In this webinar, Endocrinologists from Penn Medicine review a series of challenging cases, and the application of the most recent clinical care guidelines for patients with type 2 diabetes in the primary care setting. Discussion emphasizes individualized care, accounting for patient-specific factors and benefits beyond glycemic control. Experts also provide clinical guidance in navigating the growing number of available therapeutic options, including newer agents such as GLP-1 receptor agonists, SGLT2 inhibitors, and continuous glucose monitoring.
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Good afternoon and welcome to the first of our endocrine spotlight series webinars. Thank you for joining us today for a session on the management of type two diabetes expert guidance for challenging cases. I'm Serena Cardillo, the program chair and moderator for today's session and joining me today are my colleagues from the robot diabetes center at Penn doctor Anastasia Tomorrow dr Carey Burns and Dr Mark Xu to we're happy to announce that we have partnered with the Perlman School of Medicine Office for continuing Medical Education to be able to provide you with CME credit for attending today's event. At the conclusion of the event today you will have the opportunity to complete an evaluation of today's webinar. You will then receive an email communication from the CMI office directly to enable you to formally register uh and obtain CMI credit for um for attending today. Here are our financial disclosures During today's session. We're really hoping to provide you with a framework to approach your patients with type two diabetes with an emphasis on individualist patient centered care. We also want to provide you with some guidelines and guidance in the use of newer agents and uh modes of technology to enhance the care that you provide to patients in the primary care setting. Most of you are likely familiar with the ADA algorithm for the management of type two diabetes, which takes into account patient specific factors and comorbidities in providing guidance for clinical decision making for complex patients. There's clearly no one size fits all approach. And this algorithm provides us with a complex framework that we're hoping to break down and put into action through the discussion of several complex clinical cases. This afternoon. We welcome your questions through the Q. And a box and um we'll attempt to answer as many of those as possible throughout the course of the webinar today. So let's get started. So we'll start first with a case of a 69 year old gentleman with type two diabetes complicated by neuropathy uh apathy and progressive C. K. G. He was diagnosed in 2009 uh and was insulin treated since 2018. He's currently taking dead a mere 15 units at bedtime and extended release Metformin 1500 mg. in addition to an air b. and a statin. An exam. Pertinent features include a bmi of 28 and evidence of neuropathy and diminished pedal pulses on foot exam with a pre ulcerative callous on the right plantar surface. In terms of laboratory evaluations, Hemoglobin, a one c 6.9 G. F. R. Is 45 urine albumin to creatinine ratio 61. So here we have a patient with longstanding disease um and underlying complications including C. K. D. N. C. A. D. And if we return to our A. D. A guidelines will likely focus our attention on the left side of the algorithm which outlines an approach to halting the progression of complications in these patients with the use of your agents such as GLP one receptor Agnes and S G L. T two inhibitors. Mark. There have been numerous recent studies demonstrating the benefit of these agents in patients um similar to the one I just presented. Can you walk us through some of the evidence behind these guidelines? Sure, Serena. So, um just a couple of sort of 30,000 ft perspectives on this. So these um these studies were mandated by the FDA in response to the rosy glitches. Own study Published the New England Journal of Medicine Back in 2007. And um you can see that the outcomes are sort of divided into three basic areas, Mace, which is a major adverse cardiovascular events, all cause death and then hospitalization for heart failure. But I don't want you to get caught up in the details of this. But there's some trends that I think that are really, really important to point out. And you can see that there are three classes of drugs that are sort of the three agents that have come out over the last 10 years or so that we have really helped us take care of diabetic patients. So, the GLP one receptor agonists in Red, the SGL T two inhibitors in Green and the DPP fours. And if you look at the top mase panel, you can see that with the GLP one receptor agonists. There's a demonstrated improvement and hazard ratio in those drugs. Less so with the SGL T two s and the DPP fours are relatively neutral. It's important to point out that these studies were really meant to be non inferiority studies. The FDA was concerned that there could be medications coming to market that had an adverse cardiovascular risk for patients right now the great thing that happened was through these studies we've got some really positive results that are now sort of guiding our therapies. So if you look at mace you see GLP one receptor agonists really positive some more so than others. But I don't want you to sort of concentrate on specific drugs. Um Just look at the classes all cause death. Similar thing. The GLP one receptor agonists look like they're really terrific the S. G. L. T. To etcetera. Um And then the DPP fours are relatively uh neutral. Although there are some uh negative outcomes with a couple of them as well. If you go down to the bottom and look at hospitalization for heart failure. Again the GLP one receptors do really well. The S. G. L. T. Two s seem optimal and the best. And then the D. P. P. Four's are sort of