Figure 1: Continuous glucose monitoring profile (top) with sensor communicating insulin pump automating insulin delivery (bottom) by increasing insulin delivery for predicted hyper-glycemia (red diamonds). User input is required for estimated carbohydrate intake to provide prandial insulin boluses (middle) and can be added for sleep (Zzz) and exercise (not shown).
Researchers at the Penn Rodebaugh Diabetes Center are conducting an enrolling clinical trial to assess the safety and efficacy of both hybrid closed-loop control and predictive low-glucose insulin suspension technology on hypoglycemia and other glycemic outcomes, quality of life (QOL), and usability compared with sensor-augmented pump therapy in older adults with type 1 diabetes (T1D).
Current Diabetes Technologies
The introduction of insulin pumps, continuous glucose monitoring sensors and their combination (sensor-augmented pumps), hold great promise for the improvement of glycemic control for patients with type 1 diabetes (T1D) and advanced type 2 diabetes (T2D). However, despite the wide adoption of these technologies, a 2019 report found that only 21% of American adults with diabetes had achieved the American Diabetes Association HbA1c goal of <7.0% (53 mmol/mol), and that 7% of adults report having experienced a severe hypoglycemic episode resulting in seizure or loss-of-consciousness in the previous three months.
Automated closed-loop systems (known informally as artificial pancreas systems) offer a further step towards reducing the burden of diabetes management. The object of closed-loop systems is to replicate the physiology of the pancreas while requiring less input from the patient for insulin dosing decisions than is required with open-loop control. These systems have three interconnected components: a real-time continuous glucose monitoring sensor; a control algorithm device (or CAD); and an insulin pump directed by the dosing control algorithm.
In closed-loop mode, the insulin pump uses the control algorithms to respond to measured glucose levels, decreasing insulin delivery when a patient's sensor glucose is predicted to be low and increasing insulin delivery when a patient's sensor glucose is predicted to be high. Closed-loop systems can be designed to deliver insulin alone, or insulin and glucagon or another hormone (dual hormone systems), and are classified as "hybrid" when basal insulin delivery is automated, but user input is required to bolus for carbohydrate intake or administer additional corrective insulin doses. Hybrid closed-loop (HCL) systems have been in development for more than a decade, but it is not yet known whether their complexity provides additional glycemic benefit for individuals with hypoglycemia unawareness or older adults, populations with T1D at greatest risk for experiencing life-threatening episodes of severe hypoglycemia. Moreover, problems with mechanical insulin delivery and variability of insulin absorption present challenges to closed-loop control of blood glucose.
Critical Research Needs in the T1D Population
Older adults with recent severe hypoglycemia (SH) have a remarkably high prevalence of hypoglycemic unawareness (the loss of physiological symptoms associated with low blood glucose). In addition, aging is associated with normative decline in cognitive functioning that may impact diabetes self-management and contribute to hypoglycemia risk. Among much else, hypoglycemia unawareness is associated with a 20-fold increased risk for experiencing life-threatening hypoglycemia.
Studies suggest that for those with SH within the prior year, 58% have hypoglycemic unawareness, compared to 25% in those with no SH in the prior 3 years.
To date, studies of automated insulin delivery technologies have not included older adults in sufficient numbers to allow for focused evaluation of efficacy and QOL impacts that may differ from those observed in younger age groups.
In persons with long-standing T1D, impaired glucose counterregulation when combined with hypoglycemic unawareness may substantially increase the risk for severe hypoglycemia. Glucose counterregulation is the body's physiologic response to restore normal glucose in the wake of hypoglycemia and becomes progressively impaired with longer duration of T1D and with more frequent exposure to even mild degrees of hypoglycemia.
Individuals with impaired glucose counterregulation and hypoglycemic unawareness are perhaps most in need of new therapeutic strategies. However, in automated insulin delivery, sensor overestimation of blood glucose may be a concern for older persons, since the patient's awareness of hypoglycemia would then be dependent upon his or her capacity to recognize low blood glucose. Thus, it is critical to understand the effects of hybrid closed-loop insulin delivery on physiologic defense mechanisms against the development of low blood glucose before fully closed-loop control may be acceptable in this population.
