Hello. Thank you very much for joining us for the set of lectures. I'm very pleased to be with you, despite the fact that we are not face to face. It's very strange times that we all hope we land very soon. I would like to share with you a little bit how I see the integrated continuous glucose monitoring technology in recent months, if you want and how I believe it's a good way to use it and to go ahead to dio even better job to our people with diabetes, those are more disclosures for you to review. And what I would like to propose to you today is a little bit off a background as to why I believe it's important what we discussed the striking efficacy of technology. I believe it's really something that we did not see in diabetes in the last 30 years and then a little bit off the new management philosophy, the time in range targets for the end. If we start with something doesn't go well. It's fair to famous slides demonstrating that despite all the new technology, there is a deterioration off. Listen me control, particularly in large registries in the United States, which is a real discrepancy in between the use of technology and also new drugs. For the matter of fact, the insolence and the outcomes that we are seeing. The good news comes from the severe hypoglycemia study. Two studies were pulled into this analysis, published in diabetes care, demonstrating that when you go down with, like, oscillated hemoglobin, severe hypoglycemia also goes down. This is against the D. C. City paradigm, and it's a real effect off technology. So actually, the D C city paradigm doesn't hold anymore, and this is a very, very important message. Truth is that the Silver study, the gold Studies, actually did show an increase in hyperglycemia with a decrease in K one c. But interestingly enough, this was not seen in the European trials. The second thing is that I would like toa persuade you tonight that glucose is dangerous. This is an interesting study. Healthy individuals were recruited more than 30 years ago in the United States and followed that prospectively, and at some point when they were around 50 they realized that some of them actually have cognitive impairment and they tried toe correlate to different parameters and they realized it was the fasting glucose variability that was associated with worse cognitive processing attention and memory in midlife. And they, of course, did not have diabetes. No therapy, no hypoglycemia whatsoever. And then it was interesting that not only to the to the brain functions, but also to the coronary calcification, the same group of people. This is quarter tiles off glucose variability, fasting, glucose variability. As you can see first quartile here. Here is the coefficient of variation quite normal, and then in the fourth quartile, the variability is becoming closer to diabetes. But these people were healthy, did not have diabetes or any medication for it. And interestingly enough, the higher the quartile. This is data after 15, 20 and 25 years. As you can see, the higher the artery calcification. So fasting glucose variability is associate ID with artery calcification in people without diabetes. Then they did a medallion random ization study. 117,000 people were included, and random glucose pre meal, post mill, whatever during the day was used in this analysis, and people were actually then grouped by this random glucose. And please focus on this group. It's 8000 people where the glucose was within 117 and 134 which for many people with diabetes is not a bad range yet. Please look at this retinopathy. Risk in this group was five time elevated, as compared to the very, very low glucose as well as the diabetic. The property risk was five time increased. So in people without diabetes, with random glucose within arrange, that seems to be quite reasonable five time increased risk for retinopathy and the property. Another study, another point of few published only a couple weeks ago from the Karolinska University in Sweden, demonstrated that also, prediabetes actually has a huge impact on disability in people. Please look here, the summary. Actually, this is without diabetes. This is well controlled diabetes, and this is uncontrolled diabetes. And please observe how the disability actually increases with this conditions. And finally, the most recent study published a couple days ago, 300,000 Europeans included from a United Kingdom bio bank without diabetes, so purposefully selected, not toe, have diabetes, linear and non dinner. Mandela Random Ization Analysis Association with a one C and with several genetic factors to be more controlled. And they saw actually that a huge relation between people without diabetes, where the A one c was within normal range. This is 4.9% a one C. This is 54 days of both are below the a d. A threshold of diabetes. And please look how the risk that hesitation for coronary hard is is increases within the normal population. So even within the normal population, the lower the glucose, the mean glucose in this particular case, the less the chance off cardiovascular event. Finally, a recent study with functional memory. You know the lessons with type one diabetes. The impairment was visible with diabetes and this the earlier the start of diabetes, the more impaired to the brain function in this particular case, the spatial working memory. But this is chronic complication house about acute hyperglycemia, and we did a very similar study with functional Emery and people actually were. You glaze Simic inside the memory and then we clamp them toe hyperglycemia for two hours and they had to do cognitive testing and again spatial working memory. So same same situation severely impaired in acute hyperglycemia, which, of course, has an impact on daily life, and this is quite new data to conclude this first part. Glucose variability and time above range. Remember once again people that I showed you in this population studies did not have diabetes. No hyperglycemia whatsoever. Just Lucas variability and time above range is associated with brain and cardiovascular system. This is why we actually wrote this commentary, saying that Lucas variability seems to be a dangerous thing and that we should change something in orderto address it. What's also important and this is for a discussion, is