problem in that they'll get more of the side effects. Speaker 1 26:02 And so even talking about shelf life, it's even shorter with this agent, it's 14 days after one first use. But the counter argument to this is that if you have patient maximize the dose and, you know, titrate the dose is recommended, most likely they won't have any wastage because they're using they're most likely going to be done with that one pen in the 14 days. Dr. Sean Kane 26:23 So you're saying that the volume of the pen is small enough that a 14 day expiration date is reasonable for most patients. Correct? Okay, so, Speaker 2 26:31 Dr. Patel, the main thing, obviously, is indeed, do these medications work? What do they actually do for the patients? Could you tell us a little bit more about that? Speaker 1 26:38 So by the nature of having both basal insulin and GLP, one, as we established earlier, and Dr. Kane said, it will help us get control on both fasting blood glucose and postprandial glucose control. But really, the studies, the data that we looked at, did not really specify or emphasize a whole lot on postprandial control. They looked at even C control and fasting blood glucose control and so meat of all that, looking at A and C control, we are seeing anywhere from point eight to 1% reduction when patients were changed from either individual agents to Xultophy, and if you look at Soliqua, that difference between Lantus versus the combination (Lantus plus lixisenatide) was 6.9% versus 7.5% with Lantus only. Dr. Sean Kane 27:28 So Dr. Patel, as I mentioned earlier, as someone who doesn't treat a lot of outpatient diabetes, just seems weird to me that we wouldn't be having that bolus dose with the mealtime to help control the postprandial glucose. And obviously an A 1c of we'll say 1% doesn't capture the difference between fasting and postprandial glucoses. So what do we actually know about postprandial glucose control with this kind of a regimen? Speaker 1 27:51 So when these two combination products were approved, they were approved based on their individual components versus the combination, and that individual component was really the basal insulin and not really the bolus therapy. The data you were talking about is really coming from separate use of basal regimen and GLP one versus basal and bolus combination therapy. Yes, that's equivalent in terms of giving us a and c reductions in both fasting as well as postprandial glucose reductions. Xultophy has a trial. There's a slew of trials (DUAL 1–7). One of the trials does mention better postprandial glucose control with this agent, Dr. Sean Kane 28:36 and that is probably why the ADA is now recommending that as a valid treatment approach. Then Right, correct. What do we know about the safety profile of this GLP one plus basal insulin therapy? Speaker 1 28:47 So when you look at or think about safety for these two agents, you're going to think about safety issues for individual agents. So obviously hypoglycemia could be of a risk nausea and diarrhea, those are gi side effects, mainly coming from the GLP one agents and then some insulin as well as the GLP one related minor side effects could be upper respiratory infection, nasopharyngitis and headache that we're seeing commonly. Interesting to note that the side effect of nausea and vomiting were more common at the beginning of the therapy, just because after being on the GLP one for 10 to 14 days, your body kind of get used to it, and the nausea and vomiting should subside. And that's what they saw. So that was very obvious. The very important piece here is the hypoglycemia. And what they found is there were expected number of hypoglycemia with the combination therapy over here, so they saw more hypoglycemia than either of the agents alone, which makes sense. Here we are looking at insulin degludec, which has an extended (~42‑hour) duration of action. Or if you look at Soliqua, which contains glargine, it has about a 24‑hour duration of action. So they're saying is, if hypoglycemia occurs, the recovery can be a little bit slower because of that basal insulin component to it. So there is rems criteria available. And that really emphasizes the education piece, not only for patients, but also for the providers. Dr. Sean Kane 30:18 And from the from the education component, I would assume, again, I don't treat a lot of outpatient diabetes, but I would assume that that component would include a fast acting, quickly absorbable glucose molecule and then some longer acting carbohydrate to prevent hypoglycemia after that initial sugar goes away. Is that correct? Correct? Speaker 1 30:39 And that's, that's the rule of 15. I think you're, you're kind of referring to, Dr. Kane, yes, that would be the education that needs to be provided and really screening out patients if there are at risk of, you know, frequent hypoglycemia, nocturnal hypoglycemia. Perhaps this combination is not the way to go. So, Dr Dr. Sean Kane 30:55 Patel, when I think about these GLP ones, I always think about weight loss. And the reason I think about it is, again, I mentioned a couple times saxenda, which