neutral. But there's a red flag for sacks of Lipton. Which is angle is a where there seemed to be an increased incidence in congestive heart failure. Now you can remember that these studies enrolled about 7000 patients. They were real world studies though these were patients who had art high cardiovascular risk. Um A one CS that were not necessarily well controlled and these agents were added on and then the patients were followed. Um So you know the one thing I would just point out regarding heart failure is um in the DPP Four category there is a very small risk of peripheral oedema which may be related to the heart failure that we saw in the patients on sax and Lipton. Um but at this stage we don't really know if that was just an outlier or a real problem. But in general, in my patients with heart failure, I avoid facts of Clifton. So serena I don't know if we'd like to move on to the credence trial. Now. They have also been some studies just looking at renal outcomes. Again, real world patients with chronic kidney disease. So in this case with credence on the left side, um these were patients who had um you know, G. F. R. S. That were categorized as moderate to severe renal insufficiency. Um They had, You're in microbe in your area ranging from 300 to 5000, so much higher than the patient that we're looking at. And the outcome that they were looking at was um risk reduction in doubling, creating. Right? So if you look on the bottom part of the panel in the credence study, you can see the change from baseline and estimated G f R and again, there's progression of loss of of of renal function. But what you see with mechanical flows in group and that's in makana and this is something that we always see with these patients. Right. The first thing that you see, is there actual renal function deteriorates initially These drugs behave like busy diuretics? Right. So you're decreasing intravascular volume a little bit and you would expect that the creatinine would rise a little bit. But then you can see that over time the two pathways sort of crossover um and the cannibal flows and actually is better than placebo and decreases risk. Um In in a similar thing, in the top panel with urinary albumin to creatinine ratio, you see a dramatic improvement with cannibal flows in versus placebo. Um On the right panel with Dapa CKd Similar sort of outcomes. Just looking at again, doubling of creatinine. And the reduction in both of these studies was roughly 30 to 34%. Um in the case of the credence trial, this study was supposed to go um 4-5 years. It was stopped prematurely after 2 2.5 years because the results were so positive. A couple other things just to add. Um in both of these trials, there were secondary analysis looking at cardiovascular outcomes and they were both incredibly positive with decreased risk of heart failure and other cardiovascular events. Um there's been some concern about cannibal flows in in in the early studies um regarding amputations. There were no amputation scene in the patients treated with chemical fozie. Thanks Mark. So, returning back to our patient and applying um the data that you just presented to his care in the office. So we have a patient with C. K. D. And C. A. D. Um And you know, how do you decide between SGL t to inhibit therapy and GLP one um based therapy um and when deciding between those two agents, how do you adjust the pre existing regimen in terms of medication? Right, so um this is a conversation that we have with all of our patients now that are coming to see us. And you may recall that in 2018 when the American Diabetes Association and um the American College of Cardiology partnered together with something called know your heart. Um The branch point here about deciding between these medications was a conversation with your patients. So what I do is I sort of point out to the patients, look here are your risks. Here are the things that we're trying to mitigate. Um and there are several drugs that we could apply here, and we have to decide which one is best for you. Now, as everybody in this audience knows, there are a lot of patients who are are adverse to adding new drugs. Um they may want to replace a drug, they might might go for that. Um but it's sort of our job to just sort of tell them the risks and benefits. So in this case, we have a guy who's got both microvascular, macro vascular disease, he's had his diabetes for about 10 years. Um and but I would tell you that The actuarial data says that this man is going to live into his early to mid 80s, so we really need to try to do something to help him. So um you know, in my view, uh you know, I again, if this man's B. M I was higher than I would be very interested in adding a GLP one because I'd be more concerned about weight loss. The GLP one receptor agonist typically induce weight loss of about £10 in most patients. In the case of the S GLT two inhibitors, the patients lose about 4 to £5. If this was a woman who had a history of urinary tract infections and yeast infections, I would really stay away from the hotel S. GT two inhibitors. Um So, and then the real situation here is also that this patient is on 11 year, 15 million units per day. And the thing that we also want to mitigate against is hypoglycemia in these patients. Right. So we want to do this safely. When the American Diabetes Association says, our target should be an a one c of less than 7%. They also say that you can individually is that for every patient. And they say if you can make the DNC lower and do so safely without risk of hypoglycemia, you should have that conversation and individual is it for the patients. So in this case, you know, you could make an argument. You can put this patient on both the GLP one receptor agonist and NSG LT two inhibitor because he would get benefit from both of those, right. He has established cardiovascular disease. We