this study is also very recent and demonstrated that repeated, actually, the fact that lower target setting is actually associated with better outcomes. So it's not just the technology, but it's also us, the diabetic teams. Actually, that has to do its part in the whole story. Let's move on and check the efficacy off technology. First, the penetration. This is the pre cove it years off course, this was around 40 to 50% in Europe and in the United States, both adults and Children. Now in a year, this came close to 60% which, of course, is due to the very special situation we are in and we have several long term outcome studies. One of them is the rescue study for real time C G M. As you can see here, a beautiful, sustained effect off. See GM over 24 months over two years, which is a really important message. So it's not something that acts and then fades away, but it stays its effects. Positive effects stay for two years, possibly mawr, and it's a sustained reduction. Here is you can see in several actually parameters in hypoglycemia, commas, hospitalizations and in addition to the improvement improvement in a one C and those particular parameters, of course, influences cost the most. So the cost saving off this technology also remains over two years, which, of course, is a very important message for the players. This is the other story. This is the intermittently scan C. G. M. And here, of course, we have a couple off very important success stories. This is the first publication. This is the year when intermittently scanned glucose monitoring was started to be used, as you can see, actually, how this declines when the Ennis at N. H. S decided to reimburse the therapy, But the most famous paper from the NHS Success in the United Kingdom Is this a B C D national White audit? The demonstrated actually not on Lee the like oscillated hemoglobin improved as you can see in the stable. But more importantly, the gold score improved. Half of the population reduced the gold score below the threshold of four, which I think is an immense success unheard of so far. And there were significant improvements in the quality off life and in treatment satisfaction, as stated by feeling overwhelmed by the demands of living with diabetes, improved and feeling that I'm often failing with my diabetes regimen also significantly improved if you look actually, the Spanish and worldwide experience from this study, 200,000 sensors were downloaded. You see that you need basically 30 scans a day to reach this target. So again it helps, but it also needs effort. This is why I said that we still have some work to do with people with diabetes in order to together, you know, with the shared efforts. Actually, we really reach the target that we want. Also, with 30 scans, we become close to the time in range target. We unfortunately still do not reach the time below rage targets completely either below 70 or below 54 as we also don't reach the targets for hyperglycemia. If we compare this to to real time glucose monitoring queasy, actually that the story is not very different. This is the the the presentation off a one c and hypoglycemia on the same graph. Here is the both both targets, as you can see here when the targets cross actually, real time See, GM almost gets there, but not completely Same is for time below range of 54 they want C. And for those of you that already switched to the time in range targets, as you can see here the time in range Target almost reached with the real time the blue lines here for the below 70 threshold That even closer, of course, for the below 54 targets. For this real times GM, The Cardia study actually directly compared real time. See GM and intermittently scan C g m. It's a smaller trial. 30 participants randomized to each group. As you can see, they had a initial baseline, messy GM running period where the two were exactly the same and then actually, when they started the the exercise face and then the home faces, you will see the time in range and time below range was consistently slightly higher with real time. See GM as compared to intermittently scan. See gm off course. There are questions as to why and the most likely think of course, are the alarms. This word. This was the difference in between the two and basically the behavioral effect off the alarms off continuous remembering. Unfortunately, not all studies show success. This is a high profile study from the United States in adolescence, and here is you can see actually, this is the A one c target and as you can see here, they're not even close, even with the C g m. And when we go to the to the timing range, targets here is you can see with the continuous glucose monitoring this is real time. He reached the 43% of the time. So this is a little bit better than have the way towards the target. Yes, it was a significant improvement, which is a good news for those of you that still remember the jdrf. But it is way, way how to say below what we really want to see. This is the hyperglycemia. So 50% of the time this young people were in hyperglycemia And of course, that's why I'm saying it is the device. But it's also our targets. And what we what we suggest to people with diabetes to do with this real time. See GM data that that really matters. There are actually some studies that are in preschool Children. This is one of them here. They were able to reduce hypoglycemia. But a Z you can see here. Actually, this is time in range, way below the target of arrest with real time. See, gm, the hypoglycemia target was rich. Why? Because very likely this study was focused on hypoglycemia and somehow put the time in range target into the second place. This is also why that in January 11, which is a couple weeks ago, this paper was published actually claiming for a more stringent targets and more attention to pediatric population and and again please remember, technology works. But what we say what we believe, What we tell what we teach is still off utmost importance. People can get help One of the possibilities is Automatic Advisors, which is artificial intelligence. This is a publication from nature Medicine. From a couple months ago, we compared centers like like jostling at Harvard like like Desmond shots from from Florida, like Denver, Colorado, like Yale, like