Thank you so much, Ashtrin for that wonderful presentation on the use of CGM as a behavioral modification tool because this really figures in prominently in the way CGM has helped us in the diabetes management space. I I'm going to now use this as a segue to a discussion on CGM mediated improvements in. A glycemic control and adherence regimens in the setting of GLP-1 receptor agonist therapy. I'm Dr. James Gavin, and I have the privilege of serving as the chief medical officer for healing our village, and I'm on the faculty at Emory University School of Medicine and then I work as a consultant on chronic diseases for the Closing the Gap program in the state of Florida. Now when we look at Diabetes, it's really important to think of it in my view as a journey that progresses towards various goals and and along this journey there are opportunities for changing uh directions and for preventing certain outcomes based on the different kinds of interventions. For example, we know that prediabetes as a for. to diabetes can be interrupted. You can prevent the progression to full blown type 2 diabetes by utilizing the interventions that have been documented in the diabetes prevention program, for example, with lifestyle and with certain modifications. We can prevent early and even late complications after diagnosis by the appropriate use and Adherence to uh medical uh regimens, particularly with some of the new agents and so prevention works we can prevent and delay the onset of diabetes, we can preserve beta cell function, we can uh prevent and delay complications and even death, and importantly we can reduce uh resource utilization uh in this uh disease. The problem is while there are many interventions that are known to. Make a difference and to affect the course of this diabetes journey we've not really done well at reducing or curbing the monumental impact of cardiovascular complications or risk factors and when we look for example at data from this study. Over 6000 adults with self-reported cardiovascular disease in the setting of diabetes, what you see is that glycemic control has actually worsened. Uh, only 52% have an ideal profile with all of the tools that we have. Uh, blood pressure has not been ideally controlled. Less than 50% have an ideal profile according to the current standards of care, and that profile is worse in blacks. And when we look throughout all of these different risk. Profile trends we find that BMI is moving in the wrong direction. Smoking trends are not moving like we want them to, and even physical activity trends show worsening, and this is across population groups. Well, let's not lose sight of the fact that when we think about diabetes, glycemia is extremely important. It's still important. While there are many things that we focus on in diabetes management, there is no diminution of the importance of glycemic control, and in fact, the 10 year follow up of the United Kingdom prospective diabetes study showed that there is an important legacy effect. There is continued risk reduction for various complications uh if you can uh uh achieve reduction of A1C. So for every 1% reduction in A1C, what we see is that over time you see 43% reduction in amputation of peripheral vascular. Disease, a significant reduction in microvascular complications and even a reduction in things like myocardial infarction and all cause mortality. So, um, even when you adjust it for all other kinds of background factors and risk factors, glycemia matters, OK? But what that means is that. The uh risk uh for progression of diabetes in this journey um has we've we've shifted our focus to going beyond glycemia. Glycemia remains important, but now we have to think about multi morbidity, glycemia, as well as other risk factors, uh, and comorbidities in diabetes, and so the current standards of care and. the kind of paradigm that we see here. After the diagnosis has been made and documented, we have to introduce appropriate lifestyle modifications and start with early management of multifactorial risk factors. Then we have to make sure that there is early intervention with appropriate pharmaco therapy that is designed to get people to go and keep them there. So what you is that there is no clinical inertia, that there is progression of therapy, intensification of therapy all along the way uh at different durations of the diabetes journey, and that's why the the use of agents like the SGLT2 inhibitors and the GOP-1 receptor agonists in particular, uh, had become so important. In diabetes management, because now we have the ability to pursue the goal of reducing both micro and macrovascular complications with agents that truly are uh therapeutically affected. Now, what the currents of standards of care have done is to recommend a person-centered holistic model of care that comprises multiple components of care that you see in this outer ring, whether that's cardio renal protection or modification of glycemic management, weight management, or cardiovascular risk reduction. All of these components of care are supported by uh the same array of principles of care that you see on the inner ring, and that includes a lot of things. It includes appropriate monitoring. It includes it includes health behavior modification uh it includes shared decision making and a variety of other inputs in the principles of care. If we just look at glycemic management. As an example, what we now know by the standards of care is that we have to choose approaches that are efficacious and that can get people to go and help sustain them at goal. That means we, we use combination therapy, uh, in, uh, most instances, but more importantly, we've identified the most effective. Glucose lowering tools and now those that are in the very high group of glucose lowering effectiveness include the GOP-1 receptor agonists at high doses, imagnotide, triceppatide, combinations of insulin with oral agents combination of regimens like GOP ones and