Diabeter

"Are you getting it? …automated insulin delivery', AID".

Henk-Jan Aanstoot

Fifteen years ago, in 2007 Steve Jobs introduced the iPhone with a historic speech. He told the audience that Apple would introduce three new groundbreaking products: 'The first is a wide screen iPod with touch controls, the second is a revolutionary phone and the third is a breakthrough internet communications device… He went on repeating these three new devices a couple of times and then asked the audience "Are you getting it? These are not three separate devices, this is one device, … and we are calling it …iPhone'. The rest is history. Since that moment smartphones have reshaped our life and the world.

We are experiencing a similar development in type 1 diabetes (T1D). But this development has yet to 'reach the public'. Change is imminent, but difficult. This blog tries to identify why and how to proceed.  

These are not three separate devices…

The healthy pancreatic beta-cells 1) makes insulin, 2) constantly measures glucose and 3) has a build-in system that automatically regulates the glucose level and keeps it exactly and constantly between 3.9-7.8 mmol/l. In type 1 diabetes (T1D) the beta-cell is destroyed or broken and all three functions disappear. Thus, optimal treatment of T1D requires these three beta-cell functions to be fixed. For many years we could only fix the first (insulin) and the second task (glucose measurement), but could not combine them together. But now it is possible to 'repair' all three in one device:  Are you getting it? These are not three separate devices, this is one device, … and we are calling it …automated insulin delivery', AID". And AID's will reshape our diabetescare with unsurpassed outcomes towards normalization of glucose levels and similar improvement of quality of life. These experiences are now largely in type 1 diabetes, but studies show comparable impact and outcomes in every person with insulin requiring diabetes, including type 2 diabetes.

Are you getting it?

We have just published a paper (1) on predictors for outcomes of this new technology for people with type 1 diabetes (T1D). Pooled data from 12,870 users of automated insulin delivery (AID using Medtronic-Minimed 780G system = insulin-pump+ continuous glucosesensor+ algorithm) gave impressive results on glucose-regulation (2). In our paper we learned even more on how to reach and keep this optimal succes. Never in our entire career (HJA started as a first-year medical student-project in 1977 on 'something new' at that time: HbA1c, MA started as a Pharmacist, including education of people with diabetes), we have seen such excellent outcomes in so many patients in such a short period of time by AID-systems. With AID's and their future developments, we are embarking on a future without diabetes-complications: secondary prevention in T1D, prevention of complications, less suffering and lower costs. It is therefore amazing and frustrating that this technology can not be used at it's full potential due to reimbursement issues, lack of knowledge and stepwise-introduction of technologies that only solve part of the problem. Change is imminent, but difficult

No longer waiting for the 'artificial pancreas': it is there!

Similar to Jobs' iPhone, we now have one device: Automated insulin delivery or AID, sometimes (aberrantly) called 'artificial pancreas'. Six different AID systems are now available (2-9), plus different open source AID solutions (#wearenotwaiting) (10, 11) The available systems are still hybrid: they need input from the user to 'close-the loop'. Additional single hormone and dual hormone systems are under development that will be fully closed-loop (12, 13). Together, they are the beginning of a revolutionary change in T1D care and have the potential to deliver a future without diabetes-related complications.

But, like in many steps to improve T1D care and outcomes over the last 100 years it is difficult to implement, use and convince authorities to reimburse, healthcare professionals to prescribe and even people with diabetes to start using technologies. But similar to what happend with smartphones, AID's will become standard. Change is imminent, but difficult...

Recognizing the pathophysiology of the beta-cell

It is 100 years since insulin became available and people with type 1 diabetes (T1D) no longer died within weeks/months after the appearance of symptoms. It became quickly apparent however, that insulin was not a cure and that glucose-regulation was key and glucose measurements were needed. After one beta-cell-task replaced (insulin-administration), the second task (glucose-measurement) took decades to develop and it took another 50 years before glucose-measurements 'came home'. Even in those days, doctors doubted if patients would ever appreciate this self-measurement of bloodglucose (14). But eventually self-measurement of bloodglucose became the cornerstone for self-regulation in T1D: people with diabetes learned to 'play pancreas'. But we still lacked a third 'task' of the beta-cells. Change is imminent but difficult…

Change is imminent, but difficult…….I TOLD YOU SO!!!