Hanover. And, like Tel Aviv with this automatic adviser. And they were equal in the intention to treat analysis and in Per protocol Analysis Advisor. So the program was even slightly better as compared to US physicians, which in a way is a good news because this advisor actually can help and bring another specialist to the team for a very quick consultation. If you look the demand analysis for either intermittently scan C G M or real time, See GM, this is a nice study published for intermittently scan. See GM Big numbers, all subjects. Adults and Children. As you can see a sustained improvement off half percent a one C, which is, of course, considered clinically meaningful. Another analysis, actually a a European one prior to intermittently scan C G M and after as you can see, a very meaningful decrease in a one C off 10.9% which, of course, is almost double the clinical significance. So my second suggestion to you is that C, g, m and intermittent. This can see GM significantly improve a one seed but more importantly, time in range, time below range and time above range. And we didn't discuss. But of course, because off the reduction of severe hypoglycemia, mostly it also reduces the cost. However, we need a recent analysis of randomized controlled trials, and it seems that more the more technology we use, the better or the outcomes. This is the C G M alone. This is predicted low glucose suspend and this is the closed loop. So just a small excursion into the closed loop studies to most recent with the most recent devices, the advanced hybrid close look, this publication from the fall in the New England Journal It was actually a largely a largely pediatric study closed up 78 people control 23 ABC. A significant difference here they reach almost reached the target of 70% of timing range and of course, with much, much less involvement off these people. This is the extended use and again, very important message. Actually, this success almost 70% is sustained, so 101 in one child actually participated here, and those that were control group before were switched to the advanced habit. Close look here at the end of the randomized trial, both of them actually very close to the target with with the use of advanced Robert Close Look. The second big trial was published just three weeks ago, and this is the second option on the market with Advanced habit Closed Loop this one Also at dinner String Bolasie's Automatic Bolas Corrections. This was a publicly funded study by the National Institutes of Health the and I dedicate from the United States. So we were. We were actually free to include also people that usually have most troubles with diabetes, which is the lessons that young adults and we included. Also people that used FBI and had an A one C off 11 or less so really people that struggled with their diabetes and they were directly included into this advanced hybrid closed loop study, you know, to give everybody a chance and experience with this new option. The comparator was the existing close look, so we compared the regular clothes look that's on the market with the most advanced system that was developed that also used automatic correction Bolasie's so not only the basil rate is automatically changed, but the system applies. Correction, Balu says. As another means off increasing time in range. As you can see, the advanced rabbit close look really, really pushed the system towards towards the goal. As you can see here, this is the cumulative distribution. And here you have the automatic correction. Bolus is this is the blue is the basil and the gray actually is automatic bullets. This is the regular and this is the new system, As you can see. Ah, third quarter to a third off the daily insulin basically comes from the automatic correction policies, which is why this system is superior to the previous one and very, very few adverse events. There was only one severe hypoglycemia and no diabetes ketoacidosis. This hypoglycemia was actually related to a to a coincidence off bad events and no decay so robustly safe system. Actually, that did. A zai showed you previously a very good job. Lower carb intake is cell is often a question, and this study is interesting because they used it within advanced hybrid close look, and please note if the carbon take was around 100 g a day, so eso basically the timing range was very significantly improved, with no increase in hypoglycemia. This is time below range. As you can see, a 2.52 point 4% with low carb 2.8 with medium and 2.3 with high carb, so no difference way within the target. This is the target is 4% as you know, for time below range off 70 and an improvement in time in range if we reduce, not abolished carbs. But if we reduce the daily intake of carbs and another study that actually showed the value off the off the ultrafast insulin just another option to discuss it. So perhaps so. This system, which is an older version of closed loop, recognized, as you can see here, a significant difference in between the ultra fast insulin and regular fast insulin analog, which perhaps will bring additional benefit to this treatment modality. Finally, I would like to propose to you that the time enraged target is a new management philosophy. You all know this stable by now, and the most important part probably is this traffic light distribution and this Professor Rich Bergen style says Mawr green less red. This is kind of a mantra that really, really goes well with people with diabetes. Mawr green less red is intuitive, intuitive, and what's very important this more green and less red also reduces the coefficient of variability within the target off 36 or 34 whichever you prefer. So if we actually are able to get more green and less threat within the targets, we also fix the daily glucose variability. Why, we believe so, too. Independent studies confirmed this one from Louis Monier. He put a threshold of 34% for confessions of variation, and this actually was exactly 1% off time below three, which is below 54. So exactly the same as the targets. A very nice independent confirmation that if you reach this threshold, you automatically also reach a trash off coefficient of variation. And the second study comes from Jocelyn in older individuals. Very, very beautiful study. And here they