know the GLP one receptor agonists are great at reducing risk of secondary events. Um So you could do that. Um Now the issue then is going to be well, what do we do with the other drugs? Um And in my view, I would keep the patient on Metformin. That's the number one first line therapy for type two diabetes. I wouldn't stop it. But the lab Amir could be a problem because when patients get added drugs obviously they are at a risk for hypoglycemia. And then Mark Mark a comment on how you approach prescribing Metformin in patients with progressive CKD. Sure. So the FDA has now established new guidelines for this. There really has not been any evidence that patients who have a G. F. Are greater than 30 are at increased risk for lactic acidosis. So the current recommendations and these are the guidelines that I you know prescribed by as long as the G. F. R. Is greater than 45 I think you're safe to keep the patient on the current dose of Metformin in the 30 to 45 range, I typically reduce the drug by 50% and if it's less than 30 I stop it. Remember that meth foreman is not metabolized, it's cleared through the kidney unchanged and it is not actually toxic to the kidneys. So one of the clinical pearls that I try to convey to our fellows who are training with us and how staff is do everything you can to keep your patients on Metformin because it's a wonderful drug. It's really inexpensive and it has proven benefit and even cardiovascular risk reduction. Um, so that's that's my approach serena. Okay, thank you. Let's move on to the next case. So we have here an 83 year old man with Type two diabetes complicated by C. A. D. C. K. D. And a frothy, his longstanding disease, and has been insulin treated since 2010. He's currently prescribed a 70 30 insulin regimen uh, with 30 units in the morning, In 20 units in the evening Pertinent physical exam findings included Bmi of 30 and evidence of neuropathy and diminished pedal pulses. On exam, his uh finger stick blood glucose law reveals fasting blood sugars ranging from 60 to 1 80 the remainder of the day 90 to 1 60. His hemoglobin a one C. Is 6.3 and he has evidence of renal dysfunction. So carry this patient is using a lee brae continuous glucose monitor. And you walk us through the interpretation of his G. P. Report. Um. Sure. Absolutely. So this is a standard GDP report that you would see and it sometimes looks a little scary but it's really quite simple. So when you look at, I first looked at the average glucose. So for him it's 109 which is quite low. And then the line below that is his glucose management indicator. So that's an A one c estimate Um of 5.9 and for him that is definitely below our target. So um then I go and I look at time and range. Um and for him his target range is 90%, so really almost too good. We like to see a Target range around 70% 75%. Um and then more importantly he is low about nine of the time. So someone who's 83 um that is a big red flag. Um The next thing I do is I look at the daily glucose profile so you can see he's on 70 30 fixed split dozing and you can see there, I look for patterns, right? So there looks like there's a pattern in the afternoon where he's going low on more than one occasion and I think even more concerning, I see one or two overnight hypoglycemic episodes happening. Um, so that's basically what I look at, look at in kind of a snapshot view and just goes to show you how how helpful a continuous sensor can be. Now this patient is resolved with multiple complications and comorbidities. The endocrine society put forth a set of guidelines for management of type two diabetes and yelled or adult just a few years ago, can you walk us through these guidelines and explain to us how you know how you would apply these to the patient that I just described, Right. So based on data that we've learned in the last And 15 years, such as the accord trial setting targets in patients who have high cardiovascular risk that lower is not better. Uh, these guidelines have come into being and really helpful to try to look at targets and and as mark had suggested when when we're training our fellows, one of the first things we like to do when we're seeing a patient together um Coming over the treatment plan is just addressing what their a one C target is and what we need to get there. What I like about these guidelines um is number one. It really looks at functional status. Uh So group one is going to show your highly functional patients that really don't have a lot of impairments who are motivated who have support. Um And then your group to uh show patients who maybe they have some functional issues but um have some chronic conditions but overall have a relatively good quality of life and and a reasonable um amount of time ahead of them hopefully. Um And then you have your group three and your poor health in which your goals are going to be um More geared towards preventing dehydration, preventing super infection. Um So I like that the functional status is incorporated here. What I also like if you look at the bottom of the of the table um for patients who are on medications that cause hypoglycemia, there is a floor to that A one C. So if they are taking insulin or taking a cellphone Yuria for example um You you want the A. One C. To be greater than 7.5 in that group to or greater than eight in that group three. Um So that's how how I look at this chart and what I also like in what we all try to strive for is shared decision making. Um So I think a big big thing here is making sure you have the discussion with your patient of why an A. One C. Under seven is not what we're going for. Like well I want to get it even lower. Well well not necessarily. And I explained the cord you know very briefly um Why and in other studies why lower is not always better and actually is harmful. Um But again if you have a patient who is on a little bit