insulin. And then even high effective uh glucose lowering efficacy will include uh the GOP1 receptor agonists along with other drugs. So we have now really effective tools and the data are very compelling. If we look at this uh meta-analysis of over 40 different trials that look at uh the effectiveness of glucose lowering agents for changing A1C, reducing body weight, and avoiding hypoglycemia, what you see is that the agents that are most effective in lowering A1C in the left box. The agents that are most effective in changing or reducing body weight in the center box and those that are most effective at avoiding hypoglycemia, what migrates to the top of the pecking order, the GOP 1 receptor agonists. The GOP ones have emerged as the most effective non-insulin glucose lowering agents in type 2 diabetes uh therapy. Now there are documented clinical benefits of these GOP 1 receptor agonists. In addition to their robust lowering of A1C, they have a consistent ability to lower weight. They modify eating behaviors as you've heard. It helps to reduce blood pressure, and you can use them with simple dosing regimen. And now we have begun to see their effects across other organ systems, protective cardiovascular and renal effects. And a reduction of liver fat and, and, and liver fibrosis. But how can you achieve these benefits? Well, you have to couple the use of GOP ones with the right tools that allow the GOP ones to exert their most robust beneficial effects. That means you have to have effective reliable monitoring of these effects utilizing the new technologies. You got to make sure people are appropriately educated, make sure that you evaluate any adverse events and be prepared uh to make modifications of therapy based on a person's response, and then escalation and monitoring of dosing, all those are very important steps for uh utilizing these tools, uh, effectively. Now, all of the current standards of care from ADA, the EASD um point out that technology can be useful in patients with type 2 diabetes, but it needs to be part of a holistic plan of care and clearly supported by diabetes self-management education services. There is a recommendation for the use of CGM for diabetes management to youth and adults with diabetes on any type of insulin therapy. That's a clear cut evidence-based recommendation, but we're also seeing that the, the guidelines are recommending that we consider. Using CGM in adults with type 2 diabetes that are on any other kind of medication for lowering glucose other than insulin in order to achieve and maintain individualized uh glycaemic goals, and we are seeing the appearance of, of, of the recommendations like in circumstances where consistent use of CGM is not feasible, use it periodically. Uh, uh, either personally or professionally to adjust medication or lifestyle. Now if we ask, well, how has CGM really changed the management of type 2 diabetes? Well, we have a variety of devices now that have made the monitoring of glycemia in real time uh highly feasible, effective, and uh. Essentially, uh, user friendly because we no longer have to depend on people pricking their fingers we can get um uh information uh generated con conveyed virtually, um, electronically to readers or to smartphones. The information can be stored in the cloud or can be conveyed to electronic health records. And what we now know is that the generation of ambulatory glucose profiles, the AGPs, provide a very powerful way of looking in real time at what is the glycemic pattern and what do the various interventions and behaviors of a person do to those patterns in real time. And in terms of outcomes we see in this particular slide that when we look at things like reduction in hypoglycemic events that after the introduction of CGM versus self-monitoring of blood glucose in the traditional way, you get a substantial a 70+% reduction in hypoglycemic serious hypoglycemic events. So CGM has been a major game changer. Now, Real time glucose data um um uh over the period of wear of the different sensors uh has now uh generated the ability to collect a variety of very useful types of, of information. This is our way of mapping the glucose journey so we can now see how long. Was the sensor actually in use? We can see based on the standardized ranges that have been adopted for our targets, we can see what percent of the time a person has spent in those various ranges and most importantly, we can get a summarized version of the glucose profile over the entire period of where. Made to look like it's one day. This is all of the data summarized and collected uh in a pattern that says for this period of time, this is what your patterns tend to look like, and then you can break that down. Into individual days so you can see what particular uh events were important in either lowering the blood glucose or raising uh the blood glucose. So the ambulatory glucose profile has emerged as a very powerful tool because it tells us how to to detect where's the problem. We can see where the journey is going off track. What it tells us is. Are we in the target range? And that target range has been defined based on the levels of glucose that we know will keep us out of trouble on the diabetes journey. We can find out when we are in troublesome zones, when we are in the ranges that are low or even very low. These are the red flags because these are the um glycaemic variations that require our most immediate and urgent attention because this is when you can start getting neurological damage, OK? But at the other extreme. It lets us know when you're high or very high, because this is when you want to know whether or not uh your medications are working appropriately or what the effect might be of various uh uh dietary habits on your glucose profile and once you identify where the problems are, now you can uh devise strategies for intervention. Well, With the emergence of CGM. What we have found is that uh we have new standards for um glycemic