Today coincides with the fifth Chinese Physician's Day. I would like to pay high tribute to the doctors who take it as their duty to protect the health and well-being of the people! In order to allow endocrinologists to keep abreast of the latest developments in closed-loop therapy and better protect the health of diabetes patients, cutting-edge information in related fields is specially presented.
As the development of closed-loop therapy continues to make significant progress, the road to "artificial pancreas" has entered a new era. Hybrid closed-loop therapy (HCL), which has emerged in recent years, is currently the leading mainstream trend in automated insulin infusion (AID) systems, leading the management of type 1 diabetes (T1DM) into a new era of artificial pancreas. What are the latest research progresses of the world's first automatic insulin infusion system internationally and in China? What are the prospects for clinical application? At the recently held AID system hybrid closed-loop therapy seminar, experts in the field of diabetes at home and abroad conducted an in-depth discussion on this issue.
Technological iterations and clinical research innovations leading to the "artificial pancreas": U.S. critical research and real-world evidence on the AID system
Professor Robert Vigersky, former president of the American Endocrine Society, conducted a review of the technology iterations and clinical research evidence of the insulin automatic infusion system introduce.
01 Review of technical iterations of the AID system
In 2009, the first MiniMed™ 530G insulin pump with threshold suspension function (SmartGuard Suspend on Low) was launched. The ASPIRE-IN-HOME study confirmed that it can significantly reduce the risk of nocturnal hypoglycemia in T1DM patients, per patient The weekly hypoglycemia event rate was reduced by 32% (P0.001), and the nighttime TBR (3.9 mmol/L) reduced by 40% (P0.001) without affecting blood sugar control [1]. In 2015, MiniMed™ 640G with predictive threshold suspension function (SmartGuard Suspend before Low) was launched on the market. PILGRIM, SMILE and other studies have shown that applying the predictive hypoglycemia management algorithm (PLGM) of Suspend before Low can make T1DM patients have low blood sugar levels. The occurrence of blood sugar further dropped, and the incidence of severe hypoglycemia dropped by 84%[2,3].
In 2016, the automatic insulin infusion system (hybrid closed-loop therapy equipped with SmartGuard Hybrid closed loop algorithm) MiniMed™ 670G system was launched, realizing automatic infusion of basal insulin, and T1DM blood sugar management entered a new era of artificial pancreas; in 2020, the Bluetooth version of MiniMed™ 670G (i.e. MiniMed™ 770G) expands Bluetooth connectivity to make data sharing and control more convenient. In the future, with the advancement of science and technology, the treatment and long-term management of T1DM patients will move in a more personalized and humane direction, and it will eventually be possible to achieve the ideal goal of a fully closed loop.
02 AID system U.S. pivotal studies and real-world evidence: In patients ≥2 years old with T1DM, the AID system improves glycemic control while significantly reducing the risk of hypoglycemia
The first automated insulin infusion system was approved by the U.S. FDA in 2016 for use in patients aged 14 years and older and above T1 For patients with DM, the age range of target indications was expanded twice in 2018 and 2020 to T1DM patients aged 7 to 13 years old and ≥2 years old, respectively, and this was mainly based on three key clinical studies of in the United States (Figure 1) [4 -7], these 3 studies confirmed:
Figure 1. AID system US pivotal study design
In adolescents and adults (14 to 75 years old) T1DM patients, the application of the AID system reduced the HbA1c level from 7.4% to 6.9%, and the proportion of patients with HbA1c ≤ 7% increased from 38% to 62% %[4,5].
In children (7-13 years old) T1DM patients, the application of the AID system reduced the HbA1c level from 7.9% to 7.5%, and the proportion of patients with HbA1c ≤ 7% increased from 36.2% to 51.4% [6].
The TBR of patients of all ages was significantly reduced after the application of the AID hybrid closed-loop system (all P0.001). Among them, the overall TBR (3.9 mmol/L) of adolescents and adult patients aged 14 to 75 dropped from 5.9% to 3.3%, and the nighttime TBR (3.9 mmol/L) dropped from 6.4% to 3.1%; the overall TBR (3.9 mmol/L) dropped from 4.7% to 3.0%[4-6]. This result confirms that the hybrid closed-loop therapy is extremely effective in reducing the risk of hypoglycemia and greatly improves safety while effectively controlling blood sugar.
In more than 12,000 patient days in adults and 10,000 patient days in children, there was not a single case of severe hypoglycemia and diabetic ketoacidosis (Figure 2, top) [4-6].
Similar results were obtained in young children (2 to 6 years old) T1DM patients.The application of the AID system reduced the HbA1c level from 8.0% to 7.5%, and the proportion of patients with HbA1c ≤ 7% increased from 32.4% to 51.8%. Among 6697 young children, no case of severe hypoglycemia or diabetic ketoacidosis occurred (Figure 2, bottom) [7].
Figure 2. Results of the US pivotal study of the AID system
In addition to significantly improving the efficacy and good safety of HbA1c, the application of the AID system can also significantly reduce blood glucose variability and improve glucose time within the target range (TIR). Regardless of whether the patient was previously treated with an insulin pump or multiple daily insulin injections, or whether the patient had experience with CGM, switching to the AID system can control TIR at a higher level [8,9].