of Metformin and their A one C. Is a little under 7.5 that's probably okay but that's where that shared decision making comes in. Um And as far as where our patient hits I would put him in group two. Um So an A. One C. Target of between 7.5 and 8%. Great. So keeping that in mind um you're likely going to be selective in your choice of agents. Um With priority the prioritization of minimizing hypoglycemic risk. So this is a snapshot of that larger ada algorithm that I had presented at the start of the webinar. Can you can you explain to the group how you choose among the different agents in our older adult population, especially keeping in mind hypoglycemic risk. Sure. So as this chart shows type of leukemia risk is at the forefront when you're looking at at the patient like this one. So the agents you're going to start thinking about our agents that don't cause hyperglycemia. So DPP Four inhibitors GLP one receptor agonists S. G. L. T two inhibitors. Um I am not so much of an adopter of the T. C. D. Class. Um However the benefit of A. T. C. D. Is lower cost at this time. However, I don't use them as much anymore due to increased edema and and they don't work for for some so I don't use them as much as I used to but go looking at the DPP four. Um They're they're really benign medications are well tolerated there a pill once a day, very minimal. Side effects. Usually get an A. One c reduction about 10.5 to 1 but closer to 10.5 typically. Um and then um and their weight neutral. Um And then your GLP one receptor agonist again for your weight loss. Um Keeping in mind um someone like like our patient who has a lower G. F. R. I. You can initiate doula glue tide which is a weekly GLP one receptor agonist With the G. Fr around 40. The other ones you cannot initiate with that low of a G. F. Far. So just keep that in mind. Um And then your SGL T two's a patient like this with renal protection. Um And as Mark had mentioned you have to be careful with our female patients with the higher genital urinary tract infection risk about 10% in women. Um So I look at those first. Um And then as the chart indicates, sometimes you add one or two of them. You have to look at cost. Cost is a big issue, especially in our older patients on a fixed income. So you do have to look at cost. But then for our patients who are insulin, a Penick um as you know I'm a fan of insulin. Um and but you have to think about insulin sometimes you need it but then you think about your longer acting insulin analogue um your concentrated insulin's or your longer acting um um medications such as like chris iba that will cause less um less hypoglycemia if you do need to use a basil insulin. So keeping that all turning back to our patient with the history of C. K. D. And C. A. D. Who had evidence of hypoglycemia on C. G. M. What changes would you recommend making to his regiment at this time? Right. So 70 30 is not is not my choice for a man in which uh of severe hypoglycemic episode could be catastrophic. Right? It could cause a fall, hip fracture, motor vehicle crash, an arrhythmia cardiac death. So definitely a fixed split regiment has its place. Um It's usually lower cost, which is nice. But unless your patients are taking it Exactly 12 hours apart, they're eating similar amount of carbohydrate content in their meals at the same time every day. They are less likely to have success with that regiment. So I would mix the 70-30 insulin. I would expect somebody who is on 50 units today and who has had diabetes for a longer period of time. Might not have a lot of data self reserve. So he may need a basil insulin. Um So I probably would consider a longer acting basil insulin for him at a low dose um lower dose. Um Something around point to uh times his unit uh times his weight in kilograms somewhere around there. And then for him I would really strongly consider um SGL T two inhibitor because of his G. F. R. However he does have obesity. So you could consider gialloblu tied for him and the benefit of that. It's a weekly injection. So he could do basil plus a weekly GLP one. Or he could do basil plus the daily SD lT two inhibitor and then you can see how he looks and if how and then I would get another um sensor study and see how he's doing. So the C. G. M. Was very helpful in guiding the decision making it really uncovering pretty profound hypoglycemia for this patient who has a tight A. One C. Who do you think is a good candidate for C. G. M. Um And can you can you walk us through who might be eligible for um for C. G. M. Either diagnostically or for personal use? Right So I'm going to start with diagnostic. So diagnostics E. G. M. I would say anyone who is not a target um is a good person for a diagnostic see Gm. To see what's going on. It gives you so much more information than just random finger sticks. Um So you could you could just place one of these on for a week if you use the decks com two weeks if you use a lead grey um and then download the data and see what the patterns are. And then you can really fine tune individualize their regimen um when you need to as frequently as you need to. Um And you can get compensated for that time if you're you know thinking about that. But really it's it's best for the patient. Um And you really can uncover hypoglycemia and really target their therapy as far as a continuous like home use sensor. For the Medicare population, it's very specific. So for the Medicare population you have to be using insulin three times a day or more. And you have to have evidence of finger sticks four times a day for at least a month to show that they meet that criteria. Um And for people who are on commercial insurance, It's pretty, pretty wide open. Um sometimes you will have to pay about at maximum about $45 a month is the maximum you have to pay for a library. Ux dex combat varies but that is opening up and becoming more available