control. The metrics for what qualifies as appropriate glycemic control have have shifted because what you now have is a way of assessing what is your glucose doing. In this journey in real time as opposed to the uh the A1C, the A1C is still important, but it doesn't give you the kind of information that you need for making treatment decisions on a day to day, moment to moment basis, which is what's critical in a dynamic journey. Like diabetes. So time and range goes beyond the A1C, OK, so we basically have bridged, OK. It captures variations, the highs, the lows, and those in range values that really represent, uh, our ideal, uh, targets in a person living uh with uh diabetes. Now, importantly, when we're making a shift in what our metrics are for defining um appropriate glycemic uh uh uh management, we have to make sure that it's been validated. And here what we see is that the use of time and range has been in fact clinically validated. What you see in the top part of this graph is that as you have greater periods of time and range, if Look at the far right, more than 70% time and range, you see the lowest percentage of frequency of uh retinopathy. By the same token, uh, in the lower part of the panel, you see that with the highest time and range. You have the lowest frequency of microalbuminuria, so two important diabetes related outcomes correlate very powerfully with uh the amount of time spent in range uh in target. At the other extreme, when you have very little time in range, your frequency of these complications are much higher. And even in the case of people who are on non-insulin therapy, this is a story out of a study out of France which looked at um the hospital admission rates for acute diabetes events in people with type 2 who were on oral uh uh insulin secretagol drugs in the 12 month periods before and after the initiation. of CGM. Look at the striking reduction in DKA or hyperglycemia and uh uh overall uh reduction in acute diabetes-related events with the introduction of uh uh CGM using uh the freestyle Libre uh system uh in this particular study. Now the question becomes then. If CGM can have such powerful effects, even when a person is using. Less effective uh forms of, of therapy. Uh, what is the effect of CGM when used on a background of what has emerged as the most effective therapies in type 2 diabetes, namely the uh the GOP-1 receptor agonists. Well, uh, this is actually. Been uh uh evaluated and studied uh by um, a very nice uh study done by my colleague, Dr. Eden Miller, uh, and, and what they've done is to show that if you look at patients. And, and here they looked at over 1400 patients who were um suboptimally controlled, that is with A1Cs greater than 8% prior to the introduction of GOP-1 receptor agonist uh therapy. It was retrospective. It was a real world evidence-based observational study, and, and what they did was they determined or defined baseline as the period um anywhere from the index day or the baseline A1C determination day back to 180 days. Anytime between that that period in baseline and then the follow up period of assessment uh for looking at the follow up A1C uh was the value that was obtained somewhere closest to the 180 day mark that that anywhere in that period that you see on the right side here. What did they find? Well, what they found was that there was better glycemic control with initiation of CGM that at the uh baseline A1C you see here uh was almost 10. There was a substantial reduction in A1C at follow up using the the paradigm that I just outlined in terms of their timing of assessments. The level of glyceemic control at that follow-up period. 18% had A1Cs less than 7% and almost 50% had now dropped below that 8% mark where most of them were um uh in excess of at baseline. Not only that, but the effects. are consistent No matter what type of regimen the, the, the patients uh were on, whether they were on an insulin intensive uh regimen, you can see that the before and after, um uh the introduction of CGM there was a substantial. reduction of A1C, an improvement in outcomes, and even in patients who were on non-insulin regimens akin to that study that we saw from France that namely you don't have to be on insulin regimens to see this kind of improvement with the use of CGM. In addition, it didn't matter what type of formulation of GOP one you use. It could be a weekly GOP one or a daily GOP one. The trend for improvement following the introduction of CGP. Of uh of uh uh CGM in the presence of a GOP one showed that there was a substantial improvement uh with whatever the GOP one formulation uh might have, uh, might have been. And it didn't matter how long a person has been on the GOP 1 receptor agonist, whether it's a fairly short period of time that is less than a quarter of a year or greater than 2 years, the same trend for improvement showed up. Namely that with the introduction of CGM use uh in the face of GLP1 receptor agonist therapy, there was substantial uh uh improvement across the board with respect to types of aging, duration of therapy, uh, and levels of glycemic control achieved. Now, the results uh that we've seen um beg the question, well, what happens with resource utilization? I mean, you see these improvements in in glycemia, but does that translate really into um a reduction in healthcare resource utilization? Well, this is a study, the Frontier study actually looked at that. It looked at healthcare resource utilization and changes in A1C at a population level before and after adoption of CGM in older people, greater than 65 years of age on non-insulin therapies, and that included GLP-1s and or oral therapies. Over 1700 patients were included. And you can see the breakdown in terms of GRP one, oral therapies, and so forth. After starting CGM, A1Cs were statistically significantly reduced in all groups. With a larger mean reduction in the GOP 1 group than in the oral therapy group, you can see that twice as much