It took 71 years since the discovery of insulin 1922 to understand the importance of adequate glucose-regulation: the DCCT trial ((15)Diabetes Control and Complications Trial) and its successor EDIC (Epidemiology of Diabetes Interventions and Complications (15, 16)) showed that intensive insulin schedules and frequent glucose-measurements resulted in significant reduction of both the onset and the extend of diabetes-complications. Until 1993 many doctors and researchers doubted this role of glucose-regulation and suggested even not to fund this trial. However, after nine years this trial was prematurely stopped because of the significant reductions of microvascular complications in the intensive treated group versus the 'control' group, using what was at that time 'regular' diabetes care. It was clear and proven that glucosecontrol matters. The Joslin researchers, presenting the data at a scientific meetings, wear buttons with the text: I told you so! Despite the clear message and outcomes it took more than a decade to pursue doctors, scientists and patients to adapt their care towards intensive treatment. Change is imminent, but difficult…

The burden of type 1 diabetes

We now know that a safe regulation required an HbA1c below 53 mmol/l (7.0%) (17, 18). This is also reflected in the currently used glucometrics-data (19). Despite all this knowledge and developments, 'playing pancreas' to the level that will prevent you from acute and chronic complications remained extremely difficult. Currently, in many countries fewer than 50% (and in many countries fewer than 35%) of people with T1D reach a level that will more or less save them from complications and premature dead (20-22). Despite enormous efforts by patients with T1D, playing pancreas at a level that keeps you safe from acute and chronic complications, day in-day out, week in week out, year in year out, without any holiday, break or remission, is impossible for most. Moreover, it is difficult (42 factors that influence your glucoselevel) and creates a significant burden that also feeds psychosocial- and psychological problems and -disease (23).

Not solved with just two of the three….this is one device!

Many people will say: 'But al these new insulins, technologies, apps, continuous glucosesensors, don't they solve all this'. 'No, the human brain is not able to constantly play pancreas 24x365. 'But' they will say:  data from studies using that technology (RT-CGM, FGM,IS-CGM) show improvements! Isn't that enough?  Yes, the emergence of continuous glucose monitoring (real-time as well as intermediate scanning methods) has improved glucose-regulation, reduced acute complications and admissions and significantly reduced the burden. But no, the constant need for the patient who plays like a pancreas show that the use of just factor 1 (insulin) and factor 2 (constant glucose measurement) don't bring enough people with T1D in the 'safe zone' of HbA1c < 7.0% (53 mmol/mol) without significant time in too low (hypoglycemia) or too high (hyperglycemia) values (as indicated in international guidelines (19)). Thus, they remain at risk for complications and premature death.

.."this is one device"…from 'playing pancreas 24/7' to AID

The third task of the beta-cell, constantly regulating glucose within a narrow range, was missing for almost 100 years. Insulin delivery was 'open loop': not connected to the ambient glucose value. The 'open' part was filled in 24/7 by the person with T1D (or the parents/care-takers): they did glucose-measurements as many as possible, dosing when ever possible and needed, or correcting with food when the amount of insulin already injected ('on-board'), worked out as too much lowering the glucoselevel and going towards -or causing- hypoglycemia.

Without the third factor solved, glucose-regulation is open-loop and 'playing pancreas' is your only option: your brain as a 24/7 glucose-regulating algorithm. The availability of an algorithm as a 'third factor' has changed that forever: it closes the loop. OK, we agree… there is still a human-in-the-loop. The current systems are hybrid closed loops (HCL) and not yet fully closed loop (CL). They regulate glucoselevels automatically during large parts of the day, but still need input and adjustments/adapted settings for example on carbohydrate intake/food and in special circumstances such as sport and activities. However, they regulate most of the day and are extremely useful to regulate overnight. They already come with self-learning capacities. And all this results in significant improvements of glucose-regulation, quality of sleep, quality of life (24-26) and will significantly lower the risks for complications.

Changing the future of diabetes care

We strongly believe that the AID's will, just as the Iphone did in our lives, reshaped the diabetescare. Together with the possibilities it gives to improve outcomes, it also will change the way we deliver our care. If glucosemanagement is automated and people with T1D will lose that burden, we need another approach. From the traditional 3-4 clinic-visits a year (landings on the healthcare-airport), a once a year visit may suffice when no additional issues are present. Remote care, automated analyses of (AID ) data can change the function of the diabetes-clinic into an air-traffic control-like center where landings are only necessary when issues rise or patients request such visits. We have created a management tool (Cloudcare), that will help the patient and clinic to manage data  based on a 'service level agreement' with the user.