to many of our patients. Okay. Thank you. Let's move on to another case where um that illustrates the benefits of C. G. M. And the additional information that you can obtain and sort of uncovering uh some of the disconnect that we might see. So here you have a 58 year old woman With again with longstanding disease has been insulin treated since 2014. She does have neuropathy is a complication. She's currently taking large in 50 50 units at bedtime demagogue tied one mg, weekly metformin max dose, flipside max dose. She's 100 kg on exam and her finger sticks uh log reveal a fasting blood sugar range of 90 to 1 60 with the hemoglobin a one C. Of 9.2%. So there's a again this is a scenario in which there's a disconnect clearly between her a one c. And fasting blood sugars of which about 50 are falling within range. So this is a scenario in which uh diagnostic see GM can actually help us uncover what's happening during the course of the day Anastasia. Would you be able to walk us through this GM interpretation? You are excellent case. So this discrepancy between patients report and the evidence that you get in the blood work. A one C. Actually would immediately prompt diagnostic evaluation. So here, unlike the previous GM report that Kerry walked us through here, we only have one day a slice in the patient's life from midnight to midnight. And what you see here immediately is that fasting blood glucose reported by the patient when she wakes up between seven and 8 30 in the morning is in ranged between 90 and 1 60 for the most part, However, and she is compliant. Very likely and adhering to her regimen. She takes all her medications as prescribed as soon as she starts eating. However, her blood sugar goes up and never declines below 180. Actually, for the most part of the day, it stays over 200, pretty much until the time when she is Um done consuming meal meals and taking her 50 units of Lebanese Orlando's long acting insulin and goes to bed at which time her blood sugar declines into normal and sometimes abnormal range. So it's clear that this patient is overprescribed basil insulin and is lacking targeted therapy for her postprandial excursions with meals over the course of the day. And this is a very common scenario and an important teaching point that, you know, if the basil insulin doses the correct dose for the patient, they should roughly go to bed and wake up at about the same number. So the downward trend that we're seeing overnight is really an indication that the basil insulin dose for this patient is too high and has probably been increased over time in an attempt to match postprandial requirements. So this patient would be better served with, you know, more of a focus on her postprandial excursions and likely require some intensification of her insulin regimen. Harry. How do you approach intensification of insulin therapy for those patients who are uncontrolled on basil insulin alone? Right, so you have three options. Um you can start fast acting analog insulin with the largest meal of the day. And I think this is a really nice option for this patient because it does appear she is insulin api nick. Um And I think it's a nice starting point I think um asking this patient to commit to multiple daily injections a day of like four injections a day is a lot Um to kind of ask our patients to do all at once and I'll show you in a minute. Um there's some pretty good evidence that this is helpful. So I would I would start by a reduction of her basil insulin. Um and then um start probably either four units with the biggest meal or .1 units per kilo. Um So probably for this patient a little more than four, probably maybe eight with with dinner. Um If that's your biggest meal um and then um have her come back in a short period of time and see how we're doing with those post dinner excursions. Um And then another option is that you could do premix premix insulin if um if this is somebody who has a relatively stable schedule and is regimented or if cost is an issue for the analog insulin which we know is a big problem. Um You could consider um to third one third um um injection regimen for her but you do have to worry about hypoglycemia um and missing those peaks. Um If the dozing isn't right and it's not time right? Um Or you could go to a multiple daily injections um with a reduction in the basil dozing um starting four units with every meal. So those are kind of our three options for intensifying her insulin regimen. And then for those patients who are averse to multiple daily injections a day and in whom you think maybe a premixed insulin is not not a good fit for their lifestyle or their dietary schedule. Is there a benefit to prescribing just one injection of rapid acting insulin? And what type of a one C reduction can we expect in that situation? Right. So I this is a favorite study of mind. This is the Guardian +12 or three. Um And this was a study done with patients on multiple oral drugs who did not have a goal. In fact they were really highly 10% a one C. Um And then this study they did a run in where they started patients on large jean once a day and they had a self titrate in protocol. Um and in fact about 37 of patients actually met goal with just the guard gene and their oral meds. But for the patients who were not a goal um they then randomize them to either 12 or three doses of a fast acting and allow glue I seen with meals. Um And as you can see another 23 met goal in that whole group. But if you go to week 24 you can see there was not a lot of difference and they really did well right. They went down to mid sevens or low sevens. Um Either having a obviously you would expect the best control with three doses is 7.29 but the patients are just one dose today. Got to 7.44 which is an excellent response. Um So it really shows that they could do quite well with just one additional injection