Ladies and gentlemen, I'm delighted to be here today to be discussing CGM for people living with type 2 diabetes in the setting of basal insulin with modern therapies such as SGLT2 and GLP-1, discussing the results of the Freedom 2 study. My name is Emma Wilmott and I'm associate Professor at the University of Nottingham. I am a diabetes consultant leading a large diabetes technology service in Derby in England and the UK. And as a tech enthusiast, I'm also the founder of the er Diabetes Technology Network UK. These are my disclosures. So, I am going to be presenting the results of a study which is hot off the press, recently published in The Lancet, Diabetes and Endocrinology. I was chief investigator of this study alongside Doctor Lala Lee Ranathna, and together we led this large UK multi-centre randomized control trial, and I'm delighted to be here today sharing the results with you. So what's the rationale for the Freedom 2 study? Well, you'll be aware that individuals treated with basal insulin, SGLT2, GLP1, represent an increasing proportion of those living with type 2 diabetes. But I'm sure you're equally aware that despite this combination of modern therapies, many still fail to reach the glycemic targets designed to protect their long-term health. Furthermore, despite decades of research into CGM, we still have a fairly lacking evidence base in terms of the impact of CGM and basal insulin in the context of modern therapies and type 2 diabetes. And furthermore, our understanding of the behavioral changes that underpin the use of CGM remain fairly limited. So the aim of the Freedom 2 study was to determine whether the use of the Freestyle Libre 3 CGM system would improve HbA1c over 32 weeks when compared to self-monitoring of blood glucose in adults with type 2 diabetes and suboptimal glycemia. So how did we do this? Well, this is a UK based study with 24 sites across both primary and secondary care. And to support recruitment, we were also open to self-referral from across the country. The key inclusion criteria were type 2 diabetes on basal insulin only, plus either an SGLT2 GLP-1 or GIP GLP-1 receptor agonist. Combined with an elevated HbA1c of between 59 and 97 millimoles per mole, or 7.5 and 11%. So participants underwent screening on a baseline visit and they were then randomized 2 to 1 to CGM or to usual care. During the 1st 4 months of our trial, it was a phase of self-management, so during this period, The participants could alter their insulin doses and their behaviors, but that was the only changes that could be made. They were then assessed at 4 months and then entered phase 2, which was a clinician supported phase where if they weren't meeting their glycemic targets, we as clinicians could look at their therapies and think about adding in additional therapies to support them to meet their glycemic targets. We also had an optional phase which will be presented during the ESD this week and where those that were in the control arm had the option of using the Freestyle Libre 3 for 4 months during that optional extension phase at the end. So the primary endpoint in this trial was the between group difference in HbA1c at 16 weeks, with a key secondary endpoint of the between group difference in HbA1c at 32 weeks. The trial looked at a range of different secondary endpoints including CGM metrics, accelerometer data, changes to therapy, safety, patient reported outcomes, and qualitative interviews to really understand the participant journey. So overall this was a really large trial, we screened 469 individuals and 303 were randomized with 105 in the control group and 198 in the intervention group. Here you can see the baseline demographic and medical history. You'll note that the average age was around 61 years, 67% were male, and the BMI was just in the obese range with a long diabetes duration of around 17 years. In keeping with that duration of diabetes, you can see the prevalence of complications with 50% having ocular complications, 1 in 5 having renal or cardiovascular complications, and a small proportion having foot disease. Here we have the medication history, and you'll note that those in the trial came into the trial on roughly around 34 units of insulin per day, about 0.36 units per kilogram. And when we look at the distribution of other therapies that were used, you can see that in keeping with our inclusion criteria, the vast majority were on SGLT2, around the same proportion were on Metformin, with lower proportions on sulfurias. At the top right-hand side here, you'll note that most people were needing at least 2 agents to achieve their current level of glycemia. And when we look at the um inclusion criteria as I mentioned, most on SGLT2, around a quarter on GLP or GIP GLP 1 receptor agonist, and 19% were on a combination of those. So what did the glycemic metrics look at the baseline for the Freedom II study? Well, you can note here that HbA1c on entry to the study was 8.8% and well balanced in both arms. And the participants at that point were doing around 2 finger stick tests per day. We gave them blinded CGM at the start of the study, and you'll note that their time and range in keeping with the HbA1c was low at around 40%, with very low rates of hypoglycemia, 0.5% time below range, under 3.9 millimoles per liter. So, you've heard about the baseline characteristics. Let me take you on and share with you the key outcome data from the Freedom 2 trial, looking at the impact on HbA1c. So our intervention arm started with an HbA1C of 8.8%, and during that 1st 16 weeks where they had self-driven changes in management with their insulin doses and behavior, they were able to reduce their HbA1C to 8.1%. In comparison, the control group arrived at an HbA1c of 8.6%, and that gives us a between group difference in HbA1c of 0.6% in favor of the use of continuous glucose monitoring. The participants then entered the second phase of the study, which you'll recall was the clinician supported phase where we could add in additional therapies to help them achieve their glycemic targets. And you can see that the intervention