divided people by coefficient of variation below 36 above 36 which is the official trash hold. Yes, the time in range was better. The time above range was better. But most importantly, hypoglycemia improved. And when they plotted there And here is the 36 threshold this exactly correlated to 4% off time below 70. So once again, the beautiful correlation If you reach the target off time below range below 4% you automatically reach also the target for glucose variability. That's why we actually wrote a commentary saying that continuous glucose monitoring derived data are simply a better management tool. And we can easily and more efficiently manage the disease. The recalculation off the Jocelyn data here. As you can see, this is low variability. This is high variability. Here you have the same. A one. See exactly the same a one C in the two groups. So you cannot distinguish these people using a one C. If you look the time in range considerably more green, considerably less threat. So more green, less red. And also the variability target is achieved with this And here you just have the recommended targets. Time in range is now more and more also related to heart and points. And this actually was published online in in the end of October It's a large study that actually looked the divided people with Type two diabetes based on only one measurement off. See GM in tow very high time in range and then lower and lower. And you'd be surprised this is the all cause mortality. And this is the cardiovascular mortality over years and here is you can see, actually is a huge difference not only significant, but huge difference in cumulative survival when you divide these people by the time in range, when they measured it, so time in range, connected to cardiovascular mortality and or cause mortality as two very serious heart and points that we have. Let me just a little bit. Focus also on this very special time that we have during this pandemic here. Actually, unfortunately, diabetes is a risk factor for higher mobility and higher mortality. And what's what's even more important that ISS crew data from the beginning is that basically it's not just higher risk off severe cove it and higher hospital mortality due to cove it. But what's the most important? It depends on the glucose control, so it depends on Lazy Mia. This is controlled diabetes, 14% mortality, and this is poorly controlled diabetes three time almost three times higher. So the message here is really straightforward. The management off Lizzie Mia during Co it Actually, it's crucial and may change the outcome. Fatal outcome. Almost three times so very, very, very important message and, of course, was conveyed in several professional papers. And I do believe we all know it now. And it emphasizes, actually, that it does matter how we teach and what we do with our people with diabetes when they get this terrible infection and how we have to focus and treat Lizzy Mia very strictly. And obviously this is why that c g, m or intermittently scan see GM is actually a must. When we treat these people now, we can really say a mast when we treat these people toe, actually improve, improve their outcomes. Just a couple of examples. This is a British exam were using either see GM or intermittently skills. See GM. The timing range was better, the variability was lower and another study from from if you want from Children exactly the same. So this is the center in modern in Italy, exactly the same experience there. Several publications, like this just two examples from different parts of Europe. So technology see GM really helps. This is the spring wave here in Moderna, actually, that you can show this difference. So to sum up when you use technology also during Cove it lower ming glucose lower values of the estimated A one C or D glucose management indicator how we call it now increasing time in range and also a decrease in glucose variability. The other thing that is important. And let let us use the exam off intermittently. Scan C G M is the remote possibility so people with diabetes can upload their data to the to the platforms. And then clinicians can directly use this uploads if the a person with diabetes permits. So just another very important possibility for remote monitoring and for the digital clinic. When we did the digital clinic consensus at the 80 TD, we didn't even imagine how. Actually, this will come into daily practice within a couple of weeks. Allow me, please to propose a couple of conclusions for you today. One is C G, M or intermittently. CGM Technology brings individuals closer to time in range and time below range targets and please remember with this two more green, less red. We also meet the glucose variability targets. Evidence is mounting and support the timing rate center. Diabetes management simply is better, even may reduce long term may improve long term outcomes. Closed loop and particularly advanced hybrid Closed loop brings individual to the highest time in range, with the lowest time below range for the moment, obviously, because it's an artificial intelligence help, similar effects may be seen for people that use advisers with the connected pens or or other technology now being more and more used in diabetes and finally, telemedicine. A. I think new reality for all of us, particular importance during the pandemic, but may probably, at least for a part of our visits, stay with us longer than than we ever thought. With all this, we hope not only our metrics will improve, but also people with diabetes will feel reduced burden with this prospective philosophy off timing range When they see for lunch, the time in range is still not good. They can actually say no trouble. I'll do my best till the dinner. I'll improve it so they always have a chance to improve and to close the day to close the week to close the month prospectively within the target and thus actually improve their long term outcomes. Our a d d d this year, unfortunately, is online. Please join us. June 2 to 5. We are preparing a very, very big program with a lot of new things, and we're looking forward to connect with you. Unfortunately, this year it remotely with this. I would like to thank you very much for your attention. And this is my team. They have toe work while I speak. Thank you.