a day. Um And you can always start and go up. I mean so I think you may get more adherent. You may get more buy in from your patient if you're not just kind of beating them with a big whammy of an additional three injections a day at that visit. Um So I think buying that trust and say well let's let's try it and let's see. Um and we can always go up from there. I think that's a really nice option and it's an option. I do frequently with my patients and I think that's it's a nice compromise and being able to gradually phase in uh mealtimes. That gives the patient time to really acclimated to the concept of multiple daily injections a day. So I find I agree I find phasing these in gradually really well. So if we if we go back to our patient and now apply what we've just discussed um Mark can you can you walk us through how you would practically address the notion that this patient is prescribed too much basil insulin and not enough Crandall insulin. Can you can you give us a sense of how much you would cut back by on her basil insulin and how much Brandel insulin you would give her to start? Sure. So um you know i i there's a there's a concept about insulin um that um I think it's important for people to understand and this was a study that was done a long time ago. Um When you inject insulin underneath the skin, it sort of forms a depot. Um and when that happens, the absorption of the insulin is curtailed and you don't get the proper absorption as you should write. Um Now, having said that, you know, I sort of based this on the patient's Bmi weight et cetera. But once I see a patient who's on sort of more than 30 units of basil insulin, that's where I start to get concerned that were causing a problem. The problem that we're causing is that these patients are over insulin Ist insulin is an anabolic hormone. And when you're just giving somebody high doses of basil insulin, it's non physiologic. And it makes it really challenging for those patients to mobilise fat and lose weight because they're constantly having this insulin signal. So my approach would be to reduce that the guard gene, You know, in this case, I would probably pull it back 30-35 units. And then I think I agree exactly with Kerry. Um starting somebody on a perennial dose of insulin with their meals and we've gone through the titillation of how to do that. I think four units is a reasonable place to start. Um You could wait base it if you think about it this way. Um in general, we want to find a balance of about 50 to 50 right? Uh, you know, 50% of the incident should be basil, 50% should be Crandall. Right? So, if you were doing 30 units, you could argue that that patients should be on something like 8 to 9 units with their meals, but I think starting just with 4 to 5 units. The other thing that you really want to avoid impatience is hypoglycemia. Right, So, um I think I err on the side of being a little conservative at the beginning, getting some data back from them is carrie and Anastasia mentioned, and then sort of slowly tight trading things up. The other important thing, that's that's key here is these are not patients who are carbohydrate counting with a carb ratio and adjusting their insulin based on that. So, it's very important that you convey to them the importance of consistency with their meals, consistent amount of calories and carbohydrates, right? Because if they change that dramatically, then they're at risk for hypoglycemia. And Mark, if you're if you're going to pull back on the basal insulin and start some Crandall insulin, would you adjust any of the other medications that she's taking? Right? So um you know, to me, um I'm not I don't know that having blip aside and you know, some form of basil bolas insulin is really appropriate. So that that's a drug that I would consider um pulling back on a little bit. Um But but then again if you if the clippers it has some effect and you're pulling back on it, the patient actually may need more basal insulin. Uh In this case the patient's maximized on their met foreman, their G fr 60 that's perfectly fine. Um So, you know, other than perhaps adding another agent um like an SD lT two or something like that, that's kind of where I would start. Okay and then Mark I just want could you address there was a couple of questions in the Q. And A about logistically how to set up obtaining a diagnostic see Gm. In a primary care setting if it. No. Um You know actually that's that's pretty simple. Um And what I would say is you you're talking about like a pro or something like that where somebody could just get the information right? So to me um you need to use your resources out there right? So the companies that make these uh you know dex calm and uh freestyle libra. Um Their their sales team is available to provide these to your practice. You just need to contact them, bring bring bring bring those in, make sure that you have them on hand and then you have to train, you know, your nurses, uh and how to put these on and they're actually very easy to do. Um Initially, when we were giving out starter kits to patients with uh for libres et cetera, they had a jump drive that had, you know, you can plug into your computer and had instructions for how to put it on. We tell our patients to go to youtube, etcetera. It's actually a very simple process to do. But these are placed by the nurse on the patient. The patient then takes them home after they've used them for the designated period of time. They just take the sensor off. They put it in a plastic bag and they bring it back to the center for interpretation. Okay, Thank you. Let's move on to our final case. So here we have a 62 year old woman with type two diabetes, obesity, Hyperloop oedema and hypertension. She was diagnosed with diabetes in 2015. She has no known complications. He is currently taking that foreman blame a fried and Januvia. Uh