Clinical Studies At Penn Medicine
Currently, the Penn Rodebaugh Diabetes Center is enrolling patients for a clinical study in older adults with type 1 diabetes that is evaluating automated insulin delivery in the context of hypoglycemia and other glycemic outcomes. This study is being sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
Automated Insulin Delivery in Elderly Patients with Type 1 Diabetes (AIDE T1D)
The primary objective of this study in older adults (>65 years) with T1D is to assess the safety and effectiveness of a 12-week period of HCL technology use and a 12-week period of predictive low-glucose insulin suspension (PLGS) on hypoglycemia and other glycemic outcomes, QOL and usability in comparison to a 12-week period of sensor-augmented pump (SAP) therapy. Secondary objectives include identifying participant characteristics associated with optimal outcomes with and preference for SAP therapy, HCL technology or PLGS during a 12-week patient preference extension period. During all four 12-week study periods participants will receive a Tandem (t:slim) insulin pump and Dexcom (G6) continuous glucose monitoring system.
Enrollment
Enrollment information for this trial can be obtained by contacting Cornelia V Dalton Bakes at 215-746-2085 or corneliv@pennmedicine.upenn.edu.
Additional clinical studies can be found listed here: pennmedicine.org/for-patients-and-visitors/patient-information/clinical-trials
Published on: October 7, 2021
References
Rickels MR, Evans-Molina C, Bahnson HT, et al. High residual C-peptide likely contributes to glycemic control in type 1 diabetes. Journal of Clinical Investigation 130(4): 1850-1862, April 2020. PMCID: PMC7108933.
About the Penn Rodebaugh Diabetes Center
The Penn Rodebaugh Diabetes Center at the Hospital of the University of Pennsylvania is a state-of-the-art facility dedicated to the treatment and prevention of diabetes. The Center, unique to the Philadelphia region, provides comprehensive care exclusively for patients with type 1 diabetes, type 2 diabetes, pancreatogenic diabetes, hypoglycemia disorders, and related metabolic diseases.
Learn more about the Rodebaugh Diabetes Center
ACCESS
Penn Rodebaugh Diabetes Center
Perelman Center for Advanced Medicine
West Pavilion, 4th Floor
3400 Civic Center Boulevard
Philadelphia, PA
Clinical Research Team
Clinical Research Coordinators and Support
- Paola Alvarado, CCRC
- Cornelia Dalton-Bakes, CCRC, MA
- Patti Bourne, BSN
- Eileen Markmann, BSN
- Amy J. Peleckis, CNRP
- Huong-Lan Nguyen, BS
Recent Research Publications Involving Penn Medicine Patients with T1D (2020-2021)
Riddell MC, Li Z, Beck RW, et al. More time in glucose range during exercise days than sedentary days in adults living with type 1 diabetes. Diabetes Technology and Therapeutics 23(5): 376-383, May 2021. PMCID: PMC Journal - In Process
Carlson AL, Kanapka LG, Miller KM, et al. Hypoglycemia and glycemic control in older adults with type 1 diabetes: baseline results from the WISDM study. Journal of Diabetes Science & Technology 15(3): 582-592, May 2021. PMCID: PMC Journal - In Process
Markmann JF, Rickels MR, Eggerman TL, et al. Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. American Journal of Transplantation 21(4): 1477-1492, April 2021. PMCID: PMC Journal - In Process
Malone SK, Peleckis AJ, Grunin L, et al. Characterizing glycemic control and sleep in adults with long-standing type 1 diabetes and hypoglycemia unawareness initiating hybrid closed loop insulin delivery. Journal of Diabetes Research 6611064: 1-8, February 2021. PMCID: PMC7896863
Gillingham MB, Li Z, Beck RW, et al. Assessing mealtime macronutrient content: patient perceptions versus expert analyses via a novel phone app. Diabetes Technology & Therapeutics 23(2): 85-94, February 2021. PMCID: PMC7868577
Casu A, Kanapka LG, Foster NC, et al. Characteristics of adult- compared to childhood-onset type 1 diabetes. Diabetic Medicine 37(12): 2109-2 115, December 2020
Sherk VD, Vigers T, Pyle L, et al. Acute hyperinsulinemia alters bone turnover in women and men with type 1 diabetes. JBMR Plus 4(9): e10389, August 2020. PMCID: PMC7507374
Agarwal S, Kanapka LG, Raymond JK, et al. Racial-ethnic inequity in young adults with type 1 diabetes. Journal of Clinical Endocrinology & Metabolism 105(8): e2960-e2969, August 2020. PMCID: PMC7457963
Pratley RE, Kanapka LG, Rickels MR, et al. Effect of continuous glucose monitoring on hypoglycemia in older adults with type 1 diabetes. JAMA 323(23): 2397-2406, June 2020. PMCID: PMC7298607
Rickels MR, Evans-Molina C, Bahnson HT, et al. High residual C-peptide likely contributes to glycemic control in type 1 diabetes. Journal of Clinical Investigation 130(4): 1850-1862, April 2020. PMCID: PMC7108933.