arm now have an HbA1c of 7.8% compared to 8.8% at the start of the trial, whereas the control arm managed to get down to 8.3%, delivering a between group difference in HbA1c of 0.5% in favor of CGM yet again. So both during that um self-supported phase and then the clinician supported phase, we see significant between group differences in HbA1C which are in favor of CGM use in this population with type 2 diabetes. But let's break that down and look at it in a different way. Here we have the data on the achievement of HbA1c targets, and what you can see is that the poor proportion achieving HbA1c targets, whether that's 8%, 7.5%, or 7%, was far more likely in those with access to CGM compared to the control group. And again at 8 months you're more more likely to achieve an HbA1c of less than 8% or 7.5% with access to CGM compared to the control group with 62% having now achieved an HbA1c of less than 8% and 39% less than 7.5 in the intervention arm. What about the magnitude of improvements, and again, a very similar message coming through here, by 4 months, those with access to CGM were far more likely to have substantial reductions in their HbA1c. We can see that 2/3 of the intervention group had a reduction in HbA1c of more than 0.5% compared to only a third of those in the control arm. And by 8 months this further increased. By now we have 70% of the intervention arm achieving an HbL1C reduction of more than 0.5%. And actually half of them have now reduced their HbL1C by more than 1% compared to only a third in the control arm. So again, regardless of how we look at it, the HbL1C improvements were more staggering and substantial in those in the intervention arm with access to CGM. So let's look at that in a different way. We can now move from HbA1c onto what you and I are more used to looking at in clinic, which is of course sensor-based metrics. So let's start with time and range. So you can see that at baseline and those were, we've got an average of around 40% time and range, but you can see for those in the intervention arm, they were able to increase their time and range from 39.7 to 54%. That gives a between group difference of 10.4% in favor of CGM after those first four months. And actually, over the subsequent four months, up to eight months of follow-up, the intervention arm further increased their timing range to 60.2% with a between group difference of 10.6% in favor of CGM compared to control. And actually a question that we're asked often is how quickly do these benefits of CGM come about? And here we have the week by week data from the intervention arm looking at their time and range over time. And what you can see is a staggering and large improvement in their time and range within a couple of weeks of use before they even got to see a clinician for further support, suggesting that those in the intervention arm were able to take the data from the CGM and use that to improve their glycemic outcomes very quickly. And we can also see that when we then get at the end of the self-management phase and start getting into the clinician supported phase, you can see that with the addition of further therapies and further optimization, there's another step up in the time and range there during that last 4 months as well. Now of course any intervention in diabetes which improves HbA1c needs to ensure that it's not doing that at the expense of an increase in hypoglycemia. And what we can see here is that that was definitely not the case. We can see that there were very low rates of hypoglycemia at baseline, at follow-up, um, both for the thresholds of less than 3.9 millimoles per liter and also for less than 3 millimoles per liter across the duration of the trial, which is really reassuring. Of course, what we're used to looking at in terms of CGM data is the ambulatory glucose profile. And so here we have the data for the control group and the intervention group on the left and right respectively, and what you can see is what what that glucose data looked like across the day. And just glancing between the two, you get the impression that those with access to CGM were achieving more time and range. Um, over that during that overnight period by 4 months and actually a little perhaps less variability during the day as well, but overall more time and range reflecting the figures that I've already presented. But letting me show you how that then moves on at 8 months, and you can see that the glucose levels are moving down further with further improvements, particularly in the intervention group which now have uh that overnight period largely in range um with less escape during the day than we see with the control group on the left-hand side there. So, you've heard about the HbAL and C changes, you've heard about the CGM metrics, and you're probably starting to think, well, what's going on here, what sort of medi medication changes underpin the changes that we're seeing here? So let me walk you through that. So as you know, uh these were patients on basal insulin, so let's look at the changes to their total daily dose of insulin during the trial. So the first thing to say is that by 4 months, there is no between group difference in insulin dose between the two groups, whether looked at as total daily insulin dose or in units per kilogram. So no difference in insulin at 4 months. But equally, when we look at the dosing at 8 months, again, no between group difference in insulin doses at 8 months in in either units or units per kilogram. So that suggests there's something other than insulin dosing underpinning this. What about those starting on bolus insulin? Well, if we look at the data for 4 months, none of the control group had bolus insulin initiated. 