an exam. Her B. M. I. Is 35. She's had an £8 weight gain this past year. To piers you bulimic. Her. A one C. Is 7.9% with a normal G. F. R. And uh urine albumin to creatinine ratio is within normal limits. So Anastasia, can you, can you walk us through how you think about anti diabetic medication in terms of their impact on weight? Clearly this patient, her BMI is 35. She's continuing to gain weight on the therapeutic regimen that she's currently taking. How how do you think about uh these meds in terms of prioritizing the potential for weight loss above all else. Sure. So in this busy table we will only focus on the line that says wait. So you see that's two classes that are marked in bright orange are insulin and sofronio Yuria together with finite but my bright blip aside and Brandon repair green eyes. Um They work on decreasing blood sugar by increasing insulin levels. These two classes do not address the issue of insulin resistance. Clearly, they will be associated with weight gate because the action of insulin at the level of adipose tissue is to grow to expand and absorb extra triglycerides for storage. And now the medication that is listed in yellow is another classes. T. C. D. S. We currently only have papaya, glitter zone. The weight gain with paragliders on has a multitude of aspects. Some people would gain weight by the mechanism of fluid retention. It is probably the the same corporate of people who were pretty supposed to chf exacerbation clinical trial. Others however, would not display any fluid retention or pedal edema. They may actually see redistribution of adipose tissue there. Subcutaneous, deep insights will increase in size, start absorbing more um extra calories in the form of triglycerides or storage in subcutaneous. People at the same time there this thorough fat or ectopic fat and liver may actually go down. So in my opinion T. C. D. S. You have a role. Um we're we're yet to probably reanalyze some data about their effect on the bones, bladder cancer signal that didn't confirm at a much closer look. So they do have a role but I do understand why they are not popular at the moment. Now we're moving to the blue classes and among those are DPP four in alpha glucose oxidase inhibitors. Speaker Bose. Speaker Bose is pretty much almost never used in diabetes because of its mild efficacy. We do use it however, when treating post very erratic oftentimes or any kind of um reactive hypoglycemia. It works by preventing absorption of glucose from the lumen of the gut. And DPP four is um is a kind of a class that is neutral and pretty much everything. So then we're moving to classes that are listed in green and on the far right there is Kremlin Night, which is an analogue of naturally occurring hormone called Emelin, also produced by pancreas and lacking in diabetes physiology of um Ellen is still still needs more research. So this medication, even though it has been available for for a while, has never become popular. It's an injection three times a day that our continent medication expensive and the effect on glucose metabolism is actually very modest. So I have several people with Taiwan diabetes who actually benefits from it greatly, but you will not see it frequently and now we're moving to the left of the line and here are our main medications that those are the drugs that I prescribed on a daily basis, Metformin, that the patient is already GLP one receptor agonists and as guilty to inhibitors, even though as guilty to inhibitors and GLP one receptor agonists have never been Compared side by side and one clinical trial in terms of weight loss. If we look at the average weight loss in GLP one trials, it is much greater than in as guilty to inhibit a trial. And in the next slide um I will, in the next two slides, I will walk you through most recent evidence For the class for GOP one just after agonist. So in just this year, two major companies publish their data on weekly GOP one receptor agonists. This is a word, 11 o'clock low tide which is to elicit Felicity had been on the market at the dose up to 1.5 for a while now. And now this is the data to demonstrate those dependent effects on it came along and they want to see in the left panel and wait in the right path. So currently available Doses announced 1.5 3.0 and 4.5 mg weekly. But when I look at the results, The study had 1800 participants. So when I look at the results, even though I see that both hemoglobin a one c and weight were Joe's dependent. I see bigger benefits for for the weight with the increase in the dose you get about a kilogram extra for each dose adjustment at 30 36 weeks. Whereas for hemoglobin a one c reduction, you get extra 10.3 point 4% reduction in agency and then another. So this slide is a little bit bigger. But this is the slide that made headlines in many media outlets as a medication that's gonna change um the way we think about obesity management. So this is some envelope tied weekly GLP one receptor agonists currently available by the commercial name of olympic at the dose up to 1.0 mg weekly. This study is in people without diabetes And the does goes up to 2.52.4 mg A week. So the data is presented. There are two analysis presented in this slide. So in the top two panel we have mean weight loss and it was analyzed with an intention to treat plan and in um complete ear's only met people who were able to stay on the medication. Both are quite significant and impressive. The placebo to deduct said weight loss Is between 14 and 15 depending how which analysis you follow. And this is um this is huge. It appeared in the media as a breakthrough. I wouldn't say it's a breakthrough. It wasn't a breakthrough for me. I knew it was coming and each next GLP one receptor agonist. Um it's kind of more and more efficacious and probably so this is the whole point to to develop efficacious and specific drugs while