is the branded version of laraglutide that is indicated not for diabetes, but for weight loss, because we're taking advantage of the nausea and anorexia side effect that we get from these GLP ones. So when we start combining these products, what did we end up seeing with regards to weight loss? Speaker 1 31:20 So it's not as simple as you know, weight loss versus weight gain, because the studies were in different patient population, so most of the studies show some weight loss, but it's not as prolific as if you were using a GLP one by itself. So for example, Soliqua showed about 1.4 kg of weight loss and Xultophy could show up to 2.5 kg of weight loss. in patients who were switched from basal insulin alone to now a combination where you're adding a GLP one that brings that weight loss benefit. Speaker 2 31:56 Let's just say that on the flip side, though, somebody who is already getting a GLP one agonist, who's now switched to a combination of GLP, one agonist plus insulin, may actually maybe see a little bit of weight gain. Speaker 1 32:06 That is correct, and so about a mean of two kilogram of weight gain was seen in Xultophy patients. I don't have data for Soliqua patients yet, but I think it's going to be more of the phase‑4 trial results, collecting more data as the trials go on to solidify what the stance is here for weight loss versus weight gain. It just depends on where your patient was at baseline. Dr. Sean Kane 32:29 And just for clarity, are roughly, we'll say two kilograms is that typically what we're seeing if we use the GLP‑1 in other circumstances, outside of insulin therapy. Speaker 1 32:39 So GLP‑1 trials, average weight loss has been about 2.5 kilograms, but you can see up to even some GLP ones. You can see up to 3.5 kilogram weight loss, but on average it has been about 2.5 Dr. Sean Kane 32:53 so we're seeing roughly a similar weight loss when you are adding the GLP one, as long as you're not also adding a new insulin product to the patient, correct, right. Speaker 2 33:02 So somewhere, what we expect then for a patient, you know, maybe new to the combination, somewhere, again, there's that middle ground in between, somewhere between the GLP, the weight loss, somewhere between the insulin weight gain, somewhere in that Dr. Sean Kane 33:13 middle, correct. You know, there are some other kind of warnings that come along with the GLP ones. Pancreatitis is something that always comes to my mind with the GLP one agonists. In addition to that, they all have a warning regarding the medullary thyroid carcinoma. And this type of very rare cancer was seen more commonly in rats and mice who got GLP one. So if you're at risk for this very rare type of cancer because of your family history, this would be a great diabetic regimen to be put on. Speaker 1 33:39 Yeah, and this is clearly listed in the Xultophy prescribing information, but for some reason, it's not part of the contraindication list of the Soliqua. But as a clinician, you should be aware that that could be Dr. Sean Kane 33:50 a risk. So you know, we've talked a lot about the trials and kind of how it's provided and things like that. Dr. Patel on the front lines of treating these diabetes patients, where do these combo products fit in to the armamentarium of agents that we have? Speaker 1 34:06 What it boils down to is having the fixed dose combination, and that therefore these two products have very small niche. You're going to use it for somebody who's already on either individual agents, maybe patients who do not want multiple injections a day. So that's maybe a benefit, wanting maybe less number of co pays. Instead of paying two co pays, they're on one co pay. But overall, there is the rigidity when it comes to dosing or modifying the dosing. So you can view this very similarly to the issues that come along with pre mixed insulin. And if I can give you a couple of examples, the fixed combination allows for less strength of the each agents administered. So for example, if a patient could be on 50 units of bolus insulin and a mid‑range GLP‑1 dose when dosed individually. Three. But when you are trying to put this combination instead, you kind of have to back it down to either that 15 units with Soliqua, or even lower with Xultophy, so you may lead to some blood glucose control disruption. Dr. Sean Kane 35:16 And just to put it into context, is there a scenario where you would be going up on your GLP one or down on your GLP one, but not be touching your basal insulin. Speaker 1 35:25 Yeah, I'm looking at the postprandial control. So if you don't have sufficient postprandial control, you may want to up from 1.2 milligrams of Victoza to 1.8 milligrams of Victoza, which is the higher (1.8 mg) dose. So in those cases, you increase it, but then you also increase the basal insulin, so they may lead to morning or bedtime hypoglycemia. Dr. Sean Kane 35:45 So I can definitely appreciate the lack of flexibility. Then if you have one problem, but not both problems in terms of postprandial and basal glucose control, then correct. Speaker 2 35:55 You can also imagine a scenario