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Efficacy and Safety of Mini-dose Glucagon for Treatment of Non-severe Hypoglycemia in Adults with Type 1 Diabetes
Haymond MW, DuBose SN, Rickels MR, Wolpert H, et al.
Glucose Outcomes with the In-Home Use of a Hybrid Closed-Loop Insulin Delivery System in Adolescents and Adults with Type 1 Diabetes
Garg SK, Weinzimer SA, Tamborlane WV, Buckingham BA, Bode BW, et al.
Editorial Comment by Sarah Cvach
Artificial pancreas is a long awaited dream for generations of endocrinologists. Technological advances made closed loop systems a reality and the dream comes closer. Hybrid closed-loop (HCL) Insulin Delivery Systems use various combinations of control algorithms, glucose sensors data, and insulin pumps to automatically and safely increase, decrease, and suspend insulin delivery.
In a pivotal trial, Minimed 670G HCL system was investigated with sufficient number of participants and a duration of three months to demonstrate its safety and effectiveness. This single-arm study was performed in a multicentre setup in 10 sites (9 diabetes centres in the United States and one in Israel). The primary endpoint of the study was safety of HCL system use. 124 participants thereof 30 adolescents and 94 adults with Type 1 diabetes for more than 2 years using Insulin pumps with or without continuous glucose monitoring for more than 6 months have been included in this study. There was a 2-week in-home period (run-in phase), in which subjects used the system in Manual Mode followed by a 3-month in-home study phase in which Auto Mode was enabled. The HCL algorithm included a high alert setting of 300mg/dL and low alert setting of 70mg/dL. Several alarms were set for rapid value decrease. Target was fixed at 120mg/dL. Participants had to calibrate the sensors, 3-4 times a day, enter carbohydrate for meal boluses and perform finger prick BG values for correction insulin boluses. HCL system could be stopped by users any time.
Previous results already reported by Bergenstal RM, Garg S, Weinzimmer SA et al. proved that adolescents and adults with Type 1 Diabetes in an outpatient setting could use this HCL system safely. No episode of severe hypoglycaemia or diabetic acidosis was reported in over 12.000 patient days.
The results of this pivotal trial showed further a clinically important reduction of HbA1c in both cohorts. HbA1c in adolescents decreased from 7.7% to 7.1% and for adults from 7.3% to 6.8%. The time within target range increased for adolescents from 60.4% to 67.2% and for adults from 68.8% to 73.8%. The corresponding time below and above target was less in both groups. All these results were highly significant.
Because of the robust data from this pivotal trial, FDA approved recently the Minimed 670G system for HCL therapy in the United States.
This Hybrid closed-loop (HCL) system represents a promising option to improve glycaemic control and reduce the risk of hypoglycaemia in type 1 diabetes therapy and thereby brings the dream of an artificial pancreas closer to reality.
Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, et al.
Editorial comment by Vivian Fonseca
Achieving optimal glycemic control in type 1 diabetes remains challenging despite advances in insulins, pumps CGM etc. It is particularly hard to reduce variability in blood glucose from day to day with frequent high and low blood glucose causing patients a lot of distress. The application of knowledge gained from treating type 2 diabetes with new drugs may help alleviate these problems.
SGLT2 inhibitors are approved for treating type 2 diabetes and lower glucose by increasing glycosuria and work independent of insulin secretion / action etc., thus raising the possibility of using the drugs in type 1 diabetes. Small clinical trials have previously demonstrated a benefit with this class. Sotagliflozin is a new drug in this class that also inhibits SGLT1, which is present in the kidney and also the gut. It could therefore increase glycosuria further and decrease glucose absorption in the gut as well – both independent of insulin.
This large clinical trial demonstrates a beneficial effect of the drug in improving glucose control and getting more patients’ A1c below 7 % than with insulin alone. Further addition of the drug led to weight loss and a decrease in blood pressure (both known effects of the class), as well as reduction in hypoglycemia (perhaps due to less insulin use). Thus, the benefits appear very promising. There was, however, an increase in keto acidosis – a problem previously recognized with this class, and some caution is needed with this possible side effect as it may not be always recognized.
Cumulative Kidney Complication Risk by 50 Years of Type 1 Diabetes: The Effects of Sex, Age, and Calendar Year at Onset
Costacou T, Orchard TJ.
Editorial comment by Vivian Fonseca
Over the last 2-3 decades glycemic control has improved in type 1 diabetes, and other advances in health care have led to improved life expectancy in this disease with a large number of patients living with the disease for > 50 years. This gives us an opportunity to study the long term effect of the disease, that previously resulted in premature death at a young age. Interestingly a proportion of people with type 1 diabetes remain free of complications, though most get some degree of microvascular disease.
This new study by Castacou and Orchard focuses on kidney disease in a cohort with long-standing disease. Despite a decline in rate of this complication in the last few years (perhaps related to widespread use of RAAS blockade), a significant proportion of patients develop end-stage renal disease (ESRD). Some of this may relate to hypoglycemia, complexity and cost of optimal treatment (pumps and CGMS etc.) leading to suboptimal control of both glucose and BP in a lot of patients. However, further research is needed to identify treatment targets beyond the RAAS system to treat advancing renal disease in patients with long standing diabetes.
Accuracy and Longevity of an Implantable Continuous Glucose Sensor in the PRECISE Study: A 180-Day, Prospective, Multicenter, Pivotal Trial
Kropff J, Choudhary P, Neupane S, Barnard K, Bain SC, Kapitza C, Forst T, Link M, Dehennis A, DeVries JH
Editorial comment by Sarah Cvach
Continuous Glucose Monitoring (CGM) has reached a certain level of use in the diabetes population. People with diabetes frequently use fingerstick capillary measurements to guide their dosing decisions. CGM systems provide glucose data in real time and detect hyper- and hypoglycaemic events and allow receiving trend information, which would not be known with fingerstick measurements alone. People with diabetes get temporal information from some systems which are able to alarm for hypo- or hyperglycaemic events. CGM systems on the one hand reduce the need for fingerstick testing and effectively lower mean glucose, but on the other hand the wear time of current transcutaneous CGM is low in some populations. Implantable CGM systems may provide additional ease of use over transcutaneous CGM.
The current study used Eversense, an implantable CGM sensor in 71 participants with type 1 and 2 diabetes in a 180-day multinational, multicentre, pivotal trial. CGM accuracy was assessed with the mean absolute relative difference (MARD) for venous reference glucose values >4.2mmol/L (75mg/dL) as the primary endpoint. Secondary endpoints included alarm performance and Clark Error Grid Analysis. The primary safety outcome was device-related serious adverse events.
The primary efficacy outcome over the study duration showed a MARD for reference samples >4.2mmol/L (75mg/dL) of 11.1%. Eighty-one percent of hypoglycaemic events were detected by the CGM system within 30 minutes. No device-related serious adverse events occurred during the study. Clarke Error Grid Analysis showed 99.2% of samples in the clinically acceptable error zones A and B.
A quality of life questionnaire indicated a high device acceptance: “Using the system helped minimize the burden of diabetes in my life” got a 90% rating of 5 or higher on the scoring range from 1–7.
Sensor survival at day 90 was estimated to be 82%. Median sensor lifetime is 149 days.
The results seem to indicate the safety and accuracy of this new type of implantable CGM system and support it as an alternative for current transcutaneous CGM.