benefit in the GOP 1 group. Overall, emergency department and hospitalization emergency department visits and hospitalizations fell in both groups, but with a statistically significant reduction in the oral therapy group. Lower trends were seen in emergency department visits and hospitalizations for DKA and hypos. For people with type 2 diabetes in the older age group on GLP-1s and or oral therapies, the initiation of CGM was associated with a significant mean reduction in their A1Cs. Now, whether or not uh you, you can see that that whether you're on a GOP1 or an oral regimen, there is in fact a meaningful difference in A1C after starting CGM here again we see uh with the uh before and after the introduction of the freestyle Libre uh system. So what do we learn? Well, what we've learned is that adults with type 2. who on prior GOP-1 therapy had significant improvements in the A1Cs 6 months after initiating CGM irrespective of the duration of GOP-1 therapy or the type of GOP-1 or the type of insulin therapy regimen they're on. We've also learned that adults with suboptimally controlled type 2, who initiate GLP-1 with CGM had a greater improvement in A1C compared with those treated with a GLP-1 receptor agonist only. The presence of the CGM. Coupled with the use of the most effective glucose lowering therapy in diabetes, showed a greater improvement. Now, when we look at these data. From the uh uh uh on therapeutic inertia, which really is a huge barrier for us in diabetes management because um this has been a, a huge mountain to climb in this diabetes uh journey that this was looked at, uh, with this particular study, uh from the uh Canadian National Private Drug Claims database and what they did was. They had a selection period of 12 months, um, and, and you see the index date when they started the observation period, and that, in that selection period. Uh, they identified multiple patient groups across a wide range of, of, of treatments, and then they followed them for the next 24 months, OK, a 6 month grace period and then an 18 month period of. Active intervention. Now they could be treated with a variety of different types of regimens. There was a native a naive cohort rather that that had no treatment, no blood glucose monitoring during that 12 month selection period that was called a naive cohort. The experienced cohort. Identified in that selection period were people who were on treatments that could be in category 1 through 6 or category 7. Any of these treatment programs could be used um monotherapy, dual therapy, triple therapy, um, uh, injectable therapies, GOP ones, uh basal insulin. The only one that was not included with multiple daily injections of insulin. OK, so what did they find? Is that in patients with type 2 diabetes using CGM. There was a greater probability for treatment progression, in other words, avoidance of therapeutic inertia. Now what you can see in this graph is that for those patients uh on CGM shown in gold, the yellowish uh uh colored lines, regardless of treatment type. Had a greater probability of treatment progression. In other words, they had a greater probability that they would avoid. Treatment inertia going forward over this two year period of follow up compared to those persons in the blue who um no matter what type of uh of therapy they want, what they depended on was traditional blood glucose monitoring. So utilization of CGM made a huge difference in the likelihood that therapeutic inertia would be avoided. Now, if we think about what the next most critical question is, it's discontinuation. What is the effect of using CGM on discontinuation with GLP-1 uh receptor agonist therapy? Well, This particular study that that uh is summarized here was a retrospective matched cohort study that analyzed data from claims databases in adults diagnosed with type 2 who were on basal insulin or non-insulin therapy, as well as CGM naive uh uh persons before uh they were started on a GOP1. What did they find? Well, There was a matched group of 878 consistent CGM users, and they were matched with 3500 non-CGM users. Now, one year after starting GLP ones. 31% of those consistent CGM users had discontinued their GLP1 compared to almost 50% of non-CGM users. After you adjusted for all of the different covariants, the consistent CGM users were significantly less likely to discontinue their GOP1 compared to non-CGM users. Now, what this study suggests. Is that regardless of the therapy that you're on. Consistent CGM use is associated with a significantly lower risk of GPL1 discontinuation. Potentially enhancing a patient's adherence to this highly effective therapy and thus improving long-term glycemic control in people living with type 2 diabetes on non-intensive therapy. So our key takeaways, I think then. Would be while GOP-1s have been shown to be highly effective agents in the management of people with type 2, their effectiveness is highly dependent on consistency of use and the adequacy of monitoring their therapeutic impact. Using the right tools is extremely important in demonstrating the benefit of these agents. Adults with type 2 and prior GOP-1 receptor therapy. Experienced significant improvements in A1Cs 6 months after initiating CGM in these studies with freestyle Libre systems, irrespective of GOP-1 duration, formulation, or the insulin therapy type. In adults with suboptimal control of type 2 on other agents, initiating GOP-1s with CGM and we Using the freestyle Libre and these observations resulted in greater improvements in A1C compared with those treated with GLP-1 using traditional blood glucose monitoring. Importantly, use of CGM has been shown to reduce therapeutic inertia. That's a huge barrier that we can mitigate in this journey of type 2 diabetes, and we see greater adherence and fewer discontinuations of GOP-1 therapy facilitated with the use of CGM. So thank you very much for your kind attention.
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