We realize that this sounds great for those enthusiastic and adaptive to new technologies, but will remain challenging for those not yet ready to embrace this hightech, encounter barriers or are not able to use it (27). However, this is also comparable to the smartphone introduction: better results and quality of life will help people to think about this change and will help to reshape the clinic into place for personalised care: which next step can we offer you to improve your life and diabetes-outcomes?

NEXT STEPS URGENTLY NEEDED!!

Currently, studies are publications on AID's on a weekly basis, describing the outcomes including randomized trials. The amount of evidence is growing quickly. We are collecting our Diabeter data and will combine them when appropriate, with a number of (brand-agnostic prescription) datasets from other clinics to show similar and stable improvements from different brands in the Netherlands. As a value-based clinic we will add health technology assessments to identify costs  and savings (28, 29). Using AID's as THE method for secondary prevention (prevent or ameliorate the complications of T1D). The longer we wait with introducing this to our patients, the more complications will arise, the more suffering, the more costs

 

Bibliography

1.         Castaneda J, Mathieu C, Aanstoot HJ, Arrieta A, Da Silva J, Shin J, et al. Predictors of Time in Target Glucose Range in Real-world users of the MiniMed 780G System. Diabetes Obes Metab. 2022.

2.         Arrieta A, Battelino T, Scaramuzza AE, Da Silva J, Castaneda J, Cordero TL, et al. Comparison of MiniMed 780G system performance in users aged younger and older than 15 years: Evidence from 12 870 real-world users. Diabetes Obes Metab. 2022;24(7):1370-9.

3.         Amadou C, Franc S, Benhamou PY, Lablanche S, Huneker E, Charpentier G, et al. Diabeloop DBLG1 Closed-Loop System Enables Patients With Type 1 Diabetes to Significantly Improve Their Glycemic Control in Real-Life Situations Without Serious Adverse Events: 6-Month Follow-up. Diabetes Care. 2021;44(3):844-6.

4.         Franc S, Benhamou PY, Borot S, Chaillous L, Delemer B, Doron M, et al. No more hypoglycaemia on days with physical activity and unrestricted diet when using a closed-loop system for 12 weeks: A post hoc secondary analysis of the multicentre, randomized controlled Diabeloop WP7 trial. Diabetes Obes Metab. 2021;23(9):2170-6.

5.         Boughton CK, Hartnell S, Thabit H, Mubita WM, Draxlbauer K, Poettler T, et al. Hybrid closed-loop glucose control compared with sensor augmented pump therapy in older adults with type 1 diabetes: an open-label multicentre, multinational, randomised, crossover study. Lancet Healthy Longev. 2022;3(3):e135-e42.

6.         Forlenza GP, Lal RA. Current Status and Emerging Options for Automated Insulin Delivery Systems. Diabetes Technol Ther. 2022;24(5):362-71.

7.         Sherr JL, Bode BW, Forlenza GP, Laffel LM, Schoelwer MJ, Buckingham BA, et al. Safety and Glycemic Outcomes With a Tubeless Automated Insulin Delivery System in Very Young Children With Type 1 Diabetes: A Single-Arm Multicenter Clinical Trial. Diabetes Care. 2022.

8.         Templer S. Closed-Loop Insulin Delivery Systems: Past, Present, and Future Directions. Front Endocrinol (Lausanne). 2022;13:919942.

9.         Ware J, Allen JM, Boughton CK, Wilinska ME, Hartnell S, Thankamony A, et al. Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes. N Engl J Med. 2022;386(3):209-19.

10.       Braune K, Lal RA, Petruzelkova L, Scheiner G, Winterdijk P, Schmidt S, et al. Open-source automated insulin delivery: international consensus statement and practical guidance for health-care professionals. Lancet Diabetes Endocrinol. 2022;10(1):58-74.

11.       Knoll C, Peacock S, Waldchen M, Cooper D, Aulakh SK, Raile K, et al. Real-world evidence on clinical outcomes of people with type 1 diabetes using open-source and commercial automated insulin dosing systems: A systematic review. Diabet Med. 2022;39(5):e14741.