Real-world research further validates the results of the pivotal study. Real-world data from nearly 120,000 people in the United States shows that the overall TIR of T1DM patients using the AID system reaches 71.3%, which is basically consistent with the key research results, and better TIR control can be achieved in all age groups [10].
Professor Robert Vigersky emphasized that the automatic mode of the AID system can observe subtle changes in blood sugar and calculate the appropriate insulin dose, automatically infuse basal insulin to easily control blood sugar, and the predictive threshold pause infusion function minimizes The occurrence of hypoglycemia. This helps T1DM patients manage their blood sugar more easily and have more energy to return to normal life.
China registered clinical research evidence: In T1DM patients aged 14 to 75 years old, AID is safe and effective when used in a home environment
As the coordinating researcher of the China registered clinical research on the AID system, Professor Mu Yiming from the Chinese People's Liberation Army General Hospital introduced the research situation . This Chinese "bridging" trial among Chinese adolescents and adults (14-75 years old) with T1DM is a prospective, single-arm, multi-center study, including a total of 62 T1DM patients from 4 centers. The other 3 centers (in order of center number in the study) and their principal investigators include Professor Bi Yan from Drum Tower Hospital Affiliated to Nanjing University School of Medicine, Professor Peng Yongde from Shanghai First People's Hospital, and Professor Li Yanbing from the First Affiliated Hospital of Sun Yat-sen University . The results of
show that the average time subjects used in automatic mode (closed loop) during the study period was 93.5%. The overall TIR (3.9~10.0 mmol/L) of increased from 75.3% in the introduction period (baseline) to 80.9% in the study period (P0.001); the TBR (3.9 mmol/L) decreased from 4.7% in the introduction period to 2.2% in the study period (P0.001). P0.001); the average glucose standard deviation (SD) and glucose coefficient of variation (CV) of blood glucose fluctuation indicators were significantly improved (Table 1). Subgroup analysis results showed that the higher the baseline HbA1c level, the greater the increase in TIR during the study period. After Chinese adolescents and adults with T1DM use the AID hybrid closed-loop system (automatic mode), international consensus recommends a TIR (3.9~10.0 mmol/L) of 70% (74%→95%) and a TBR (3.9 mmol/L) of 4% (52 % → 89%), the proportion of meeting the standards has increased significantly.
Table 1. Results of the Chinese registered clinical study of the AID system
The Chinese registered clinical study confirmed that the MiniMed™ 670G hybrid closed-loop system is safe to use in the home environment. During the study period, no severe hypoglycemia, diabetic ketoacidosis or severe adverse events.
AID system international clinical research evidence summary
Currently, the AID system has received evidence-based support from a number of traditional clinical trials and real-world studies. The study duration ranges from 6 months to 12 months, covering children, adolescents, and adults with T1DM. patient.
In terms of sugar control effectiveness , the AID system helps reduce HbA1c to 7.0%, TIR to 70%, and TBR (3.9 mmol/L) to 4%, and improve blood sugar fluctuations;
In terms of sugar control safety , the AID system reduces the frequency and severity of hypoglycemia, reducing or eliminating severe hypoglycemia/ ketoacidosis ;
In terms of improving the quality of life, the AID system can help reduce the burden related to diabetes management, reduce patients' fear of hypoglycemia, and improve sleep quality; it is also cost-effective when compared with traditional insulin therapy for T1DM.
Experts at the meeting highly recognized the AID system and looked forward to its future applications.
Through the summary and analysis of international and domestic clinical research evidence, the experts unanimously believed that the AID system has excellent efficacy and safety, and is an important step in the intelligent, visual, and intelligent way of insulin injection. An important milestone in the progress of informatization. The automatic insulin infusion system (hybrid closed-loop) has accumulated a lot of evidence-based and clinical experience internationally. In view of my country's national conditions, experts expect that its clinical application may not be limited to T1DM patients, and also hope that more related clinical trials can be carried out in the future. The efficacy and safety of the hybrid closed-loop system will be explored in a wider range of populations including type 12 diabetes , gestational diabetes , and perioperative patients to obtain more evidence support. Of course, for it to work better, it also relies on the joint efforts of medical staff and patients to improve their cognition and learning abilities.
Editor's note:
AID, as the most advanced insulin infusion therapy at present, will revolutionize the treatment of diabetic patients. Domestic endocrinology academic circles have long been looking forward to it. Once the AID system is launched in China, it will bring great benefits to diabetic patients in my country. With the successful completion of the bridging trial, AID's arrival in China is just around the corner!
Reference
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2. Danne T, et al. Diabetes Technol Ther. 2014; 16(6): 338-347.
3. De Valk HW, et al. Diabetes Technol Ther. 2018; 20(11): 758-766.
4. Bergenstal RM, et al. JAMA. 2016; 316(13): 1407-1408.
5. Garg SK, et al. Diabetes Technol Ther. 2017; 19( 3): 155-163.
6. Forlenza GP, et al. Diabetes Technol Ther. 2019; 21(1): 11-19.
7. https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160017S076B.pdf
8. Cordero T, et al. Diabetes Technol Ther. 2017; 19(12): 749-752.
9. Diabetes. 2018; 67(Supp 1): A55.
10. Medtronic data on file
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