minimizing their side effect potential. So that's that's the result of many years of work. Um but clearly seeing that in the lower panels, now we are looking at the categorical um categorical wait boss. That more than 80 of Of people, even with the intention to treat analysis, lose more than five of weight. And that number goes up to 90 in the right panel and the people who actually took the medication on the long. This is huge. We do know that it requires at least five of weight loss to demonstrate clinically meaningful outcomes, such as reduction in anyone seeing people with pre diabetes or reduction in blood pressure medications or cholesterol lowering medication. So this is the drug that even in in about third of the patients subjects in that style study, 30 20 or more of weight loss was achieved. So this is big and it should be on the market in late 2021. However, um coverage will remain an obstacle. I am quite you're back. So in terms of prioritizing, await favourable approach, you've walked us through nicely which medications are, you know, more favorable in terms of promoting weight loss and which of the medications uh will increase the risk of weight gain or make weight loss difficult. And clearly you know, the patient that we presented um would would likely benefit from medications such as GLP one receptor agonists or S. G. LT to therapy which you've you've nicely outlined. Um So this patient is again a perfect candidate for one of those therapies. If you were to pursue GLP one receptor agonist therapy for this particular patient, can you give us a sense practically of how you get those started and titrate up the doses? And then in turn, are there any changes to the existing regimen that you would make when starting a GOP one receptor agonist? All excellent questions that we face on a daily basis. So whether or not to cut something down before adding GOP one agonists pretty much depends on the current degree of glycemic control. So this patient has a one c of 7.9. So clearly Metformin is staying, Genovia is clearly going because there is no point in core prescribing GLP one receptor agonist with DPP four inhibitors. So the question is are we keeping them up right or are we are we holding it immediate? In this case I probably would keep glen map right in the first couple of weeks Of uh of the initial high trading dose of GLP one receptor agonist. We work with GLP one quite carefully. We don't rush. We start with the lower dose explain high possibility of nausea as a side effect. It's about 30%. So three out of 10 will develop some degree of nausea and discomfort. So we work with it by going really, really slow infiltration. So it is first two or four weeks people will stay on the lowest dose before advancing to the next one And probably by the time this person is ready to advance to 1.5 of Felicity or .5 of the Olympic, I would probably stop the map right. And then can you speak to the association or concerns about the risk of pancreatitis with this class of medications? Because that often comes up in conversations with patients as we're discussing prescribing these nets. Also excellent question. And I also think it emphasizes yet another observation in clinical trials in obesity, abdominal pain associated not necessarily with pancreatitis, but more so with global area attacks have been really demonstrated to be slightly higher when people successfully lose weight regardless of the mode. So part of the abdominal pain that people report may be explained by go very attacks. So I really keep my eyes open for that when people hold back with the pain. Um as far as pancreatitis, the evidence is inconclusive at the moment, the report there, there were more reported cases in the literature trial, but not in some agility trial. So practically speaking, um I definitely discuss it with the patients. I assess their risks of pancreatitis in general. So they are triglycerides there smoking their family history, their personal history of recurrent pancreatitis. That will probably be the true red flag against prescribing if they had pancreatitis and distant past with a known ideologies such as global added disease. Um I will consider GLP one receptor agonist and the gold bar is done. I will consider jail if you under separate agonist at this time. Okay, thank you. Thank you, Kerry Mark and Anastasia for sharing a really valuable take home clinical pearls for approaching patients with type two diabetes. We've really focused our attention during the last hour on Pharma co therapy and individualizing selection of medications for patients with type two diabetes. But as we all know, this is one only one component of the patient centered care model um that we need to put into play to really optimize the care that we're delivering to our patients. We all know that diabetes education and nutritional counseling as well as really thoughtful consideration of socio economic factors and support systems uh and underlying mental health issues are all really, really critical components of a comprehensive care model for diabetes care. And ultimately, these conversations are happening in a shared decision approach with our patients in these visits. And it's it's really through those conversations that will ultimately decide what direction to move forward in in prescribing medication therapy. I want to thank you all for attending today's webinar. We welcome your feedback and ask you to complete the evaluation that you'll be directed to at the conclusion of this meeting. You should also be on the lookout for an email from Penn cmi office to obtain credit for attending today's event. Uh and finally, please save the date for the next webinar in our series, expert guidance for primary care approach to common adrenal and pituitary disorders that will take place on May 21 2021 at 12:15. Have a great weekend and thank you for joining us.