3% of the CGM group did, um, 2 of these were for participants' safety due to hyperglycemia, um, and 3 were due to protocol deviations, but this is not a significant difference between the two groups. When we then look at 8 months, you can see that 13% of the intervention arm were started on bolus insulin compared to 3%, and this is a significant difference, and we can discuss why that might be from my perspective, the fact that those with CGM we can see the postprandial excursions and perhaps as a clinician, we're more likely to identify that and treat it, but again, we can discuss that later. What about other new non-insulin lowering medications? Well, at 4 months there was no between group difference in the other um glucose lowering medications and also at 8 months no between group difference. So an interesting tale emerging, no changes in insulin, no changes in other therapy. And again we can uh visualize this differently, so um this list down the left hand side. The variety of potential agents that could have been used or added, um, and you can see that for baseline 4 months and 8 months, what the addition, so in green we've got anything that started in red we've got anything that was stopped and glancing down both sides, the key take home message here is there's no between group difference for any of the specific agents or class of agents between the two groups. So if insulin doesn't explain the changes, if other medications don't explain the changes, what is going on here to deliver these changes and improvements in HbA1c and time and range? Well, the Freedom 2 trial looked at patient reported outcomes, physical activity and diet, and I'll walk you through some of our findings just now. So let's start with diet. We use the UK Diabetes and Diet Questionnaire, which is a 21 item tool to assess dietary habits in type 2 diabetes. And what's interesting is at 4 months we did actually pick up a difference um in the dietary options, suggesting that those in the intervention arm were perhaps selecting 2 healthier choices per week. However, by 8 months, this difference disappeared and there's no between group difference. So, um, an interesting finding and a secondary endpoint that probably requires more exploration, um, but, um, some interesting insights into what might be happening there. We also objectively measured physical activity. Professor Tom Yates was part of the Freedom 2 trial. He's a professor of physical activity in Leicester, um, and we use the gene active triaxial accelerometers, um, for a period of 2 weeks to really understand behaviors across the full 24 hour period. Typically one milligravitational unit is recognized as the minimum clinically important difference, um, and we were able to explore whether that was met in this trial. So here we have data on overall activity, moderate to vigorous activity, light activity, and inactivity or sedentary behavior. And the key take-home message for you here is that we did see a significant difference in overall activity at 4 months. And we also saw a significant difference in light activity at 4 months with the intervention arm being um more active um and with greater light intensity activity overall compared to the control group. But similar to what we saw with the diet. Data, actually by 8 months there is no between group difference. So again, interesting insights to complement what we know about the glycemic impact of CGM in this population with type 2 diabetes treated with basal insulin. We worked with Kath Barnard Kelly to undertake qualitative interviews and we also did a range of patient reported outcome measures during Freedom II. And what we can see is, as you might expect based on previous studies, that glucose monitoring satisfaction was high in those with access to CGM. There are also improvements in hypoglycemia confidence, and some of the quotes really drive home the the participant experiences. CGM made life more manageable, more normal, impacting positively on quality of life. People were anxious as well about the study ending and not having access anymore because typically we don't get reimbursement for this patient group in the UK currently. But many, and this for me is the crux of the matter, many of the participants that I saw coming back talked about the impact on their diet. I've changed how I eat, I was snacking a lot between meals, but I've learned a lot about food and what food does to blood sugars. So, overall, the use of real-time CGM when people living with type 2 on basal insulin led to a clinically and statistically significant improvement in HbA1c compared to control at 4 and 8 months. We saw improvements in sensor-based metrics, we saw improvements in participant reported outcomes, and crucially, these improvements were all delivered without an increase in hypoglycemia. But for me what's really unique about Freedom 2 is the fact we were able to look at what happened during that period of self-management and also following clinician intervention, and these improvements were observed during both of these periods. So you've heard about the trial, but let me bring this to life, a couple of clinical cases to really highlight some of the issues. So I want to introduce you to this gentleman who has had type 2 diabetes for a long time. Uh, he's on metformin, Eagliflozin, Humulin I twice a day, and he checks his glucose once a day with an HbA1c of 8.2%. So he comes to see you in clinic and you can see that his glucose levels, these are millimoles per liter, range between 9.3 and 11.2 or 12.5. So they're elevated. We've not got any other glucose data, so here's our options. So Humulin I doses are 22 in the morning and 9 in the evening. What are your recommendations for insulin titration? Are you going to increase the evening dose, increase the morning dose, increase both doses, add in a prandial insulin, or say no changes, more glucose data is needed? Well, I think if we're honest, a lot of people say go away, get some more glucose data and we'll look at it then. And I think if we're honest, this is part of the clinical inertia that we experience day in and day out in diabetes services. Because often we, they come back, we don't have the full glucose data we need and we're still left in the dark trying to make decisions about how to optimize. But this gentleman was in the trial, so we were able to look at his glucose profile and actually when you actually see the CGM data, you really get to understand where the difficulties are. So what