12.       Blauw H, Onvlee AJ, Klaassen M, van Bon AC, DeVries JH. Fully Closed Loop Glucose Control With a Bihormonal Artificial Pancreas in Adults With Type 1 Diabetes: An Outpatient, Randomized, Crossover Trial. Diabetes Care. 2021;44(3):836-8.

13.       Castellanos LE, Balliro CA, Sherwood JS, Jafri R, Hillard MA, Greaux E, et al. Performance of the Insulin-Only iLet Bionic Pancreas and the Bihormonal iLet Using Dasiglucagon in Adults With Type 1 Diabetes in a Home-Use Setting. Diabetes Care. 2021;44(6):e118-e20.

14.       Ward EA, Phillips MA, Ward GM, Simpson RW, Mullins R, Turner RC. Clinic- rather than self-monitoring of home blood samples: relevance of day-to-day variability to decision making. Diabetes Care. 1980;3(1):171-4.

15.       DCCTstudygroup. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977-86.

16.       Riddle MC, Gerstein HC, Home PD. Lingering Effects of Hyperglycemia in Recently Diagnosed Diabetes During Long-term Follow-up of the DCCT/EDIC and UKPDS Cohorts: More Evidence That Early Control Matters. Diabetes Care. 2021.

17.       Lind M, Svensson AM, Kosiborod M, Gudbjornsdottir S, Pivodic A, Wedel H, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371(21):1972-82.

18.       Lind M, Pivodic A, Svensson AM, Olafsdottir AF, Wedel H, Ludvigsson J. HbA1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study. BMJ. 2019;366:l4894.

19.       Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes Care. 2019;42(8):1593-603.

20.       Foster NC, Beck RW, Miller KM, Clements MA, Rickels MR, DiMeglio LA, et al. State of Type 1 Diabetes Management and Outcomes from the T1D Exchange in 2016-2018. Diabetes Technol Ther. 2019;21(2):66-72.

21.       Albanese-O'Neill A, Grimsmann JM, Svensson AM, Miller KM, Raile K, Akesson K, et al. Changes in HbA1c Between 2011 and 2017 in Germany/Austria, Sweden, and the United States: A Lifespan Perspective. Diabetes Technol Ther. 2022;24(1):32-41.

22.       Prigge R, McKnight JA, Wild SH, Haynes A, Jones TW, Davis EA, et al. International comparison of glycaemic control in people with type 1 diabetes: an update and extension. Diabet Med. 2022;39(5):e14766.

23.       Kremers SHM, Wild SH, Elders PJM, Beulens JWJ, Campbell DJT, Pouwer F, et al. The role of mental disorders in precision medicine for diabetes: a narrative review. Diabetologia. 2022.

24.       Polonsky WH, Fortmann AL. The influence of time in range on daily mood in adults with type 1 diabetes. J Diabetes Complications. 2020;34(12):107746.

25.       Gilbert TR, Noar A, Blalock O, Polonsky WH. Change in Hemoglobin A1c and Quality of Life with Real-Time Continuous Glucose Monitoring Use by People with Insulin-Treated Diabetes in the Landmark Study. Diabetes Technol Ther. 2021;23(S1):S35-S9.

26.       Polonsky WH, Hood KK, Levy CJ, MacLeish SA, Hirsch IB, Brown SA, et al. How Introduction of Automated Insulin Delivery Systems May Influence Psychosocial Outcomes in Adults with Type 1 Diabetes: Findings from the First Investigation with the Omnipod(R) 5 System. Diabetes Res Clin Pract. 2022:109998.

27.       Pauley ME, Berget C, Messer LH, Forlenza GP. Barriers to Uptake of Insulin Technologies and Novel Solutions. Med Devices (Auckl). 2021;14:339-54.

28.       Jendle J, Buompensiere MI, Holm AL, de Portu S, Malkin SJP, Cohen O. The Cost-Effectiveness of an Advanced Hybrid Closed-Loop System in People with Type 1 Diabetes: a Health Economic Analysis in Sweden. Diabetes Ther. 2021;12(11):2977-91.

29.       Lambadiari V, Ozdemir Saltik AZ, de Portu S, Buompensiere MI, Kountouri A, Korakas E, et al. Cost-Effectiveness Analysis of an Advanced Hybrid Closed-Loop Insulin Delivery System in People with Type 1 Diabetes in Greece. Diabetes Technol Ther. 2022;24(5):316-23.