where, again, you have somebody who has very poor glucose control, and perhaps, you know, we're needing to crank up the insulin doses, but maybe we're limited a little in terms of our GLP one habits, how high we can go. Would that be a concern too Right? Speaker 1 36:08 Because if you titrated them too fast or too rapidly, or patient just doesn't tolerate more than certain doses, they're going to have more gi side effects like nausea and vomiting. Dr. Sean Kane 36:19 And of course, if you exceed the 50 units of degludec as part of that first agent that we talked about, you're going to end up going into the Saxenda dosing scheme (a weight‑loss indication). Speaker 1 36:32 and not only for diabetes, exactly. So there is little benefit seen in patients whose agencies are between seven to 9% who are not on either of the agents. So again, they have to be on either of the agents. Because if they and honestly, even if they're on either of the agents, greater flexibility comes if you just titrate those individual agents rather than taking them off of that and putting them on a fixed combination. Again, Max doses are very limited, and so with that, if we need a higher blood glucose control, you can't really do that with the fixed dose combination. And if we talk about these agents, liraglutide and lixisenatide (the GLP‑1 components of the combination products), these are once‑daily GLP‑1 injections. Keep in mind, we have GLP one agents out there that are longer acting, where patients can do one injection a week. So if the concern is fewer injections, why not consider those long‑acting, once‑weekly agents, which may have lower nausea/vomiting and injection‑site effects, and perhaps better A1c control than these once‑daily agents. Dr. Sean Kane 37:39 At least from my point of view, it does seem like this is an incredibly niche product in a very specific glycemic control group, and who are currently on probably both of these agents that they're trying to decrease the needle burden that they have, and it happens that they can get a good copay out of it. Yeah, it Speaker 2 37:56 certainly seems otherwise you're literally you're paying yourself into a corner as far as what you can do once you get up to those certain doses, or once you have to back down, right? Speaker 1 38:05 I still have to pick brains of my colleagues, who are, you know, doing the same thing I do in the clinic. But I can't seem to place this on top of my list when it comes to choosing for a lot of different reasons we talked about today. Dr. Sean Kane 38:19 So to summarize a couple key points from today's podcast. I think for me, one is that those ADA guys are excellent about coming out with yearly updates every January, and especially given all the new products that are on the market, it's really important that all clinicians are taking a look at these to know what is new in diabetes and how to change your practice. Speaker 2 38:37 And one of those newer developments is the idea this fixed dose combination of a basal insulin and a GLP, one agonist product, which helps kind of decrease the number of injections given in a day. And then it is specifically the with type two diabetes who do need both fasting and postprandial blood glucose control. Speaker 1 38:55 And these parts specifically are Xultophy (insulin degludec + liraglutide) and Soliqua (insulin glargine + lixisenatide). Speaker 2 39:09 So as with any combination product, one of the negatives is reduced dosing flexibility. For example, if somebody has side effects as we titrate up the GLP‑1 agonist we may need to pull back the GLP‑1 dose — that will also reduce the insulin dose in the fixed combination. If a patient is switched to the combination, you may be required to reduce their basal insulin to 16 units of degludec and then titrate the combination from there; patients on higher baseline insulin doses may therefore experience a significant reduction in insulin and loss of flexibility, which is a concern. Speaker 1 39:49 So to summarize, the adverse effects over here, the issue of weight loss versus weight gain. Weight loss benefit is not as high if you were to use this combination versus GLP one. Only therapy. But if the patient switched from GLP only therapy to this combination, you're going to expect some weight gain because of that basal insulin component. And as far as hypoglycemia is concerned, we want to make sure that we have proper patient and provider education happening because of that basal insulin component, which may delay recovery from the hypoglycemic episode. Dr. Sean Kane 40:23 So with that, that concludes episode 66 of HelixTalk. We hope that our audio quality is much better, and if it is, we'd love for you to leave a five star review on iTunes to let us know that, or even email us. We love hearing from the listeners. We're available at HelixTalk.com, on Twitter at HelixTalk, with that, I'm Dr. Kane, I'm Dr. Shimon Speaker 1 40:41 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 40:45 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 Narrator - ? 40:56 to 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.