would you be your recommendations now? Are you going to go for the evening dose, the morning dose, both doses, adding prandial insulin, or no changes glucose data is needed, but we've got the glucose data. So I, I bet you're all thinking about which doses you might target. You might consider targeting the, the, um, adding in a prandial insulin to deal with the postprandial spikes. But that is not what happened here. This gentleman had access to real-time CGM for the first time, and he was able to take that data and use it to alter his behavior and his glycemic outcomes. He was able to improve his HbA1c from 8.2 to 6.4, and he did that by avoiding the foods that spike his glucose and reducing his portion sizes. And he came back to clinic saying I'm looking at my glucose data all the time, is this OK? And I was like, well, if you use it find it useful, that's absolutely fine because we know that often those that look at the glucose data the most tend to get the best outcomes. The only change he made in his therapy was a 2 unit increase in his morning dose of insulin, but a vast improvement in outcomes. And we can see here the before and after glucose data with time and range improving from 39 to 87% with an Hb1C of 6.4. But I can hear the skeptics from here, I can hear you thinking, well, that's fine, it's just 4 months in, will he be able to sustain that? Well, the answer is yes, he absolutely was able to sustain that. And by the time he came back at 8 months, the timing range had improved from 39 to 72%. HbA1c maintained its 6.8%. So, um, a resounding success story. So here's another case just again to help bring the components of the trial to life for you. So this is somebody with type 2 diabetes, a female who's a smoker, a BMI of 29. HbA1c has been stuck around the 9.6 mark for many years, chronically elevated, and she tends to only check her glucose levels for a few days before she comes to clinic. She's on Humulini 19 units twice a day, and pugliflozin, uh, having previously declined the statin and been intolerant of both metformin and GLP-1. So, she comes in with these glucose levels, so in target, 4.9, 5.2, 6.3, 5.1. But we've got an HbA1c of 9.6%. So what on earth are you going to do here? So how will you alter her insulin dosing? Are you going to increase the morning dose, increase the evening dose, add in prandial insulin, wait for more blood glucose data first, or give a trial of CGM? And I think based on the last case I've just presented, I bet most of you are thinking let's go for the trial of CGM, um, but in parts of the world where we've not got access to that, a lot of people go down the route of asking for more glucose data. But looking back through her notes, you can see that that's been done multiple times. The same situation, she comes back with the same data, and we never get anywhere. So we desperately need more data to really understand what's going on here. And actually this was her CGM trace and what is clear here is that the morning glucose levels she's reporting are are really true. And what we're seeing here is glycemic escape during the day, um, and actually she admits that during the day she likes to snack on sweets, etc. and she can't see that her glucose levels are high during that time, um, because she's not checking her glucose then. So she went on to use real-time CGM for 4 months. She gained unique insights into the impacts of foods on her glucose levels, and she came back and said to me, Emma, I had no idea, you know, I had been snacking on sweets and chocolates, and I just didn't understand the impact they were having. But with the data, she was able to witness that and make informed choices about how she changed her diet. She start she had reduced the amount of chocolate she was having, she avoided sweets, uh she was eating less bread, and by watching the changes and the impact of that, she was able to actually reduce her insulin dose from 19 twice a day to 14 twice a day, and her time and range improved from 41 to 85%. Um, her HbA1c also improved dramatically from 9.6 to 6.9%. And looking at the ambulatory glucose profile, you can see that there is a vast improvement in the glucose metrics there, uh, improvements in HbA1c, improvements in time and range. And then um by 8 months she had further reduced her insulin dose again to 10 units and 12 units with sustained improvements in dietary intake. Time and range was 85%, and you can see that up to 12 months she was actually able to sustain that improvement in HbA1c 6. 6% at 12 months with a reduction in her weight reduced from 96 to 87 kg and actually there is systematic review evidence suggesting that CGM use can be associated with improvements in weight as well as glycemic outcomes in the population with type 2 diabetes. So Chair, ladies and gentlemen, in conclusion, CGM in people living with type 2 diabetes improves HbA1c and improves glucometrics. The visualization of that data really supports people with diabetes to understand their diabetes in a level that SMBG just doesn't allow for, and it allows them to finally achieve the outcomes that have escaped them for so many years. Access to CGM and those with type 2 diabetes, certainly in the UK where I work, is a postcode lottery, and we need to use the data from the Freedom 2 trial to really address that and argue the case for wider access to CGM for these this group of patients. We need to ensure that we're also addressing the barriers to an equitable access to CGM technology across the population with type 2 diabetes, because from my perspective, certainly from the Freedom 2 trial and wider, uh, the benefits are clear. So I'd like to finish by acknowledging everybody that's been involved in the Freedom 2 trial. Um, it's been running for many years. Uh, huge thanks to Lalali Ranathna, my joint chief investigator, and to the team at Abbott, who sponsored the study, and to all the investigators who are not only colleagues but friends from across the UK and of course to all the participants who took part. So thank you very much indeed, thank you.
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